leuprolide and Puberty--Precocious

GnRH analogues (GnRHa) are the treatment of choice for central precocious puberty (CPP), with the main objective to recover the height potential compromised by the premature fusion of growth cartilages. The aim of this review was to analyze long-term effects of GnRHa on height, body weight, reproductive function, and bone mineral density (BMD) in patients with CPP, as well as the potential predictors of outcome. Because randomized controlled trials on the effectiveness and long-term outcomes of treatment are not available, only qualified conclusions about the efficacy of interventions can be drawn. GnRHa treatment appears to improve adult height in girls with CPP, especially if diagnosed before the age of 6, whereas a real benefit in terms of adult height is still controversial in patients with the onset of puberty between 6 and 8 years of age. No height benefit was shown in patients treated after 8 years. Gonadal function is promptly restored in girls after cessation of treatment, and reproductive potential appears normal in young adulthood. Data are conflicting on the long-term risk of polycystic ovarian syndrome in both treated and untreated women. Fat mass is increased at the start of treatment but normalizes thereafter, and GnRHa itself does not seem to have any long-term effect on BMI. Similarly, analogue treatment does not appear to have a negative impact on BMD. Owing to the paucity of data available, no conclusions can be drawn on the repercussions of CPP and/or its treatment on the timing of menopause and on the health of the offspring.

Topics: Body Height; Body Weight; Bone Density; Child; Child, Preschool; Delayed-Action Preparations; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Polycystic Ovary Syndrome; Puberty, Precocious; Reproductive Health; Treatment Outcome; Triptorelin Pamoate

There are many questions which cannot be answered without a very sensitive estradiol assay. A recombinant cell bioassay (RCBA) for estradiol was developed in 1994. The sensitivity of the bioassay is 0.02-0.2 pg/ml (0.07-0.7 pmol/L), more than 20 times more sensitive than commercial RIAs and 10 times more sensitive than newer mass spectrometry assays. The RCBA for estradiol opened the door to study low levels of estradiol equivalents (EE) across the physiological spectrum of life from prepubertal children through menopause and across the spectrum from normal physiology, in boys as well as girls, to pathology, including: premature thelarche; estradiol suppression in children treated with GnRH analogues for precocious puberty; aromatase inhibition in boys with growth hormone deficiency; the differences between oral and transdermal routes of estrogen administration in girls with Turner's syndrome; women with breast cancer treated with aromatase inhibitors; and women with urogenital atrophy treated with low dose vaginal estrogen. A bioassay also allows study of endocrine disruptors, like phytoestrogens and other environmental compounds, which are relevant to public health and alternative medicine options. This paper reviews the assay and the last 20 years of applications. A bioassay for estrogen has a role because measuring biological effect is theoretically useful, increasing the understanding of physiology in addition to biochemical levels, giving different information than other assays, and opening the door to measure very low levels of estrogen activity in both humans and the environment.

Topics: Anastrozole; Aromatase Inhibitors; Biological Assay; Breast Neoplasms; Child; Estradiol; Female; Humans; Leuprolide; Male; Nitriles; Puberty, Precocious; Radioimmunoassay; Recombinant Proteins; Reference Values; Saccharomyces cerevisiae; Sensitivity and Specificity; Triazoles; Turner Syndrome

Gonadotropin-releasing hormone analogues are used in the treatment of prostate cancer, breast cancer, endometriosis, and uterine leiomyomas in adults and often in the treatment of precocious puberty in children. Many adverse effects have been reported for gonadotropin-releasing hormone analogues, but anaphylaxis is rarely reported as an adverse effect. Frequent cross-reactions, particularly during childhood, and diversity of the time of onset of anaphylactic manifestations complicate the diagnosis. A patient who exhibited anaphylactic allergic reactions to two different agents used in the treatment of central precocious puberty presented here because the case has an atypical course and is the first in the literature.

Topics: Adult; Anaphylaxis; Antineoplastic Agents, Hormonal; Child; Female; Humans; Leuprolide; Prognosis; Puberty, Precocious; Triptorelin Pamoate

Topics: 11-beta-Hydroxysteroid Dehydrogenases; Adrenal Hyperplasia, Congenital; Body Height; Bone Development; Child; Dwarfism; Female; Hirsutism; Hormones; Humans; Hydrocortisone; Leuprolide; Physical Examination; Prognosis; Puberty, Precocious; Triptorelin Pamoate; Ultrasonography

Precocious puberty is a common problem affecting up to 29 per 100,000 girls per year. The earliest identified neuroendocrine change in early puberty thus far is increased kisspeptin secretion from the arcuate nucleus and the anteroventral paraventricular nucleus of the hypothalamus. The regulation of kisspeptin secretion is not well understood, but neurokinin B and dynorphin provide autocrine regulation. The etiologies of precocious puberty may be subdivided into GnRH-dependent and GnRH-independent causes. GnRH-dependent precocious puberty, often called central precocious puberty (CPP), is usually treated with GnRH analogs. Newer developments in the treatment of CPP include expanded data on the safety and efficacy of the subdermal histrelin implant, which is useful for long-term treatment, although removal may be difficult in some cases. Preliminary data suggest that the implant may be left in place for up to 2 years without loss of biochemical suppression. In the last 2 years, more data have been published concerning extended-release leuprolide acetate injections that indicate that the 11.25-mg dose may not provide full biochemical suppression but may clinically suppress signs of puberty, including the accelerated growth velocity and advanced skeletal maturation seen in CPP. Treatment options for familial male-limited precocious puberty and McCune-Albright syndrome are expanding as well, although data are preliminary. Long-term outcome studies of CPP indicate overall good menstrual and reproductive function, but the prevalence of polycystic ovary syndrome may be higher than in the general population. Remarkably few studies have evaluated the behavioral and psychological outcomes of precocious puberty, in contrast to early normal maturation. Additional outcome studies of endocrine, metabolic, and psychological effects of CPP are clearly needed.

Topics: Delayed-Action Preparations; Drug Implants; Female; Gonadotropin-Releasing Hormone; Humans; Kisspeptins; Leuprolide; Male; Puberty; Puberty, Precocious; Treatment Outcome

Thanks to recent advances in biotechnology, the use of peptides and proteins as drugs has become a concrete clinical reality, and consequently an interesting challenge has emerged for non-parenteral drug delivery. Leuprolide is a synthetic nonapeptide agonist to the luteinizing hormone-releasing hormone (LH-RH) receptor with principal clinical applications for prostate cancer. Although a large number of formulations available, they mainly consist in depot subcutaneous injections or implantable devices. Both of these routes of administration present multiple limitations considering the large clinical applications of this active substance.. The objective of this review is to critically discuss the formulations currently available on the market for leuprolide optimization and to consider how drug delivery plays an important role in improving the bioavailability of this compound.. Due to its physicochemical properties and its economical market, leuprolide is an interesting candidate for drug delivery to improve the efficacy of existing treatments, dose adjustments, and patient compliance and safety.

Topics: Administration, Cutaneous; Administration, Intranasal; Administration, Oral; Administration, Sublingual; Amino Acid Sequence; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemistry, Pharmaceutical; Endometriosis; Female; Genital Diseases, Female; Gonadotropin-Releasing Hormone; Humans; Infusions, Parenteral; Injections, Subcutaneous; Leuprolide; Male; Prostatic Neoplasms; Puberty, Precocious; Receptors, LHRH

Leuprolide acetate is a synthetic nonapeptide that is a potent gonadotropin-releasing hormone receptor (GnRHR) agonist used for diverse clinical applications, including the treatment of prostate cancer, endometriosis, uterine fibroids, central precocious puberty and in vitro fertilization techniques. As its basic mechanism of action, leuprolide acetate suppresses gonadotrope secretion of luteinizing hormone and follicle-stimulating hormone that subsequently suppresses gonadal sex steroid production. In addition, leuprolide acetate is presently being tested for the treatment of Alzheimer's disease, polycystic ovary syndrome, functional bowel disease, short stature, premenstrual syndrome and even as an alternative for contraception. Mounting evidence suggests that GnRH agonist suppression of serum gonadotropins may also be important in many of the clinical applications described above. Moreover, the presence of GnRHR in a multitude of non-reproductive tissues including the recent discovery of GnRHR expression in the hippocampi and cortex of the human brain indicates that GnRH analogs such as leuprolide acetate may also act directly via tissue GnRHRs to modulate (brain) function. Thus, the molecular mechanisms underlying the therapeutic effect of GnRH analogs in the treatment of these diseases may be more complex than originally thought. These observations also suggest that the potential uses of GnRH analogs in the modulation of GnRH signaling and treatment of disease has yet to be fully realized.

Topics: Animals; Endometriosis; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Leiomyoma; Leuprolide; Male; Prostatic Neoplasms; Puberty, Precocious; Receptors, LHRH

Topics: Biomarkers; Buserelin; Diagnosis, Differential; Diagnostic Imaging; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Prognosis; Puberty, Precocious

Topics: Anastrozole; Aromatase Inhibitors; Female; Fibrous Dysplasia, Polyostotic; Gonadotropins, Pituitary; Humans; Leuprolide; Male; Nitriles; Prognosis; Puberty, Precocious; Surgical Procedures, Operative; Triazoles

Topics: Androgen Antagonists; Aryl Hydrocarbon Hydroxylases; Cyproterone Acetate; Cytochrome P450 Family 2; Diagnosis, Differential; Estrogens; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Leuprolide; Male; Prognosis; Puberty, Precocious; Steroid 16-alpha-Hydroxylase; Steroid Hydroxylases

Topics: Diagnosis, Differential; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Progesterone Congeners; Prognosis; Puberty, Precocious; Spermatogenesis; Testis; Testosterone; Urologic Surgical Procedures, Male

Topics: Causality; Child; Diagnosis, Differential; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Nurse Practitioners; Nurse's Role; Primary Health Care; Puberty, Precocious; Testosterone

This chapter describes several aspects of the management of treatment in girls and boys with central precocious puberty. Although there is some controversy about the indication for gonadotrophin releasing hormone (GnRH) agonist treatment in the literature, a list of clear indications is presented and monitoring requirements for treatment are discussed with reference to the pertinent literature. The development of clinical, psychological, hormonal, sonographical and auxological parameters that can be expected during GnRH agonist treatment is described in detail. In view of the scant evidence-based knowledge, we review the final outcome of patients treated with GnRH agonists with respect to reversibility of hormonal suppression, reproductive function, final height and side effects. The data published so far show that GnRH agonist treatment using the modern depot preparations is not only convenient but also safe, with relatively minor side effects. The outcome in terms of final height is favourable in the majority of patients.

Topics: Adolescent; Child; Female; Humans; Leuprolide; Male; Puberty, Precocious; Treatment Outcome; Triptorelin Pamoate

Topics: Child; Diagnosis, Differential; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Puberty, Precocious

Leuprorelin (leuprolide acetate) is a gonadotrophin-releasing hormone (GnRH) analogue used to treat a wide range of sex hormone-related disorders including advanced prostatic cancer, endometriosis and precocious puberty. It acts primarily on the anterior pituitary, inducing a transient early rise in gonadotrophin release. With continued use, leuprorelin causes pituitary desensitisation and/or down-regulation, leading to suppressed circulating levels of gonadotrophins and sex hormones. Clinical trials in men with advanced prostatic cancer demonstrate that leuprorelin (usually monthly depot injections of 3.75 or 7.5 mg) is less likely to cause serious adverse cardiovascular effects than diethylstilbestrol, and has comparable efficacy to bilateral orchiectomy or other GnRH analogues. Therefore, the choice between leuprorelin and orchiectomy may be made on the basis of the patient's treatment preference, along with specific patient characteristics and cost implications. Monthly intramuscular or subcutaneous administration of depot leuprorelin 3.75 mg was superior to placebo, and comparable to oral danazol 800 mg/day or intranasal buserelin 900 micrograms/day, in achieving objective and subjective responses in women with endometriosis. Thus, leuprorelin is an effective alternative to other treatments for women with endometriosis, but the recommended duration of its use in this clinical setting is limited to 6 months because it reduces bone mineral density. In children with central precocious puberty, leuprorelin (usually monthly intramuscular or subcutaneous injections of depot leuprorelin 3.75 to 15mg) decreases mean growth velocity and signs of sexual maturation and increases predicted adult height compared with baseline measurements. Although effects on final adult height are predicted from available data and require confirmation in long term follow-up studies, the absence of effective alternatives to GnRH analogues makes leuprorelin a first-line therapy for children with this rare disease. In women with uterine leiomyomata, monthly intramuscular administration of depot leuprorelin 3.75 mg for 6 months markedly reduces uterine volume and fibroid-related symptoms, but, as with other GnRH analogues, these effects dissipate following discontinuation of the drug. As adjuvant therapy in women undergoing in vitro fertilisation or gamete intrafallopian transfer, leuprorelin (usually 0.5 to 1 mg/day subcutaneously) reduces the risk of cancelled cycles for oocyte re

Topics: Amino Acid Sequence; Androgen Antagonists; Animals; Antineoplastic Combined Chemotherapy Protocols; Controlled Clinical Trials as Topic; Endometriosis; Female; Fertility; Gonadal Steroid Hormones; Half-Life; Humans; Leiomyoma; Leuprolide; Male; Metabolic Clearance Rate; Molecular Sequence Data; Prostatic Neoplasms; Puberty, Precocious; Uterine Neoplasms

Topics: Central Nervous System Diseases; Child; Female; Humans; Leuprolide; Male; Nafarelin; Puberty, Precocious

Leuprorelin is an analog of gonadotropin-releasing hormone that is used for the therapy of central precocious puberty (CPP). The aims of this prospective, open label, multicenter clinical trial were to establish its efficacy and safety during long-term use.. Patients, who were all children, were treated with 1.88 to 3.75 mg leuprorelin subcutaneously once every 4 weeks for a total of 96 weeks between 2015 and 2018. The primary endpoint was the rate of occurrence of adverse events (AEs) and the secondary endpoint was no progression in the Tanner stage or regression by week 96 compared to baseline.. A total of 307 CPP patients, 305 (99.3%) females and 2 males (0.7%), completed the 96-weeks of treatment. Due to limited data for male patients, they are not discussed in the efficacy results. Treatment-emergent AEs (TEAEs) were reported for 252 (82.1%) patients, mostly (79.5%) being mild or moderate and only 33 (10.7%) of patients experienced TEAEs related to leuprorelin therapy. The most frequent (>2%) drug-related TEAEs were injection site induration (4.6%, 14/307) and vaginal bleeding (2.3%, 7/305). After treatment, 83.5% of patients had regression or no progression in the Tanner stage (95% confidence interval: 78.68%, 87.62%) and the majority had decreased gonadotropin-releasing hormone-stimulated peak luteinizing hormone and follicle-stimulating hormone concentrations, as well as reduced sex hormone concentrations and a reduction in the bone age/chronological age ratio compared to baseline.. The trial revealed that CPP was effectively treated in most patients who received leuprorelin for nearly 2 years. Any drug-related AEs were reported with low incidence (<5%) and were consistent with the known safety profile of leuprorelin.. The trial was registered at ClinicalTrials.gov (registration number: NCT02427958).

Topics: Child; China; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Prospective Studies; Puberty, Precocious

Gonadotropin-releasing hormone agonists (GnRHas) are standard of care for central precocious puberty (CPP). A 6-month subcutaneous injection has recently been approved by the Food and Drug Administration.. Determine efficacy, pharmacokinetics, and safety of 6-month 45-mg subcutaneous leuprolide acetate for CPP.. Phase 3 multicenter, open-label, single-arm study.. 25 sites in 6 countries.. 64 GnRHa-naïve children with CPP (age: 7.5 ± 0.1 years) received study drug: 59 completed the study.. 2 doses of 45-mg subcutaneous leuprolide acetate (0.375 mL) at 0 and 24 weeks; children were followed for 48 weeks.. Percentage of children with serum luteinizing hormone (LH) <4 IU/L 30 minutes following GnRHa stimulation at week 24.. 54/62 (87%) children achieved poststimulation LH <4 IU/L at week 24; 49/56 (88%) girls and 1/2 boys maintained peak LH <4 IU/L at week 48. Mean growth velocity decreased from 8.9 cm/year at week 4 to 6.0 cm/year at week 48. Mean bone age was advanced 3.0 years beyond chronological age at screening and 2.7 years at week 48. Breast pubertal stage regressed or was stable in 97% of girls and external genitalia development regressed in both boys. Adverse events were mild and did not cause treatment discontinuation.. A small volume of 45-mg subcutaneous leuprolide acetate administered at a 6-month interval effectively suppressed pubertal hormones and stopped or caused regression of pubertal progression. This long-acting GnRHa preparation of leuprolide acetate is a new, effective, and well-tolerated therapy for children with CPP.

Topics: Child; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Male; Puberty, Precocious; Treatment Outcome

Children with central precocious puberty (CPP) are treated with gonadotropin-releasing hormone agonists (GnRHa) to suppress puberty. Optimizing treatment outcomes continues to be studied. The relationships between growth, rate of bone maturation (bone age/chronological age [ΔBA/ΔCA]), luteinizing hormone (LH), predicted adult stature (PAS), as well as variables influencing these outcomes, were studied in children treated with depot leuprolide (LA Depot) Methods: Subjects (64 girls, seven boys) with CPP received LA Depot every 3 months for up to 42 months. Multivariate regression analyses were conducted to examine the predictors affecting ΔBA/ΔCA, PAS and growth rate.. Ninety percent of subjects (18 of 20) were suppressed (LH levels <4 IU/L) at 42 months. Over 42 months, the mean growth rate declined 2 cm/year, the mean BA/CA ratio decreased 0.21 and PAS increased 8.90 cm for girls (n=64). PAS improved to mid-parental height (MPH) in 46.2% of children by 30 months of treatment. Regression analysis showed that only the Body Mass Index Standardized Score (BMI SDS) was significantly associated (β+0.378 and +0.367, p≤0.05) with growth rate. For PAS, significant correlations were with MPH (β+0.808 and +0.791, p<0.001) and ΔBA/ΔCA (β+0.808 and +0.791, p<0.001). For ΔBA/ΔCA, a significant association was found only with BA at onset of treatment (β-0.098 and -0.103, p≤0.05). Peak-stimulated or basal LH showed no significant influence on growth rate, ΔBA/ΔCA or PAS.. Growth rate and bone maturation rate normalized on treatment with LA Depot. LH levels were not significantly correlated with growth rate, ΔBA/ΔCA or PAS, suggesting that suppression was adequate and variations in gonadotropin levels were below the threshold affecting outcomes.

Topics: Adult; Age Determination by Skeleton; Biomarkers; Body Height; Bone Development; Child; Child Development; Female; Humans; Leuprolide; Male; Prognosis; Puberty, Precocious; Tablets; Treatment Outcome

Antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog (GnRHa) treatment normalizes growth rate and bone maturation and increases predicted adult height (AH) in boys with familial male-limited precocious puberty (FMPP). To evaluate the effect of long-term antiandrogen, aromatase inhibitor, and GnRHa on AH, boys with FMPP who were treated were followed to AH.. Twenty-eight boys with FMPP, referred to the National Institutes of Health, were started on antiandrogen and aromatase inhibitor at 4.9 ± 1.5 years of age; GnRHa was added at 6.9 ± 1.5 years of age. Treatment was discontinued at 12.2 ± 0.5 years of age (bone age, 14.4 ± 1.3). AH was assessed at 16.4 ± 1.3 years of age (bone age, 18.5 ± 0.6).. AH (mean ± SD) for all treated subjects was 173.6 ± 6.8 cm (-0.4 ± 1.0 SD relative to adult US males). For 25 subjects with pretreatment predicted AH, AH significantly exceeded predicted AH at treatment onset (173.8 ± 6.9 vs 164.9 ± 10.7 cm; P < .001), but fell short of predicted AH at treatment discontinuation (177.3 ± 9.0 cm; P < .001). For 11 subjects with maternal or sporadic inheritance, the mean AH was 3.1 cm (0.4 SD score) below sex-adjusted midparental height (175.4 ± 5.8 vs 178.5 ± 3.1 cm [midparental height]; P = .10). For 16 subjects with affected and untreated fathers, AH was significantly greater than fathers' AH (172.8 ± 7.4 vs 168.8 ± 7.2 cm; P < .05).. Long-term treatment with antiandrogen, aromatase inhibitor, and GnRHa in boys with FMPP results in AH modestly below sex-adjusted midparental height and within the range for adult males in the general population.

Topics: Adult; Anastrozole; Androgen Antagonists; Aromatase Inhibitors; Body Height; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Nitriles; Puberty, Precocious; Spironolactone; Testolactone; Treatment Outcome; Triazoles; Triptorelin Pamoate

Aromatase inhibitors have been used to increase predicted adult height (PAH) in boys but in girls only in McCune-Albright syndrome. We investigated whether anastrozole combined with leuprorelin for up to 2 years is safe and effective in improving PAH in girls with early puberty and compromised growth, compared to leuprorelin alone.. The "GAIL" study: girls treated with an aromatase inhibitor and an LHRH analogue, ISRCTN11469487, was a 7-year prospective phase IIa study with parallel design, performed at Athens Medical Center (C-A), and Attikon University Hospital, Athens, Greece (C-B). Forty girls, consecutively referred for early puberty (onset 7.5-9 years) with a PAH <-2 or >1.5 SD lower than their target height (TH), were included. Twenty started on leuprorelin sc/im 0.3 mg/kg/month plus anastrozole 1 mg/d p.o. (group-A, C-A) and 20 on leuprorelin (group-B, C-B) for 2 years or until the age of 10 years. Groups did not differ in age, height, BMI, bone age advancement (BAA), and distance of PAH from TH. Follow-up was at 6, 12, 18, and 24 m.. Reduction in BAA was significantly higher in group-A compared to group-B already by 6 m. Despite the transiently significant decrease in height velocity in group-A, gain in PAH SD was almost double by 12 and 18 m vs group-B and reached the maximum of +1.21 ± 0.45 (7.51 cm) vs +0.31 ± 0.37 (1.92 cm, p = 0.001) in group-B at 24 m. Group-A had no clinical or biochemical hyperandrogenism, unchanged normal bone density, and lumbar spine X-rays.. The co-administration of anastrozole with leuprorelin safely improves PAH in girls with compromised growth.

Topics: Anastrozole; Aromatase Inhibitors; Body Height; Bone Density; Case-Control Studies; Child; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Greece; Growth Disorders; Humans; Leuprolide; Nitriles; Prognosis; Prospective Studies; Puberty, Precocious; Sexual Maturation; Triazoles

Peak gonadotropin-releasing hormone or agonist (GnRHa) stimulated luteinizing hormone (LH) testing with leuprolide acetate (LA) is commonly used to document suppression during therapy for central precocious puberty (CPP). The objective of the study was to investigate suitability of using basal LH levels to monitor GnRHa treatment and to determine optimal transition from 1-month to 3-month LA formulations via a post hoc analysis of a randomized, open-label, 6-month study.. A total of 42 children with CPP, pretreated with 7.5-, 11.25-, or 15-mg 1-month LA formulations were randomized to 11.25- or 30-mg 3-month LA. Basal LH/peak-stimulated LH levels were measured at weeks 0, 4, 8 and 12. Positive/negative predictive values and sensitivities/specificities were determined for basal LH vs. LH-stimulation results.. Pretreatment with any 1-month formulation for the most part did not affect continuation of suppression after transitioning to 3-month formulation (mean peak-stimulated LH levels remained < 4 IU/L). Basal LH predicted suppression escape (basal LH-level cutoff ≥ 0.6 IU/L predicted 70% of those failing suppression). Tolerability was similar, regardless of dose.. Our data indicate that a basal level of <0.60 IU/L is adequate for monitoring suppression approximately two-thirds of the time. Furthermore, the effectiveness and safety of 3-month LA treatments are not influenced by previous CPP therapies.

Topics: Child; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Female; Follicle Stimulating Hormone, Human; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Leuprolide; Luteinizing Hormone; Male; Microspheres; Ovary; Puberty, Precocious; Reproductive Control Agents; Retrospective Studies; Testis

In central precocious puberty (CPP), the pulse secretion and release of gonadotropin-releasing hormone (GnRH) are increased due to early activation of the hypothalamic-pituitary-gonadal axis, resulting in developmental abnormalities with gonadal development and appearance of secondary sexual characteristics. The CPP without organic disease is known as idiopathic CPP (ICPP). The objective of the study was to evaluate the clinical efficacy and safety of domestic leuprorelin (GnRH analog) in girls with ICPP.. A total of 236 girls with ICPP diagnosed from April 2012 to January 2014 were selected and were randomized into two groups. One hundred fifty-seven girls in the test group were treated with domestic leuprorelin acetate, 79 girls in the control group were treated with imported leuprorelin acetate. They all were treated and observed for 6 months. After 6-month treatment, the percentage of children with peak luteinizing hormone (LH) ≤3.3 U/L, the percentage of children with peak LH/peak follicle stimulating hormone (FSH) ratio <0.6, the improvements of secondary sexual characteristics, gonadal development and sex hormone levels, the change of growth rate of bone age (BA) and growth velocity, and drug adverse effects between two groups were compared.. After the treatment, the percentage of children with a suppressed LH response to GnRH, defined as a peak LH ≤3.3 U/L, at 6 months in test and control groups were 96.80% and 96.20%, respectively, and the percentage of children with peak LH/FSH ratio ≤0.6 at 6 months in test and control groups were 93.60% and 93.70%, respectively. The sizes of breast, uterus and ovary of children and the levels of estradiol (E 2 ) were significantly reduced, and the growth rate of BA was also reduced. All the differences between pre- and post-treatment in each group were statistically significant (P < 0. 05), but the differences of the parameters between two groups were not significant (P > 0.05).. Domestic leuprorelin is effective and safe in the treatment of Chinese girls with ICPP. Its effectiveness and safety are comparable with imported leuprorelin.

Topics: Body Height; Body Weight; Child; Child, Preschool; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Treatment Outcome

A pharmacokinetic substudy was conducted within a phase 3 clinical trial that evaluated the efficacy and safety of two leuprolide acetate 3-month depot formulations in children with central precocious puberty (CPP), where the pharmacokinetics of leuprolide and the exposure-response relationship between leuprolide concentration and the probability of luteinizing hormone (LH) suppression were assessed.. Children diagnosed with CPP (N = 42 in each dosing cohort), who were treatment naïve or previously treated, received a total of two intramuscular injections of either leuprolide acetate depot 11.25 or 30 mg formulations administered 3 months apart. Serial blood samples were collected for leuprolide concentration determination in a subset of subjects (N = 24 in each cohort). One-way analysis of covariance was used to assess dose proportionality. The probability of LH suppression (peak-stimulated LH concentrations <4 mIU/mL) exposure-response relationship was modelled using repeated measures logistic regression. The predicted probability of LH suppression and the corresponding 95 % confidence interval at the mean leuprolide concentration of each dose group and at each time of measurement were computed.. Mean leuprolide concentrations between weeks 4 and 12 for 11.25 and 30 mg doses were relatively constant and dose proportional, with no accumulation of leuprolide upon repeated administration. Body weight and age were not found to be significant covariates on leuprolide pharmacokinetics. Higher leuprolide concentrations were associated with higher probability of LH suppression and both doses provided LH suppression levels <4 mIU/mL.. Leuprolide pharmacokinetics were characterized for 11.25 and 30 mg 3-month depot injections. An exposure-response model was developed to link leuprolide concentrations and probability of peak-stimulated LH suppression.

