leuprolide and Body-Weight

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

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

The aim of the study was to compare the onset, incidence and frequency/intensity of hot flushes during androgen-deprivation therapy with a gonadotropin-releasing hormone antagonist (GnRH) blocker versus an agonist using data from a randomized Phase 3 clinical trial. In total, 610 prostate cancer patients received monthly degarelix (s.c., 240/80 mg, n=207, or 240/160 mg, n=202) or leuprolide (i.m., 7.5 mg, n=201) for 12 months. Data on hot flushes was collected as self-reported adverse events and in a subgroup of 254 patients with electronic diaries. The onset of hot flushes was faster on degarelix versus leuprolide, and was accompanied by higher median hot flush scores during the first 3 months. However, there were no significant differences in overall incidence rates and median hot flush scores over the entire 12 months. After the third month, incidence rates dropped below 6%, whereas prevalence rates remained constant in all the three treatment arms. In multivariate analysis, body weight and heart rate at baseline were independent predictors of hot flushes (P<0.05). Except for a more rapid onset with the GnRH antagonist, there were no major differences in the overall pattern of hot flushes between treatment options. Weight control may help to minimize the incidence of hot flushes.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Body Weight; Flushing; Follow-Up Studies; Gonadotropin-Releasing Hormone; Heart Rate; Humans; Leuprolide; Male; Middle Aged; Oligopeptides; Prostatic Neoplasms; Risk Factors; Self Report; Treatment Outcome

A prospective, randomized trial compared hormonal changes induced with intranasal leuprolide 1.6 mg/day to danazol 800 mg/day for treatment of endometriosis. Both regimens induced anovulation and ovarian suppression in all subjects. Mean estradiol (E2) and progesterone (P) levels were suppressed with both regimens, but were lower with leuprolide. There was no difference in cumulative follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, although at times during treatment mean levels of these hormones were lower with leuprolide. Higher P levels in the danazol group, most likely of adrenal origin, indicated a suppressive effect on adrenal steroidogenesis. Symptomatic improvement was significant in both groups. Laparoscopy after treatment also demonstrated a decrease in endometriosis scores in both groups. At 12 months after treatment, cumulative pregnancy and live birth rates were similar in both groups. Leuprolide offers an attractive alternative to danazol for the medical treatment of endometriosis.

Topics: Administration, Intranasal; Adult; Body Weight; Danazol; Endometriosis; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormones; Humans; Laparoscopy; Leuprolide; Luteinizing Hormone; Pelvic Neoplasms; Pregnadienes; Pregnancy; Progesterone; Prognosis; Prospective Studies; Random Allocation

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

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

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

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

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

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

A physiological increase in androgen levels occurs during adolescence. Measuring androgen concentrations is the best method to distinguish normal evolution processes from hyperandrogenic disorders.. The increase in circulating androgens during puberty is inversely associated with insulin sensitivity in normal weight girls.. To assess circulating levels of ovarian androgens and anti-Müllerian hormone (AMH) at baseline and after GnRH analogue (GnRH-a) stimulation in normal pubertal girls across different Tanner stages. We also studied the association between this response and insulin sensitivity.. Prospective study of healthy girls (6-12 years) from the local community (n = 63).. Tanner I (n = 23) subjects were assessed cross-sectionally, and Tanner II girls (n = 40) were evaluated every 6 months until they reached Tanner V. Early morning dehydroepiandrosterone sulphate (DHEA-S), AMH, sex hormone-binding globulin (SHBG), androstenedione, glucose and insulin levels were measured. A GnRH-a test (500 μg/m(2) ; sc) and oral glucose intolerance test (OGTT) were performed. Differences throughout puberty were evaluated.. Basal and/or stimulated Testosterone DHEA-S and 17-hydroxyprogesterone (17OHP) were inversely associated with insulin sensitivity (WIBSI) from the beginning of puberty, whereas androstenedione was directly associated with gonadotrophins. AMH was inversely associated with basal and stimulated gonadotrophins and directly with insulin area under the curve (AUC) only in the early stages of puberty. 17OHP and testosterone responsiveness increased significantly during puberty in all subjects, whereas testosterone levels changed less consistently. This pattern of ovarian-steroidogenic response was most evident during mid- and late puberty. Moreover, during late puberty only, basal 17OHP, testosterone and DHEA-S were positively associated with gonadotrophins.. In normal nonobese girls born appropriate for gestational age, androgen synthesis was associated with insulin sensitivity in early puberty and with LH only in late puberty.

