nafarelin and Polycystic-Ovary-Syndrome

Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents.. When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe, an equal male/female ratio, and a balanced spectrum of professional seniority and expertise.. Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence was insufficient, conclusions were based on expert opinion.. Participants were put into working groups with assigned topics and specific questions. Written materials were prepared and distributed before the conference, revised on the basis of input during the meeting, and presented to the full assembly for final review. If consensus could not be reached, conclusions were based on majority vote. All participants approved the final statement.. The efficacy of gonadotropin-releasing hormone analogs in increasing adult height is undisputed only in early-onset (girls <6 years old) central precocious puberty. Other key areas, such as the psychosocial effects of central precocious puberty and their alteration by gonadotropin-releasing hormone analogs, need additional study. Few controlled prospective studies have been performed with gonadotropin-releasing hormone analogs in children, and many conclusions rely in part on collective expert opinion. The conference did not endorse commonly voiced concerns regarding the use of gonadotropin-releasing hormone analogs, such as promotion of weight gain or long-term diminution of bone mineral density. Use of gonadotropin-releasing hormone analogs for conditions other than central precocious puberty requires additional investigation and cannot be suggested routinely.

Topics: Adolescent; Body Height; Bone Density; Child; Female; Gonadotropin-Releasing Hormone; Humans; Hypothyroidism; Luteinizing Hormone; Nafarelin; Organ Size; Ovary; Polycystic Ovary Syndrome; Puberty, Precocious; Uterus

We have found that women with typical polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to a 100-micrograms test dose of the gonadotropin-releasing hormone agonist nafarelin without evidence of hindered estrogen secretion. To understand the basis of this response, we computed the apparent efficiency of the steps in steroid biosynthesis from the pattern of plasma steroids in response to nafarelin. The proximate cause appears to be excessive 17 alpha-hydroxylase activity and high, yet partially down-regulated, 17,20-lyase activity in the delta 4-pathway. These results suggest that this pattern of steroid secretion results from abnormal regulation (dysregulation) of these activities, possibly involving the enzyme cytochrome P450c17. To determine the usefulness of nafarelin testing for the diagnosis of ovarian hyperandrogenism, we then prospectively studied 40 hyperandrogenic women. The plasma 17-PROG response to nafarelin was supranormal in 58% of the women. The responses of 17-PROG to nafarelin and free testosterone to dexamethasone correlated well and were concordant in approximately 85% of cases. Baseline serum luteinizing hormone concentration was elevated in only 48% of cases. To understand ovarian structure-function relationships, we studied another 20 consecutive hyperandrogenic women. Among seven women with polycystic ovaries, five had an elevated LH level, and four of these five (80%) had an elevated 17-PROG response to nafarelin. Conversely, about half of patients with the PCOS-like disorder of ovarian function did not have polycystic ovaries. Ovarian stromal area, but not LH levels, correlated significantly (r = 0.45) with the 17-PROG response to nafarelin. Thus, both stromal hyperplasia and dysregulation of steroidogenesis seem to be manifestations of abnormal intraovarian regulation of cell growth and function. We conclude that a PCOS-like disorder of ovarian function in response to nafarelin testing is found in approximately half of hyperandrogenic women. The pathogenetic implication of our results is that abnormal intraovarian modulation of LH action seems to be a major factor in ovarian hyperandrogenism. The diagnostic implication of our data is that ovarian androgen excess will often be missed by use of common diagnostic criteria for PCOS.

Topics: Androgens; Animals; Dexamethasone; Female; Humans; Luteinizing Hormone; Nafarelin; Polycystic Ovary Syndrome

Effects of exogenous LH on ovarian androgen secretion during ovulation induction have not been clearly characterized in polycystic ovarian syndrome (PCOS). The purpose of this study was to compare androgen secretion in PCOS women during ovarian stimulation with either recombinant FSH (rFSH) alone or combined with recombinant LH (rLH).. Clomiphene-resistant women with PCOS were allocated, in a factorial study design, to receive either daily injections of rFSH (n = 24) or rFSH + rLH (n = 24) in a 1:1 ratio starting: (i) on day 2-3 of progestogen-induced menses (n = 8); (ii) after 6 weeks of GnRH agonist treatment (nafarelin, 400 micro g twice daily; n = 8); or (iii) after nafarelin treatment as in (ii) plus dexamethasone (n = 8). The effects of rFSH with rFSH + rLH under these three hormone conditions on serum LH, 17alpha-hydroxyprogesterone (17-OHP), androstenedione (DeltaDelta(4)) and testosterone were contrasted by analysis of variance with specific treatment days as a repeated measures factor.. Pre-study hormone levels were similar for all groupings. Nafarelin significantly suppressed LH levels, which remained at the lower limit of assay sensitivity (0.5 IU/l) during stimulation with rFSH but increased significantly to >1 but <2 IU/l when rLH was added. As expected, 17-OHP, DeltaDelta(4) and testosterone levels fell following nafarelin treatment. Dexamethasone further suppressed 17-OHP, DeltaDelta(4) and testosterone levels and unmasked a small but significant rise in these ovarian steroids 24 h following the first dose of rFSH + rLH, a rise that was absent with rFSH alone. Secretion of these steroids then appeared to 'catch-up' after 5 days of rFSH stimulation.. Despite profound LH, 17-OHP, DeltaDelta(4) and testosterone suppression, comparable E(2) response, follicle development and successful pregnancies in PCOS subjects receiving rFSH alone to those receiving rFSH + rLH would argue that circulating LH at levels as low as 0.5 IU/l are sufficient to sustain adequate follicle development and function when FSH is present in abundance. Whether the observed dichotomy between rFSH and rFSH + rLH treatment in temporal secretion patterns reflects a greater reliance on evolving paracrine mechanisms as the follicles mature under profound LH suppression remains to be explored but may influence the optimal LH threshold for ovulation induction in PCOS.