Topics: Administration, Oral; Chemistry, Pharmaceutical; Child; Child, Preschool; Female; Humans; Infant; Leuprolide; Male; Puberty, Precocious; Time Factors

We have recently demonstrated short-term (6-month) efficacy and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with central precocious puberty (CPP).. To assess long-term (36-month) hypothalamic-pituitary-gonadal axis suppression and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with CPP.. Open-label, 36-month extension.. Twenty pediatric endocrine centers.. Seventy-two children (mean age, 8.5 ± 1.6 y; 65 females) with CPP completed and showed maintenance of LH suppression after a 6-month lead-in study.. Leuprolide acetate depot (11.25 or 30 mg) administered im every 3 months.. Peak-stimulated LH, estradiol, T, growth rate, pubertal progression, and adverse events (AEs).. Twenty-nine of 34 subjects in the 11.25-mg group and 36 of 38 subjects in the 30-mg group had LH values < 4 mIU/mL after day 1 at all time points. All seven subjects who escaped LH suppression at any time still maintained sex steroid concentrations at prepubertal levels and showed no signs of pubertal progression. AEs were comparable between groups, with injection site pain being the most common (26.4% overall). No AE led to discontinuation of study drug. The safety profile over 36 months was comparable to that observed during the 6-month pivotal study.. The two doses of leuprolide acetate 3-month depot were associated with an acceptable safety profile and provided maintenance of LH suppression in the majority of children with CPP during the 36 months of the study or until readiness for puberty.

Topics: Androgens; Antineoplastic Agents, Hormonal; Child; Child, Preschool; Dose-Response Relationship, Drug; Estradiol; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Sexual Maturation

GnRH agonist (GnRHa) monthly injections are frequently used in the treatment of central precocious puberty (CPP). The 3-month leuprolide depot 11.25- and 30-mg formulations are newly approved treatment options.. The aim of the study was to investigate the safety and efficacy of leuprolide acetate 3-month depot formulations for the treatment of CPP in children.. This was a phase III, randomized, open-label, dose-ranging 6-month study.. Twenty-two U.S. medical centers (including Puerto Rico) participated.. Children diagnosed with CPP (n = 84), who were either treatment naive or previously treated with GnRHa, were recruited. Chronological age at onset of pubertal signs was less than 8 yr in girls and less than 9 yr in boys, and bone age was advanced over chronological age at least 1 yr.. Leuprolide acetate depot (11.25 or 30 mg) was administered im every 3 months.. Biochemical [peak-stimulated LH, estradiol (girls), and testosterone (boys)] and anthropometric (growth rate, bone age acceleration, pubertal progression) parameters and safety were assessed.. Peak-stimulated LH was suppressed in the 11.25- and 30-mg dose groups in 78.4 and 95.2%, respectively, of children from months 2 through 6. There were nine treatment failures (peak-stimulated LH >4 IU/liter) in the 11.25-mg group and two in the 30-mg group. Basal sex steroid suppression, growth rates, pubertal progression, bone age advancement, and adverse events were similar with either dose.. Treatment with leuprolide acetate 3-month depot formulations (11.25 and 30 mg) effectively suppressed the GnRH axis, was well tolerated, and may positively impact patient convenience and compliance.

Topics: Child; Child, Preschool; Dose-Response Relationship, Drug; Estradiol; Female; Follicle Stimulating Hormone; Humans; Infant; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Testosterone; Treatment Outcome

To evaluate whether serum antimüllerian hormone (AMH) levels are affected in early maturing girls, and whether pituitary suppression by long-acting GnRH agonist (GnRH-a) affects AMH.. Secondary analyses of a prospective clinical study.. Tertiary pediatric center.. Fifteen girls followed during GnRH-a treatment. Evaluations before, 3 and 12 months after initiation, as well as 6 months after discontinuation of treatment. To evaluate whether AMH levels were affected in early maturing girls, baseline levels were compared with levels in healthy girls (matched for age, n = 129; matched for pubertal Tanner stage, n = 119).. Patients were treated with SC injections of leuprolide acetate (LA; Procren 3.75 mg every 28th day).. Basal serum levels of AMH, E(2), inhibin B, FSH, and LH, as well as GnRH-stimulated levels of FSH and LH.. At baseline, the median (range) of AMH levels in the patients was 20.3 pmol/L (2.0-30.0 pmol/L). After 3 months of GnRH-a treatment, AMH declined to 10.4 pmol/L (range, <2.0-27.0 pmol/L). The AMH suppression was maintained after 12 months of treatment (14.4 pmol/L [range, <2.0-29.6 pmol/L]). Six months after discontinuation of GnRH-a treatment, AMH levels were similar to pretreatment levels (18.8 pmol/L (range, 5.8-46.9 pmol/L)). Before treatment, AMH levels in early maturing girls did not differ significantly from AMH levels in healthy age-matched girls (median, 20 vs. 23 pmol/L) or Tanner-matched girls (median, 20 vs. 19 pmol/L).. The partial suppression of AMH by GnRH-a treatment is consistent with previous studies suggesting partial gonadotropin-dependence of AMH.

Topics: Anti-Mullerian Hormone; Biomarkers; Child; Child Development; Denmark; Drug Administration Schedule; Estradiol; Female; Fertility Agents, Female; Follicle Stimulating Hormone, Human; Gonadotropin-Releasing Hormone; Humans; Inhibins; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Prospective Studies; Puberty; Puberty, Precocious; Time Factors; Treatment Outcome

To compare 1-month and 3-month depot formulations of leuprolide acetate (DL), a gonadotropin-releasing hormone analog, in the treatment of central precocious puberty (CPP).. Subjects with CPP naïve to therapy were randomized to 7.5 mg of 1-month DL, 11.25 mg of 3-month DL, or 22.5 mg of 3-month DL. Stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and estradiol levels, growth velocity, and bone age progression were examined in a 2-year period.. Forty-nine female and 5 male subjects with CPP were randomized. Mean stimulated LH and FSH levels during treatment were higher in the low-dose 11.25-mg 3-month DL group, and more LH levels >4 IU/L were observed, in comparison with the other two dose groups. Mean LH and FSH levels in the 22.5-mg 3-month group were not different from the monthly DL. No differences in estradiol levels, growth velocity, or bone age progression were observed in dosing groups.. All DL doses resulted in prompt and effective suppression of puberty, but higher LH and FSH levels were seen with the 11.25-mg 3-month DL dose. Multi-monthly DL is effective in treating CPP, but higher dosing may be required in some circumstances.

Topics: Child; Delayed-Action Preparations; Drug Administration Schedule; Female; Humans; Leuprolide; Male; Puberty, Precocious; Time Factors

Depot luteinizing-hormone releasing hormone (LHRH) agonist have been widely used for the treatment of central precocious puberty (CPP), but the optimal doses to obtain hormonal suppression are still unknown, especially in patients with higher weights. The goal of our study was to compare the efficacy of three leuprolide acetate (LA) preparations, suppressing gonadotropin secretion in patients with CPP.. In an open 12-month protocol, we evaluated LA 7.5 mg/month, 11.25 and 22.5 every 3 months.. Fourteen girls with CPP and weights over 30 kg.. Clinical, radiological and laboratory follow-up: GnRH test plus LH, FSH 40 min post analogue was performed periodically.. Pretreatment basal and LHRH stimulated LH levels between groups were not different. Basal and LHRH stimulated LH levels decreased significantly between baseline and from 3 up to 12 months of therapy in all groups (P = 0.001). GnRH stimulated LH peak <2 IU/l, the main efficacy criterion was met in 80, 75 and 100% of the children at 6 months in the 7.5, 11.25, 22.5 mg doses respectively. By 12 months, 100% of patients had LH suppressed to <2 IU/l.. These results affirm that 3-month injections may be a satisfactory alternative for the therapy of children with CPP to avoid monthly injections. In addition, suppression of LH occurs sooner in the 3-month 22.5 mg LA dose compared to the 3-month 11.5 mg; therefore, adequate dosing may be important for optimal outcome. Further investigation is needed in more patients over 30 kg, with longer treatment duration, and ultimately final height consideration.

Topics: Age Determination by Skeleton; Child; Female; Gonadal Steroid Hormones; Humans; Leuprolide; Puberty, Precocious; Treatment Outcome

To evaluate if 3 months of gonadotropin-releasing hormone analogue (GnRHa) treatment results in sufficient suppression of pubertal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) profile patterns in short pubertal small for gestational age (SGA) boys. To compare growth hormone (GH) profiles and fasting insulin-like growth factor (IGF)-I and IGF-binding protein-3 (IGFBP-3) levels after 3 months of GnRHa treatment with those at baseline.. After measurement of baseline overnight profiles and IGF-I and IGFBP-3 levels, 14 short pubertal SGA boys received leuprorelide acetate depots of 3.75 mg subcutaneously, every 4 weeks.. At baseline, mean GH levels were comparable with those of controls, whereas IGF-I and IGFBP-3 standard deviation scores (SDS) were significantly lower than zero SDS. After 3 months of GnRHa treatment, all boys showed clinical arrest of puberty. The area under the curve above zero, mean and maximum LH and FSH had significantly decreased to prepubertal levels. Peak LH during the GnRH agonist test, however, indicated insufficient pubertal suppression in 43% of boys. Overnight GH profile characteristics and IGF-I and IGFBP-3 levels did not significantly change.. Puberty was sufficiently suppressed by GnRHa treatment, as shown by the prepubertal LH and FSH profiles. After 3 months of GnRHa treatment, overnight GH profile characteristics had not significantly changed, reflecting that GH levels are comparable for prepubertal and early pubertal boys.

Topics: Body Height; Child; Follicle Stimulating Hormone; Growth Disorders; Human Growth Hormone; Humans; Infant, Newborn; Infant, Small for Gestational Age; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious

To determine utility of luteinizing hormone (LH) estimation, post intramuscular (IM) depot leuprolide in comparison with subcutaneous leuprolide stimulation test. Test for monitoring therapy in patients with gonadotropin dependent precocious puberty (GDPP). In seven patients of GDPP, who were treated with 11.25 mg depot leuprolide, the LH peak after subcutaneous (sc) test was compared with LH at hourly interval for 4 h after IM depot leuprolide for 13 tests and 3rd hour value for next ten tests. These two values were compared both before and after therapy. Before therapy, the mean +/- SD LH peak after subcutaneous leuprolide stimulation test was 20.6 +/- 7.85 IU/l (range 9.64-30.4 IU/l), and it was 27.3 +/- 12.21 IU/l 3 h after the first depot leuprolide injection (range 10.5-45.4 IU/l). During therapy, the mean +/- SD of LH peak after sc stimulation test was 1.96 +/- 0.75 IU/l (range 1.1-3.1 IU/l), and it was 2.58 +/- 0.54 IU/l (range 1.4-3.4 IU/l) 3 h after depot leuprolide injection. Three-hour LH value following IM depot leuprolide injection (11.25 mg) can be used for monitoring therapy in patients with GDPP because of its convenience and cost effectiveness.

Topics: Child; Child, Preschool; Female; Fertility Agents, Female; Humans; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Luminescent Measurements; Luteinizing Hormone; Male; Puberty, Precocious; Time Factors

The effect of the variation in hormonal suppression on bone maturation, growth velocity, and adult height prediction was examined during treatment with leuprolide acetate for central precocious puberty (CPP).. Ten girls on variable doses of Lupron were studied for one year. Height, weight, body mass index, luteinizing hormone (LH), estradiol, and growth velocity were measured every 3 months. Bone age and predicted height were assessed every 6 months.. LH range changed from 0.5-1.4 IU/I to 0.1-2.8 IU/I. The average Lupron dose decreased from 0.33 +/- 0.11 to 0.26 +/- 0.08 mg/kg. Predicted adult height averaged 158.33 +/- 9.5cm at the start of the study and increased to 161.45 +/- 6.26 cm (p <0.01). LH and estradiol did not correlate with the rate of bone maturation, growth velocity, predicted height, or with leuprolide dose.. Variable dosing of leuprolide acetate is needed to achieve similar amounts of hormonal suppression, yet small changes in dose did not significantly change LH or estradiol levels or predicted height.

Topics: Body Height; Body Mass Index; Bone and Bones; Bone Development; Child; Child, Preschool; Dose-Response Relationship, Drug; Estradiol; Female; Fertility Agents, Female; Growth; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious

Precocious puberty may reduce final adult height, and affected children may suffer social and emotional problems. The efficacy of treatment with a long acting agonist analogue of the gonadotropin releasing hormone (aLHRH) has been well demonstrated.. To evaluated the efficacy of a new formulation of aLHRH (leuprolide, Lupron) for the suppression of gonadotropin activation and clinical signs of puberty.. Eleven children (ten females) with idiopathic central precocious puberty, with a mean chronological age of 7.5+/-1.8 years and a bone age of 9.7+/-1.8 years were recruited. Testicular volume in the male was 15 ml. In females, Tanner stage for breast development was between 2-4 and mean ovarian volume was 2.3+/-0.8 ml. They were treated during 18 months with aLHRH, 11.25 mg administered intramuscularly every three months.. Clinical, hormonal and ultrasonographic signs of puberty regressed in all patients. The degree of suppression of LH was 87.7+/-5.1% at the end of the 18 months. No significant changes in bone mineral content were observed during the treatment period.. Leuprolide (aLHRH) 11.25 mg, injected every three months, is effective for the control of central precocious puberty and allows to reduce the number of yearly injections from 12 to 4.

Topics: Age Determination by Skeleton; Body Height; Bone Density; Bone Development; Breast; Child; Female; Fertility Agents; Gonadotropin-Releasing Hormone; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Male; Ovary; Puberty, Precocious; Testis; Testosterone

We evaluated the effect of leuprorelin treatment on adult height (AH) and followed recovery of reproductive function in 63 girls and 13 boys with central precocious puberty (CPP). Mean treatment durations were 3.8 +/- 2.0 and 4.1 +/- 2.5 yr, and posttreatment follow-up durations were 3.5 +/- 1.3 and 2.6 +/- 1.1 yr for girls and boys, respectively. AH was 154.5 +/- 5.7 cm for girls, and 89.5% of girls reached AH within their target height range. For boys, AH was 163.2 +/- 13.0 cm, and 90.9% reached target height range. It appeared that the Bayley-Pinneau method, modified for Japanese children, using a table for advanced bone age (BA), overestimated AH in CPP; and this method, using a table for average BA and projected height for BA, was suitable for prediction of AH in CPP. Menarche or remenarche occurred in 96.8% of girls at the age of 13.1 +/- 1.5 yr. Of 11 girls who contributed urine samples, all seven idiopathic and two organic cases were considered to have ovulation. Serum testosterone levels reached normal adult level in all boys. In conclusion, long-term leuprorelin treatment for children with CPP improved AH and had no adverse effects on recovery of reproductive function.

Topics: Adolescent; Adult; Body Height; Child; Female; Fertility Agents, Female; Follow-Up Studies; Humans; Japan; Leuprolide; Male; Menarche; Ovulation; Prospective Studies; Puberty, Precocious; Recovery of Function

To distinguish which children with precocious puberty (PP) and early puberty (EP) should be treated and which followed without therapy. To determine the effect of GnRH analog treatment on the final height of treated patients and compare the effect of two different analogs on gonadotropin suppression and final height.. Sixteen females with PP or EP with a mean chronological age (CA) of 8.8 +/- 1.4 years and a mean bone age (BA) of 10.8 +/- 1.3 years were treated for a mean of 2.7 +/- 1.0 years with a GnRH analog (triptorelin or leuprolide acetate; group A), while 21 girls with a mean CA of 8.5 +/- 1.0 years, a mean BA of 9.7 +/- 1.4 years and a predicted adult height of >155 cm were followed without therapy (group B). Criteria for treatment were one of: a. predicted adult height (PAH) of <155 cm initially or at any time during follow up; b. PAH over 155 cm with a dramatic decrease in PAH over a 6-month follow-up period; c. advanced and rapidly progressing breast development for age (Tanner 3 before the age of 9 years).. GnRHa therapy suppressed gonadotropins in group A, while gonadotropins increased gradually in group B. Height velocity (HV) decreased in group A, while it remained accelerated in group B; BA increased a mean of 1.7 +/- 0.5 years in group A and 3.2 +/- 0.3 years in group B. This resulted in a height increase in group A from a baseline PAH of 153.7 +/- 1.2 cm to a final height (FH) of 160.9 +/- 4.0 cm (p <0.001), clearly above their target height (TH) of 157.7 +/- 4.2 cm. The height of group B children did not change over time (164.1 +/- 4.1 cm before therapy and 166.0 +/- 6.0 cm at FH), both above their TH. The mean leuprolide acetate dose utilized in this study decreased during treatment, while both the initial and final triptorelin dose remained unchanged. Adequate gonadotropin suppression (peak level of LH and FSH of <2 IU/l after i.v. GnRH stimulation) was noted with both leuprolide acetate and triptorelin, although LH suppression was slightly more pronounced with triptorelin. BA advanced 1.8 +/- 0.4 years during leuprolide acetate treatment and 1.5 +/- 0.3 years with triptorelin, so that FH increased a mean of 5.5 +/- 1.3 cm with leuprolide acetate and 8.7 +/- 2.2 cm with triptorelin.. PAH of <155 cm before or during therapy, PAH of >155 cm with a dramatic decrease in predicted height over a 6-month follow-up period and/or advanced and rapidly progressing breast development in girls with PP or EP were useful parameters in deciding which patients to treat. GnRHa therapy suppressed gonadotropins, HV and bone maturation in children with an accelerated form of PP or EP, resulting in a significant height increase. Final height remained stable over time in untreated patients. Adequate gonadotropin suppression was noted with both analogs, although with the doses of analog used in our study, LH and BA suppression were more pronounced with triptorelin, resulting in a larger height gain.

Topics: Body Height; Bone Development; Child; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Gonadotropins; Growth Disorders; Humans; Leuprolide; Puberty; Puberty, Precocious; Severity of Illness Index; Statistics, Nonparametric; Triptorelin Pamoate

The aim of this study was to compare vertebral bone mass values of patients with central precocious puberty (CPP) with healthy age and puberty matched controls and to determine the effect of gonadotropin releasing hormone (GnRH) analogs on bone mass in patients who had been treated at least for 1 year. Girls with idiopathic CPP, 11 pretreatment, 14 post-treatment, and 19 pubertal girls as controls were enrolled in the study. The mean ages of the controls and the patients with CPP pre- and post-treatment were 10.25 +/- 1.06, 8.23 +/- 1.11, and 10.36 +/- 1.82 years, respectively. Leuprolide acetate (Lucrin) 3.75 mg was administered s.c. monthly. Bone measurements were performed by dual energy X-ray absorptiometry (DEXA) (Norland) at the anterior-posterior vertebrae (L2-L4). The post-treatment group's mean BMD value was 0.66 +/- 0.12; Z scores according to CA and BA were 0.32 +/- 10 and 0.30 +/- 1.1, respectively. In the study group, BMD values compared to the control group were normal. No significant change in BMD values was observed after treatment. Neither osteopenia nor osteoporosis was observed in patients taking GnRH analog.

Topics: Absorptiometry, Photon; Anthropometry; Bone Density; Child; Female; Humans; Leuprolide; Matched-Pair Analysis; Puberty, Precocious; Reference Values; Spine

Depot GnRH agonists are widely used for the treatment of precocious puberty. Leuprorelin 3-month depot is currently used in adults but has not been evaluated in children. We evaluated the efficacy of this new formulation (11.25 mg every 3 months), for the suppression of gonadotropic activation and pubertal signs in children with central precocious puberty. We included 44 children (40 girls) with early-onset pubertal development in a 6-month open trial. The inclusion criteria were clinical pubertal development before the age of 8 (girls) or 10 (boys), advanced bone age, enlarged uterus (>36 mm), testosterone more than 1.7 nmol/liter (boys), and pubertal response of LH to GnRH (peak >5 IU/liter). The principal criterion for efficacy assessment, GnRH-stimulated LH peak less than 3 IU/liter, was met in 81 of 85 (95%) of the tests performed at months 3 and 6. The remaining four values were slightly above the threshold. The levels of sex steroids were also significantly reduced and clinical pubertal development was arrested. Plasma leuprorelin levels, measured every 30 d, were essentially stable after d 60. Local intolerance was noted after 10 of 86 injections (12%), and was mild in four cases, moderate in five cases, and severe in one. Among these 10 events, 4 consisted in local pain at injection's site. In conclusion, leuprorelin 3-month depot efficiently inhibits the gonadotropic axis in 95% of children with central precocious puberty studied for a 6-month period. This regimen allows the reduction of the number of yearly injections from 12 to 4.

Topics: Child; Delayed-Action Preparations; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Testosterone; Time Factors

The aim of the study was to evaluate serum acid-labile subunit (ALS) concentrations and their relationship with other parameters of the human ternary IGF-I-binding protein (IGFBP) complex in girls with central precocious puberty (CPP) before and after pharmacological arrest of puberty. We studied serum ALS, free IGF-I, total IGF-I, IGFBP-3 levels and IGFBP-3 protease activity in 13 girls, aged 1.6-7.8 yr (mean, 5.9 +/- 2.2), diagnosed as having CPP before and after 6 and 12 months of GnRH analog (GnRHa) therapy. The ALS SD score before treatment was high (1.4 +/- 0.72) and decreased significantly after 6 and 12 months of GnRHa therapy [0.4 +/- 0.54 (P < 0.01) and -0.4 +/- 0.61 (P < 0.01), respectively]. Serum IGF-I and IGFBP-3 were also increased before treatment, but both of these factors remained elevated after 6 and 12 months of GnRH-A therapy [IGF-I SD score, 3.20 +/- 1.64, 2.92 +/- 1.82, and 3.68 +/- 1.94 (P = NS), respectively; IGFBP-3 SD score, 1.02 +/- 0.53, 0.94 +/- 0.68, and 1.22 +/- 0.87 (P = NS), respectively]. Serum free IGF-I levels and IGFBP-3 proteolytic activity did not vary significantly from their pretreatment values during GnRHa therapy. In conclusion, serum ALS levels were elevated in girls with CPP and decreased significantly during the first year of GnRHa therapy. Serum IGF-I and IGFBP-3 levels were also increased before therapy, but their levels were not influenced by treatment. The ALS decrease seems to be the sole GH-dependent factor that parallels the decreases in steroid levels and growth velocity during GnRHa therapy.

Topics: Carrier Proteins; Child; Child, Preschool; Endopeptidases; Female; Glycoproteins; Humans; Infant; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leuprolide; Puberty, Precocious

We studied bone mineral density (BMD), bone metabolism, and body composition in 47 children with central precocious puberty (n = 36) or early puberty (n = 11) before, during, and after cessation of GnRH agonist. Bone density and body composition were measured with dual energy x-ray absorptiometry and expressed as SD scores. Bone age and biochemical parameters of bone turnover were assessed. Measurements were performed at baseline, after 6 months, and on a yearly basis thereafter. Mean lumbar spine BMD SD scores for chronological age were significantly higher than zero at baseline and decreased during treatment. Lumbar spine bone mineral apparent density and total body BMD did not differ from normal at baseline and showed no significant changes during treatment. In contrast, BMD SD scores for bone age were significantly lower than zero at baseline and at cessation of therapy. Two years after therapy, bone mineral apparent density and BMD SD scores for bone age and chronological age did not differ from normal. Markers of bone turnover decreased during treatment, mainly in the first 6 months. Patients had increased percentage of fat and lean body mass at baseline. After an initial increase of percentage body fat during treatment, percentage body fat decreased and normalized within 1 yr after cessation of treatment. Our longitudinal analysis suggests that peak bone mass or body composition will not be impaired in patients with precocious or early puberty after GnRH agonist therapy.

Topics: Aging; Body Composition; Bone Density; Child; Child, Preschool; Delayed-Action Preparations; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Puberty; Puberty, Precocious

Leptin is a metabolic signal that may be involved in signaling adequacy of energy metabolism for the onset of reproductive function. The aim of this study was to investigate the relationship between leptin serum levels and pubertal development in girls with progressive central precocious puberty (CPP). We investigated longitudinally 14 girls with CPP before and during treatment with depot leuprorelin acetate. Mean (+/-SEM) chronological age and bone age at start of therapy were 6.0+/-0.6 y and 9.5+/-0.7 y, respectively. Leptin was determined by RIA. Girls with CPP showed no significant difference in leptin levels at pretreatment and after 1 and 2 y of treatment compared with healthy girls of the same body mass index (BMI). Mean leptin SD score adjusted for BMI was 0.31+/-0.4, 0.24+/-0.2, and 0.49+/-0.3, respectively (not significant). In a stepwise regression analysis model with BMI, bone age, chronological age, basal and stimulated LH, estradiol, dehydroepiandrosterone, androstenedione, and clinical pubertal signs, BMI was the only parameter that showed a significant correlation with leptin (p = 0.006). In conclusion, these data suggest that serum leptin levels are not significantly elevated at the onset of CPP compared with normal girls. Treatment with depot gonadotropin releasing hormone agonist seems to have no influence on leptin concentrations. As in normal girls, serum leptin levels in girls with CPP are mainly determined by BMI. Thus, we have no evidence that alterations of leptin are related to premature onset of puberty.

Topics: Androstenedione; Body Height; Body Mass Index; Child; Child, Preschool; Dehydroepiandrosterone; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leptin; Leuprolide; Luteinizing Hormone; Proteins; Puberty, Precocious; Radioimmunoassay; Reference Values

CRH is an adrenal androgen secretagogue in men and has been proposed as a candidate regulator of adrenarche. CRH also affects androgen production by theca cells and may be involved in the pathogenesis of ovarian hyperandrogenism (OH). Precocious pubarche (PP) in girls can precede adolescent OH, a condition characterized by a high ovarian 17-hydroxyprogesterone (17-OHP) response 24 h after GnRH agonist challenge. In adolescent girls with a history of PP, we assessed the early androgen response to CRH, as well as the CRH effect on the late ovarian response to GnRH agonist. Within a randomized cross-over design, saline or CRH (human CRH 1 microg/kg x h in saline) was infused over 3-h (1100-1400 h) into 12 adolescent girls (age 17+/-2 yr; body mass index 21.4+/-0.9 Kg/m2) who had been pretreated with dexamethasone (1 mg at 0 h) and GnRH agonist (leuprolide acetate 500 microg sc at 0800 h = time 0). All adolescents had hirsutism, irregular menses, hyperandrogenemia, and hyperinsulinemia after PP. Serum LH, FSH, androstenedione, dehydroepiandrosterone (DHEA), and DHEA-sulfate (DHEAS) were measured at time 0, 3, 6, and 24 h, and ACTH and 17-OHP were measured at time 0, 6, and 24 h. ACTH concentrations at the end of saline or CRH infusions were less than 45 pg/mL; neither saline nor CRH infusions evoked early changes in 17-OHP levels. Within 3 h of CRH infusion, DHEAS increased by 46%, on average; androstenedione increased 2.5-fold and DHEA increased 5-fold duringCRH infusion (all P < 0.0001 compared with saline). There was no detectable CRH effect on the responses of LH, FSH, DHEA, DHEAS, 17-OHP, androstenedione, testosterone, and estradiol 24 h after GnRH agonist administration; five of 12 girls had elevated 17-OHP responses suggestive of OH. In conclusion, CRH was found to be a potent adrenal androgen secretagogue in adolescent girls with hyperandrogenism after PP. In this study, CRH failed to detectably affect the ovarian androgen response to gonadotropins.