Topics: 17-alpha-Hydroxyprogesterone; Androgens; Androstenedione; Anthropometry; Anti-Mullerian Hormone; Area Under Curve; Blood Glucose; Body Mass Index; Body Weight; Child; Cross-Sectional Studies; Dehydroepiandrosterone Sulfate; Female; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Humans; Insulin; Leuprolide; Ovary; Prospective Studies; Puberty; Sex Hormone-Binding Globulin; Testosterone

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

Biomarkers that predict musculoskeletal response to anabolic therapies should expedite drug development. During collagen synthesis in soft lean tissue, N-terminal propeptide of type III procollagen (P3NP) is released into circulation. We investigated P3NP as a biomarker of lean body mass (LBM) and muscle strength gains in response to testosterone and GH.. Community-dwelling older men received GnRH agonist plus 5 or 10 g testosterone gel plus 0, 3, or 5 microg recombinant human GH daily. P3NP levels were measured at baseline and wk 4, 8, 12, and 16. LBM and appendicular skeletal muscle mass (ASM) were measured by dual-energy x-ray absorptiometry.. One hundred twelve men completed treatment; 106 underwent serum P3NP measurements. P3NP levels were higher at wk 4 than baseline (6.61 +/- 2.14 vs. 4.51 +/- 1.05, P < 0.0001) and reached plateau by wk 4 in men receiving testosterone alone. However, wk 8 P3NP levels were higher than wk 4 levels in men receiving testosterone plus recombinant human GH. Increases in P3NP from baseline to wk 4 and 16 were significantly associated with gains in LBM (r = 0.26, P = 0.007; r = 0.53, P < 0.001) and ASM (r = 0.17, P = 0.07; r = 0.40, P < 0.0001). Importantly, for participants receiving only testosterone, P3NP increases at wk 4 and 16 were related to muscle strength gains (r = 0.20, P = 0.056 and r = 0.36, P = 0.04). In stepwise regression, change in P3NP explained 28 and 30% of the change in ASM and LBM, respectively, whereas change in testosterone but not IGF-I and age provided only small improvements in the models.. Early changes in serum P3NP levels are associated with subsequent changes in LBM and ASM during testosterone and GH administration. Serum P3NP may be a useful early predictive biomarker of anabolic response to GH and testosterone.

Topics: Aged; Aged, 80 and over; Biomarkers; Body Weight; Growth Hormone; Hematocrit; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Leuprolide; Male; Muscle Strength; Peptide Fragments; Procollagen; Recombinant Proteins; Regression Analysis; Testosterone; Time Factors

Topics: Adiponectin; Adipose Tissue; Antineoplastic Agents, Hormonal; Body Mass Index; Body Weight; Cholesterol, HDL; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Metabolic Syndrome; Prostatic Neoplasms

Topics: Body Mass Index; Body Weight; Drug Administration Schedule; Humans; Leuprolide; Male; Obesity; Peptides; Prostatic Neoplasms; Time Factors; Treatment Outcome

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

Previous studies have shown that the growth hormone (GH) axis is important for timing the later stages of puberty in female monkeys. However, it is not clear whether these growth-related signals are important for the initiation of puberty and early pubertal events. The present study, using female rhesus monkeys, used two approaches to answer this question. Experiment 1 tested the hypothesis that reduced GH secretion would blunt the rise in nocturnal LH secretion in young (17 mo; n = 7) but not older adolescent ovariectomized females (29 mo; n = 6). Reduced GH secretion was induced by treating females with the sustained release somatostatin analogue formulation, Sandostatin LAR (625 microg/kg). Morning (0900-0930 h) and evening (2200-2230 h) concentrations of bioactive LH were higher in older adolescent compared to young adolescent females. However, diurnal concentrations were not affected by the inhibition of GH secretion in either age group when compared to the placebo-treated, control condition. Experiment 2 tested the hypothesis that reduced GH secretion induced in young juvenile females would delay the initial increase in nocturnal LH secretion and subsequent early signs of puberty. In order to examine this hypothesis, puberty in control females (n = 7) was compared to those in which puberty had been experimentally arrested until a late adolescent age (29 mo) by the use of a depot GnRH analogue, Lupron (750 microg kg(-1) mo(-1); n = 7). Once the analogue treatment was discontinued, the progression of puberty was compared to a group treated in a similar fashion but made GH deficient by continuous treatment with Sandostatin LAR (n = 6). Puberty occurred as expected in control females with the initial rise in evening LH at 21 mo, menarche at 22 mo, and first ovulation at 30 mo. As expected, Lupron arrested reproductive maturation, but elevations in morning and evening LH and menarche occurred within 2 mo of the cessation of Lupron in both Lupron and Lupron-GH-suppressed females. In contrast, first ovulation was delayed significantly in the Lupron-GH-suppressed females (41 mo) compared to the Lupron-only females (36 mo). These data indicate that within this experimental model, reduced GH secretion does not perturb the early stages of puberty but supports previous observations that the GH axis is important for timing the later stages of puberty and attainment of fertility. Taken together, the data indicate that factors that reduce GH secretion may have a d