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Androgens; Body Mass Index; Corticotropin-Releasing Hormone; Cross-Over Studies; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Dexamethasone; Female; Follicle Stimulating Hormone; Glucocorticoids; Humans; Hyperandrogenism; Leuprolide; Luteinizing Hormone; Puberty, Precocious

The optimal timing for discontinuing treatment with a long-acting gonadotropin-releasing hormone (GnRH) analog (TAP-144SR) was investigated in patients with central precocious puberty (CPP). Thirty-five girls with CPP (21 with idiopathic disease and 14 with organic disease) were treated with the analog for 3 to 5 years. No significant differences were seen between the idiopathic and the organic CPP in the suppressive effect of bone maturation. Advancement of bone maturation was noticeably suppressed during the period between bone ages (BA) of 11.0 and 11.9. The height standard deviation score (Ht-SDS) for BA was consistently improved from 10 to 11.5 years of BA, and patients reached peak Ht-SDS at a BA of 11.5 years. The deltaHt-SDS (annual change in Ht-SDS) was noticeably decreased at BA over 12 years in spite of prolongation of the treatment. In the eight patients who have reached final height, the average Ht-SDS was -0.49 at end of the treatment (BA 11.7 years) and the final Ht-SDS was - 1.1 SD, respectively. Predicted adult height at the end of the treatment was significantly higher than the actual final height (P<0.01). The results suggest that a fall in Ht-SDS for BA which usually occurs at approximately 12 years of BA, is an indication for cessation of the treatment with TAP-144SR, and residual growth potential judged solely from BA may be decreased in girls with CPP after discontinuation of the treatment.

Topics: Age Determination by Skeleton; Analysis of Variance; Child; Delayed-Action Preparations; Drug Administration Schedule; Female; Humans; Leuprolide; Puberty, Precocious

We evaluated the pituitary and gonadal suppression in 40 girls and nine boys treated with depot leuprorelin (3.75 mg sc if body weight > or = 20 kg, 1.87 mg if body weight < 20 kg) every 28 days for central precocious puberty. Gonadal suppression was obtained in most of the children with this dose: 3 months after initiation of the treatment, 85% of children had a peak plasma luteinizing hormone response to gonadotropin-releasing hormone < 3 IU/l and the gonadal axis remained suppressed throughout the duration of the study (up to 24 months). Four patients required higher doses of leuprorelin to achieve suppression. In two girls, a cutaneous reaction to the drug was associated with incomplete suppression and the treatment had to be interrupted. Plasma leuprorelin levels tended to increase from day 3 to day 28 after injection. Residual leuprorelin levels measured 28 days after injection were stable during the first year of the study. We conclude that an initial dose of depot leuprorelin of 3.75 mg sc every 28 days is efficient in most children with central precocious puberty.

Topics: Bone Development; Child; Delayed-Action Preparations; Drug Eruptions; Drug Tolerance; Female; Gonadotropin-Releasing Hormone; Growth; Headache; Humans; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious

The effect of leuprolide acetate (D-Leu6-[des-Gly10-NH2]-LH-RH ethylamide acetate) for depot suspension (TAP-144-SR), a synthetic analog of luteinizing hormone-releasing hormone, was examined in three doses in 36 patients (34 girls, 2 boys) with central precocious puberty. TAP-144-SR was injected subcutaneously every four weeks for twelve weeks, and clinical symptoms and plasma and urinary levels of various hormones were followed every four weeks. Eleven girls given 10 micrograms/kg showed a significant decrease in peak plasma LH and FSH responses to LH-RH test, but basal plasma LH and FSH did not change significantly. In 13 patients (11 girls and 2 boys) given 30 micrograms/kg and 12 girls given 90 micrograms/kg, both basal and peak LH and FSH were significantly suppressed. Urinary excretion of LH decreased significantly in all groups except in the 10 micrograms/kg group. Urinary excretion of FSH did not change significantly in the 10 and 30 micrograms/kg groups, but it decreased significantly in the 90 micrograms/kg group. In girls, plasma and urinary estradiol also fell greatly, but the difference was insignificant except in the 90 micrograms/kg group. Regression of sexual characteristics was observed in almost half of the patients at the 12th week of the treatment. Side effects were minimal. A dose of more than 30 micrograms/kg of TAP-144-SR is effective in suppressing gonadotropins and causing improvement of clinical symptoms, and appears to be useful in treating children with central precocious puberty.

Topics: 17-Hydroxycorticosteroids; 17-Ketosteroids; Adrenal Glands; Analysis of Variance; Child; Child, Preschool; Dehydroepiandrosterone; Delayed-Action Preparations; Dose-Response Relationship, Drug; Estradiol; Female; Follicle Stimulating Hormone; Humans; Immunoradiometric Assay; Infant; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Testosterone

To assess further the relationship between gonadal sex steroids and PRL, GH, and insulin-like growth factor-I (IGF-I) secretion and to help clarify the mechanism underlying the pubertal growth spurt, we studied 11 children (10 girls) with central precocious puberty before and during gonadal suppression with the GnRH agonist (GnRH-a) leuprolide acetate. Nocturnal sampling for plasma levels of GH and PRL, GH response to GH-releasing factor-(1-44), and plasma IGF-I levels were determined before and 3-6 months after pituitary-gonadal suppression. Treatment caused a significant decrease in the LH and FSH responses to GnRH (P less than 0.01) and the plasma concentration of estradiol (P less than 0.05). The patients' mean height velocity SD score for chronological age, initially 3.8 +/- 1.9, decreased significantly to 0.9 +/- 0.9 with treatment (P less than 0.005). Nocturnal GH secretion (mean GH concentration, sum of GH pulse areas, sum of GH pulse amplitudes, and GH pulse frequency) and mean IGF-I levels (1.38 +/- 0.6 vs. 1.72 +/- 0.34 U/mL) were not significantly altered by treatment. However, the mean peak GH response to GH-releasing factor-(1-44) was 29.2 +/- 6.8 micrograms/L before treatment and declined significantly to 17.7 +/- 3.4 micrograms/L after gonadal suppression (P less than 0.05). PRL secretion was similar before and after GnRH-a-induced suppression. These results indicate that the decrease in height velocity noted during GnRH-a treatment occurred independently of changes in nocturnal GH secretion and IGF-I levels. These data are consistent with the premise that sex steroids can modulate growth by a direct action on skeletal growth.

Topics: Antineoplastic Agents; Body Height; Child; Child, Preschool; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonads; Growth; Growth Hormone; Humans; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Male; Pituitary Gland; Prolactin; Puberty, Precocious

Long-acting preparations of LHRH (LHRHa), such as leuprolide acetate, have been shown to selectively and reversibly suppress the clinical and biochemical features of central precocious puberty (CPP). The withdrawal of gonadal sex steroids results in a decline of growth velocity and a decrease in the rate of bone age maturation, with resultant improvement in predicted adult stature. The purpose of this study was to define GH secretory dynamics in children treated with leuprolide acetate. Twelve-hour nocturnal GH studies were performed in five children (four girls and one boy) with CPP before and after 6 months of treatment with leuprolide acetate. Mean GH levels, GH secretory rate, and number of GH secretory episodes were determined. Secretory profiles were analyzed using the Cluster program. Growth velocity, somatomedin-C, and dehydroepiandrosterone sulfate were measured before and after 6 months of therapy. By 6 months of therapy, there was a significant decrease in mean growth velocity from 10.5 +/- 3.3 to 6.7 +/- 1.6 cm/yr. Somatomedin-C levels remained the same at 46.90 +/- 9.51 and 52.5 +/- 12.40 nmol/L. Levels of dehydroepiandrosterone sulfate remained unchanged at 118.6 +/- 71.4 and 139.0 +/- 61.3 mumol/L at 0 and 6 months of the study. By 6 months, there was a significant decrease in mean GH levels from 13.6 +/- 5.3 to 6.4 +/- 3.4 micrograms/L (P less than 0.05). Total GH levels decreased from 1367.9 +/- 687.3 to 447.0 +/- 186.5 ng/12 h. The number of GH secretory episodes remained the same at 5.4 +/- 1.5 and 4.8 +/- 1.0/12 h at 0 and 6 months of study. Therefore, the decrease in GH that occurs during the withdrawal of gonadal sex steroids with LHRHa in children with CPP is an amplitude-modulated phenomenon, as the number of secretory peaks remains unchanged.

Topics: Antineoplastic Agents; Child; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Growth Hormone; Humans; Insulin-Like Growth Factor I; Leuprolide; Male; Puberty, Precocious; Time Factors

Topics: Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Puberty, Precocious; Triptorelin Pamoate; Vasculitis

It is important to understand what variables influence change in predicted adult height (PAH) throughout GnRHa treatment for central precocious puberty (CPP) to individualize treatment decisions and optimize care.. Changes in PAH, chronological age (CA), bone age (BA), BA/CA, and height velocity (HV) were evaluated in girls with CPP throughout treatment with leuprolide acetate (n=77). A second analysis focused on changes in the 3 years preceding the first observed BA of ≥12 years. Relationships were characterized using plot inspection and linear mixed-effects analyses. Association between treatment duration and last assessed PAH was examined using multiple linear regression models.. BA/CA and HV showed a nonlinear change during treatment, with the largest changes and improvement in PAH observed in the first 6-18 months. Rate of BA advancement tended to decrease more slowly in girls initiating treatment at a younger BA. On-treatment change in PAH was predicted by concurrent BA/CA change, HV, and BA, as well as CA at treatment initiation. Last assessed PAH was positively associated with longer treatment durations (primary/exploratory models cut-offs of ≥33/≥55 months).. These findings support individualized monitoring during GnRHa treatment. Initial response should be interpreted with caution until 6-18 months after treatment initiation and failure should not be assumed based on continued bone maturation in girls starting therapy at a younger age. Treatment cessation should not be automatically based on a diminishing change in PAH or HV, as ongoing treatment may result in continued increase or maintenance of PAH.

Topics: Adult; Age Determination by Skeleton; Age Factors; Body Height; Duration of Therapy; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Precision Medicine; Puberty, Precocious

GnRH agonists have been used to halt the development of puberty in children with precocious puberty since the 1980s. Recently, drugs like Lupron Depot. The present study tested the effects of daily leuprolide treatment (50 µg/kg, postnatal day (PD) 25-50) on pubertal onset in female (i.e., vaginal opening) and male (i.e., preputial separation) Long-Evans rats. The first estrous cycle immediately after vaginal opening was also measured. Sexual behavior and sexual motivation were tested using the partner-preference paradigm. Female rats were tested during the first behavioral estrus after treatment ended (between PD 51-64). Male rats were tested weekly for four consecutive weeks starting three days after treatment ended (PD 53).. Consistent with previous findings, leuprolide significantly delayed pubertal onset in both female and male rats. In addition, the first estrous cycle during the treatment period was disrupted by leuprolide, as indicated by a failure to cycle into estrus after vaginal opening until treatment ended. However, leuprolide affected neither sexual motivation nor fertility when female rats were tested within 14 days of leuprolide treatment ending. In contrast, the development of copulatory behavior and sexual motivation was significantly delayed by leuprolide in male rats; however, mature reproductive behavior was observed by the fourth week post-treatment.. Taken together with previous findings, the present results indicate that male rats may be more sensitive to periadolescent leuprolide administration, taking longer to overcome the effects of leuprolide than female rats. Nevertheless, not long after leuprolide treatment is discontinued, sex-typical reproductive physiology and behavior emerge fully in female and male rats, indicating that the drug's effects are not permanent. If translatable to humans, leuprolide may be a reversible option to give adolescents more time to consider their gender identity with minimal long-term effects on sexual development.

Topics: Adolescent; Animals; Child; Estrus; Female; Gender Identity; Humans; Leuprolide; Male; Puberty, Precocious; Rats; Rats, Long-Evans

For several decades, gonadotropin releasing hormone analogs (GnRHa) are the medical treatment selected for central precocious puberty (CPP) in girls and boys. They generate an inhibition of the hypothalamus-pituitary-gonadal axis decreasing LH, FSH, estradiol and testosterone secretion and, in this way, they produce a regression of secondary sexual characters under treatment. In the last years, these analogs are also used in trans adolescents, in adolescents and young adults with oncological diseases, in some very particular situations in children with short stature and in patients with neurodevelopmental disorders. In Argentina the most commonly used formulations are triptorelin and leuprolide acetate depot forms. These analogs have proven both their efficacy and their safety. The aim of this paper is to review and update about the use of GnRHa in children and adolescents.. Desde hace varias décadas, los análogos de la hormona liberadora de gonadotrofinas (aGnRH) son el tratamiento de elección en la pubertad precoz central (PPC) en niñas y en niños. Causan una inhibición del eje hipotálamo-hipófiso-gonadal, disminuyen la secreción de gonadotrofinas, estradiol y testosterona; como consecuencia, producen una regresión de los caracteres sexuales secundarios durante el tratamiento. En los últimos años, estos análogos también se utilizan en adolescentes transgénero, en adolescentes y adultas jóvenes con enfermedades oncológicas, en algunas situaciones muy particulares en niños y niñas con talla baja, y en pacientes con trastornos del neurodesarrollo. En Argentina, los más utilizados son el acetato de triptorelina y el acetato de leuprolide en sus formas de depósito. Estos medicamentos han demostrado eficacia y seguridad. El objetivo de esta publicación es realizar una revisión y actualización del uso de los aGnRH en niños, niñas y adolescentes.

Topics: Adolescent; Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Triptorelin Pamoate

Sotos syndrome (SS) is characterized by overgrowth, distinctive facial appearance, and learning disability. It is caused by heterozygous mutations, including deletions of NSD1 located at chromosome 5q35. While advanced bone age can occur in some cases, precocious puberty (PP) has only been reported in three cases previously. Here, we reported a case of SS diagnosed in the infancy period with central PP. The discovery of potential factors that trigger puberty is one of the central mysteries of pubertal biology. Depot gonadotropin-releasing hormone analogs constitute the first-line therapy in central PP (CPP), which has proven to be both effective and safe. In our cases, leuprolide acetate at maximum dose was not successful in controlling pubertal progression, and cyproterone acetate (CPA) was added to therapy, with successful control of pubertal progression. In some specific syndromes with PP, such as SS, treatment can be challenging. CPA may be an asset for effective treatment.

Topics: Gonadotropin-Releasing Hormone; Humans; Infant; Leuprolide; Mutation; Puberty; Puberty, Precocious; Sotos Syndrome

Topics: Clinical Trials as Topic; Delayed-Action Preparations; Estrogen Antagonists; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Testosterone

A consensus on how to monitor girls with central precocious puberty (CPP) during gonadotropin-releasing hormone agonist (GnRHa) treatment is lacking. Increased, unstimulated basal luteinizing hormone (LH) concentrations have been suggested to indicate lack of suppression. The aim was to evaluate pre-injection basal LH concentrations during GnRHa (leuprorelin 3.75 mg) treatment every four weeks in girls with CPP.. Medical records were reviewed for girls with CPP treated at a single center from 2014-2019. Clinical characteristics and laboratory findings during treatment were systematically recorded.. A total of 587 GnRHa pre-injection basal LH concentrations were analyzed in 74 girls. Basal LH was pubertal (≥0.3 IU/L) in 53.5% of blood samples and 87.8% of all girls had a pubertal basal LH concentration at least once. A GnRH test (n=29) was repeated in 23 girls due to suspicion of clinical progression, elevated basal LH or recordable estradiol concentrations. None had a stimulated LH >3.1 IU/L. The predictability of treatment suppression (specificity) of basal LH concentrations was 12.0% when compared to repeated GnRH stimulation tests. Despite shortening the GnRHa injection interval to three weeks, basal LH concentrations remained pubertal in 85.7% girls. A significant reduction in height standard deviation score (p<0.001) and bone age advance (p<0.001) was observed during treatment.. Pre-injection basal LH remains at pubertal concentrations during treatment with leuprorelin 3.75 mg in girls with CPP. Clinical monitoring of pubertal progression is preferable to routine basal LH concentrations. Repeat GnRH stimulation testing should be regarded as the gold standard.

Topics: Child; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Retrospective Studies

The present study was designed to compare the changes in ovarian and uterine parameters in girls with idiopathic central precocious puberty (ICPP) before and after gonadotropin-releasing hormone analogues (GnRHa) treatment to determine which sensitive indexes effectively reflect the therapeutic effect.. Sixty girls diagnosed with ICPP were enrolled in the present study. Relevant data were recorded before treatment. Leuprorelin acetate microspheres were injected at a dose of 30-180 μg/(kg four weeks). Relevant parameters were measured and recorded every three months. Changes in each parameter were analyzed to evaluate the clinical effect of leuprorelin in the treatment of girls with ICPP.. 1) The height grew at a constant rate. 2) The breasts retracted. 3) Changes in pelvic parameters: the volume of the ovary and uterus and major axes of the ovary, uterus, and cervix were reduced; there were no significant changes in vaginal thickness or the uterine fundal-cervical ratio (FCR). 4) Body mass index (BMI) increased.. Pelvic ultrasound is helpful in evaluating the efficacy of GnRHA treatment. The changes of ovarian volume and the major axes of the ovary, uterus, cervix can be used as sensitive observation indexes.

Topics: Body Mass Index; Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Ovary; Puberty, Precocious; Ultrasonography; Uterus

Gonadotropin-releasing hormone analogs are the treatment of choice for central precocious puberty (CPP). This study characterizes patients treated with histrelin implant or leuprolide injection.. A US claims database was used to identify patients aged ≤20 years with ≥1 histrelin or leuprolide claim (index treatment) between April 2010 and November 2017 and continuous enrollment ≥3 months before and ≥12 months after the index treatment date.. Overall, 4,217 patients (histrelin, n=1,001; leuprolide, n=3,216) were identified. The percentage of patients with CPP diagnosis was greater in the histrelin (96.5%) vs. leuprolide (68.8%; p<0.0001) cohort. In patients with CPP (histrelin, n=966; leuprolide, n=2,214), mean age at treatment initiation was similar for histrelin (9.0 ± 2.0 years) and leuprolide (9.1 ± 2.3 years), with >50% of patients aged 6-9 years. Mean treatment duration was significantly longer for histrelin (26.7 ± 14.8 months) vs. leuprolide (14.1 ± 12.1 months; p<0.0001), and was longer in younger patient groups. More patients switched from leuprolide to histrelin (12.3%) than vice versa (3.6%; p<0.0001). Median annual total treatment costs were slightly lower for the histrelin cohort ($23,071 [interquartile range, $16,833-$31,050]) than the leuprolide cohort ($27,021 [interquartile range, $18,314-$34,995]; p<0.0001).. Patients with CPP treated with histrelin had a longer duration of treatment, lower rates of index treatment discontinuation, and lower annual treatment costs vs. those treated with leuprolide.

Topics: Adolescent; Adult; Antineoplastic Agents, Hormonal; Child; Child, Preschool; Databases, Factual; Drug Implants; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Injections, Intravenous; Insurance Claim Review; Leuprolide; Male; Prognosis; Puberty, Precocious; Retrospective Studies; Subcutaneous Tissue; United States; Young Adult

Although gonadotropin-releasing hormone stimulation test (GnRHST) is the gold standard in diagnosing central precocious puberty (CPP), it is invasive, expensive, and time-consuming, requiring multiple blood samples to measure gonadotropin levels.. We evaluated whether urinary hormones could be potential biomarkers for prepuberty or postpuberty, aiming to simplify the current diagnosis and prognosis procedure.. We performed a cross-sectional study of a total of 355 girls with CPP in National Clinical Research Center for Child Health in China, including 258 girls with positive and 97 girls with negative results from GnRHST. Twenty patients received GnRH analogue (GnRHa) treatment and completed a 6-month follow up. We measured luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, prolactin, progesterone, testosterone, and human chorionic gonadotropin in the first morning voided urine samples.. Their urinary LH levels and the ratios of LH to FSH increased significantly with the advancement in Tanner stages. uLH levels were positively associated with basal and peak LH levels in the serum after GnRH stimulation. A cutoff value of 1.74 IU/L for uLH reached a sensitivity of 69.4% and a specificity of 75.3% in predicting a positive GnRHST result. For the combined threshold (uLH ≥ 1.74 + uLH-to-uFSH ratio > 0.4), the specificity reached 86.6%. After 3 months of GnRHa therapy, the uLH and uFSH levels decreased accordingly.. uLH could be a reliable biomarker for initial CPP diagnosis and screening; uLH could also be an effective marker for evaluating the efficacy of clinical treatment.

Topics: Biomarkers; Child; Child, Preschool; China; Cross-Sectional Studies; Estradiol; Female; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Leuprolide; Luteinizing Hormone; Puberty; Puberty, Precocious; ROC Curve; Triptorelin Pamoate

Longer-acting gonadotropin-releasing hormone analogs (GnRHa) have been widely used for central precocious puberty (CPP) treatment. However, the follow-up of patients after this treatment are still scarce. Our aim was to describe anthropometric, metabolic, and reproductive follow-up of CPP patients after treatment with leuprorelin acetate 3-month depot (11.25 mg).. Twenty-two female patients with idiopathic CPP were treated with leuprorelin acetate 3-month depot (11.25 mg). Their medical records were retrospectively evaluated regarding clinical, hormonal, and imaging aspects before, during, and after GnRHa treatment until adult height (AH).. At the diagnosis of CPP, the mean chronological age (CA) was 8.2 ± 1.13 year, and mean bone age (BA) was 10.4 ± 1.4 year. Mean height SDS at the start and the end of GnRHa treatment was 1.6 ± 0.8 and 1.3 ± 0.9, respectively. The mean duration of GnRHa treatment was 2.8 ± 0.8 year. Mean predicted adult heights (PAH) at the start and the end of GnRH treatment was 153.2 ± 8.6 and 164.4 ± 7.3 cm, respectively (p<0.05). The mean AH was 163.2 ± 6.2 cm (mean SDS: 0.1 ± 1). All patients were within their target height (TH) range. There was a decrease in the percentage of overweight and obesity from the diagnosis until AH (39-19% p>0.05). At the AH, the insulin resistance and high LDL levels were identified in 3/17 patients (17.6%) and 2/21 patients (9.5%), respectively. The mean CA of menarche was 12.2 ± 0.5 years. At the AH, PCOS was diagnosed in one patient (4.8%).. Long-term anthropometric, metabolic, and reproductive follow-up of patients with CPP treated with longer-acting GnRHa revealed effectivity, safety, and favorable outcomes.

Topics: Body Height; Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Menarche; Puberty, Precocious; Reproduction; Retrospective Studies; Treatment Outcome

The aim of this study was to evaluate the resilience of girls with central precocious puberty (CPP) during treatment with a gonadotropin-releasing hormone agonist (GnRHa) and compare these results with their healthy peers.. The Connor-Davidson Resilience Scale (CD-RISC) is a self-report scale used to quantify resilience, which is divided into seven subgroups (hardiness, coping, flexibility, purpose, optimism, regulation of emotion and cognition (REC), and self-efficacy). Fifty-one girls with CPP receiving GnRHa treatment and 51 healthy controls were involved in the study. Anthropometric measurements were evaluated and CD-RISC was performed at least six months after the initiation of GnRHa treatment.. There was no statistically significant difference between the anthropometric evaluations of girls with CPP and the control group. Similarly, the total score and subgroup scores of patients with CPP and the control group showed no statistically significant difference. In the correlation analysis, there was a weak negative correlation between height and flexibility (r. The resilience of girls with CPP treated with GnRHa was found to be similar to their healthy peers. The early diagnosis of the disease and adequate treatment may decrease the discrepancy of somatic changes between girls with CPP and their peers, which may help them to overcome the stress of CPP and long-term treatment.

Topics: Body Mass Index; Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Puberty, Precocious; Resilience, Psychological

Topics: Child; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Health Care Costs; Health Resources; Humans; Insurance Coverage; Insurance, Health; Leuprolide; Male; Medicaid; Multivariate Analysis; Patient Acceptance of Health Care; Private Sector; Puberty, Precocious; Retrospective Studies; United States

Besides local reactions, systemic hypersensitivity reactions such as urticaria, anaphylaxis, serum sickness and Henoch-Schönlein purpura (HSP) have been reported during gonadotropin-releasing hormone (GnRH) analogue treatment.. To present the clinical presentation of 9 cases with systemic hypersensitivity reactions to GnRH analogues and discuss the management of such reactions based on our experience.. Nine of 232 (3.8%) patients with central precocious puberty receiving GnRH analogue treatment had systemic hypersensitivity reactions in 4 years' period. Six patients had a type 1 hypersensitivity reaction (generalized hives, pruritus, and/or edema) to triptorelin acetate (TA), 2 patients to leuprolide acetate (LA), and 1 patient to both medications who also developed anaphylaxis to LA during intradermal test (IDT). Another patient on TA had skin lesions suggestive of HSP. GnRH analogue treatment was discontinued in 2 patients after discussion with the parents. Treatment was changed to another GnRH analogue preparation in 6 patients and was maintained with the same medication with antihistamines and corticosteroid premedication in 1 patient. None of the patients developed new reactions after these precautions.. Systemic hypersensitivity reactions should be carefully evaluated and cross-reaction to the other GnRH analogues should be kept in mind. Discontinuation of GnRH analogue is always an option. However, if continuation of GnRH analogue is elected, we recommend switching to an alternative GnRH analogue, which should be considered only after a skin prick test (SPT) and IDT. In the lack of the possibility to perform SPT and IDT, injections may be administered under strict medical supervision in a well-equipped facility to manage anaphylaxis. We discuss additional options in situations where alternative GnRH analogues are unavailable, which enabled us to continue treatment in most cases without further problems.