Topics: Animals; Antineoplastic Agents, Hormonal; Body Weight; Circadian Rhythm; Feedback, Physiological; Female; Growth Hormone; Insulin-Like Growth Factor I; Leuprolide; Luteinizing Hormone; Macaca mulatta; Octreotide; Ovariectomy; Ovulation; Sexual Maturation

Recent studies have demonstrated that GnRH-analogues can stimulate regeneration of spermatogenesis of rats when administered after testicular damages. Although the mechanism of this phenomenon has not been elucidated yet, stem cell factor (SCF) produced by Sertoli cells was proposed to mediate the effects of GnRH-analogues on spermatogonial proliferation and/or survival. In the present study, we quantitatively evaluated the proliferation of spermatogonia and addressed whether SCF mediates the effect of GnRH-analogue on spermatogonial proliferation, using a novel approach combining spermatogonial transplantation and laser confocal microscopic observation. In the first experiment, using wild-type mice as recipients for spermatogonial transplantation, the number of donor spermatogonia per 100 Sertoli cells in each spermatogenic colony was significantly higher in the experimental group of mice treated with leuprorelin, a GnRH-agonist, than that of the control group at 4 and 5 wk after transplantation. In the second experiment, Steel/Steeldickie (Sl/Sld) mutant mice, which lack expression of membrane bound form SCF, were used as recipients. As seen in the first experiment, the number of undifferentiated spermatogonia was significantly higher in leuprorelin-treated than in the control group. Since undifferentiated spermatogonia do not express the receptor of SCF, the present study clearly demonstrates that neither membrane-bound nor secreted forms of SCF are involved in the mechanism of GnRH-analogue's effect on spermatogonial proliferation and/or survival.

Topics: Animals; Body Weight; Germ Cells; Gonadotropin-Releasing Hormone; Green Fluorescent Proteins; Immunohistochemistry; Leuprolide; Luminescent Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Organ Size; Proto-Oncogene Proteins c-kit; Seminiferous Tubules; Signal Transduction; Sperm Count; Spermatogenesis; Spermatogonia; Stem Cell Factor

The prevalence of liver tumors throughout the world makes it imperative to seek chemopreventive agents. This tumor appears to be hormone-responsive and hormonal manipulations may therefore be beneficial. On this basis, both sexes of 12-day-old B6C3F(1) mice were injected i.p. with diethylnitrosamine (DEN) at the dose of 2.5 mg / g body weight and observed for 32 weeks (males) or 36 weeks (females). In 100% of male mice, liver tumors were observed with an average diameter of 2.72 mm and multiplicity of 60.8. Orchidectomy at 6 weeks of age in these mice inhibited the incidence, multiplicity and size to 63%, 5.6 and 1.54 mm, respectively. By further implantation with an E(2) pellet at monthly intervals, these parameters were reduced to 26%, 0.6 and 0.61 mm, respectively. Administration of a gonadotropin-blocking chemical, leuprorelin, to DEN-treated male mice significantly reduced the multiplicity and size of tumors to 18.3 and 2.54 mm (P < 0.01 compared to those of DEN only). In female mice, the incidence of liver tumor was significantly smaller than that of males. However, ovariectomy and / or testosterone supplement significantly increased the occurrence of liver tumor. An anti-estrogen, toremifene, caused a marked further decrease of liver tumors. Mitotic indices with bromodeoxyuridine in tumor tissues paralleled the occurrence of liver tumors. Serum testosterone levels were significantly reduced by orchidectomy or by leuprorelin administration. These results further confirm that liver tumor is testosterone-responsive and hormonal manipulation by surgical orchidectomy or by chemical orchidectomy i.e. by leuprorelin, could substantially prevent the appearance of liver tumors.