Topics: Adrenal Cortex Hormones; Child; Child, Preschool; Drug Hypersensitivity; Female; Fertility Agents, Female; Histamine Antagonists; Humans; Leuprolide; Puberty, Precocious; Treatment Outcome; Triptorelin Pamoate

Gonadotropin-releasing hormone analog (GnRHa) is the mainstream treatment for central precocious puberty (CPP). However, its effect on the ovarian reserve in CPP girls remains unclear. This study was designed to analyze the changes of ovarian reserve in CPP girls during and after GnRHa therapy, with an attempt to achieve the early prediction of the effect of GnRHa treatment on the reproductive function of CPP girls, eliminate the concerns of girls and their parents on the potential toxicities of GnRHa treatment, and improve the patients' adherence to treatment.. The clinical data of 383 CPP girls who had been treated with GnRHa for more than half a year in our hospital within the past 10 years were retrospectively analyzed. The serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), FSH/LH, estradiol (E2), and anti-Müllerian hormone (AMH) levels, as well as uterine and ovarian volumes, were measured before treatment, at various time points during treatment, and after menarche or resumption of menses (ROM) after treatment discontinuation.. GnRHa treatment had similar effects on uterine/ovarian volumes, LH, FSH, and E2: these indicators were significantly inhibited during the treatment (compared with the pre-treatment levels), gradually returned normal after drug withdrawal, and became significantly higher than the pre-treatment levels after menarche or ROM (both P<0.05 for LH and FSH levels and P>0.05 for E2 and uterine/ovarian volumes). AMH level transiently decreased 6 months after GnRHa treatment (2.70±1.76 vs. 3.56±2.21, t=3.227, P=0.001); however, the AMH levels after 12, 18, and 24 months of treatment were similar to the pre-treatment level (P>0.05). The FSH/LH ratio significantly increased after 12 months of treatment compared with the pre-treatment (P<0.05), and the FSH/LH ratio after menarche or ROM was significantly lower than the pre-treatment value (1.34±0.66 vs. 5.69± 6.85, t=3.068, P=0.006). When FSH/LH and FSH level were used to reflect the ovarian reserve, the proportion of CPP girls with normal ovarian reserve after menarche or ROM was higher than at pre-treatment (FSH/LH ratio: 100% vs. 46%, χ2=27.586, P<0.05; FSH level: 100% vs. 99%, P>0.05). When AMH level was used to reflect the ovarian reserve, the proportion of CPP girls with normal ovarian reserve after menarche or ROM was slightly lower than at pre-treatment (87% vs. 93%, P>0.05).. The ovarian reserve of CPP girls is somehow inhibited during GnRHa treatment but is gradually restored after drug discontinuation. Thus, GnRHa treatment does not affect ovarian reserve in CPP children after the treatment stops.

Topics: Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Medication Adherence; Ovarian Reserve; Puberty, Precocious; Retrospective Studies; Triptorelin Pamoate

Objective To determine whether first-voided urinary LH (FV-ULH) - level measurement can adequately assess pubertal suppression as much as standard tests can. Subjects and methods The study group included patients with central precocious puberty and rapidly progressing early puberty who received up to 3 - 4 doses of GnRHa therapy monthly and did not have adequate hormonal suppression after GnRH stimulation (90-minute LH level > 4 IU/L). Design: All of the participants underwent an LHRH test just after admission to the study. According to the stimulated peak LH levels, the patients were divided into 2 groups and followed until the end of the first year of treatment. The concordance between FV-ULH and stimulated LH levels was assessed. Results The FV-ULH levels in patients with inadequate hormonal suppression were significantly high compared to patients with adequate hormonal suppression. FV-ULH levels were very strongly correlated with stimulated LH levels (r = 0.91). Its correlation with basal LH levels was significant (r = 0.65). However, this positive correlation was modestly weakened after the first year of treatment. The cutoff value for FV-ULH of 1.01 mIU/mL had the highest sensitivity (92.3%) and specificity (100%). Conclusion FV-ULH levels, using more reliable and sensitive assay methods, can be used to monitor the adequacy of GnRHa therapy.

Topics: Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Prospective Studies; Puberty, Precocious; ROC Curve; Sensitivity and Specificity; Treatment Outcome; Triptorelin Pamoate

Gonadotropin-releasing hormone (GnRH) analogs represent the treatment of choice in patients with central precocious puberty (CPP). Recently, GnRH analogs that can be administered every 3 months have been developed and appear to be as safe and effective as one-monthly formulations. However, there are limited data regarding its long term safety and efficacy profile. We aimed to evaluate the long-term safety and efficacy treatment of CPP with GnRH analogs every 3 months.. We prospectively studied all patients who were diagnosed with CPP in our center between January 2015 and December 2019. All patients were treated with intramuscular leuprolide acetate 11.25 mg every 3 months.. Twenty-four patients with CPP were included in the study. Mean follow-up was 3.1 years. Height gain ranged between 4 and 6 cm. Bone mineral density (BMD) was not affected. Body mass index (BMI) increased in all subjects but none was obese at the end of follow-up.. Treatment of patients with CPP with GnRH analogs every 3 months induces substantial increases in height and does not affect BMI or BMD. Therefore, it represents an attractive option for these young patients.

Topics: Body Height; Body Mass Index; Bone Density; Child; Drug Administration Schedule; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Treatment Outcome

Idiopathic central precocious puberty (iCPP) presents a disproportionate advancement of bone age and maturation, as well as metabolic and endocrinological changes that may be related to effects on telomere biology.. To investigate the telomere length in iCPP girls treated with GnRHa.. Observational case-control study with 85 girls, including 45 iCPP treated with GnRHa and 40 controls. It was analyzed age, height, weight and body mass index (BMI), insulin, triglycerides, testosterone, insulin resistance by HOMA, and telomere length by real-time PCR. Statistical analyses were determined by Wilcoxon test and Spearman correlation was carried out.. We did not observe any difference in the telomere length in the iCPP and control group. Even though, some characteristics of the disease, such as increased weight and body fat, negatively influence the telomere biology.

Topics: Adolescent; Age Factors; Body Composition; Body Mass Index; Body Weight; Case-Control Studies; Child; Electric Impedance; Female; Gonadotropin-Releasing Hormone; Humans; Insulin; Insulin Resistance; Leuprolide; Puberty, Precocious; Telomere; Telomere Homeostasis; Young Adult

Gonadotropin-releasing hormone agonist (GnRHa) treatment improves the potential for gaining height in patients with central precocious puberty (CPP). However, most studies have focused on girls because CPP in boys is relatively rare. Therefore, we aimed to determine the effect of GnRHa treatment on auxological outcomes in boys with CPP.. Eighty-five boys with CPP were treated with leuprolide or triptorelin acetate 3.75 mg over 2 years. Anthropometry, bone age, sexual maturity rating, and predicted adult height (PAH) were assessed every 6 months. Furthermore, 20 boys were followed up after treatment discontinuation until achievement of the final adult height (FAH).. The mean chronological age (CA) and bone age (BA) of the patients with CPP at treatment initiation were 9.5 ± 0.5 years and 11.7 ± 0.9 years, respectively. The mean duration of treatment was 2.87 ± 0.63 years. The PAH at treatment initiation was 172.1 cm (-0.23 ± 1.05 PAH standard deviation score). The PAH at treatment discontinuation (176.2 ± 6.6 cm) was significantly higher than the pretreatment PAH. In addition, the mean final adult height in the 20 boys who were followed up after discontinuation of treatment was 173.4 ± 5.8 cm, which was significantly higher than the initial PAH (170.1 ± 4.5 cm; p = 0.006). In multivariate analysis, the height gain (the difference between the FAH and PAH at treatment initiation) significantly correlated with the target height.. Long-term GnRHa treatment significantly improved the growth potential and FAH in boys with CPP.

Topics: Adolescent; Body Height; Child; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Puberty, Precocious; Triptorelin Pamoate

Doses of gonadotropin releasing hormone (GnRH) analogues used to treat idiopathic central precocious puberty (iCPP) vary among clinicians. Study aims were to evaluate the efficacy of a monthly 3.75 mg dose of leuprolide acetate (LA) to suppress the hypothalamo-pituitary-gonadal (HPG) axis in girls with iCPP and to determine factors that may have an impact on the supressing dose.. Study subjects were 220 girls receiving LA for iCPP. LA was started at a dose of 3.75 mg/28 days. Suppression was assessed using the GnRH test at the third month. To assess clinical suppression signs and symptoms of puberty were also evaluated. The dose of LA was increased to 7.5 mg/28 days in those who had a peak luteinising hormone (LH) ≥2 IU/L and in whom adequate clinical suppression of puberty was absent. Receiver operating characteristic curves were used to determine thresholds for clinical and hormonal factors affecting the suppressing dose of LA. Logistic regression analyses were used to investigate thresholds which might differentiate between those requiring high dose for suppression and those in whom lower dose LA was adequate.. Peak stimulated LH <2 IU/L was achieved in 88.6% with a dose of LA of 3.75 mg (0.11±0.03 mg/kg). Significant variables for differentiating the two doses were body weight (Wt) of 36.2 kg and/or body mass index (BMI)-standard deviation scores (SDS) of 1.64 (p<0.001). Multiple logistic regressions showed that Wt and BMI-SDS values above thresholds indicated requirement of LA at a dose of 7.5 mg/28 days (p<0.001).. Monthly injections of 3.75 mg LA is an effective treatment in the majority of girls with iCPP. However, a higher initial dose may be preferred in patients with a Wt ≥36 kg or BMI-SDS ≥1.6 for effective suppression of the HPG axis.

Topics: Body Mass Index; Body Weight; Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Outcome Assessment, Health Care; Puberty, Precocious

Objective This study was done to evaluate the emotional and behavioral status of precocious puberty patients and analyze the effect of gonadotropin-releasing hormone agonist (GnRHa) treatment. Methods Sixty-six female precocious puberty patients were enrolled prospectively for the study at Kangdong Sacred Heart Hospital of Hallym University Medical Center from September 2011 to December 2012 and self-administered questionnaire was completed during the GnRHa treatment initiation period and after 12 months from the first injection. The patients were evaluated using the Korean version of Child Behavior Checklist (K-CBCL) and Children's Depression Inventory (CDI). Results A total of 30.3% (n = 20) of the patients scored within the clinical range for one or more scales of K-CBCL at the initiation of GnRHa treatment, but only 10.6% (seven patients) were within the clinical range after 1 year of treatment. Average CDI scores of the patients decreased from baseline 6.5 ± 6.0 to 4.9 ± 4.7 after GnRHa therapy. Conclusions This study shows that both K-CBCL and CDI scores improved from baseline score ranges after 1 year of GnRHa treatment in female central precocious puberty patients while significant psychological problems of clinical range amongst them were not noted.

Topics: Child; Depression; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Incidence; Leuprolide; Prognosis; Prospective Studies; Puberty, Precocious; Republic of Korea; Stress, Psychological; Surveys and Questionnaires

Background The use of gonadotropin-releasing hormone agonists (GnRHa) for pubertal suppression has been associated with increased body mass index (BMI) in female subjects with central precocious puberty (CPP), although results have been so far conflicting. This study examined the effects of GnRHa therapy in both genders and in subjects treated for CPP, early puberty or short stature. Methods This was a longitudinal retrospective study of subjects followed at outpatient pediatric endocrinology clinics of an academic medical center from 2005 to 2014 receiving GnRHa therapy. Results At 12 months, subjects on depot GnRHa had a statistically significant increase in BMI standard deviation score (SDS) from baseline (0.13 ± 0.35, p < 0.02). Subjects with short stature (0.17 ± 0.34, p < 0.02) but not early or precocious puberty, and subjects with normal baseline BMI (0.18 ± 0.38, p < 0.02) had significant increases in BMI SDS; no significance was noted at 24 months. Male subjects did not have a significant increase in BMI SDS, whereas female subjects did (0.11 ± 0.36, p < 0.01). Conclusions Subjects with short stature, normal BMI at baseline and female sex had significant increases in BMI SDS at 12 months. This is the first study to show an increase in BMI SDS in children treated with GnRHa for short stature, and is one of the few studies to assess BMI changes in males.

Topics: Biomarkers; Body Composition; Body Mass Index; Body Weight; Child; Dwarfism; Female; Fertility Agents, Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Longitudinal Studies; Male; Prognosis; Puberty, Precocious; Retrospective Studies; Sexual Maturation

There are no doubts about the clinical benefits of treatment with GnRH analogs for patients diagnosed with central precocious puberty (CPP). However, laboratory monitoring of CPP is still a matter of considerable controversy in the literature. Therefore, the main objective of this study was to evaluate the cut-off values of stimulated LH that determine gonadotrophic suppression.. Twenty-four girls, on treatment with leuprorelin acetate (LA) at 3.75 mg IM every 28 days, were studied. The clinical parameters used to indicate clinical effectiveness were regression or maintenance of sexual characteristics according to the Tanner stage, growth velocity reduction, reduction or maintenance of the difference between bone age and chronological age and maintenance or improvement of the final height prediction. For the laboratory effectiveness test, basal estradiol, LH, and FSH levels were collected before and 1 and 2 h after the administration of 3.75 mg LA.. Eleven girls showed improvement in all clinical parameters, and their effectiveness tests were compared to those of the other patients to calculate the cut-off values, which were ≤3.64 IU/L (p=0.004*) for LH after 1 h and ≤6.10 IU/L (p<0.001*) for LH after 2 h.. The LH response after the LA stimulation test, associated with clinical data and within a context of CPP, constitutes a reliable and feasible resource and can assist in monitoring the effectiveness of treatment.

Topics: Case-Control Studies; Child; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Puberty, Precocious; Treatment Outcome

Longitudinal data regarding random luteinizing hormone (LH) concentrations in patients with idiopathic central precocious puberty (ICPP) during treatment are limited. Therefore, we sought to evaluate random LH and estradiol concentrations during monthly leuprolide injection and their associations with pubertal progression and final adult height (FAH) in girls with ICPP.. Medical records of 27 girls with ICPP who had attained FAH were reviewed. Patients’ height, weight, Tanner stage, growth rate (GR), bone age, random LH measured by both immunoradiometric and immunochemiluminescent methods, follicular-stimulating hormone (FSH) and estradiol levels were monitored until FAH.. Treatment was started at a mean (±standard deviation) age of 8.1±0.6 years with mean duration of 3.9±0.2 years. At six months of follow-up, random LH (p=0.048), FSH (p<0.001) and estradiol (p=0.023) concentrations were decreased compared with baseline. Thereafter, random LHs were well suppressed. GRs gradually decreased to prepubertal norm by month 12. Seventeen patients (63%) exhibited pubertal LH concentrations at least once during treatment visits. Furthermore, 43 of a total 116 (37%) LH measurements were found elevated. However, those patients with elevated random LH did not show signs of pubertal progression. After treatment, mean FAH was greater than predicted adult height (p<0.0001) and target height (p=0.03). At no time points of treatment did random LH, FSH and estradiol correlate with GRs or FAH.. Elevated random LH is commonly found in ICPP girls during monthly leuprolide treatment. However, these elevations were not associated with clinical progression of puberty or decreased FAH, suggesting that it is not a reliable method for CPP monitoring.

Topics: Biomarkers; Body Height; Body Weight; Child; Female; Follow-Up Studies; Humans; Leuprolide; Luteinizing Hormone; Male; Prognosis; Puberty, Precocious; Retrospective Studies; Sexual Maturation

A 7-year-8-month-old boy with cardiofaciocutaneous syndrome caused by the D638E mutation of the B-Raf proto-oncogene (BRAF) presented with new-onset seizures. He was incidentally found to have advanced Tanner staging on physical examination. Hormonal testing revealed pubertal levels of gonadotropins and sex steroid hormones. On brain imaging, a lack of visualisation of the posterior pituitary bright spot was observed, in addition to mild thinning of the corpus callosum and the lateral gyri of the cerebellar hemispheres. A diagnosis of idiopathic central precocious puberty was made and the patient was started on leuprolide depot treatment. Pituitary hormone testing revealed hyperprolactinemia for which the patient did not receive treatment as he was asymptomatic. During a subsequent hospital admission for seizures, the patient was diagnosed with transient central diabetes insipidus for which he required treatment with a desmopressin infusion.

Topics: Antineoplastic Agents, Hormonal; Child; Deamino Arginine Vasopressin; Diabetes Insipidus, Neurogenic; Ectodermal Dysplasia; Facies; Failure to Thrive; Heart Defects, Congenital; Hemostatics; Humans; Leuprolide; Male; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Puberty, Precocious; Seizures; Treatment Outcome

Central precocious puberty (CPP), early onset of puberty caused by the premature activation of the hypothalamic-pituitary-gonadal axis, is a rare disease affecting children of both sexes. There is limited evidence that quantifies the economic burden of CPP.. To characterize the health care resource utilization (HRU) and costs among patients with CPP who were treated with gonadotropinreleasing hormone (GnRH) agonists, for those insured commercially and with Medicaid.. Eligible CPP patients for this retrospective cohort analysis were aged ≤ 12 years; were diagnosed between January 1, 2010, and September 30, 2014; and had at least 1 prescription for an FDA-approved GnRH agonist: leuprolide or histrelin (first prescription = index date). CPP patients had to be continuously enrolled in the MarketScan Commercial or Medicaid Database for at least 12 months before and after the index date. Control patients were randomly selected from all eligible non-CPP patients and N:1 matched on demographic characteristics with up to 20 controls per case. Clinical comorbidities, HRU, and costs were compared between study cohorts. Health care costs were examined via multivariable analysis to adjust for baseline differences between patients and controls. Treatment patterns among CPP patients were also characterized.. There were 1,236 CPP patients and 24,206 controls with commercial insurance and 673 CPP patients and 11,965 controls with Medicaid insurance who met the inclusion criteria. Across payers, the mean age of CPP patients ranged from 7.6 years (Medicaid) to 8.5 (commercial), and 80%-87% were female. The mean observed duration (SD) of treatment with any approved GnRH agonist was 1.51 (0.98) years for commercial patients and 1.22 (1.04) for Medicaid patients. The mean age of discontinuation among patients who ceased GnRH agonist treatment ranged from 8.7 to 9.6 years. In the first year post-index, CPP patients had a greater number of unique diagnosis codes, unique medications, and comorbid conditions than controls. They also had significantly higher all-cause and diseasemonitoring related HRU. After adjusting for baseline characteristics, CPP patients with Medicaid insurance spent 6.42 times more ($16,768 [$31,460] vs. $2,610 [$4,897]), and patients with commercial insurance spent 12.25 times more ($19,940 [$20,132] vs. $1,628 [$1,645]) on health care in the year following treatment initiation than matched controls.. Patients with CPP have substantially more comorbidities and greater HRU and costs than their non-CPP peers.. All funding for this study was provided by AbbVie, which participated in analysis and interpretation of data, drafting, reviewing, and approving the publication. All authors contributed to the development of the publication and maintained control over the final content. Soliman and Grubb are employed by AbbVie and hold stock in AbbVie. Bonafede and Nelson are employed by IBM Watson Health, which received funding from AbbVie to conduct this study. Klein is a paid consultant of AbbVie but was not compensated for any work on development of this manuscript for publication. Portions of this work were presented at Pediatric Academic Societies (PAS) 2018 Meeting, May 5-8, 2018, in Toronto, Canada, as a poster presentation titled "Examination of Economic Burden Among Commercially Insured Patients with Central Precocious Puberty (CPP)."

Topics: Child; Child, Preschool; Cohort Studies; Cost of Illness; Female; Gonadotropin-Releasing Hormone; Health Care Costs; Humans; Insurance, Health; Leuprolide; Male; Medicaid; Patient Acceptance of Health Care; Puberty, Precocious; Retrospective Studies; United States

Nesfatin-1, an anorexigenic neuropeptide, is expressed mainly in the central nervous system and in some peripheral tissues. The role of nesfatin-1 in energy balance has been investigated. Despite the suggestion of a role for nesfatin-1 in reproductive function, data are limited on the role of nesfatin-1 in human puberty.. The aim of this study was to investigate the following: i) the role of nesfatin-1 in puberty, and ii) relationship between nesfatin-1 and anthropometric measurements and gonadotropin levels in girls with idiopathic central precocious puberty (CPP). Twenty-four girls with CPP (7.68±1.02 years) and 20 female, prepubertal, healthy controls (7.48±0.88 years) were enrolled in the study. All patients with CPP were treated by the intramuscular administration of leuprolide acetate at a daily dose of 3.75 mg for 28 days. Nesfatin-1 was measured before and during treatment.. There was no difference in serum nesfatin-1 levels in girls with CPP and healthy controls [5.67 (2.5-20.6) mmol/L and 5.75 (2.51-9.64) mmol/L], respectively. There was a negative correlation between nesfatin-1 levels and body weight and body mass index-standard deviation score (p=0.01, r=-0.83; p=0.025, r=-0.81, respectively). No correlation was found between nesfatin-1 and gonadotropin, estradiol levels, uterine length or endometrial thickness.. The results of this study suggest that there are no differences between girls with CPP and healthy, prepubertal girls regarding nesfatin-1 levels.

Topics: Body Mass Index; Body Weight; Calcium-Binding Proteins; Child; DNA-Binding Proteins; Female; Fertility Agents, Female; Humans; Leuprolide; Nerve Tissue Proteins; Nucleobindins; Puberty, Precocious

Data concerning subnormal growth velocity (GV) and factors that influence this during gonadotropin-releasing hormone analog (GnRHa) therapy for idiopathic central precocious puberty (ICPP) are scarce. We investigated the incidence of subnormal GV and associated factors in patients receiving GnRHa therapy for ICPP.. In this retrospective cohort study, the records of 50 girls who had been diagnosed with ICPP and started on GnRHa treatment before the age of eight years were investigated. Subnormal GV frequency, related factors during GnRHa therapy and the effect on final height were examined.. In girls with ICPP the risk of subnormal GV appears highest at the 3

Topics: Child; Cohort Studies; Female; Gonadotropin-Releasing Hormone; Growth; Humans; Leuprolide; Puberty, Precocious; Retrospective Studies

Gonadotropin-releasing hormone agonists (GnRHa) are the treatment of choice for central precocious puberty (CPP) and have been widely used for several decades. We determined the effect of GnRHa treatment on the auxological outcomes of girls with idiopathic CPP.. This study included 84 girls treated monthly with depot leuprolide acetate who had reached adult height. We compared their final adult height (FAH) with their initial predicted adult height (PAH). We performed a multivariate analysis of the factors associated with FAH on all girls diagnosed with CPP.. We performed the final evaluations at a mean age of 14.1 ± 0.8 years after a mean treatment duration of 2.98 ± 0.73 years (ranging from 1.5-4.8 years). Menarche had occurred at 12.6 ± 0.6 years of age, which was 16.5 ± 6.1 months after discontinuation of GnRHa therapy. Mean FAH was 160.1 ± 5.0 cm, which was significantly higher than the initial PAH (156.1 ± 5.7 cm; P < 0.001). To investigate whether growth outcomes were influenced by the age at initial treatment, we divided all patients into two groups, those treated between 6 and 8 years (n = 23) and those treated after 8 years (n = 61); no significant differences were observed in FAH between the two groups. FAH was significantly and positively correlated with the height standard deviation score (SDS) at the end of treatment and with the target height, whereas the difference between bone age and chronological age at the start and end of treatment was negatively correlated with FAH.. FAH was significantly higher than the initial PAH in girls with CPP who were treated with GnRHa. Also, GnRHa treatment was still effective even after 8 years of age in girls with CPP.

Topics: Adolescent; Body Height; Delayed-Action Preparations; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Puberty, Precocious

Deficiency in 11β-hydroxylase as a cause of congenital adrenal hyperplasia is uncommon. It should be considered in the differential diagnosis of hypertension with virilization in any prepubescent child.. A 12-year-old Asian boy from eastern Nepal presented with pain in his abdomen and hypertension. He was raised as a male but had absent testicles since birth and had precocious puberty. Plasma testosterone, follicle-stimulating hormone, and luteinizing hormone were below baseline level. Basal 17-hydroxyprogesterone was elevated. Magnetic resonance imaging of his pelvis showed presence of Müllerian structures and karyotyping revealed 46,XX genotype. A clinical diagnosis of 11β-hydroxylase deficiency was made in view of hypertension with severe virilization in a 46,XX individual. Our patient's legal guardian was unwilling for our patient to change gender and because our patient is underage, the condition was well explained to his parents. He was managed with steroids and antihypertensive drugs. He was on regular follow-up; after 2 years there was no hypertension but he developed true puberty with functional ovaries. He was prescribed leuprolide (gonadotropin-releasing hormone analogue), letrozole (aromatase inhibitor), and a continuation of antihypertensive drugs.. This case highlights the importance of a thorough physical examination of the external genitalia at birth and appropriate referral, and addresses issues in the management of such a disorder. Ethical issues pertaining to consent and who is entitled to give it should be clear so that the affected individual will have optimal psychological development and quality of life.

Topics: 46, XX Disorders of Sex Development; Abdomen; Adrenal Hyperplasia, Congenital; Child; Female; Gonadotropin-Releasing Hormone; Humans; Hypertension; Leuprolide; Magnetic Resonance Imaging; Male; Nepal; Puberty, Precocious

The adult height of children with early onset puberty is limited by the premature maturation of hypothalamic-pituitary-gonadal axis. To evaluate the effects of gonadotropin-releasing hormone analog (GnRHa) treatment on the final height (FH) and bone maturation rate (BMR) in girls with early puberty (EP) or idiopathic central precocious puberty (ICPP), we examined data from girls who were diagnosed with EP or ICPP and underwent GnRHa (Leuplin Depot: 3.75 mg/month) at China Medical University Hospital, in Taiwan, between 2006 and 2015. Patients were observed until the achievement of FH and divided into an "EP group" (T-ep) and "ICPP group" (T-icpp) according to the age of onset of puberty. Eighty-seven patients were enrolled (T-ep, N = 44, puberty onset at 8-10 years; T-icpp, N = 43, puberty onset before 8 years). The demographic data of girls with EP or IPP was characterized. BMR, change in predicted final height (PFH) after GnRHa treatment, target height (TH) and FH were measured. After GnRHa treatment, the study groups (T-ep: 160.24±6.18 cm, T-icpp: 158.99±5.92 cm) both had higher PFH than at initiation (T-ep: 159.83±7.19 cm, T-icpp: 158.58±5.93 cm). There was deceleration of BMR in both groups (T-ep: 0.57±0.39; T-icpp: 0.97±0.97) and a significant difference between the groups (p = 0.027). The gap in FH standard deviation scores (SDS) and TH SDS had a significant difference in T-ep (p = 0.045) but not in T-icpp. Moreover, there was no difference in the gap of PFH SDS between the 1st and final treatment in both groups. We concluded that GnRHa decelerated BMR in girls with earlier puberty. Further prospective clinical studies are warranted.

Topics: Body Height; Child; Female; Humans; Leuprolide; Puberty, Precocious; Retrospective Studies

Few studies have investigated the long-term effects of gonadotropin-releasing hormone (GnRH) agonist treatment on the reproductive function of central precocious puberty (CPP) girls. In this cross-sectional study, we assessed the ovarian function by analyzing the serum anti-Müllerian hormone (AMH) levels of CPP girls. Our study included 505 CPP girls subdivided into 5 groups according to the GnRH agonist treatment stage: group A (before treatment, n = 98), group B (3 months after initiation, n = 103), group C (12 months after initiation, n = 101), group D (24 months after initiation, n = 101), and group E (6 months after discontinuation, n = 102). We compared the serum AMH levels of the CPP girls with those of 100 bone age-matched controls (before treatment: n = 55; after discontinuation: n = 45). At baseline, the mean AMH level of the CPP girls was 5.9 ± 3.6 ng/mL. The mean AMH level after 3 months of the GnRH agonist treatment was lower (4.7 ± 3.2 ng/mL, P = 0.047) than that at baseline and recovered after 12 months of treatment. Six months after discontinuation, the AMH levels were similar to those at pre-treatment. Before and after the GnRH agonist treatment, the AMH levels were similar to those of the bone age-matched controls. In the precocious puberty girls, the AMH levels based on the GnRH agonist treatment stage were all within the normal reference range. The results of this study suggest that GnRH agonist treatment has no adverse effects on the reproductive function.