Topics: Animals; Antineoplastic Agents, Hormonal; Body Weight; Crosses, Genetic; Diethylnitrosamine; Estradiol; Female; Leuprolide; Liver Neoplasms; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mitotic Index; Organ Size; Ovariectomy; Sex Characteristics; Testosterone

The goals of this study were to determine the CDB-4022 dose-response relationship for induction of acute decreases in testicular weight and germ cell depopulation in rats; establish the threshold dose of CDB-4022 required to induce infertility; and investigate whether CDB-4022-induced testicular damage could be prevented by a GnRH agonist (Lupron Depot). Reduction of testis weight and germ cell depopulation were observed 7 days after a single oral dose of 1 mg CDB-4022/kg, whereas 0.5 mg/kg had no observable effect. These effects were maximal at 12.5 or 25 mg CDB-4022/kg. After a single oral dose of either 2.5 or 5 mg/kg, CDB-4022 induced infertility in five of five treated rats by Week 5, whereas only one of five males was rendered infertile at a dose of 1 mg/kg. Proven fertile male rats (6/group) were treated with vehicle, CDB-4022 alone (2.5 mg/kg on Day 0), CDB-4022 plus Lupron Depot (on Weeks -1, 2, 5, and 8), or Lupron Depot alone. Control males demonstrated normal fertility throughout a 32-wk cohabitation period. Five of six rats were rendered transiently infertile with Lupron Depot alone, but all recovered fertility. CDB-4022 treatment resulted in infertility in all six rats, and only one of six regained fertility. Combined treatment also caused infertility in all six rats, but four of six recovered fertility (P = 0.08 compared to CDB-4022 alone). Testicular weight was decreased in the three treatment groups compared to vehicle controls; testicular weights were ranked from highest to lowest as follows: vehicle > Lupron Depot > Lupron Depot + CDB-4022 > CDB-4022. The tubule differentiation index of Lupron Depot-treated rats (96 +/- 4%) was not different from vehicle-treated rats (100%). CDB-4022 treatment decreased the number of differentiating tubules (15 +/- 8%). Lupron Depot plus CDB-4022 treatment resulted in a greater number of differentiating tubules (53 +/- 12%) than CDB-4022 alone, but this was still lower than vehicle- or Lupron Depot-treated rats. These data indicate that 2.5 mg/kg of CDB-4022 was the oral threshold dose that caused testicular damage rendering the majority of adult male rats permanently infertile within the study interval; 12.5 mg/kg of CDB-4022 induced maximal testicular damage. Suppression of gonadotropins and/or testosterone production by treatment with Lupron Depot before and after CDB-4022 prevented the CDB-4022-induced irreversible testicular damage.

Topics: Animals; Antispermatogenic Agents; Body Weight; Contraceptive Agents; Delayed-Action Preparations; Dose-Response Relationship, Drug; Fertility Agents, Female; Indenes; Leuprolide; Male; Organ Size; Piperidines; Rats; Testis

Sex difference has been shown to play a major role in susceptibility to the development of hepatocellular carcinoma in humans and rodents. In order to clarify the necessity of androgens in hepatic tumorigenesis in transgenic mice overexpressing transforming growth factor (TGF) alpha (MT42), androgen supplement after castration and the LH-RH analogue, leuprolerin acetate, were tested in an experimental model in MT42.. Male MT42 mice were castrated and supplemented with dihydrotestosterone (DHT) every three months up to 15 months and hepatic tumorigenesis was observed. Leuprolerin acetate was administered to both male and female MT42 mice once a month from 2 months after birth to 15 months to observe the effect on hepatic tumorigenesis. Northern hybridization was performed to detect messenger RNA (mRNA) of TGFalpha expression and the rate of proliferative cell nuclear antigen (PCNA) staining compared with the castrated and non-treated mice.. Castration tended to decrease both body and liver weight in MT42 mice which was then restored by DHT. Untreated MT42 males developed 11 liver tumors in 6 mice. Hormonal treatment including castration and DHT supplementation did not change the expression of TGFalpha-mRNA. Castrated transgenic mice developed 2 liver tumors in 2 out of 6 mice and DHT supplementation after castration restored the number of liver tumors to 9 in 5 of 6 mice. PCNA labelling indexes of liver tumors and adjacent non-tumorous-liver were 7.1% (p<0.05): 0.6% in untreated MT42, 3.2%: 0.2% in castrated MT42 and 10.1% (p<0.05): 0.5% in MT42 with castration and DHT supplementation (significant difference compared with castrated mice). Leuprolerin acetate-treated MT42 males developed one liver tumor in 6 mice compared to MT42 administered with saline as a vehicle control in which group 7 liver tumors in 6 male MT42 were observed. Tumors in castrated-MT42 and leuprolerin treated-MT42 were smaller than those in control MT42 mice.. TGFalpha related hepatocarcinogenesis and hepatocyte proliferation are increased by androgenic stimulation. Suppression of androgens may be useful for the treatment of TGFalpha related liver tumors.