Topics: Anti-Mullerian Hormone; Case-Control Studies; Child; Cross-Sectional Studies; Drug Administration Schedule; Estradiol; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Immunoassay; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Retrospective Studies

Gonadotropin independent sexual precocity (SP) may be due to congenital adrenal hyperplasia (CAH), and its timing usually depends on the type of mutation in the CYP21A2 gene. Compound heterozygotes are common and express phenotypes of varying severity. The objective of this case report was to investigate the hormonal pattern and unusual genetic profile in a 7-year-old boy who presented with pubic hair, acne, an enlarged phallus, slightly increased testicular volume and advanced bone age. Clinical, hormonal and genetic studies were undertaken in the patient as well as his parents. We found elevated serum 17-hydroxyprogesterone (17-OHP) and androstenedione that were suppressed with dexamethasone, and elevated testosterone that actually rose after giving dexamethasone, indicating activity of the hypothalamic-pituitary-gonadal (HPG) axis. An initial search for common mutations was negative, but a more detailed genetic analysis of the CYP21A2 gene revealed two mutations including R341W, a non-classical mutation inherited from his mother, and g.823G>A, a novel not previously reported consensus donor splice site mutation inherited from his father, which is predicted to be salt wasting. However, the child had a normal plasma renin activity. He was effectively treated with low-dose dexamethasone and a GnRH agonist. His father was an unaffected carrier, but his mother had evidence of mild non-classical CAH. In a male child presenting with gonadotropin independent SP it is important to investigate adrenal function with respect to the androgen profile, and to carry out appropriate genetic studies.

Topics: Adrenal Hyperplasia, Congenital; Amino Acid Substitution; Child; Gonadotropin-Releasing Hormone; Heterozygote; Humans; Introns; Leuprolide; Male; Mutation; Puberty, Precocious; Steroid 21-Hydroxylase; Testosterone; Treatment Outcome

Gonadotropin-releasing hormone agonists (GnRHa) have been widely used for decades to treat patients with central precocious puberty (CPP). Several studies have investigated changes in body composition in patients with CPP following GnRHa treatment, but the results are inconsistent. The aim of this study was to investigate changes in body mass index (BMI) in children treated with GnRHa for 2 years. We also assessed whether BMI affects treatment outcomes. This study included 383 girls (214 girls with central precocious puberty and 169 girls who underwent early puberty) treated with depot leuprolide acetate monthly for at least 2 years. We analyzed changes in BMI standard deviation score (SDS). Furthermore, blood luteinizing hormone (LH) levels were determined 30 min after depot leuprolide acetate administration every 6 months to evaluate adequate suppression of the hypothalamic-pituitary-gonadal axis. Pretreatment mean BMI SDS values were 0.07 ± 0.69, 1.29 ± 0.16, and 1.95 ± 0.32 in the normal weight, overweight, and obese subjects, respectively. Mean BMI SDS values after 2 years of treatment increased significantly only in normal weight children (0.07 ± 0.69 vs. 0.25 ± 0.73, P < 0.001). LH levels 30 min after leuprolide injection after 2 years of treatment were not different among normal weight, overweight, and obese subjects. Although the difference in BMI SDS was relatively small, it standard deviation score increased significantly after 2 years of treatment in normal weight girls with early pubertal development.

Topics: Body Composition; Body Mass Index; Body Weight; Child; Estradiol; Female; Follicle Stimulating Hormone; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Treatment Outcome

This study aims to investigate the effect of Gonadotropin-releasing hormone analogues (GnRHa) treatment on anterior pituitary hormones in female children with central precocious puberty (CPP).. There were 62 female children who had been diagnosed with CPP and received GnRHa (Leuprolide acetate, 3.75 mg intramuscular/subcutaneous/28 days) included in the study. All subjects were clinically evaluated prior to treatment and every 3 months during treatment with serum LH, FSH, ACTH, TSH, PRL as pituitary hormones, and the end hormones such as plasma E2, cortisol, fT3, fT4 levels were measured. IGF-1 and IGFBP-3 levels were measured, and SDS was evaluated according to age and gender.. Prolactin levels were higher during GnRHa treatment compared to pre-treatment values although the increase was statistically significant only at month 3. In addition, while 2 (3.2%) of the patients had hyperprolactinemia before treatment, 11 (17.7%) patients developed hyperprolactinemia at different time points during treatment.. This study concluded that GnRHa treatment resulted in hyperprolactinemia and had no significant effect other pituitary hormones.

Topics: Child; Child, Preschool; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Male; Prolactin; Puberty, Precocious; Thyrotropin; Treatment Outcome

To determine the best cutoff value on the leuprolide stimulation test for the diagnosis of central precocious puberty (CPP) in a Brazilian population.. This observational study included 60 girls with CPP, as shown on the basis of serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) before and 3 hours after subcutaneous administration of 500 μg leuprolide acetate and by measuring serum estradiol concentrations 24 hours later. Six months later, each subject was clinically evaluated to determine whether she had experienced progressive or nonprogressive puberty.. Analyzing the best cutoff for LH after subcutaneous administration of 500 μg leuprolide acetate.. The best cutoff was a 3-hour LH level of greater than 4.0 mIU/mL, providing the highest sensitivity (73%) and specificity (83.1%), whereas a 3-hour LH level greater than 8.4 mIU/mL had a specificity of 100%. A 24-hour E2 concentration greater than 52.9 pg/mL had a sensitivity of 68% and a specificity of 74%. There was no association between pubertal development and disease progression. Signs such as thelarche and pubarche did not determine the evolution of the disease (P = .17). Clinical condition was associated with bone age/chronological age (P = .01), basal LH (P < .01), 3-hour LH (P = .02), baseline LH/FSH indices (P < .01) and after 3 hours (P < .01), and E2 at 24 hours (P = .02).. The optimal parameter indicating hypothalamic-pituitary-gonadal axis activation in our sample was a 3-hour LH level greater than 4.0 mIU/mL. A diagnosis of CPP, however, should be based on a set of criteria and not on an isolated measurement, because typical laboratory findings associated with CPP may not be present in all patients.

Topics: Adolescent; Brazil; Child; Child, Preschool; Estradiol; Female; Gonadotropins, Pituitary; Humans; Leuprolide; Prospective Studies; Puberty, Precocious; ROC Curve; Sensitivity and Specificity; Sexual Maturation

Little has been published on treatment of precocious puberty in girls with Williams-Beuren syndrome (WBS), a condition occurring frequently in this group. We analyzed our own data on growth/age at menarche of now adult female patients with WBS being diagnosed with central precocious puberty or early puberty. Data of patients treated with gonadotropin-releasing hormone (GnRH) analog (n=13) were compared with those not treated (control group, n=11).. Longitudinal data on the somatic development of 24 now adult female patients were analyzed.. Medium final height was 157.2±6.5 cm compared to 151.4±5.6 cm in the control group. No significant difference could be found in the discrepancy of genetic target height and final height. Prepubertally girls were normal weight in both groups; in adulthood the majority of patients were overweight/obese. Menarche commenced 11 months after cessation of therapy.. As already known from other studies, hormonal suppression via GnRH analog was well tolerated.

Topics: Adolescent; Body Height; Body Weight; Child; Female; Fertility Agents, Female; Humans; Leuprolide; Puberty, Precocious; Treatment Outcome; Williams Syndrome

To report our experience of treating central precocious puberty (CPP) with a GnRH analogue with respect to the final heights (FH) attained in patients who completed treatment.. Among 105 records of children diagnosed with precocious puberty, 62 cases (54 girls and 8 boys), who were treated with leuprolide acetate/3.75 mg/monthly, were selected, and divided into 4 groups: group 1 (G1), 25 girls who attained FH; group 2 (G2), 18 girls who completed treatment but did not reach FH; group 3 (G3), 11 girls still under treatment; and group 4 (G4), 8 boys, 5 of which attained FH. Treatment was concluded at a bone age of 12 years, and follow-up continued until FH was achieved.. In both G1 and G2 groups, height standard deviation score (SDS), weight-SDS and percentile of body mass index (PBMI) did not show intra/intergroup differences at the beginning and at interruption of treatment, but when added, G1+G2, height-SDS and weight-SDS differed significantly (p = 0.002 and 0.0001, respectively). In G1, 19 of 25 cases attained TH, and average height gain was 16.7 cm (7.7- 27.1); there was significant difference between FH and prediction of FH at the start (PFH at start) (p = 0.0001), as well as between PFH at interruption vs TH and vs FH (p = 0.007) with FH higher than TH (p = 0.004). Significant correlation was identified between FH and height gain after treatment.. As shown by some studies, GnRH analogue treatment was effective in children with CPP reaching FH near the genetic target.

Topics: Age Determination by Skeleton; Body Height; Brazil; Child; Child, Preschool; Estradiol; Female; Fertility Agents, Female; Follicle Stimulating Hormone, Human; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Infant; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Retrospective Studies; Testosterone; Treatment Outcome

A male infant was diagnosed with partial androgen insensitivity caused by a novel mutation in the androgen receptor. At 3.5 months of age, he received 100 mg of testosterone intramuscularly over the course of 3 months to increase phallic size. He developed pubic hair after 5 months and signs of progressive central precocious puberty when re-examined at 17.5 months, which subsequently was suppressed with depot leuprolide.

Topics: Aggression; Amino Acid Substitution; Androgen-Insensitivity Syndrome; Androgens; Delayed-Action Preparations; Exons; Gonadotropin-Releasing Hormone; Hemizygote; Humans; Hypospadias; Infant, Newborn; Leuprolide; Luteinizing Hormone; Male; Mutation; Penis; Puberty, Precocious; Receptors, Androgen; Scrotum; Testosterone

Central precocious puberty (CPP) diagnosis is based on clinical evaluation, but hormonal evaluation is crucial. The aim of the study was to evaluate the usefulness of the leuprolide stimulation test for diagnosis of idiopathic CPP. Sixty-one girls, aged 5-8 years, were evaluated retrospectively for premature breast development. According to clinical evolution, 28 had progressive puberty and 33 nonprogressive puberty. All underwent a leuprolide stimulation test. Cutoff points, sensitivity, and specificity for gonadotropins and estradiol were determined by receiver operating characteristic (ROC) curves. Cutoff points for CPP were: baseline LH: > 0.1 mUI/l, FSH: > 2.3 mUI/l, LH/FSH ratio: > 0.23, estradiol: > 12 pg/ml; and stimulated LH: > 5.5 mUI/l, LH/FSH ratio: > 0.24, estradiol: > 79.67 pg/ml. The best diagnostic efficiency for progressive puberty were stimulated LH/FSH ratio (sensitivity: 100%, specificity 94%) followed by stimulated LH (sensitivity: 93%, specificity: 100%). Stimulated LH/FSH ratio and LH resulted in the most useful parameters for the diagnosis of CPP. Stimulated estradiol did not add more information.

Topics: Child; Estradiol; Female; Follicle Stimulating Hormone; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; ROC Curve

Obesity, age and hormone imbalances including hypothyroidism and growth hormone deficiency and therapy, but not gonadotropin-releasing hormone agonist (GnRHa) therapy, have been identified as risk factors for slipped capital femoral epiphysis (SCFE). Five of 7 reported cases describe SCFE in children shortly after GnRHa therapy cessation.. We report 3 cases of SCFE that occurred in children on GnRHa therapy for the treatment of central precocious puberty (CPP) and discuss possible promoting factors.. An otherwise healthy 8.75-year-old girl [body mass index (BMI) Z score +1.75] developed SCFE 6.75 years into GnRHa therapy for idiopathic CPP. A second girl (with a history of acute lymphoblastic leukemia requiring total body irradiation) was 10.6 years old (BMI Z score +1.06) when she developed SCFE 3.3 years into GnRHa therapy. The third case was an 8.75-year-old female with CPP secondary to a hypothalamic hamartoma (BMI Z score +1.65) who developed bilateral SCFE 5.6 years into therapy.. Increasing evidence suggests an association between GnRHa therapy for CPP and the occurrence of SCFE. We suggest that a lack of adequate sex hormone exposure at a 'critical period' of bone formation may result in a weakened epiphysis that becomes susceptible to slipping. © 2013 S. Karger AG, Basel.

Topics: Age Determination by Skeleton; Child; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Diseases; Infant; Leuprolide; Overweight; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Puberty, Precocious; Slipped Capital Femoral Epiphyses

We describe a case of an 8 year old girl with central precocious puberty. She was commenced on 3 monthly intramuscular depot Leuprorelin acetate therapy, as a result of which she developed sterile abscesses. She was converted to daily subcutaneous Leuprorelin acetate therapy with no recurrence of the abscesses. The possible mechanisms for this reaction are described in the article.

Topics: Abscess; Child; Delayed-Action Preparations; Female; Humans; Injections, Intradermal; Leuprolide; Puberty, Precocious

Intravenous GnRH stimulation test has often been used as gold standard test for the evaluation of hypothalamic-pituitary-gonadal axis in the diagnosis of central precocious puberty (CPP) and in the assessment of pubertal suppression. However, this test is time-consuming, costly and uncomfortable for the patients. We aimed to analyse the validity of single LH sample 90 min after GnRH analogue (GnRHa) administration in the evaluation of gonadotrophin suppression during CPP therapy and to determine a cut-off level for LH indicating adequate suppression.. Prospective study.. One hundred and forty-two patients with CPP were included in this study. Peak LH level during iv GnRH stimulation test after the third dose of GnRHa was compared with LH level 90 min after injection of the 3rd dose of GnRHa.. There was a positive correlation between LH level following a GnRHa injection and peak LH during standard iv GnRH stimulation test (r = 0·83; P < 0·0001). A LH value of 2·5 mIU/ml or less 90 min after GnRHa injection was considered to be the cut-off for the determination of pubertal suppression (sensitivity and specificity was 100% and 88%, respectively). In 117 patients, gonadotrophin suppression was existed according to both GnRHa and iv GnRH tests. In 25 patients, gonadotrophin suppression was not found in the GnRHa test. However, 16 of them were suppressed according to the iv GnRH test.. Single LH determination 90 min after GnRHa administration using a cut-off level of 2·5 mIU/ml reflects pubertal suppression with a high sensitivity and specificity. However, this test may fail to show pubertal suppression in some cases. Those patients who appear to be inadequately suppressed should be reassessed using standard iv GnRH stimulation test for optimal dose adjustment.

Topics: Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Leuprolide; Luteinizing Hormone; Prospective Studies; Puberty, Precocious; Reproducibility of Results; Sensitivity and Specificity

We assessed the pharmacodynamics of a 3-hour leuprolide stimulation test in 11 girls with precocious puberty to determine an optimal single sampling time. Luteinizing hormone level following leuprolide stimulation was near maximum by 30 minutes in girls with central precocious puberty, whereas it continued to rise slowly in girls with nonprogressive puberty.

Topics: Child; Child, Preschool; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Humans; Infant; Leuprolide; Luminescent Measurements; Luteinizing Hormone; Puberty, Precocious; Radioimmunoassay

X-linked adrenal hypoplasia congenita (AHC) is typically characterized by a DAX-1 gene mutation and hypogonadotropic hypogonadism. However, rare cases with precocious puberty or normal puberty have been reported. Currently, the mechanism of action of the DAX-1 gene on puberty is not clearly known.. We report a male who was diagnosed as having AHC in the newborn period and detected as having stop codon Q155 X mutation in the DAX-1 gene. This subject developed central precocious puberty when he was 9 months old.. This paper is the first case report of AHC, central precocious puberty and a mutation in the DAX-1 gene. DAX-1 gene mutations can result in various phenotypes.. In cases with AHC, central precocious puberty can develop rather than hypogonadotropic hypogonadism, which is the most frequently observed puberty disorder related to DAX-1 gene mutations.

Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; DAX-1 Orphan Nuclear Receptor; Genetic Diseases, X-Linked; Gonadotropin-Releasing Hormone; Humans; Hypoadrenocorticism, Familial; Infant; Leuprolide; Male; Puberty, Precocious

Topics: Child; Female; Fertility Agents, Female; Humans; Leuprolide; Magnetic Resonance Imaging; Pituitary Gland; Puberty, Precocious

To compare the ovarian and uterine structure demonstrated sonographically with baseline and leuprolide-stimulated luteinizing hormone (LH) and estradiol values in females with suspected precocious puberty.. Retrospective chart review. Fifty females (age 3.1 to 9.5 years) underwent stimulation testing with leuprolide (20 μg/kg) and pelvic ultrasonography. Subjects were grouped as (1) prepubertal (baseline and stimulated LH and estradiol in prepubertal range); (2) early pubertal (baseline LH and estradiol in prepubertal range but stimulated LH or estradiol in pubertal range); and (3) pubertal (baseline and stimulated LH or estradiol in pubertal range). Sonographic data were compared with baseline and leuprolide-stimulated LH and estradiol.. Baseline and stimulated LH and stimulated estradiol significantly correlated with ovarian and uterine volumes. Ovarian and uterine volumes were significantly higher in females in the pubertal group than in females in the prepubertal group. No significant differences were noted in the ovarian or uterine dimensions between the prepubertal and early pubertal groups. There was significant overlap in ovarian and uterine volumes among females in all three groups.. Contrary to leuprolide stimulation, pelvic ultrasonography alone cannot distinguish between prepubertal females and those in the early stages of puberty.

Topics: Child; Child, Preschool; Estradiol; Female; Fertility Agents, Female; Humans; Leuprolide; Luteinizing Hormone; Organ Size; Ovary; Puberty, Precocious; Retrospective Studies; Ultrasonography; Uterus

To analyse the urinary steroid metabolome in a boy who had true precocious puberty after a Leydig cell tumour.. Case report and detailed description of clinical and metabolic findings in a 7-year-old-boy with a Leydig cell tumour..   Before surgery, the urinary steroid metabolome showed an activation of an alternative route to gonadal androgens independent of dehydroepiandrosterone (DHEA). After surgery, the boy entered true precocious puberty. Under leuprolide acetate treatment, clinical and laboratory findings normalized.. Central precocious puberty after precocious pseudopuberty may be more common than expected and should be considered in children with persistent or recurrent symptoms after initial treatment of precocious pseudopuberty. Patients with a Leydig cell tumour seem to reactivate the so-called 'back door pathway' of androgen production, which is independent of the classical route via DHEA.

Topics: Androsterone; Antineoplastic Agents, Hormonal; Child; Dehydroepiandrosterone; Etiocholanolone; Humans; Leuprolide; Leydig Cell Tumor; Male; Metabolome; Pregnanolone; Puberty, Precocious; Testicular Neoplasms; Testosterone

Central precocious puberty (CPP) is defined as pubertal development caused by activation of the hypothalamic-pituitary-gonadal axis before 8 years of age in girls and 9 years in boys. Failure to recognize and/or treat this condition can result in short adult stature.. To determine the etiology, clinical presentation and near-final height (NFH) of Thai children with CPP with or without gonadotropin-releasing hormone analog (GnRHa) treatment.. In a longitudinal observational study, 73 CPP patients who attended Songklanagarind Hospital between 1995 and 2009 were followed up every 3-6 months until they attained their NFH.. The etiologies observed were idiopathic CPP, hypothalamic hamartoma and central nervous system diseases. The mean age at time of diagnosis was 6.4 +/- 2.9 years. Bone age was on average 4 years more advanced than chronological age. Of the 52 patients who reached their NFH during the study, 32 were treated with GnRHa and 20 were not. The mean age at menarche was significantly greater for GnRHa-treated than for untreated girls (11.6 +/- 0.8 vs 10.1 +/- 1.1 years, p < 0.001). The median NFH of GnRHa-treated girls was 152.4 +/- 5.2 cm, which was significantly greater than the 144.4 +/- 5.0 cm for untreated girls (p < 0.001).. GnRHa treatment can preserve the genetic height potential of children with CPP.

Topics: Age Determination by Skeleton; Body Height; Central Nervous System Diseases; Child; Child Development; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Growth Disorders; Hamartoma; Humans; Hypothalamic Diseases; Leuprolide; Longitudinal Studies; Male; Menarche; Puberty, Precocious; Thailand; Treatment Outcome

To evaluate ovarian function, especially ovulation rate, in adolescents with McCune-Albright syndrome (MAS) and a history of peripheral precocious puberty.. Prospective cross-sectional study.. Academic center.. A total of eight adolescents with MAS were compared with 15 healthy adolescents matched by age, Tanner stage and body mass index.. We determined basal gonadotropins, sex steroids, sex hormone binding globulin, anti-Müllerian hormone, glucose and insulin. A leuprolide acetate test was performed to measure luteinizing hormone (LH) and follicle stimulating hormone (FSH) (at 0 and 3 h), and 17B-estradiol, testosterone and 17-OH-progesterone (at 0 and 24 h). Salivary progesterone levels were used to assess ovulation during the 13th, 18th, 23rd and 28th days of each menstrual cycle for three to five consecutive cycles, and one pelvic ultrasound was performed during the follicular phase.. Ovulation rate in adolescents with MAS.. The proportion of ovulatory cycles was 52.6% in controls compared with 35.7% in patients with MAS.. The adolescent girls with MAS appear to have a lower ovulatory rate compared with controls.

Topics: Adolescent; Adult; Cross-Sectional Studies; Female; Fibrous Dysplasia, Polyostotic; Follicle Stimulating Hormone, Human; Follicular Phase; Gonadotropin-Releasing Hormone; Humans; Hyperandrogenism; Leuprolide; Luteinizing Hormone; Ovary; Ovulation; Prospective Studies; Puberty, Precocious; Ultrasonography; Young Adult

Low concentrations of serum LH and/or oestradiol (E(2)) in girls with early physical signs of precocious puberty pose a diagnostic challenge.. To assess the diagnostic value of the leuprolide stimulation test in female precocious puberty.. Retrospective Chart Review.. Outpatient clinic.. Thirty-nine girls, 6.9 (1.4) years, with premature stage II-III breast development, with or without pubarche, underwent stimulation testing with subcutaneous leuprolide (20 microg/kg) with the following hormonal measurements in serum: FSH, LH, oestradiol at baseline; FSH and LH at 1 and 2 h; oestradiol at 24 h. Twelve girls with isolated pubarche were also tested with leuprolide.. A pubertal hormonal pattern was defined as at least one of the following: a baseline serum level of LH > or = 0.3 U/l, a baseline oestradiol > or = 37 pmol/l (10 ng/l), a stimulated (peak) LH > or = 5.0 U/l, a stimulated oestradiol > or = 184 pmol/l (50 ng/l) to leuprolide. The hormonal response was related to the clinical course during a period of observation of at least 6 months.. Following leuprolide stimulation, the hormonal response was concordant with pubertal progression (n = 23) or lack thereof (n = 16) in all children. At baseline, pubertal serum concentrations of LH and/or oestradiol were associated with pubertal progression in all, while serum prepubertal LH and/or oestradiol concentrations were associated with pubertal progression in approximately 50% of the patients.. In girls with early clinical signs of precocious puberty and low serum concentrations of LH and oestradiol in random samples, the LH and oestradiol responses to leuprolide stimulation accurately predict pubertal progression.

Topics: Child; Child, Preschool; Estradiol; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Humans; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Mass Screening; Puberty, Precocious; Reproducibility of Results; Retrospective Studies; ROC Curve; Sensitivity and Specificity; Sexual Maturation

Long-acting forms of gonadotropin-releasing hormone (GnRH) receptor agonists are commonly used for the treatment of central precocious puberty (CPP). Sterile abscess formation has been reported as a complication of leuprolide acetate, but not histrelin acetate.. The aim of this study was to report an adverse drug reaction in a child with sterile abscess formation following treatment with 2 different branded long-acting forms of GnRH agonists.. An otherwise healthy 8-year-old white female (weight, 40.7 kg; height, 140.1 cm) with documented CPP and no known drug allergies developed a sterile abscess at the site of the monthly intramuscular injection of 15 mg of leuprolide acetate. Because of this site reaction, a 50-mg histrelin acetate insert was placed in the patient's left arm. A similar reaction occurred 2 weeks after insert placement on 2 separate occasions in different arms. At the time of the removal of the second insert, Gram stain and swab culture of the purulent wound discharge were negative. The child was subsequently treated with intranasal nafarelin (800 ug twice daily) and tolerated it well. The Naranjo Adverse Drug Reaction Causality Score was 10 (definite, ≥9).. This report describes a case of sterile abscess formation definitely associated with 2 different forms of long-acting GnRH agonist treatment in a child.

Topics: Abscess; Child; Delayed-Action Preparations; Drug Implants; Female; Gonadotropin-Releasing Hormone; Humans; Injections, Intramuscular; Leuprolide; Nafarelin; Puberty, Precocious; Receptors, LHRH

To compare the efficacy of goserelin and leuprolide on initial deceleration of growth and weight gain during the first 12 months of GnRH analogue treatment for precocious puberty.. Retrospective cohort analysis.. Forty children with precocious puberty treated with either goserelin or leuprolide (33 females, mean age 7.3 and 7.7 years, respectively, at the start of treatment).. The primary outcomes were baseline-to-6-months and 6-months-to-12-months change in height standard deviation score (SDS) and body mass index (BMI). Relative tall stature was calculated as the difference between height SDS and mid-parental height (MPH) SDS at baseline.. Goserelin and leuprolide were associated with similar suppression of serum LH during the first 12 months of treatment (P = 0.62). Greater relative tall stature was strongly associated with more advanced bone age, greater BMI SDS and with greater reduction in height SDS in the first 6 months. Adjusted for relative tall stature, goserelin therapy was associated with significantly greater suppression of growth than leuprolide (P = 0.025) in the first 6 months of treatment, with no subsequent change in the second 6 months. A similar, significant increase in BMI was seen with both analogues.. Both GnRH analogues were associated with effective biochemical suppression of puberty; however, goserelin was more effective at reducing linear growth during the first 6 months. Relative tall stature was a major determinant of the initial response to treatment.

Topics: Adolescent; Age Determination by Skeleton; Body Height; Child; Child, Preschool; Cohort Studies; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Infant; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Retrospective Studies; Time Factors; Weight Gain

Gonadotropin-releasing hormone agonists (GnRHa) represent the gold-standard treatment for central precocious puberty (CPP). In CPP children, GnRHa treatment slows bone age progression and preserves adult height (Ht) by suppressing sexual steroid secretion. In some patients, however, GnRHa induce an inappropriate growth deceleration impairing Ht outcome. Furthermore, slowly progressive CPP (spCPP) forms were reported which do not need GnRHa treatment.. We evaluated the growth outcome of 26 spCPP girls treated with triptorelin (TR) and 21 with leuprorelin acetate (LA) for 36.5 +/- 0.7 months.. GnRHa treatment induced a progressive growth deceleration in both spCPP groups. No difference in bone maturation was detected (p > 0.05; TR vs. LA group), however compared to LA, TR treatment resulted in significantly higher Ht after 24 months (p < 0.05; LA vs. TR group). Although target height (TH) standard deviation score (SDS) and predicted adult height (PAH)-SDS at diagnosis were similar in both spCPP groups (p > 0.05; LA vs. TR group), final height (FH-SDS) was lower in LA-treated subjects (p < 0.05; LA vs. TR group). In both spCPP groups, FH-SDS was significantly lower than TH-SDS (p < 0.001) but not lower than PAH-SDS at diagnosis (p > 0.05). Ht-SDS correlated with 17beta-estradiol (E(2)) blood levels in both spCPP groups (p < 0.0001) throughout GnRHa treatment, and E(2) values were higher in the TR- than in the LA-treated patients during the 12 months after GnRHa administration (p < 0.05; LA vs. TR group). GnRHa-induced E(2) secretion and Ht-SDS at GnRHa withdrawal correlated positively with FH (p < 0.01 and p < 0.001, respectively).. The effectiveness of GnRHa treatment in improving FH in spCPP girls was doubtful.