Topics: Animals; Blotting, Northern; Body Weight; Carcinoma, Hepatocellular; Cell Division; Dihydrotestosterone; Disease Models, Animal; Female; Gene Expression; Hormone Replacement Therapy; Leuprolide; Liver; Liver Neoplasms; Male; Mice; Mice, Transgenic; Orchiectomy; Organ Size; Proliferating Cell Nuclear Antigen; RNA, Messenger; Sex Characteristics; Testosterone; Transforming Growth Factor alpha

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

Insulin receptors (IRs) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-specific disruption of the IR gene (NIRKO mice). Inactivation of the IR had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction.

Topics: Adipose Tissue; Animals; Blood Glucose; Body Weight; Brain; Eating; Female; Hypertriglyceridemia; Insulin; Insulin Resistance; Leptin; Leuprolide; Luteinizing Hormone; Male; Mice; Mice, Knockout; Neurons; Obesity; Ovarian Follicle; Receptor, Insulin; Reproduction; Sex Characteristics; Signal Transduction; Spermatogenesis

We investigated the effects of conjugated estrogens as an add-back replacement drug, incadronate sodium as a bisphosphonate, and alfacalcidol as a vitamin D(3) analog on femoral bone mineral density (BMD) and bone mineral content (BMC) in female rats chronically treated with the gonadotropin-releasing hormone (GnRH) agonist leuprorelin acetate. The chemical castration of the rats by the administration of GnRH agonist for 16 weeks reduced the BMD values to 92.3%, 91.3%, and 93.3% of those of the normal control animals in the whole femur, metaphysis, and diaphysis of the femur, respectively. The BMC value was decreased to 91.0% of that of the normal control animals by the chronic GnRH agonist treatment. However, a simultaneous 8-week administration of conjugated estrogens, bisphosphonate, and vitamin D(3) analog markedly augmented the BMC values to 110.3%, 110.1%, and 114.4%, respectively, of those in the rats treated with the GnRH agonist alone. These findings indicate that antiosteoporotic agents could be useful for preventing induced osteopenia under the careful monitoring of biochemical markers of osteoblastic activity or bone resorption and BMD or BMC in patients undergoing GnRH treatment.

Topics: Animals; Body Weight; Bone Density; Bone Diseases, Metabolic; Diphosphonates; Estradiol; Estrogens, Conjugated (USP); Female; Femur; Fertility Agents, Female; Follicle Stimulating Hormone; Hydroxycholecalciferols; Leuprolide; Luteinizing Hormone; Organ Size; Ovariectomy; Radiography; Rats; Rats, Sprague-Dawley

This study was performed to investigate the protective effect of a luteinizing hormone-releasing hormone (LHRH) agonist, leuprorelin, against spermatogenetic damage caused by doxorubicin in rats.. Sprague-Dawley rats were divided into 4 groups: (1) a control group, (2) a group given LHRH agonist (subcutaneous injections, total dose 9 mg/kg), (3) a group given doxorubicin (intraperitoneal injections, total dose 7.5 mg/kg), and (4) a group given both LHRH agonist (subcutaneous injections, total dose 9 mg/ kg) and doxorubicin (intraperitoneal injections, total dose 7.5 mg/kg). Evaluations were made by measuring body and testicular weights, determining Johnsen's score, and conducting DNA image analysis consisting of DNA content measurement (%1C, %2C, and %4C) by image cytometry.. In the group given doxorubicin, the testicular weight was 1.47 +/- 0.24 mg, Johnsen's score was 4.4 +/- 1.2, and image analysis revealed %1C: 33.8 +/- 9.2, %2C: 43.9 +/- 16.3, and %4C: 5.0 +/- 4.4. In the group given both LHRH agonist and doxorubicin, the testicular weight was 1.32 + 0.23, Johnsen's score was 5.90 + 1.6, and image analysis revealed %1C: 46.9 +/- 15.0, %2C: 28.4 +/- 13.3, and %4C: 8.8 +/- 3.5.. The significant prophylactic effect (P < 0.05) of the LHRH agonist against doxorubicin-induced spermatogenetic damage was demonstrated by Johnsen's score and image analysis (%1C, %2C, and %4C).

Topics: Animals; Antineoplastic Agents, Hormonal; Body Weight; Doxorubicin; Leuprolide; Male; Organ Size; Rats; Rats, Sprague-Dawley; Spermatogenesis; Testis

To evaluate the effectiveness of laparoscopic myomectomy in an ethnic group with a statistically increased frequency of uterine leiomyomata.. Retrospective chart review.. Private practice of one surgeon, and Department of Obstetrics and Gynecology, Rush Medical College, Chicago, Illinois.. Forty-one consecutive African-American women who underwent laparoscopic myomectomy and were followed for 12 to 26 months.. The women received a modified protocol for gonadotropin-releasing hormone agonist treatment before laparoscopic surgery. Laparoscopic myomectomies were performed under general anesthesia using energy sources of monopolar and bipolar electrosurgery and ultrasonic coagulation-cutting (harmonic scalpel).. Seventy percent (70%, 29 women) of procedures were completed on an outpatient basis. Twelve patients were hospitalized for an average of 1.3 days. No significant operative or postoperative complications occurred, and none of the women required blood transfusions or readmission. The conversion rate was zero. Forty patients (91%) reported complete resolution or significant reduction of their symptoms.. Outpatient laparoscopic myomectomy is safe and effective in African-American women with symptomatic uterine leiomyomata of 20 weeks' size or less.

Topics: Adult; Ambulatory Surgical Procedures; Black People; Body Weight; Electrocoagulation; Female; Gonadotropin-Releasing Hormone; Humans; Laparoscopy; Leiomyoma; Leuprolide; Middle Aged; Retrospective Studies; Treatment Outcome; Uterine Neoplasms

Several investigators have demonstrated that LHRH agonists (LHRHa) inhibit ovarian follicular depletion induced by chemotherapeutic agents in rodents. It is not clear whether or not the same effects occur in primates. Six adult female rhesus monkeys underwent unilateral ovariectomy and were divided into two groups that received monthly injections of either Lupron depot (LHRHa) or placebo vehicle. Both groups received cyclophosphamide (CTX) injections. Weekly blood samples were assayed for FSH, estradiol and progesterone. Mean serum FSH levels significantly increased in the CTX group and significantly decreased in the LHRHa+CTX group. At the end of treatment, the remaining ovary was removed and serially sectioned, and ovarian follicle number and size were analyzed. CTX resulted in a significant reduction of nonprimordial follicles < 50 microns in diameter. The rate of loss of primordial follicles was expressed as a percentage of the original follicle count. During the treatment period, 64.6 +/- 2.8% of the total primordial follicles were lost in the CTX group compared to only 28.9 +/- 9.1% in the LHRHa+CTX group (p < 0.05). The percentage rate of decline per day was 0.120 +/- 0.012 for the CTX group compared to 0.057 +/- 0.019 (p < 0.05) for the LHRHa+CTX group. The findings indicate that LHRHa can protect the ovary against CTX-induced damage in rhesus monkeys.

Topics: Animals; Body Weight; Cyclophosphamide; Delayed-Action Preparations; Estradiol; Female; Follicle Stimulating Hormone; Leuprolide; Macaca mulatta; Organ Size; Ovarian Follicle; Ovariectomy; Ovary; Progesterone; Uterus

Our earlier studies have demonstrated a general suppression of leukocyte maturation upon GnRH agonist treatment in mice and suggested a potential effect at an early stem cell stage of leukocyte development.. Three-week old Balb/c and C57BL/6 female mice received 50 micrograms injections of Lupron depot or placebo. Sequential changes in Sca-1+ cells in the bone marrow, thymus, blood and spleen were studied by flow cytometry.. In bone marrow, the absolute numbers of Sca-1+ cells were significantly decreased at 2 weeks in C57BL/6 mice whereas a decreasing trend was noted in Balb/c mice following agonist administration. Concomitantly, thymocytes expressing Sca-1+ cells were significantly increased at 2 weeks in C57BL/6 mice, but were significantly decreased in Balb/c mice. Significant decreases in Sca-1+ cells were also observed in spleen and blood in Balb/c mice whereas no significant differences were observed in C57BL/6 mice.. These data suggest GnRH agonists affect hematopoietic stem cell development in mice. The effects observed vary with different genetic backgrounds. In Balb/c mice these effects are more pronounced, and appear to result in the inhibition of stem cell maturation. In contrast, GnRH agonist enhances stem cell maturation in C57BL/6 mice.