Topics: Analysis of Variance; Body Height; Bone Development; Child; Child Development; Estradiol; Female; Follicle Stimulating Hormone; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Regression Analysis; Time Factors; Treatment Outcome; Triptorelin Pamoate

Topics: Child; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Sensitivity and Specificity

To ascertain the diagnostic value of GnRHa stimulation testing in girls with CPP, single sample 30 minute post-stimulated gonadotropin levels were compared between girls with CPP and prepubertal girls. Serum LH and FSH concentrations were assayed using two third generation gonadotropin assays. Clinical data were reviewed to establish the diagnosis of CPP. GnRHa stimulation testing with one LH measurement obtained 30 minutes after stimulation is adequate for evaluating girls with CPP and as reliable as GnRH stimulation testing.

Topics: Case-Control Studies; Child; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Luminescent Measurements; Luteinizing Hormone; Puberty, Precocious; Sensitivity and Specificity; Time Factors

to evaluate predictive factors of response to GnRHa treatment in girls with idiopathic central precocious puberty.. a retrospective cohort study was conducted involving 33 girls diagnosed with idiopathic central precocious puberty and treated with GnRHa. The following independent variables were assessed: age at the beginning of therapy and at the onset of symptoms, time elapsed since the appearance of pubertal characteristics and the beginning of treatment, bone age, bone age advance, duration of GnRHa treatment, actual height and Z-score, predicted height and Z-score and hormone measurements of FSH and LH after GnRH stimulation, which were correlated with gain in height as a dependent variable at treatment discontinuation, calculated by the difference between the predicted height at the end and beginning of treatment. For statistical analysis, Pearson's linear correlation was used, in addition to multiple linear regression analysis.. the mean age at the beginning of treatment was 7.8+/-1.3 years, with a mean bone age of 10.1+/-1.6 years. Bone age advance was 2.3+/-1.1 years and was controlled during the treatment period. Gain in predicted height was 2.5+/-1.3cm. It was positively correlated with time elapsed since the beginning of symptoms and the beginning of treatment and with bone age advance, while negatively correlated with the Z-score of height at the beginning of treatment and predicted height at the beginning of treatment, and the latter was the main factor determining gain from treatment.. girls who had the most significant compromise of predicted adult height, as detected by a larger deviation from the population (Z-score) and the most considerable advance in bone age, received benefit from GnRHa therapy, and they must not be excluded from the group to be treated.

Topics: Body Height; Child; Cohort Studies; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Prognosis; Puberty, Precocious; Retrospective Studies

Several factors can affect adult height (AH) of patients with gonadotropin-dependent precocious puberty (GDPP) treated with depot GnRH analogs.. Our objective was to determine factors influencing AH in patients with GDPP treated with depot GnRH analogs.. A total of 54 patients (45 girls) with GDPP treated with depot GnRH analog who reached AH was included in the study.. Univariate and multivariate analyses of the factors potentially associated with AH were performed in all girls with GDPP. In addition, clinical features of the girls who attained target height (TH) range were compared with those who did not. Predicted height using Bayley and Pinneau tables was compared with attained AH.. In girls the mean AH was 155.3 +/- 6.9 cm (-1.2 +/- 1 sd) with TH range achieved by 81% of this group. Multiple regression analysis revealed that the interval between chronological age at onset of puberty and at the start of GnRH analog therapy, height sd scores (SDSs) at the start and end of therapy, and TH explained 74% of AH variance. The predicted height at interruption of GnRH therapy, obtained from Bayley and Pinneau tables for average bone age, was more accurate than for advanced bone age in both sexes. In boys the mean AH was 170.6 +/- 9.2 cm (-1 +/- 1.3 SDS), whereas TH was achieved by 89% of this group.. The major factors determining normal AH in girls with GDPP treated with depot GnRH analogs were shorter interval between the onset of puberty and start of therapy, higher height SDS at the start and end of therapy, and TH. Therefore, prompt depot GnRH analog therapy in properly selected patients with GDPP is critical to obtain normal AH.

Topics: Adolescent; Adult; Body Height; Child; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Goserelin; Humans; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Regression Analysis; Triptorelin Pamoate

To examine the effects of long-term gonadotropin-releasing hormone agonist (GnRHa) administration on thyroid function in children affected by central precocious puberty (CPP).. We retrospectively evaluated circulating thyroid hormones in 73 GnRHa-treated girls who were diagnosed with idiopathic CPP. Monthly depot injections (.1 mg/body kg) of leuprorelin acetate (LA) and of triptorelin (TR) were continuously administered for 40.4 +/- .7 months to 34 and 39 CPP patients, respectively. Serum levels of thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid antibodies were determined at baseline and after 6, 12, 18, 24, 30, 36, and 40 months of GnRHa administration.. While there was no difference in FT4 release (p > .05), FT3 levels significantly declined during both LA and TR treatments from untreated baseline (p < .05). Opposite to circulating FT4 and FT3 values (p > .05), FT3/FT4 ratio was significantly different among LA and TR groups (p < .05). Both GnRHa treatments did not affect TSH secretion (p > .05); however, LA induced lower TSH values than TR (p < .05).. There is no evidence of thyroid dysfunction during both GnRHa treatments, though changes in TSH, FT3, and FT3/FT4 ratios were noted. Finally, monitoring of thyroid activity during GnRHa administration is not required.

Topics: Biomarkers; Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Puberty, Precocious; Retrospective Studies; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyrotropin; Time; Triptorelin Pamoate

Topics: Algorithms; Black or African American; Child; Clinical Laboratory Techniques; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Physical Examination; Puberty, Precocious; Risk Factors

A 1-year-old male child with isosexual central (gonadotropin-dependent) precocious puberty caused by hypothalamic hamartoma is reported. Details of the diagnosis based solely on neuromaging characteristics, and satisfactory results of medical treatment with gonadotropin releasing hormone agonist analogues, are highlighted.

Topics: Hamartoma; Humans; Hypothalamic Diseases; Infant; Leuprolide; Magnetic Resonance Imaging; Male; Puberty, Precocious

It has been reported that gonadotropin releasing hormone analogue (GnRHa) therapy can improve the adult height of patients with gonadotropin-dependent precocious puberty. The purpose of this study was to evaluate the effect of GnRHa on the adult height of girls with gonadotropin-dependent precocious puberty and the adverse effects of such therapy.. Between 1989 and 2006, 11 girls with gonadotropin-dependent precocious puberty who had been treated with GnRHa and reached their adult height were enrolled in the present study. Follow-up studies of bone age, pelvic sonography and GnRH test were done regularly during the period of treatment. All patients had bone mineral density examined at least 2 years after completion of GnRHa therapy.. GnRHa therapy was initiated at the age of 8.0 +/- 1.5 years. The predicted adult height immediately before GnRHa therapy was 146.7 +/- 4.8 cm (-2.3 +/- 0.9 standard deviation [SD]). The duration of GnRHa therapy was 4.7 +/- 1.8 years. The adult height of the patients was 156.3 +/- 4.3 cm (-0.6 +/- 0.8 SD), which is similar to their target height of 157.0 +/- 4.5 cm (-0.5 +/- 0.8 SD). The uterine sizes and gonadotropin responses to GnRH stimulation were well suppressed during treatment. Menstruation resumed 9.2 +/- 5.9 months after the discontinuation of treatment in these patients. Forty-five percent of patients had lumbar bone mineral density less than 1 SD below that of normal young Taiwanese adults in the Taipei region.. GnRHa therapy can improve the adult height of patients with gonadotropin-dependent precocious puberty. However, 45% of patients had decreased bone accretion during therapy.

Topics: Adolescent; Body Height; Bone Density; Child; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Leuprolide; Luteolytic Agents; Menstruation; Puberty, Precocious; Triptorelin Pamoate

Girls with central precocious puberty (CPP) are treated with gonadotropin releasing hormone (GnRH) analogues to suppress puberty. Gonadotropin levels are used to monitor treatment, since estradiol is difficult to measure at low levels. The optimal degree of hormonal suppression is still unknown.. We hypothesized that in girls treated for CPP, estradiol levels (by ultrasensitive bioassay) would correlate with the rate of skeletal maturation and linear growth velocity. We asked whether predicted height would improve with greater luteinizing hormone (LH) and estradiol suppression. We also compared pre- and post-injection LH levels for monitoring treatment.. Thirty girls with CPP were followed for up to 2 years during treatment with leuprolide acetate depot at a dose of 0.3 mg/kg/28 days. We measured LH and estradiol levels, bone age, and growth velocity every 6 months.. Estradiol levels were suppressed to below the detection limit in three-quarters of the girls and did not correlate with the rate of skeletal maturation or linear growth. Improvement in predicted height correlated significantly with lower pre-injection LH levels. These girls have some of the lowest estradiol and LH levels, best improvement in predicted height, and least amount of bone age advancement published to date. Pre- and post-leuprolide injection LH levels were positively correlated.. Greater LH suppression may improve height outcome in girls treated for CPP with GnRH analogues. The degree of LH suppression achieved is individualized and not necessarily related to absolute dose. Pre-injection LH levels may be useful for monitoring treatment. Ultrasensitive estradiol levels were very low and usually unmeasurable, affirming the increased suppression at the higher doses of GnRH analogue used in these girls. Further investigation is needed, with longer treatment duration, a range of doses, and ultimately final height. Until such studies are completed, clinicians should be cautious when interpreting pubertal suppression.

Topics: Body Height; Bone and Bones; Child; Child, Preschool; Delayed-Action Preparations; Drug Monitoring; Estradiol; Female; Fertility Agents, Female; Growth; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Radiography; Treatment Outcome

GnRH analogs (GnRHa) are considered the treatment of choice for central precocious puberty (CPP). During GnRHa administration, the suppression of the pituitary-gonadal axis results in decreased rates of linear growth and skeletal maturation and in improved adult height. However, in some patients, the growth deceleration is so marked that the expected improvement in predicted adult height is not achieved.. The objective of this study was to assess whether the addition of oxandrolone (Ox) may affect the height outcome of patients with CPP and growth deceleration during GnRHa treatment.. This was an open-label, clinical study.. The study was performed at a pediatric endocrinology referral clinic.. Twenty patients with CPP and marked growth deceleration during GnRHa treatment were studied.. Treatment consisted of GnRHa (Leuprorelina, 3.75 mg im every 28 d) alone (10 patients) or in combination with Ox (0.06 mg/kg.d by mouth) (10 patients).. The main outcome measure was the patients' adult height.. The adult height of the patients treated with GnRHa plus Ox was significantly higher than pretreatment predicted adult height (162.6 +/- 2.3 vs. 154.8 +/- 1.7 cm, mean +/- sem; P < 0.05) and target height (162.6 +/- 2.3 vs. 158.0 +/- 1.9; P > 0.05). Patients treated with GnRHa alone reached an adult height similar to the pretreatment predicted adult height (151.9 +/- 1.2 vs. 155.4 +/- 2.1 cm) but significantly lower than target height (151.9 +/- 1.2 vs. 156.6 +/- 1.4 cm; P < 0.005). No side effects were recorded in either group of patients.. Combined GnRHa and Ox therapy is a viable treatment option for children with CPP and marked growth deceleration during treatment with GnRHa alone.

Topics: Anabolic Agents; Body Height; Bone Development; Child; Female; Follicle Stimulating Hormone; Growth; Humans; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Oxandrolone; Puberty, Precocious

Dosing of monthly depot leuprolide (DL) in central precocious puberty (CPP) varies considerably. U.S. practitioners use 7.5-15 mg, in contrast with the international standard of 3.75 mg. Pubertal suppression using the newer 3-month DL also has been reported from Europe. To date there have been no direct comparisons of these different DL doses.. In an open 12-month protocol, we tested the efficacy of three DL doses (7.5 mg- and 3.75 mg-1 month and 11.25 mg-3 month) given sequentially to subjects treated for CPP. Primary outcome measures were stimulated gonadotropin (Gn) levels at 12-wk intervals. The null hypothesis was no difference among doses.. Both existing and new patients with CPP received our standard therapy (DL 7.5 mg every 4 wk) for a minimum of 24 wk. In subjects with DL-stimulated LH 2 IU/liter or less, the dose was changed to 3.75 mg every 4 wk and evaluated 12 wk later. Subjects who met LH criteria (<4.5 IU/liter) on 3.75 mg then received a single dose of 11.25 mg-3 month and were reevaluated 12 wk later. Serum LH/FSH and sex steroids were obtained 40 min after DL injection.. Thirty subjects were enrolled (20 naive; 24 girls, 6 boys), and 21 were evaluated on all three DL doses. DL-stimulated LH levels (mean +/- sd) were 1.30 +/- 0.74, 1.73 +/- 0.99, and 2.13 +/- 1.41 on 7.5 mg, 3.75 mg, and 11.25 mg-3 month, respectively (7.5 vs. 3.75 mg, P = 0.019; 7.5 mg vs. 11.25 mg-3 month, P = 0.004, Wilcoxon ranked sign test). Mean FSH levels were 2.86 +/- 1.91, 3.91 +/- 1.98, and 3.96 +/- 1.34, respectively (7.5 vs. 3.75 mg, P = 0.017; 7.5 mg vs. 11.25 mg-3 month, P = 0.020). No differences were detected in mean sex steroid levels.. Stimulated LH and FSH levels were significantly higher during therapy with both the 3.75 mg and 11.25 mg-3 month depot leuprolide doses, compared with 7.5 mg, contradicting the null hypothesis of no difference. These data suggest that low-dose 1- and 3-month DL preparations are associated with persistently greater gonadal stimulation in most CPP patients, but the LH/FSH results were not corroborated by differences in sex steroid levels. Whether various DL doses lead to long-term therapeutic differences remains to be determined.

Topics: Child; Delayed-Action Preparations; Female; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Gonadotropins; Humans; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Reproducibility of Results

Topics: Child; Clinical Trials as Topic; Female; Humans; Leuprolide; Male; Puberty, Precocious; Treatment Outcome

An 8-year-old girl with idiopathic central precocious puberty experienced multiple episodes of anaphylaxis after receiving a goserelin acetate implant. She was hospitalized and treated with epinephrine, antihistamine, and corticosteroids. The goserelin implant was surgically excised; however, anaphylactic symptoms continued for 4 days after excision. Less severe systemic symptoms recurred 6 weeks after removal; these were possibly due to leakage of the depot drug into subcutaneous tissues. It was noted that 3 years earlier, the patient had developed a similar, milder systemic allergic reaction to leuprolide acetate that required treatment with oral prednisone and antihistamines. Intradermal testing yielded positive results for leuprolide. Gonadotropin-releasing hormone (GnRH) analogs, including leuprolide acetate and goserelin acetate, are commonly prescribed for patients with prostatic carcinoma, endometriosis, and precocious puberty. A literature review identified a single case report of a systemic hypersensitivity reaction involving goserelin acetate and several reports of systemic hypersensitivity reactions associated with leuprolide acetate. We found no reports of systemic reactions to GnRH analogs in pediatric patients. Clinicians should be aware of the potential association of GnRH analogs with systemic reactions. They should also recognize that recurrent anaphylaxis may occur due to the long half-life of these therapeutic agents in tissue.

Topics: Anaphylaxis; Child; Child, Preschool; Drug Hypersensitivity; Drug Implants; Drug Therapy, Combination; Female; Follicle Stimulating Hormone; Goserelin; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious

A 4-10/12 year-old boy presented with tall stature and advanced secondary sexual characteristics. His bone age was 13 years giving him a height prediction of 147 cm. An initial 11-deoxycortisol level of 13,770 ng/dl and associated hypertension suggested the diagnosis of 11-hydroxylase deficiency, which was confirmed by dexamethasone suppression and genotyping. Treatment strategy was based on the premise that known hypothalamic priming resulting in early pubertal development could be averted by delaying puberty with leuprolide; also that effects of hydrocortisone and leuprolide on attenuating growth could be counteracted by growth hormone. The combined treatment resulted in a final height at age 12 years which was 25.4 cm greater than predicted, and bone density above average. We conclude that delaying puberty until an appropriate age, offsetting growth suppression, and improving bone mineralization can be effectively achieved using glucocorticoids, leuprolide and growth hormone in patients with 11-hydroxylase deficiency.

Topics: Adrenal Hyperplasia, Congenital; Body Height; Bone Density; Child; Delayed-Action Preparations; Genotype; Human Growth Hormone; Humans; Hydrocortisone; Hypertension; Leuprolide; Longitudinal Studies; Male; Puberty, Precocious; Steroid 11-beta-Hydroxylase

Data concerning the effects of GnRHa on weight gain are scarce.. To assess the variation of the body mass index (BMI) in girls during GnRHa treatment for idiopathic central precocious puberty (CPP).. Semestral anthropometric data from 176 girls treated with goserelin or leuprorelin were analyzed.. BMI z-score increased from 1.5 +/- 0.1 SD before treatment (n = 176) to 1.7 +/- 0.2 SD after 24 months (n = 61, p = 0.008). In girls with normal weight before treatment, this variation was greater (n = 112, 0.2 +/- 0.1 SD, p = 0.01) than in those who were overweight (n = 63, -0.9 +/- 0.2 SD, p = 0.7). In the goserelin group the weight change adjusted for bone age was greater (n = 28, 0.4 +/- 0.1 SD) than in the leuprorelin group (n = 5, 0.04 +/- 0.1 SD, p = 0.05).. A slight increase in BMI was noted, mainly in girls with normal weight before treatment. The influence of different GnRHa on weight must be further investigated.

Topics: Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Longitudinal Studies; Puberty, Precocious; Retrospective Studies

Topics: Child; Clothing; Crime; Humans; Leuprolide; Male; Puberty, Precocious; Testosterone

Topics: Child; Epiphyses, Slipped; Female; Femur Head; Fertility Agents, Female; Humans; Leuprolide; Puberty, Precocious; Substance Withdrawal Syndrome

Adnexal torsion may occur in girls and adolescents. Often it is associated with ovarian diseases resulting in ovarian enlargement. Adnexal torsion may involve the ovary, fallopian tube or both, and the main symptom is acute pelvic pain. An 8-year-old girl complaining of acute pelvic and abdominal pain, who was previously diagnosed with precocious puberty and who received treatment with a GnRH analog, is reported. Ultrasound demonstrated a normal-sized uterus and bilaterally enlarged ovaries with multiple internal cysts. At laparotomy, we found a complete torsion in the right adnexa. The histological examination revealed massive edema associated with multiple antral follicles and reduction of the follicular reserve.

Topics: Adnexal Diseases; Child; Female; Fertility Agents, Female; Fibrous Dysplasia, Polyostotic; Humans; Leuprolide; Puberty, Precocious; Torsion Abnormality

Long-acting GnRH analogs represent the standard treatment for gonadotropin-dependent precocious puberty. The aim of this study was to determine the hormonal parameters for monitoring the adequacy of depot leuprolide acetate treatment in girls with clinical and hormonal diagnosis of gonadotropin-dependent precocious puberty. Eighteen girls were treated monthly with 3.75 mg depot leuprolide acetate. Adequate hypothalamic-pituitary-gonadal axis suppression during treatment was achieved in 16 of the 18 girls according to the clinical parameters and prepubertal LH levels. In these 16 well-controlled girls, the LH peak after a classical GnRH test was compared with a single LH measurement obtained 2 h after depot leuprolide acetate administration before and during GnRH analog treatment. Before therapy, the mean +/- sd LH peak after a classical GnRH test was 18.4 +/- 11.2 IU/liter (ranging from 7-41.5 IU/liter), and it was 22.6 +/- 8.3 IU/liter 2 h after the first depot leuprolide dose (ranging from 10-35.3 IU/liter). During therapy, the mean +/- sd of LH peak after classical GnRH test was 1.4 +/- 0.6 IU/liter (ranging from <0.6 to 2.3 IU/liter), and it was 2.7 +/- 1.9 IU/liter (ranging from 0.7-6.6 IU/liter) 2 h after depot leuprolide. The LH peak after a classical GnRH test and that 2 h after depot leuprolide administration correlate significantly before and during treatment. In conclusion, we established the LH cut-off values for an adequate depot leuprolide therapy as an LH peak below 2.3 IU/liter after a classical GnRH test or below 6.6 IU/liter 2 h after depot leuprolide. The latter measurement may replace the classical GnRH test as a reliable and convenient tool for monitoring therapy in female gonadotropin-dependent precocious puberty.

Topics: Child; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Humans; Infant; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Time Factors

Inhibin-B decreases and activin increases FSH secretion in adults. We investigated whether an FSH-inhibin/activin feedback loop exists before or during puberty.. FSH secretion was stimulated with 10 microg/kg leuprolide acetate (GnRH agonist) in 18 girls, ages 1.0-13.2 years, and 11 boys, ages 8.9-15.2 years, with variations in pubertal development, and in five normal 9- to 10-year-old girls. Blood, obtained at 0, 0.5, 1, 2, 4, 8, 12, 16, 20 and 24 h after GnRH agonist, was analysed for LH, FSH, activin-A, inhibin-A, inhibin-B, follistatin 288 and estradiol/testosterone.. FSH increased within 30 min of GnRH agonist administration with a peak greater in girls than boys (P=0.0006). Baseline inhibin-B was greater in boys than girls (P=0.01), while baseline activin-A concentrations were greater in girls. GnRH agonist-stimulated FSH increased inhibin-B in girls by 8 h and in boys by 20 h (P<0.05), but did not affect activin-A. Inhibin-B increases were seen only in girls older than 5 years.. An inhibin-B-FSH feedback loop exists prior to the onset of puberty in girls older than 5 years. Sex differences in activin-A and inhibin-B concentrations may be responsible for sex differences in serum FSH concentrations.

Topics: Activins; Adolescent; Age Factors; Bone Development; Child; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonads; Growth Disorders; Humans; Inhibin-beta Subunits; Inhibins; Leuprolide; Male; Pituitary Gland; Puberty; Puberty, Precocious; Reference Values; Sex Characteristics

Reported endocrine problems related to human immunodeficiency virus (HIV) infection in children are primarily growth deceleration and delayed pubertal development. We report here an African-American male with congenital HIV infection who developed precocious puberty that was diagnosed at 4-9/12 years of age.

Topics: Adolescent; Child Development; Child, Preschool; Fertility Agents, Female; HIV Infections; Humans; Leuprolide; Male; Puberty, Precocious; Testis

The efficacy of a 3-month depot preparation of the GnRH agonist leuprorelin acetate in central precocious puberty was studied.. Treatment with a 3-month depot of leuprorelin acetate was performed subcutaneously in a 7.3-year-old girl with central precocious puberty.. During treatment the hormonal suppression was constant and complete as demonstrated by suppressed GnRH stimulation tests and prepubertal estradiol plasma levels. The size and volume of the uterus and ovaries returned to the normal range. The rate of bone maturation was significantly reduced with a ratio deltaBA/deltaCA of 0.58 for 3 treatment years. Thus, the effects of treatment were comparable to those reported for treatment with 1-month depot of GnRH agonists.. Three-month depots have the advantage of a prolonged injection interval which is more convenient for the patients and reduces costs by necessitating fewer visits to the physician and being approximately 10% cheaper than the 1-month depot. We suggest that comparative and randomized studies be performed to make 3-month depots of GnRH agonists available for routine use in children with central precocious puberty.

Topics: Body Height; Child; Delayed-Action Preparations; Estradiol; Female; Follicle Stimulating Hormone; Genitalia, Female; Hormone Antagonists; Humans; Leuprolide; Luteinizing Hormone; Ovary; Pituitary Gland; Puberty, Precocious; Ultrasonography

To find the time of the serum gonadotropin peak after depot leuprolide injection in children and to show that depot leuprolide therapy can be monitored by measuring serum luteinizing hormone (LH) immediately after injections.. We measured concentrations of leuprolide, LH, and follicle-stimulating hormone (FSH) at multiple time points before and after the first dose of depot leuprolide in 14 pubertal children beginning therapy. Gonadotropins and sex steroids were measured again after the fourth dose.. Serum leuprolide, LH, and FSH levels rose rapidly after initial injection, reaching sustained elevations at 30 to 120 minutes. The median LH level increased from 2.1 mIU/mL at baseline to a peak of 27.5 mIU/mL at 45 minutes, and FSH increased from 5.2 to 16.5 mIU/mL. After 3 months on therapy, median serum LH after depot leuprolide injection was only 0.83 mIU/mL, similar to levels observed after intravenous or subcutaneous gonadotropin-releasing hormone stimulation in comparable subjects on depot leuprolide.. Our pharmacokinetic data demonstrate that free leuprolide present in a depot leuprolide injection is equivalent to gonadotropin-releasing hormone in stimulating a rapid rise in serum gonadotropin concentrations. We propose that a single serum sample for LH obtained 30 to 60 minutes after depot leuprolide injection in children provides a convenient and accurate assessment of treatment efficacy.

Topics: Adolescent; Child; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Drug Monitoring; Estradiol; Female; Follicle Stimulating Hormone; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Testosterone; Treatment Outcome

Hepatocellular dysfunction and perturbed portal hemodynamics alter steroid metabolism. Men with liver disease have gynecomastia, although women similarly affected rarely show virilization. We report a 10-yr-old girl with portal hypertension and shunting associated with precocious puberty and ovarian hyperandrogenism. This was one of premature twin girls; neither had clitoromegaly or genital ambiguity. In one child, neonatal respiratory problems led to umbilical vein catheterization with subsequent development of portal hypertension. Pubic hair was first noted at age 6 yr, breasts at 7 yr, and severe acne and clitoromegaly at 10 yr. Baseline sex hormones were elevated: androstenedione (A), 413 ng/dL; testosterone (T), 226 ng/dL; and estradiol (E2), 160 pg/mL. Liver transaminases were within the normal range, however, the coagulation profile was mildly abnormal. Cosyntropin adrenal stimulation revealed no steroidogenic defect. Dexamethasone suppression reduced A and T slightly. LH-releasing hormone stimulation produced a pubertal rise in LH and FSH. Pelvic sonography showed a large right ovary with numerous follicles. Surgical exploration revealed symmetrically enlarged ovaries with dense capsules. Histology of ovarian wedge resections showed hyperthecosis; immunohistochemistry showed stromal cells expressing steroidogenic enzymes and proteins. One month postoperatively, A and T were unchanged from baseline, whereas E2 decreased to 56 pg/mL. A single dose of depot leuprolide acetate significantly reduced T. Subsequent treatment with oral contraceptives reduced T to 50 ng/dL, and cyclical menses occurred. We conclude that precocious puberty and ovarian hyperthecosis were induced in this young girl by elevated circulating levels of sex hormones, a consequence of portasystemic shunting and impaired hepatic steroid metabolism.

Topics: Androstenedione; Child; Contraceptives, Oral; Diseases in Twins; Female; Gonadal Steroid Hormones; Humans; Hyperandrogenism; Hypertension, Portal; Immunohistochemistry; Leuprolide; Ovarian Diseases; Ovary; Puberty, Precocious; Testosterone; Theca Cells

The diagnostic significance of an enlarged pituitary gland regarding both shape and size parameters on MR imaging has previously been demonstrated in children with central precocious puberty. This study was designed to assess changes in these parameters following successful suppressive therapy of central precocious puberty with the gonadotropin-releasing hormone (GnRH) analogue.. Twelve girls (mean age 7.3 years) with central precocious puberty were prospectively enrolled in our study protocol. Sagittal and coronal MR images of the pituitary region were obtained in all patients before treatment and after at least 6 months of GnRH analogue therapy (mean 18.0 months). Parameters measured included pituitary gland height, length, width, sagittal cross-sectional area, and volume.. All patients had excellent clinical response to treatment with arrest of secondary sexual development, normalization of serum estradiol levels, and complete obliteration of the LH response to diagnostic GnRH stimulation. No significant change occurred in any pituitary size or shape parameter following GnRH analogue therapy.. Favorable clinical response to GnRH analogue therapy in central precocious puberty is not accompanied by significant a change in pituitary gland size and shape.

Topics: Antineoplastic Agents, Hormonal; Child; Child, Preschool; Female; Humans; Leuprolide; Magnetic Resonance Imaging; Pituitary Gland; Prospective Studies; Puberty, Precocious; Statistics, Nonparametric

The impact of treatment of central precocious puberty (CPP) with gonadotropin-releasing hormone agonists (GnRHa) on final height remains controversial. We analyzed the long term results of 23 girls with CPP treated with triptorelin or leuprolide. Their "near final height" (NFH) assessed at a bone age of at least 14 years and expressed as SDS, was compared either with predicted height before treatment (PAH) or with parental height (TH). We also compared NFH of 12 girls treated before 8 years of age (7.0 +/- 0.5 yr) with NFH of 11 girls treated after 8 years old (8.5 +/- 0.3 yr). The NFH of the 23 girls (-0.9 +/- 1.0 SDS) was not different either from PAH (-0.85 +/- 1.5 SDS) or from TH (-0.5 +/0.6 SDS). Earlier treated girls reached a NFH (-0.97 +/- 1.0 SDS) not different from later treated girls (-0.91 +/- 1.0 SDS; p = ns) and both groups reached parental height (NFH - TH = -0.44 +/- 1 and -0.09 +/- 0.83 SDS, respectively). In conclusion, our patients, treated either earlier or later, reached a near final height comparable to predicted height and familial target; however, these results might still improve further because the girls have not yet reached their final adult height.

Topics: Body Height; Bone Development; Brain Diseases; Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Puberty, Precocious; Triptorelin Pamoate

Body composition changes with age and sex differences become significant only after puberty. Boys and girls before the age of 8 yr do not differ in fat, lean or bone mineral mass. Hormonal influences during pubertal development determine the physiological adult male and female body composition phenotype.. The aim of our study was to evaluate body composition changes due to central precocious puberty (PP) and the specific effects of therapy on these modifications.. Sixteen patients (14 girls, 2 boys) were included in the study. They were diagnosed as affected by idiopathic PP according to standard hormonal and clinical criteria; anatomic alterations of hypothalamus-hypophysis region were excluded by MRI. Mean age at diagnosis was 5.9 +/- 1.9 yr. All patients received GnRH analog (Leuprolide or Triptorelin) treatment subcutaneously every 4 weeks for at least 1 yr. Mean period of treatment was 3.4 +/- 1.9 yr. Standard anthropometry and body composition analysis were performed at baseline and every 6-12 months. A group of healthy subjects with normal timing of puberty was matched (for age or for pubertal stage) served as the control group (CA or CP, respectively).. Patients with PP showed at baseline a significant increase of BMI and relative body weight; lean and fat compartments were also increased but not significantly. During treatment, the PP group showed increased fat mass compared to CA (p<0.05), while no difference was found between PP and CP. Lean mass was similar to CA but lower than in CP (p<0.05). During treatment a significant increase in lean mass (both as total as well as limb mass) was observed. After stopping treatment there was no difference between PP and CP, except for lower lean mass (p<0.04).. When puberty occurs precociously, lean and fat mass are not significantly different from age-matched control subjects. Data collected during treatment confirm a shortening of prepubertal lean mass development and the block of further lean mass development due to puberty itself, while fat mass accumulation continues. The net result of these modifications determines a typical body composition pattern in PP patients, after the end of therapy: lean mass is reduced by a shortening of the prepubertal growing period and by the "menopausal effect" of treatment itself. Fat mass is increased as a consequence of therapy and could lead to future obesity.

Topics: Adipose Tissue; Anthropometry; Body Composition; Body Mass Index; Body Weight; Brain Diseases; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Puberty, Precocious; Triptorelin Pamoate

Topics: Child; Female; Humans; Leuprolide; Puberty, Precocious; United States

The gonadotropin releasing hormone (GnRH) secreting hypothalamic hamartoma (HH) is a congenital malformation consisting of a heterotopic mass of nervous tissue that contains GnRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle. HH is a well recognised cause of gonadotropin dependent precocious puberty (GDPP). Long term data are presented on eight children (five boys and three girls) with GDPP due to HH. Physical signs of puberty were observed before 2 years of age in all patients. At presentation with sexual precocity, the mean height standard deviation (SD) for chronological age was +1.60 (1.27) and the mean height SD for bone age was -0.92 (1.77). Neurological symptoms were absent at presentation and follow up. The hamartoma diameter ranged from 5 to 18 mm and did not change in six patients who had magnetic resonance imaging follow up. All patients were treated clinically with GnRH agonists (GnRH-a). The duration of treatment varied from 2.66 to 8.41 years. Seven of the eight children had satisfactory responses to treatment, shown by regression of pubertal signs, suppression of hormonal levels, and improvement of height SD for bone age and predicted height. One patient had a severe local reaction to GnRH-a with failure of hormonal suppression and progression of pubertal signs. It seems that HH is benign and that GnRH-a treatment provides satisfactory and safe control for most children with GDPP due to HH.

Topics: Antineoplastic Agents, Hormonal; Child; Child, Preschool; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Goserelin; Hamartoma; Humans; Hypothalamic Diseases; Leuprolide; Magnetic Resonance Imaging; Male; Puberty, Precocious

Topics: Brain Diseases; Child; Epilepsies, Partial; Female; Humans; Leuprolide; Progesterone; Puberty, Precocious; Recurrence

The effectiveness of LHRH agonist therapy in central precocious puberty depends upon suppression of LH secretion. The iv LHRH stimulation test is the gold standard for evaluating LH suppression, but is difficult to administer because it requires an iv line and multiple blood samples. We hypothesized that a sc LHRH test followed by a single LH measurement 40 min later would be as accurate in the assessment of LH suppression in children receiving LHRH analogs. Eleven children received the sc test 1 month before or after their regularly scheduled iv LHRH treatment. Each child was receiving Lupron to suppress central puberty. Twenty-five comparisons of the iv and sc LHRH tests were completed over 14 months. We developed a clinical score for pubertal suppression using Tanner staging, skeletal maturation, and growth velocity. The best correlation between this clinical score and the iv LHRH test was achieved when biochemical suppression was defined as peak LH less than 2 IU/L (100% sensitivity, 95% specificity). Using this definition, the sc LHRH test was 96% accurate (in 24 of 25 subjects), with a sensitivity of 75% and a specificity of 100% compared to the iv LHRH test. We conclude that the single sample sc LHRH test can accurately determine LH suppression and adequacy of LHRH agonist therapy in central precocious puberty.

Topics: Adolescent; Child; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Humans; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Male; Patient Satisfaction; Puberty, Precocious; Sensitivity and Specificity

We studied the auxological effects of treatment with the GnRH agonist leuprolide acetate (Lucrin((R))) at 3.75 mg/ 28 days in 38 children with early or precocious puberty. We present our newly developed scoring system, the Puberty Suppression Score (PSS), in which clinical and biochemical parameters determine whether suppression was effective. Leuprolide acetate suppressed pubertal development in the majority of cases. During treatment there was a significant correlation between the number of times that PSS was >0 and gain in predicted adult height (PAH) compared to initial prediction at the start of treatment. After 6 months of treatment, ineffective suppression measured by PSS was associated with the magnitude of gain in PAH. We conclude that a leuprolide acetate dosage of 3.75 mg every 28 days effectively suppresses puberty. PSS is helpful in monitoring the suppressive capacity of a GnRH agonist. We recommend to start with leuprolide acetate at 3.75 mg/28 days and to increase the injection frequency or dose in case PSS is >0 after 6 months of treatment.

Topics: Age Determination by Skeleton; Body Height; Child; Dose-Response Relationship, Drug; Evaluation Studies as Topic; Female; Forecasting; Gonadotropin-Releasing Hormone; Growth; Health Status Indicators; Humans; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Retrospective Studies; Treatment Outcome

Topics: Bone Density; Buserelin; Child; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Puberty, Precocious; Receptors, Estrogen

In patients with myelomeningocele (MMC), growth is influenced by a large number of growth-retarding factors due to the neurological defect. Moreover, endocrine disorders have been found to contribute to short stature in MMC patients. Central precocious puberty (CPP) is a common problem. Due to growth disturbances and difficulties in obtaining standardized measurements, MMC patients have been excluded from gonadotropin-releasing hormone (GnRH) analogue studies in the past. We report on eight patients (six female, two male) with MMC, hydrocephalus, and CPP who were treated with GnRH analogues: triptorelin intramuscularly (N=5) or leuprorelin subcutaneously (N=3). Auxological data and hormone levels were assessed before treatment and every 6 months during treatment. The median chronological ages (CA) at the start of treatment were 8.6 years (females) and 8.4 years (males). Bone age (BA) was accelerated in all cases prior to treatment and two girls were already menstruating. Elevated gonadotropin serum levels and sex steroid levels decreased during treatment, although no complete suppression to prepubertal levels was reached. Progression of pubertal development and menses stopped in all patients. The tempo of BA acceleration (deltaBA:deltaCA) decreased, but no significant improvement in height standard deviation score BA and predicted adult height resulted. No side effects during treatment were observed. CPP in MMC patients has to be considered as early as possible to enable an early diagnosis and corresponding treatment. Further prospective studies on the effects of GnRH analogues in MMC patients are necessary.

Topics: Age Determination by Skeleton; Child; Female; Gonadotropins; Humans; Hydrocephalus; Leuprolide; Luteolytic Agents; Male; Meningomyelocele; Menstruation; Puberty, Precocious; Treatment Outcome; Triptorelin Pamoate

Major changes in bone mineral density (BMD) and body composition occur during puberty. In the present longitudinal study, we evaluated BMD and calculated volumetric BMD [bone mineral apparent density (BMAD)], bone metabolism, and body composition of children (32 girls and 2 boys) with central precocious and early puberty before and during treatment with GnRH agonist (GnRH). Patients were studied at baseline and during treatment for 6 months (n = 34), 1 yr (n = 33), and 2 yr (n = 16). Lumbar spine and total body BMD and body composition were measured with dual-energy x-ray absorptiometry. The variables were compared with age- and sex-matched reference values of the same population and expressed as SD score (SDS). Bone age was assessed. Serum calcium, phosphate, alkaline phosphatase, osteocalcin, the carboxyterminal propeptide of type I collagen (PICP), cross-linked telopeptide of collagen I (ICTP), 1,25 dihydroxyvitamin D and urinary hydroxyproline/creatinine, and calcium/ creatinine ratios were measured. Mean lumbar spine BMD SDS was significantly higher than zero at baseline (P < 0.02) and did not differ from normal, after 2 yr of treatment. Mean spinal BMAD SDS and total body BMD SDS were not significantly different from zero at baseline and had not changed significantly after 2 yr of treatment. During therapy, fat mass and percentage body fat SDS increased, whereas lean tissue mass SDS decreased. Mean lumbar spine BMD and BMAD and total body BMD SDS, calculated for bone age, were all lower than zero at baseline (BMD P < 0.001 and BMAD P < 0.05) and also after 2 yr treatment (respectively, P < 0.001, P < 0.05, and P < 0.01). Biochemical bone parameters were significantly higher than prepubertal values at baseline, and they decreased during treatment. In conclusion, patients with central precocious and early puberty had normal BMD for chronological age but low BMD for bone age, after 2 yr of treatment with GnRH. Bone turnover decreased during treatment. Changes in body composition resembled those seen in patients with GH deficiency.

Topics: Body Composition; Body Height; Body Mass Index; Bone Density; Child; Collagen; Collagen Type I; Delayed-Action Preparations; Female; Humans; Leuprolide; Longitudinal Studies; Male; Osteocalcin; Peptide Fragments; Peptides; Procollagen; Puberty; Puberty, Precocious

Nineteen girls adopted from developing countries were referred for signs of idiopathic precocious puberty. After adoption, the catch up in linear and weight growth, together with improved nutritional and psychological conditions, may trigger the onset of puberty. Precocious puberty is a frequent and unnatural event in these girls. Treatment with gonadotrophin releasing analogues is indicated in patients diagnosed early, and when height prediction is poor.

Topics: Adoption; Analysis of Variance; Body Height; Child; Child, Preschool; Developing Countries; Female; Humans; Leuprolide; Nutritional Physiological Phenomena; Puberty, Precocious

To assess the gonadotropin and ovarian steroid responses to the GnRH agonist (GnRH-a) leuprolide acetate (LA) in premature pubarche girls and in Tanner stage- and bone age-matched controls to ascertain whether the ovarian 17-hydroxyprogesterone (17-OHP) hyper-response to GnRH-a challenge present in some subsets of adolescent premature pubarche girls is detectable during puberty and whether these patients have a distinct pattern of pituitary-ovarian maturation.. Cross-sectional study.. A university teaching hospital.. Seventy-six premature pubarche girls (early pubertal [B2; n = 31], midpubertal [B3; n = 15], late pubertal [B4; n = 12], and postmenarcheal [B5; n = 18]) and 45 controls.. Gonadotropins and plasma steroid hormones (17-OHP, 17-OH-pregnenolone [17-Preg], androstenedione [A], T, DHEA, DHEAS, E2, and cortisol) were measured before and 3 and 24 hours, respectively, after LA challenge (500 micrograms SC).. Ovarian-steroidogenic responses to GnRH-a challenge.. Luteinizing hormone responsiveness increased significantly during puberty in all subjects whereas FSH levels changed less consistently. Peak E2 levels differed among pubertal stages and were significantly higher in premature pubarche girls than in controls at B4 and at B5. Both peak and incremental increases of 17-Preg and DHEA throughout puberty and of 17-OHP and A at B4 were significantly higher in premature pubarche girls than in controls. This pattern of ovarian-steroidogenic response was most evident during midpuberty and late puberty and resembled the adrenal hyper-response to ACTH of exaggerated adrenarche, suggestive of increased ovarian activity of both the 17 alpha-hydroxylase and the 17,20 lyase functions of cytochrome P450c17 alpha.. Pubertal girls with a history of premature pubarche show a distinct pattern of ovarian maturation characterized by an exaggerated ovarian androgen synthesis throughout puberty.

Topics: 17-alpha-Hydroxypregnenolone; 17-alpha-Hydroxyprogesterone; Adolescent; Androgens; Androstenedione; Child; Cross-Sectional Studies; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estradiol; Female; Follicle Stimulating Hormone; Humans; Leuprolide; Luteinizing Hormone; Ovary; Puberty, Precocious; Testosterone

Some children with congenital adrenal hyperplasia (CAH) develop true precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis. We have seen six such children who had the diagnosis of CAH with late initiation of corticosteroid treatment and/or poor compliance who developed central precocious puberty (CPP). These patients were treated with standard-dose hydrocortisone and fludrocortisone. Administration of depot leuprorelin (3.75 mg subcutaneously every 28 days) for 2 years or longer was effective in arresting the manifestations of puberty, decelerating the pretreatment growth velocity ([GV] 10.8 +/- 1.5 v3.65 +/- 0.95 cm/yr), increasing the predicted adult height ([PAHT] 147.5 +/- 7.8 v 153.4 +/- 8.3 cm), and decreasing the bone age to statural age ratio (1.26 +/- 0.13 v 1.16 +/- 0.09). Analysis of auxanological data during the first 2 years of life showed that linear growth was significantly accelerated and bone age was advanced in patients who developed CPP compared with 11 age-matched patients. It appears that proper glucocorticoid replacement to achieve adequate control of hyperandrogenemia during early life might prevent development of CPP in these patients. Gonadotropin-releasing hormone agonist (GnRHa) therapy can improve the final adult height, bringing it closer to that expected from the genetic potential.

Topics: Adrenal Hyperplasia, Congenital; Child; Child Development; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Puberty; Puberty, Precocious

The present study evaluated the FSH and LH episodic discharge in different physiopathological conditions undergoing chronic GnRH-agonist administration. Four girls with true precocious puberty and five postmenopausal women were administered GnRH-agonist (3.73 leuprolide acetate every 4 weeks; Takeda Italia, Rome, Italy) for at least 4 months. Plasma LH and FSH secretory profiles were assessed before and under GnRH-agonist administration (after 21 and 120 days). Pulsatility studies were conducted for 4 h in the girls and for 6 h in postmenopausal women, with blood sampling intervals of 10 min. Pubertal and postmenopausal patients showed the distinct episodic co-secretion of LH and FSH before GnRH-agonist administration; this co-secretion disappeared in both groups after 21 and 120 days of treatment. Moreover, while LH concentrations decreased to almost undetectable levels and LH episodic release disappeared, FSH plasma levels were only partially reduced and FSH episodic secretion was detectable in both groups. In conclusion, this study demonstrated that long-term GnRH-agonist administration blocked LH but not FSH episodic release. These data enforce the hypothesis that FSH episodic discharge might be dependent not only on hypothalamic GnRH, but also on a GnRH-independent stimulatory pathway.

Topics: Child; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Postmenopause; Puberty, Precocious; Time Factors

GnRH analogs (GnRH-a) have proven to be efficacious and have become the standard treatment for central precocious puberty (CPP). To confirm the diagnosis of CPP and to monitor the adequacy of hvpothalamic-pituitary-gonadal (HPG) axis suppression, GnRH stimulation testing has been essential. To determine whether 24-h urinary gonadotropin excretion could adequately assess HPG axis suppression, we compared the results of simultaneous GnRH stimulation tests and 24-h urinary gonadotropin determinations in 18 girls with CPP who were receiving GnRH-a therapy (leuprolide acetate, Depot-Lupron, TAP Pharmaceuticals). HPG axis suppression was defined as the absence of significant LH and FSH responses to GnRH stimulation. Simultaneous GnRH stimulation tests and urinary gonadotropin determinations had a concordance rate of 68% (42 of 62). The sensitivity and specificity of urinary LH determinations to detect inadequate HPG suppression were 75% and 64%, respectively. For urinary FSH determinations, the sensitivity and specificity were 90% and 28%, respectively. Hence, single timed urine collections lacked the sensitivity and specificity to assess HPG axis suppression and, thus, cannot replace GnRH stimulation tests for monitoring the adequacy of the GnRH-a dose.

Topics: Child; Female; Fluoroimmunoassay; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Reagent Kits, Diagnostic

Topics: Age Determination by Skeleton; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Male; Meningomyelocele; Puberty, Precocious; Triptorelin Pamoate

Topics: Antineoplastic Agents, Hormonal; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Puberty, Precocious; Triptorelin Pamoate

Treatment of adults with gonadotropin releasing hormone analogs has resulted in rapid loss in bone mineral density (BMD). We measured lumbar and femoral neck BMD by dual-energy x-ray absorptiometry during 2 years of depot leuprolide therapy in 13 girls (mean age, 7.5 years; mean bone age, 10.9 years). At baseline, BMD was elevated for age and concordant with the advanced skeletal age. During therapy with gonadotropin releasing hormone analog, BMD values increased and BMD standard deviation scores for age and skeletal age did not change.

Topics: Absorptiometry, Photon; Age Determination by Skeleton; Bone Density; Child; Child, Preschool; Delayed-Action Preparations; Female; Humans; Leuprolide; Longitudinal Studies; Puberty, Precocious; Time Factors

Bone mineral metabolism and mineralization before and during treatment were studied in 10 girls aged 6.9-8.4 years affected by central precocious puberty and treated with gonadotrophin-releasing hormone agonist (GnRHa) leuprolide acetate depot, in order to understand better the consequences of oestrogen deficiency and the reduction of growth hormone (GH)-insulin-like growth factor I (IGF-I) axis activity. Before and after 12 months of therapy, the patients underwent a clonidine stimulation test and a 4-day calcitriol osteoblast stimulation test. On day 0, day 5 and at 3-month intervals thereafter, serum calcium, phosphate, alkaline phosphatase, IGF-I, IGF binding protein 3 (IGFBP-3), GH, GH binding protein and osteocalcin levels were measured; urinary calcium, phosphate and hydroxyproline levels were evaluated in fasting spot samples. Trabecular and cortical bone mass variations, measured by dual X-ray absorptiometry in the lumbar spine and by dual photon absorptiometry in the radius, respectively were evaluated before the start and after 12 months of therapy. During treatment, a decrease of serum oestradiol levels from pubertal to prepubertal levels was observed. The GH peak following clonidine diminished significantly after 1 year. Growth hormone binding protein showed a slight increase, and IGF-I and IGFBP-3 decreased, although not significantly. Osteocalcin levels decreased significantly after 9 and 12 months of treatment, but they did not change significantly after calcitriol load, either before or after GnRHa therapy. Urinary hydroxyproline decreased significantly after 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Body Height; Bone and Bones; Bone Density; Calcification, Physiologic; Calcitriol; Child; Clonidine; Delayed-Action Preparations; Female; Growth Hormone; Humans; Hydroxyproline; Insulin-Like Growth Factor I; Leuprolide; Minerals; Osteoblasts; Osteocalcin; Puberty, Precocious; Sympatholytics

We assessed the utility of spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays in the evaluation and monitoring of precocious puberty.. We evaluated serum gonadotropin values from intravenous GnRH stimulation tests in 49 girls with clinical signs suggesting central precocious puberty (CPP). Because GnRH-stimulated LH has been considered the standard for diagnosing CPP, we used it as the basis for comparison with GnRH-stimulated FSH levels and spontaneous LH and FSH measured by immunochemiluminometric assay.. Twenty-six patients had a peak serum LH value above the +2 SD threshold for normal prepubertal female subjects (LH > 5 IU/L). The GnRH-stimulated FSH values had a narrow range and did not discriminate patients with CPP. In contrast, elevations in spontaneous LH and FSH were found to be specific for CPP. Spontaneous LH levels correlated strongly with peak stimulated LH levels in subjects with precocious puberty (r = 0.79) or in control subjects (r = 0.93, both p (0.0001). Spontaneous LH levels in excess of 0.1 IU/L detected true puberty with 94% sensitivity and 88% specificity. Random LH levels in excess of 0.3 IU/L had 100% specificity for CPP.. The GnRH-stimulated FSH levels do not adequately differentiate children with and without CPP and have limited utility in the evaluation of precocious puberty. Spontaneous FSH levels are elevated in CPP with fair sensitivity and marked specificity. Elevated random LH, measured by third-generation assay such as immunochemiluminometric assay, is strongly correlated with and highly predictive of elevated peak GnRH-stimulated LH, and is a useful screening tool for CPP.

Topics: Adolescent; Child; Child, Preschool; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Immunoradiometric Assay; Leuprolide; Luminescent Measurements; Luteinizing Hormone; Male; Puberty, Precocious; Sensitivity and Specificity

We treated a 1-year-old female with a hypothalamic hamartoma and precocious puberty with leuprolide acetate depot, a super long-acting hormone-releasing hormone analogue (Tap-144-SR; [D-Leu6-[des-Gly10-NH2] LH-RH ethylamide acetate). The infant's major symptoms were genital bleeding and gynaecomastia. The LH-RH analogue (30 micrograms/kg) was injected subcutaneously once every 4 weeks. Clinical and laboratory manifestations of precocious puberty showed marked improvement. A follow-up after 16 months of treatment, the size of the tumour decreased significantly and remained unchanged for 2 years of further follow-up. To the best of our knowledge, this is the first hypothalamic hamartoma case in whom a decrease of tumour size under treatment with LH-RH analogue has been documented. But, because diagnosis of hamartoma is only based on neuroradiological and not on histological examinations, the possibility of a gangliocytoma cannot be excluded with certainty.

Topics: Delayed-Action Preparations; Drug Administration Schedule; Female; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Diseases; Infant; Injections, Subcutaneous; Leuprolide; Puberty, Precocious

A 7-month-old girl presented with ascites and breast enlargement due to right ovarian granulosa cell tumor. After tumor removal, the clinical signs of incomplete precocious puberty regressed. Four years later, the patient reappeared with signs of precocious puberty. Our investigations proved that this was not due to tumor recurrence, but it was a true central precocious puberty. She responded well to therapy with a luteinizing hormone releasing hormone agonist, and 3 years after onset of this therapy, she is growing at a normal prepubertal rate.

Topics: Antineoplastic Agents, Hormonal; Female; Granulosa Cell Tumor; Humans; Infant; Leuprolide; Ovarian Neoplasms; Puberty, Precocious

Topics: Adolescent; Calcitriol; Diagnosis, Differential; Female; Fibrous Dysplasia, Polyostotic; Humans; Ketoconazole; Leuprolide; Male; Medroxyprogesterone Acetate; Octreotide; Ovariectomy; Propylthiouracil; Puberty, Precocious; Spironolactone; Testolactone; Thyroid Diseases

We evaluated the use of sonography in monitoring the efficacy of suppressive therapy with a gonadotropin releasing hormone analogue in girls being treated for isosexual precocious puberty. Ten girls 5 to 9 years of age underwent serial sonography and hormonal stimulation tests on the same day. Sonographic trends of decreasing ovarian volume and uterine length indicated early suppression even when absolute values were above threshold. Changes in ovarian volume were the most sensitive predictor of pituitary-gonadal suppression. Sonography is a sensitive and accurate method of monitoring medical therapy; ovarian volume and analysis of interval change are the most sensitive barometers of change.

Topics: Child; Child, Preschool; Estradiol; Female; Follicle Stimulating Hormone; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Longitudinal Studies; Luteinizing Hormone; Ovary; Pituitary Gland; Prospective Studies; Puberty, Precocious; Ultrasonography; Uterus

The pubertal growth spurt is characterized by a marked increase in the amplitude of GH secretory pulses. The high affinity GH-binding protein (GHBP) reportedly has an important role in enhancing the growth-promoting action of GH. Levels of GHBP are characteristic for an individual and increase only slightly as puberty progresses. It has been hypothesized that each individual adjusts GH production to a level appropriate for his GHBP environment. The withdrawal of gonadal steroids that occurs in children with central precocious puberty (CPP) treated with LH-releasing hormone agonist (LHRHa) therapy results in a decrease in growth velocity (GV) and GH secretion. This study was performed to determine the effect of treatment of CPP with the LHRHa leuprolide acetate for depot suspension on GH secretion and levels of GHBP. Six girls and one boy with CPP were studied before and 6 months after treatment was initiated. Within 6 months of initiation of therapy, there was a significant decline in GV, from 8.9 +/- 3.2 to 5.4 +/- 2.0 cm/yr (P < 0.05). Twelve-hour mean nocturnal GH levels decreased significantly from 8.6 +/- 3.5 to 5.1 +/- 2.3 micrograms/L (P < 0.05). This occurred via a decrease in the amplitude of GH pulses as the number of peaks remained 4.6 and 4.1/12 h. Individual levels of GHBP were variable and reflect the wide range of levels observed in normal children. Although GV and GH levels decreased substantially, mean GHBP levels remained unchanged at 139.9 +/- 46.0 and 152 +/- 39.8 pmol/L. In children with CPP, within 6 months of LHRHa therapy, the decrease in GV occurs via a decrease in nocturnal GH secretion as levels of GHBP remain unchanged. In children with CPP, the withdrawal of gonadal steroids may inhibit the child's ability to secrete the GH appropriate for his/her GH/GHBP milieu.