Topics: Animals; Antigens, Ly; Body Weight; Bone Marrow; Cell Count; Estradiol; Female; Gonadotropin-Releasing Hormone; Hematopoietic Stem Cells; Leukocytes; Leuprolide; Lymphocytes; Lymphoid Tissue; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organ Size; Spleen; T-Lymphocytes; Thymus Gland; Uterus

Reproductive tract regression and cessation of egg production was induced in 80-wk-old Hy-Line W36 strain hens by an i.m. injection of Lupron Depot at a dose calculated to release 60 micrograms of leuprolide acetate (LA)/kg of BW for 30 d, by restriction of feed intake (FR) for 28 d, or by total feed deprivation (FD) for 7 d followed by feed restriction for 21 d. Egg production in LA and FD groups dropped to 24 and 19% in the first 7 d after initiation of the treatments and to 3.5 and 0% in the 2nd wk. Production of the FR group dropped to 38% during the 1st wk and to 1.7% in the 2nd wk. Production of both nutritionally deprived groups remained near zero through the 5th wk, whereas it increased to 8.2% in the LA group at that time. Hens injected with LA reached 50% production at about 37 vs 45 d for both nutritionally deprived groups. Egg production of control groups remained unchanged during this time. Shell characteristics did not differ significantly among the molted groups throughout most of the 16 wk of the experiment. However shell weight and shell weight per unit surface area of eggs from LA-treated hens were significantly (P < or = .05) lower than those of FR, but not FD, hens at several times. Mean values for shell characteristics of eggs from unmolted hens were significantly lower than those of molted hens. There were no differences in albumen quality between any of the groups at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Animals; Body Weight; Chickens; Delayed-Action Preparations; Eggs; Feathers; Female; Food Deprivation; Injections, Intramuscular; Leuprolide; Molecular Sequence Data; Oviposition

Gonadotropin-releasing hormone (GnRH) agonists are playing an increasing role in the medical management of a variety of diseases. Recent evidence also indicates GnRH immune system interactions.. The present study investigated the sequential changes in lymphocyte subpopulations in secondary lymphoid tissues of prepubertal female mice in vivo following Lupron depot administration. A direct two-color immunofluorescence staining followed by flow cytometric analysis was employed.. Following agonist administration, white blood cell counts decreased significantly with decreases in both granulocyte and lymphocyte counts. Blood T-cell and B-cell subsets were also reduced although B cells decreased more markedly. In the spleen, B cells were again reduced more than T cells. There was no selective loss of either CD4 or CD8 subpopulations at any time point, in both spleen and blood. There were no differences in the percentage of lymph node subsets except that B cells decreased in the second week.. These data indicate that GnRH agonist alters specific lymphocyte subpopulations and, therefore, have the potential for affecting immune system function in vivo.

Topics: Animals; Body Weight; CD4-CD8 Ratio; Estradiol; Female; Immunosuppressive Agents; Leuprolide; Lymphocyte Subsets; Lymphoid Tissue; Mice; Mice, Inbred BALB C; Organ Size; Sexual Maturation; Time Factors

Leuprolide, a GnRH agonist, was administered daily to male and female rats for 90 days. Animals were sexually immature (25 days old) at the outset. Dosages were 20 and 200 micrograms/kg/day. Five males and five females were euthanized on Day 91. Sex organs were weighed and evaluated for histopathologic changes. These procedures were repeated 140 days later. Following a recovery period lasting 45 days (onset of normal-appearing estrous cycles) in females and 140 days (two spermatogenic cycles) in males, the fertility of these rats was assessed by mating with untreated animals. Treated males gained less weight while treated females gained more weight than controls. Weights of primary and secondary sex organs were reduced below control, but returned to normal following 140 days of recovery. Treated males were fertile and produced normal litters. Reproductive performance of low-dosage (20 micrograms/kg/day) females was normal 45 days after treatment cessation, but half of the high-dosage (200 micrograms/kg/day) females failed to become pregnant. However, reproductive performance of this group compared well with control performance after an additional 6 weeks of recovery. Atrophic changes were noted in male and female sex organs. Following 140 days of recovery, ovaries, uterus, vagina, prostate, and seminal vesicle were normal. Although testes and epididymides showed partial recovery at this time, multifocal or segmental atrophy and mineralization were noted in portions of some seminiferous tubules.