Topics: Body Mass Index; Carrier Proteins; Child; Child, Preschool; Female; Gonadotropin-Releasing Hormone; Growth; Growth Hormone; Humans; Leuprolide; Male; Puberty, Precocious

The high-affinity growth hormone (GH)-binding protein corresponds to the extracellular domain of GH receptor. The direct role of sex steroids in pubertal bone growth may be an increased GH receptor-coupled GH action. We examine the GH-binding protein (GHBP) activity before and after the suppression of female sex steroids and the relation of GHBP to pubertal growth.. We studied six girls with central idiopathic sexual precocity without any prior gonadal suppression therapy.. We measured GHBP activity before and 12, 24 and 48 weeks after the treatment with s.c. injection of a GnRH agonist (leuprolide acetate) every 4 weeks.. GHBP activity was measured by immunoprecipitation using anti-GH receptor monoclonal antibody.. The treatment caused a decrease in the LH and FSH responses to GnRH test and plasma oestradiol, which resulted in decreased urinary GH excretion, plasma IGF-I levels, height velocity and bone age maturation. GHBP activity before the start of the treatment was normal (75 +/- 27% relative to adult pooled serum, mean +/- SD), and it was increased above adult level (122 +/- 29% at 48 weeks, P < 0.01) by the suppression of the pituitary-gonadal axis. There were significant negative correlations between GHBP and oestradiol (r = 0.452, n = 24, P < 0.05) and between GHBP and urine GH excretion (r = -0.462, n = 24, P < 0.05).. The high-affinity GHBP is increased by the withdrawal of female sex steroid. The clinical significance of this finding may be interference with the binding of GH to its receptor resulting in a reduced IGF-I level and decreased height velocity. The mechanism warrants further study.

Topics: Body Height; Carrier Proteins; Child; Child, Preschool; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropins, Pituitary; Growth Hormone; Humans; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Puberty, Precocious

Topics: Child; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Nafarelin; Puberty, Precocious

The LHRH-secreting hypothalamic hamartoma (HH), a congenital malformation consisting of a heterotopic mass of nervous tissue that contains LHRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle, can cause true or central precocious puberty (TPP). We have suggested that it functions as an ectopic LHRH pulse generator independent of the central nervous system inhibitory mechanism that normally restrains the hypothalamic LHRH pulse generator. TPP associated with a hamartoma has all of the hormonal hallmarks of puberty, including a pubertal pattern of pulsatile LH and a pubertal plasma LH response to LHRH administration. Little is known about the natural history of HH. We present long term data on 10 children (5 females and 5 males) with TPP due to HH. Physical signs of puberty were observed at a mean age of 2.2 +/- 1.6 yr (range, 0.5-5.1). Two of 10 had a pedunculated mass, and 8 of 10 had a sessile mass. The hamartoma varied in diameter from 4-25 mm and did not change with time (3.5-8.7 yr). Four patients have a seizure disorder, 3 with gelastic seizures (1 with mental retardation) and 1 with tonic-clonic seizures. The shape of the hamartoma, sessile or pedunculated, did not correlate with the occurrence of seizures. At presentation with sexual precocity, the mean height SD for chronological age was +3.5 +/- 0.4, the mean height SD for bone age was -1.9 +/- 0.4, and the mean bone age SD for chronological age was +6.8 +/- 0.7. Baseline data were comparable to those of 10 females with idiopathic TPP. Nine of 10 HH patients and all idiopathic TPP patients were treated with a LHRH agonist. The response to therapy was excellent in both groups and indistinguishable. Nine of 10 HH children attend school regularly and, aside from those with seizures, have no neurological handicap. While surgical resection of the hamartoma has been recommended, it carries an increased risk of morbidity and mortality and, if removal is incomplete, does not arrest the sexual precocity. In our experience, LHRH agonist therapy for TPP due to HH is the preferable approach.

Topics: Child, Preschool; Female; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Neoplasms; Infant; Leuprolide; Magnetic Resonance Imaging; Male; Nafarelin; Puberty, Precocious

Topics: Delayed-Action Preparations; Drug Eruptions; Female; Humans; Leuprolide; Male; Puberty, Precocious

We used the GnRH agonist (GnRHa) stimulation test (20 micrograms/kg leuprolide sc, followed by 24-h serial sampling) to investigate the relationship between gonadotropin and estradiol (E2) secretion in the early phase of female central precocious puberty (CPP). Girls with CPP and moderately increased (early pubertal) peak E2 concentrations after GnRHa stimulation (136 +/- 11 pmol/L; range, 92-176; group B; n = 7) were compared to girls with CPP and higher (midpubertal) peak E2 responses to GnRHa (mean +/- SE, 590 +/- 63 pmol/L; range, 235-1189; group C; n = 19) and to a group of subjects with no breast development and a prepubertal hypothalamic-pituitary-gonadal axis (peak E2 response to GnRHa, 39 +/- 7 pM/L; range, 18-62; group A; n = 6). Compared to group A subjects, patients in group B had similar (P > 0.2) peak GnRHa-stimulated LH concentrations (B, 4.8 +/- 1 IU/L; A, 2.3 +/- 0.5 IU/L) and peak nocturnal LH (B, 0.81 +/- 0.2; A, 0.25 +/- 0 IU/L), but higher peak GnRHa-stimulated FSH concentrations (B, 26 +/- 7; A, 11 +/- 2 IU/L; P < 0.05) and mean nocturnal FSH (B, 4.2 +/- 1; A, 1.1 +/- 0.3 IU/L; P < 0.05) concentrations. Compared to group B, group C patients had higher (P < 0.001) GnRHa-stimulated peak LH (67 +/- 19 IU/L) and higher (P < 0.05) peak nocturnal LH (9.7 +/- 2.9 IU/L) concentrations, but similar GnRHa-stimulated peak FSH (27 +/- 3 IU/L) and mean nocturnal FSH (3.8 +/- 0.5 IU/L) levels. Group C patients with a ratio of peak GnRHa-stimulated LH to FSH concentrations below or above 1, respectively, had similar peak E2 responses to GnRHa (516 +/- 80 vs. 644 +/- 92 pM/L; P > 0.1). Stepwise regression analysis indicated that the peak LH response to GnRHa (r = 0.76; P < 0.001), but none of the FSH secretory parameters (P > 0.10), affected the E2 response to GnRHa. These data suggest that girls with CPP in the early phase of activation of the hypothalamic-pituitary-gonadal axis are capable of clinically relevant E2 production, which may occur in the face of low LH secretion and low LH/FSH ratios and cannot be explained solely on the basis of increased FSH secretion. Thus, endocrine or paracrine factors other than gonadotropins may be important in amplifying E2 secretion in the early phase of CPP.

Topics: Child; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Osmolar Concentration; Puberty, Precocious; Regression Analysis; Sensitivity and Specificity; Triptorelin Pamoate

To assess the dynamics of the pituitary-ovarian axis in exaggerated thelarche, defined as premature thelarche associated with signs of systemic estrogen effects (advanced bone age and/or growth acceleration) without progression to complete puberty.. Seven girls (age < 2.5 years) with exaggerated thelarche, 6 girls with inactive pituitary-ovarian axis (premature adrenarche) and 21 girls with activated axis (central precocious puberty) had serum FSH, LH and E2 measured serially before and 1 to 24 h after gonadotropin-releasing hormone agonist (GnRHa) administration (leuprolide, 20 micrograms/kg sc), used as a test of combined pituitary-ovarian stimulation.. Although girls in the exaggerated thelarche and adrenarche group had similar [mean (SEM)] baseline FSH [3.2 (0.9) vs 1.4 (0.3) IU/l], LH [0.36 (0.1) vs 0.27 (0.02) IU/l] and E2 [20 (1.2) vs 21 (2) pmol/l] concentrations, and similar peak post-GnRHa LH concentrations [5.5 (1.1) vs 2.4 (0.5) IU/l], girls with exaggerated thelarche achieved higher peak FSH [41 (9) vs 14 (3) IU/l, p < 0.01] and E2 [243 (40) vs 37 (6) pmol/l, p < 0.001] concentrations after GnRHa. In comparison to patients with exaggerated thelarche, girls with precocious puberty had higher (p < 0.01-0.001) baseline LH [3.6 (0.8) IU/l], baseline E2 [69(11) pmol/l], GnRHa-stimulated peak LH [68 (17) IU/l] and peak E2 [648 (58) pmol/l] concentrations, but similar FSH parameters.. Girls with exaggerated thelarche exhibit substantial E2 secretory potential that can be demonstrated by GnRHa stimulation, is predominantly FSH-driven, and probably accounts for the manifestations of estrogen effect seen in these girls.

Topics: Analysis of Variance; Bone Development; Breast; Child; Child, Preschool; Circadian Rhythm; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropins, Pituitary; Humans; Infant; Leuprolide; Luteinizing Hormone; Pituitary Gland; Puberty, Precocious

The postpubertal outcome of a group of girls diagnosed of premature pubarche during childhood was assessed 1) to determine the incidence of functional ovarian hyperandrogenism (FOH) through the ovarian-steroidogenic response to the GnRH agonist leuprolide acetate, 2) to validate leuprolide acetate stimulation in FOH diagnosis, and 3) to ascertain whether FOH-predictive biochemical markers exist at the diagnosis of premature pubarche. Of 35 patients (age, 15.4 +/- 1.5 yr), 16 showed hirsutism, oligomenorrhea, and elevated baseline testosterone and/or androstenedione (delta 4-A) levels. Subcutaneous administration of leuprolide acetate (500 micrograms) produced similar increases in gonadotropin levels in oligomenorrheic patients, regularly menstruating patients (n = 19), and controls (n = 12; age, 15.3 +/- 1.3 yr) when tested at 6 h. Of all of the steroids measured, 17-hydroxyprogesterone (17-OHP) and delta 4-A levels 24 h postleuprolide acetate stimulation were significantly higher in oligomenorrheic patients than in the other two groups (P < 0.0001). No overlapping in 17-OHP responses occurred between oligomenorrheic patients and the other groups. Baseline dehydroepiandrosterone sulfate and delta 4-A levels at the diagnosis of premature pubarche correlated with 17-OHP values postleuprolide acetate challenge (r = 0.47; P < 0.005 and r = 0.67; P < 0.0001, respectively). These results show a distinct leuprolide acetate challenge response in 45% of the postpubertal premature pubarche girls studied, suggestive of an increased incidence of FOH, and support the need for continued routine postmenarcheal evaluation of this group of patients. Responses of 17-OHP to leuprolide acetate challenge facilitate the identification of FOH patients, establish this test as a reliable diagnostic tool in FOH diagnosis, and confirm the ovaries as the source of hyperandrogenemia in most patients with androgen excess. Although increased 17-OHP responses after leuprolide acetate stimulation seem to occur more frequently in girls with elevated dehydroepiandrosterone sulfate and/or delta 4-A levels at the diagnosis of premature pubarche, specific biochemical markers predictive of FOH in this group of patients are still lacking.

Topics: Androgens; Female; Follicle Stimulating Hormone; Humans; Incidence; Leuprolide; Luteinizing Hormone; Ovarian Diseases; Ovary; Puberty; Puberty, Precocious; Retrospective Studies; Steroids

To assess the efficacy and safety of a long-acting gonadotropin-releasing hormone analogue (GnRHa), leuprolide acetate for depot suspension (Lupron Depot), in the treatment of central precocious puberty in children, and to determine the reversibility of GnRHa therapy after it has been discontinued.. Children with documented central precocious puberty were treated with Lupron Depot for 1.6 to 3.5 years. Their course of pubertal development, growth rate, skeletal maturation, and response to gonadorelin hydrochloride testing were compared before and during treatment. For those girls who finished treatment, an assessment of the reversibility of the GnRHa was performed by documenting a return to pubertal responses to gonadorelin testing, and by documenting menarche at an appropriately mature bone age.. Community teaching hospital.. Ten girls with central precocious puberty defined as pubertal maturation statistically advanced for age combined with a pubertal gonadotropin response to gonadorelin testing. Children who had been treated for less than 1.5 years were excluded, as were those with congenital adrenal hyperplasia. Patients who finished treatment have been followed up for up to 5 years, and will continue in follow-up throughout their reproductive life. SELECTION SAMPLE: A consecutive group of children with documented central precocious puberty was studied.. Lupron Depot was administered as a single monthly subcutaneous injection to each patient. Treatment was usually discontinued by 10 to 11 years of age, at which time pubertal progression was allowed to resume.. Mean peak serum concentrations of follicle-stimulating and luteinizing hormone responses to gonadorelin testing decreased significantly after the initial dose (from 21.8 +/- 4.5 [+/- SEM] to 2.4 +/- 0.2 IU/L for follicle-stimulating hormone and from 50.1 +/- 11.2 to 5.0 +/- 0.8 IU/L for luteinizing hormone) and remained suppressed for the duration of treatment. The progression of puberty slowed or reversed in all patients. Mean growth rate for chronologic age was significantly increased initially by 3.9 SDs and decreased to 0.9 SDs during treatment. The mean rates of skeletal maturation divided by the change in chronologic and height age changes over time were advanced (1.4 +/- 0.1 and 1.1 +/- 0.15, respectively) at the onset of therapy and decreased significantly to 0.7 +/- 0.1 and 0.8 +/- 0.1, respectively, on treatment. There was an increase in mean predicted height of 3.4 cm for all patients, and this was statistically significant. Thus, treatment with Lupron Depot at least maintained the predicted height at the onset of therapy. Girls who completed their course of treatment had pubertal gonadotropin responses to gonadorelin testing within 2 to 6 months, and menarche within the first year if skeletal maturation reached 13.0 to 13.5 years. No significant side effects of therapy were noted.. Treatment of central precocious puberty in children using Lupron Depot is safe and efficacious. Its effects are readily reversible after treatment is discontinued, and menarche occurs at a normal bone age. Measurement of serum luteinizing hormone concentrations using an assay that is specific for the beta-subunit is necessary to monitor chemical suppression of luteinizing hormone during treatment. Longer-term studies, including reproductive history, will be needed before the potential effects of treatment on fertility can be assessed.

Topics: Age Determination by Skeleton; Child; Child, Preschool; Delayed-Action Preparations; Female; Follicle Stimulating Hormone; Follow-Up Studies; Humans; Injections, Subcutaneous; Leuprolide; Luteinizing Hormone; Puberty, Precocious; Suspensions; Time Factors; Treatment Outcome

We report results from 2 years of therapy with the long-acting form of the gonadotropin-releasing hormone (GnRH) analog leuprolide acetate, which was previously reported in short-term trials to be efficacious in the treatment of central precocious puberty. Thirteen girls and two boys, aged 1.9 to 9.7 years, who satisfied clinical criteria including GnRH-stimulated luteinizing hormone (LH) greater than 10 IU/L (mean radioimmunoassay LH, 29.1 +/- 5.54 IU/L), received depot leuprolide, 6 to 15 mg intramuscularly every 4 weeks. Estradiol (or testosterone), insulin-like growth factor I, and GnRH-stimulated gonadotropins were obtained at baseline, at 2 months, and at 6-month intervals with bone age determinations. Pubertal progression ceased in all patients, and menses did not occur. Mean increase in height during therapy was 5.77 +/- 2.0 cm/yr. Predicted adult height increased over baseline by 5.52 +/- 1.16 cm at 18 months. Mean estradiol values in the girls declined from 3.3 +/- 0.6 to 0.60 +/- 0.03 ng/dl, with no overlap of baseline and treatment values. The mean basal LH value was unchanged by therapy; mean basal and peak LH values for all follow-up GnRH stimulation tests were 4.05 +/- 0.57 and 4.95 +/- 0.70 IU/L, respectively. Basal and peak follicle-stimulating hormone (FSH) values were suppressed from 4.10 +/- 0.62 and 10.06 +/- 1.34 IU/L, respectively, to generally undetectable levels (< 1). Comparison with untreated control patients suggested that basal LH did not completely return to prepubertal levels, whereas FSH levels were suppressed below prepubertal levels. Estradiol, FSH, and LH levels reached their nadir by 2 months; in contrast, mean serum levels of insulin-like growth factor I progressively declined from +0.57 +/- 0.19 SD score to -0.06 +/- 0.22 SD score at 24 months. Two girls were withdrawn from the study because of reactions at injection sites, with apparent sterile abscess formation in one patient. This study provides evidence that (1) long-term treatment with depot leuprolide is characterized by immediate and sustained laboratory and clinical suppression, (2) GnRH-stimulated LH and random FSH and estradiol concentrations are useful laboratory measures of efficacy, and (3) the progressive increase in predicted adult height is temporally associated with decreased serum levels of insulin-like growth factor I and striking deceleration of bone age advancement.

Topics: Child; Child, Preschool; Delayed-Action Preparations; Drug Evaluation; Female; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Growth; Humans; Injections, Intramuscular; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Treatment Outcome

We evaluated height prognosis and therapeutic efficacy of long-term, combination therapy with gonadotropin releasing-hormone agonist and growth hormone (GH) in five children (three girls) with coexistent precocious puberty and GH deficiency. Their clinical characteristics and growth response were compared with those of 12 girls with idiopathic true precocious puberty and eight prepubertal GH-deficient children (one girl). Precocious GH-deficient subjects were older than the precocious GH-sufficient children (9.5 +/- 1.8 years vs 6.5 +/- 1.3 years; mean +/- SD), but bone ages were comparable (12 +/- 3.7 years vs 10 +/- 0.9 years); their chronologic age was similar to that of the prepubertal GH-deficient children (9.6 +/- 2.1 years), but bone age was significantly more advanced (6.9 +/- 2.3 years). The mean height velocity of the prepubertal GH-deficient children (3.8 +/- 1.5 cm/yr) was lower than that of the precocious GH-deficient subjects (6.7 +/- 1.6 cm/yr) and the precocious GH-sufficient children (9.5 +/- 2.9 cm/yr). Baseline adult height prediction z scores were significantly lower in the precocious GH-deficient children (-3.7 +/- 1.0) than in either the precocious GH-sufficient children (-2.2 +/- 1.0) or the prepubertal GH-deficient subjects (-1.5 +/- 0.8). During therapy with gonadotropin releasing-hormone agonist, growth rates slowed to an average of 3.7 cm/yr in the precocious GH-deficient children but increased after the addition of GH to 7.4 cm during the first year of combination therapy. After 2 to 3 years of combination therapy, height predictions increased an average of 10 cm, compared with an increase of 2.8 cm in the precocious GH-sufficient group treated with gonadotropin releasing-hormone agonist alone. We conclude that combination treatment with gonadotropin releasing-hormone agonist and GH improves the height prognosis of children with coexistent true precocious puberty and GH deficiency, but falls short of achieving normal adult height potential.

Topics: Age Determination by Skeleton; Body Height; Child; Drug Therapy, Combination; Female; Gonadotropin-Releasing Hormone; Growth Disorders; Growth Hormone; Humans; Leuprolide; Male; Nafarelin; Prognosis; Puberty, Precocious; Time Factors

The development of GnRH analogs (GnRHa) has made it possible to treat children with central precocious puberty (CPP). This treatment may prevent adult short stature due to premature epiphyseal fusion. Achievement of this goal, however, is dependent upon adequate suppression of gonadal steroid production as a result of GnRHa-induced pituitary desensitization and decreased gonadotropin release. A depot formulation of a GnRHa [leuprolide acetate (dLA)] is being used by many clinicians for the treatment of CPP, but studies to establish the optimal dose of dLA have not been performed. In this study we evaluated the effectiveness of dLA (7.5 mg, im, every 4 weeks). Six children (7-10 yr old) with CPP treated with dLA were assessed clinically and divided into two groups: A (incompletely suppressed) and B (well suppressed). Each group had overnight blood sampling and a GnRH stimulation test the following morning. LH pulses were analyzed and compared to 11 normal prepubertal children. Mean LH concentration, LH curve area, LH pulse frequency, and mean LH pulse amplitude were significantly greater (P less than 0.03) in group A than in group B or the normal prepubertal children. There was no significant difference among the three groups in GnRH-stimulated peak LH release. These results indicate that dLA (7.5 mg, im, every 4 weeks) does not produce complete desensitization in all children with CPP and suggest that overnight monitoring of LH release is more sensitive than GnRH stimulation testing for the assessment of dLA dose adequacy.

Topics: Child; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Time Factors

Twenty-one children with early puberty have been evaluated to determine adequate dosage of depot leuprolide acetate. The minimal dosage of depot leuprolide acetate required, using intervals of 1.5 mg or less when given every 28 days, was determined. This dosage, as determined by suppression of gonadotropin responses to GnRH stimulation, was 4.14 +/- 1.33 mg (mean +/- SD) and 0.15 +/- 0.07 mg/kg.28 days. The dosage correlates with bone age and pubertal stage and is larger among patients with more advanced puberty. Five patients required a larger dosage from 5-10 months after initial suppression. Therefore, to monitor suppression, GnRH testing should be repeated at least at 6-month intervals. Samples 20 and 40 min after GnRH stimulation are sufficient to indicate adequacy of treatment, so an abbreviated test could be used.

Topics: Child; Child, Preschool; Delayed-Action Preparations; Dose-Response Relationship, Drug; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Kinetics; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious

We describe four male patients with hypothalamic hamartomas associated with sexual precocity. Our assessment of their management suggests that resection using current microsurgical techniques is a valid treatment option if the patient has a normal pubertal endocrine makeup, if the hamartoma is pedunculated, and if the patient is young enough to require years of parenteral medical treatment. Such surgical treatment can be curative, and subsequent growth and development can be normal (patients 1 and 2). However, if the patient is near to pubertal age (patient 3) or if neurosurgical or gonadotropin releasing hormone analogue treatment is not available, the natural history (patient 4) suggests that the only undesirable effects are accelerated growth, tall stature for age, and premature sexual development during childhood, as well as the psychosocial problems that may accompany them. Adult height may be compromised, although the two patients who did not undergo a surgical procedure and did not receive gonadotropin releasing hormone analogue therapy are above the lower limits of the normal range of adult male height. Therefore, if the hamartoma is pedunculated and cessation of pubertal development is desired, resection of the hamartoma is a reasonable therapeutic option.

Topics: Antineoplastic Agents; Child; Child, Preschool; Danazol; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hamartoma; Humans; Hypothalamic Neoplasms; Infant; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious; Testosterone

Leuprolide acetate (D-Leu6 des-Gly-NH2(10), Pro-ethylamide9), a synthetic non-apeptide analog of naturally occurring gonadotropin releasing hormone, was used to treat 62 children with central precocious puberty. Sex steroid levels (testosterone in boys and estradiol in girls) were suppressed during treatment lasting from 3.5 to 24.9 months. Basal follicle-stimulating hormone values and both luteinizing hormone and follicle-stimulating hormone peak responses to stimulation by luteinizing hormone releasing hormone were also suppressed, although basal luteinizing hormone values did not differ. Linear growth rate and the rate of bone age advancement decreased during leuprolide therapy. Side effects were minimal. The long-term safety of this treatment has not yet been established; however, leuprolide appears to be an effective long-term therapy for central precocious puberty.

Topics: Child; Child, Preschool; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Growth; Humans; Infant; Leuprolide; Luteinizing Hormone; Male; Puberty, Precocious

Leuprolide acetate (D-Leu 6 des-Gly-NH2(10), Pro-ethylamide9) for depot suspension has been shown to be effective in suppressing gonadotropins in 6 patients. Serum LH and FSH response to exogenous LHRH was obliterated after 4 weeks and weekly urinary gonadotropin levels during depot therapy were suppressed. This form of this drug should be effective in the treatment of precocious puberty.

Topics: Child; Child, Preschool; Delayed-Action Preparations; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious

The GnRH analog leuprolide acetate has been shown to be effective in the treatment of precocious puberty when given as a daily sc injection. We studied the effectiveness of a single im dose of a new depot form of leuprolide in suppressing estradiol and gonadotropin secretion in children with precocity. Five girls with previously untreated precocity showed significant decreases in basal serum estradiol and FSH levels and in peak LH levels (after GnRH testing) 30 days after a single im dose of leuprolide acetate for depot suspension. Mean peak FSH levels also fell greatly, but the difference was not significant. No adverse effects were noted during the first 4-6 months of monthly im injections. Depot im leuprolide appears to be effective in suppressing estradiol and gonadotropin secretion, and may be a useful method of treating children with central precocious puberty.

Topics: Child; Child, Preschool; Delayed-Action Preparations; Dose-Response Relationship, Drug; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious

Eight girls with central precocious puberty were treated with the long-acting gonadotropin releasing hormone analogue leuprolide acetate (Lupron) for a period of six to 18 months. Suppression of gonadotropin and estradiol secretion and regression of secondary sexual characteristics and menses were observed while patients received a subcutaneous dose of 35 to 40 micrograms/kg/d. Growth velocity was slowed in all but one patient, and the rate of skeletal maturation was slowed even more, resulting in a stabilization or improvement in predicted adult height. There were no major side effects. Although the long-term effects of leuprolide therapy cannot be determined with this study, it appears to be efficacious in the treatment of central precocious puberty.

Topics: Age Determination by Skeleton; Child; Child, Preschool; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Growth; Humans; Leuprolide; Luteinizing Hormone; Puberty, Precocious

The chemical structure of luteinizing-hormone-releasing hormone (LHRH) was discovered in 1971 after more than a decade of intensive effort. Subsequent physiologic studies in primates and humans showed that the biologic activity of LHRH depends on the way in which the hormone is administered. Pulsatile administration of LHRH, which mimics the natural secretory pattern, causes sustained secretion of the gonadotrophins. This method of administration has been used to induce ovulation in women with hypothalamic amenorrhea and to induce puberty and spermatogenesis in men with hypogonadotrophic hypogonadism. Continuous infusion, however, produces only transient stimulation of gonadotrophin secretion, followed by a "desensitization" response in which gonadotrophin secretion is inhibited. Thus, LHRH can either augment or inhibit gonadotrophin secretion depending on the mode of administration. Recently, long-acting synthetic analogs of LHRH have been shown to desensitize the pituitary gland and inhibit gonadotrophin release when administered as a single daily subcutaneous injection. These LHRH analogs have proved highly effective in the treatment of prostatic carcinoma and central precocious puberty. They are also being studied as a new approach to contraception and to the treatment of endometriosis and polycystic ovary syndrome.

Topics: Animals; Child; Contraceptive Agents, Male; Endometriosis; Estrogens; Female; Follicle Stimulating Hormone; Genital Diseases, Female; Genital Diseases, Male; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Hypothalamic Diseases; Infertility; Leuprolide; Luteinizing Hormone; Male; Neoplasms, Hormone-Dependent; Ovulation Induction; Polycystic Ovary Syndrome; Prostatic Neoplasms; Puberty, Precocious; Spermatogenesis; Time Factors; Triptorelin Pamoate