Topics: Animals; Body Weight; Epididymis; Female; Fertility; Gonadotropin-Releasing Hormone; Leuprolide; Male; Organ Size; Ovary; Prostate; Rats; Rats, Inbred Strains; Reproduction; Seminal Vesicles; Sexual Maturation; Testis; Uterus; Vagina

To evaluate the effects of a gonadotropin-releasing hormone agonist on non-reproductive systems, we administered [D-Leu6,Des-gly10]-GnRH ethylamide (leuprolide; 5 micrograms/day) for 21 days to female Sprague-Dawley rats. In Experiment 1, continuous infusion (Alzet minipumps sc) was compared to injection. Increased thymus and body weights and decreased estradiol and uterine weights were noted for both administration methods. Spleen weight increased only in rats treated by continuous infusion. Ovary, kidney and liver weights did not change. Only leuprolide-injected rats had elevated LH with decreased corticosterone and ACTH levels, possibly related to the injection process. Glucose, insulin, progesterone, FSH and corticosterone/ACTH were not different. In Experiment 2, intact and ovariectomized rats were implanted with minipumps delivering leuprolide or 0.9% NaCl. Body and thymus weights increased, whereas uterine weight and estradiol declined in both leuprolide-treated and ovariectomized rats. No synergism between leuprolide and ovariectomy was noted. Thymosin alpha 1, but not thymosin beta 4, increased in leuprolide-treated ovariectomized rats. Peripheral white blood cell count was elevated in leuprolide-treated intact rats and ovariectomized rats. In bone marrow, non-nucleated cell count declined in leuprolide-treated intact rats, contributing to the decreased total cell count in this group. Nucleated cell count was unaffected. Therefore, thymus weight gain was accompanied only in some cases by functional changes. Our results demonstrate that leuprolide affects non-reproductive systems, in a similar manner to ovariectomy. We suggest that such alterations may be due to the hypoestrogenic environment produced by leuprolide.

Topics: Adrenocorticotropic Hormone; Analysis of Variance; Animals; Body Weight; Corticosterone; Estradiol; Female; Gonadotropin-Releasing Hormone; Injections, Subcutaneous; Kidney; Leuprolide; Liver; Organ Size; Ovariectomy; Radioimmunoassay; Rats; Rats, Inbred Strains; Spleen; Thymosin; Thymus Gland; Uterus

The pharmacokinetic behaviour of leuprolide acetate from a controlled release parenteral dosage form has been studied in rats and dogs. The release of the drug in rats after a single subcutaneous injection exhibited pseudo-zero-order kinetics for one month in doses ranging from 0.0135 to 1.35 mg/rat; the release rate at a dose of 1.35 mg/rat was 2.8% of dose/day; after intramuscular injection the response was similar. In rats, the serum leuprolide acetate levels increased sharply immediately after injection by either route as a consequence of the initial release of the drug; subsequently, the levels attained a plateau for two weeks. The serum level profiles in dogs showed essentially the same pattern as those in rats. When the dosage form was injected into rats, the serum testosterone level (a pharmacological index) sharply peaked, abruptly decreased to below the normal level, and then was sustained at a suppressed level for over six weeks at a dose of 1.35 mg/rat (equivalent to 3 mg kg-1) and higher, while the serum testosterone level after an injection of 0.0135 and 0.135 mg/rat was not sufficiently suppressed. The profiles in dogs showed essentially the same pattern as those in rats. With multiple administrations (once every 4 weeks), serum testosterone levels in dogs did not show any sharp rise after the second and third injections. Changes in rat reproductive organ weights agreed well with the serum testosterone profile in the suppression. The results demonstrate that this dosage form releases the drug at a constant rate for one month and has a long-acting potency.

Topics: Animals; Antineoplastic Agents; Body Weight; Capsules; Chemistry, Pharmaceutical; Delayed-Action Preparations; Dogs; Drug Compounding; Genitalia, Male; Gonadotropin-Releasing Hormone; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Male; Organ Size; Rats; Rats, Inbred Strains; Species Specificity; Testosterone; Time Factors

In two girls (14 and 16 years) and one boy (19 years) with PLW-syndrome and pronounced obesity (240, 210 and 77% overweight) endocrine function tests were carried out. Growth hormone secretion was decreased but normalized after reduction of weight. Thyroxin levels as well as basal and TRH stimulated TSH concentrations were normal. HCG application in the boy induced no rise of the normal basal testosterone levels. Oral glucose tolerance test demonstrated an increased stimulation of insulin in two cases, no other symptoms of diabetes mellitus were found. In the LHRH test an insufficient rise of gonadotropins was found. However, after two weeks of pernasal application of an LHRH analogue (D-Leu6-des-Gly10-EA) the gonadotropin stimulation was distinctly improved and onset of puberty was induced in the male patient. These results are indicative of a hypothalamic disturbance in patients with PLW-syndrome.

Topics: Adolescent; Adult; Body Weight; Female; Follicle Stimulating Hormone; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Humans; Insulin; Leuprolide; Luteinizing Hormone; Male; Prader-Willi Syndrome; Puberty, Delayed; Thyrotropin; Thyrotropin-Releasing Hormone