Topics: 17-alpha-Hydroxyprogesterone; Adult; Androgens; Dexamethasone; Female; Follicle Stimulating Hormone; Glucocorticoids; Humans; Infertility, Female; Kinetics; Luteinizing Hormone; Nafarelin; Ovary; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Prospective Studies; Recombinant Proteins; Testosterone

To test the hypothesis that the increased ovarian sensitivity to gonadotropins observed in women with polycystic ovary syndrome (PCOS) may be due to changes in ovarian stromal blood flow in these patients.. Uterine and ovarian stromal arterial blood flow (with transvaginal color Doppler ultrasound) were measured in ten women with PCOS and 12 normo-ovulatory women (control group), undergoing gonadotropin stimulation before in vitro fertilization.. A careful ovarian stimulation strategy was adopted for the study group in order to avoid ovarian hyperstimulation syndrome and achieve an ovarian response which was comparable to that of the control group. Resistance and pulsatility indices (RI and PI) of the uterine and ovarian stromal arteries were calculated before the onset of gonadotropin treatment, on cycle day 5 (after commencing treatment), day of human chorionic gonadotropin injection, day of ovum pick-up as well as on the day of embryo transfer, and 7 and 12 days later.. No significant differences were found in RI and PI between the study and control groups throughout the treatment cycle.. It seems that polycystic ovaries do not bear an inherent disturbance in blood flow dynamics of the uterine and ovarian arteries, as measured by color Doppler, which would explain the increased sensitivity of polycystic ovaries to stimulation with gonadotropins.

Topics: Adult; Analysis of Variance; Blood Flow Velocity; Female; Fertility Agents, Female; Hemodynamics; Hormones; Humans; Menotropins; Nafarelin; Ovary; Polycystic Ovary Syndrome; Reference Values; Regional Blood Flow; Ultrasonography, Doppler, Color; Uterus

The aim of this study was to see whether the pathophysiology of polycystic ovary syndrome could be altered by suppressing the abnormal cycle of events associated with abnormal gonadotrophins and androgens. Fifteen women with polycystic ovary syndrome were treated with the GnRH agonist Nafarelin at a dosage of 200 micrograms twice daily intranasally for a period of 3 or 6 months. Eight of these women also had a dexamethasone suppression test 0.5 mg four times daily for 48 h before and after treatment with Nafarelin, in order to differentiate between an adrenal and ovarian source for the excess androgens. Gonadotrophins and androgens were well suppressed, LH to a mean of 1.5 IU/l, testosterone to 1.1 nmol/l and androstenedione to 6.4 nmol/l. Three months after discontinuing Nafarelin, all these hormones had returned to pretreatment levels. The ultrasound appearance of the ovaries showed no consistent reduction in ovarian volume or the disappearance of ovarian follicles. Hirsutism showed slight improvement in four out of seven patients. After treatment one patient out of the eight complaining of infertility, conceived spontaneously and one patient ovulated on a reduced dosage of clomiphene. There was no change in the menstrual pattern of the others. Despite the achievement of good hormonal suppression, there was no change in the condition after therapy was discontinued suggesting that whatever the cause of the condition it remains a permanent situation.

Topics: Dexamethasone; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Menstrual Cycle; Nafarelin; Polycystic Ovary Syndrome; Testosterone

Polycystic ovary syndrome (PCOS) is characterized by various endocrine and metabolic abnormalities, whose mutual associations and symptoms are still not clear. In the present study, fifteen PCOS patients and fifteen controls, matched for age and body weight, were investigated. Endocrine profiles were evaluated by the nafarelin and the adrenocorticotropin (ACTH) test. Insulin sensitivity was determined by an intravenous insulin tolerance test. Patients showed a significant predominance of abdominal adiposity [waist-to-hip ratio (WHR), 0.86 +/- 0.05 vs. 0.79 +/- 0.04] with markedly higher fasting insulin levels (+75%) and reduced insulin sensitivity (-37%). Fasting insulin, testosterone and free androgen index were positively correlated with the body mass index (BMI). In contrast, insulin sensitivity and BMI were inversely correlated in patients only. In the nafarelin test increases of 17-OH-progesterone and androstenedione were higher in patients and positively correlated with fasting insulin levels. Lipoprotein profiles showed trends towards higher triglycerides, lower HDL-cholesterol and a preponderance of small, dense LDL in patients. In PCOS higher triglycerides and lower HDL cholesterol were correlated with insulin sensitivity. It is concluded that PCOS patients show metabolic abnormalities combined with a more adroid type of adiposity when compared to cyclic controls of similar BMI.

Topics: 17-alpha-Hydroxyprogesterone; Adipose Tissue; Adrenal Glands; Adult; Androstenedione; Body Composition; Body Constitution; Body Mass Index; Body Weight; Cholesterol, HDL; Fasting; Female; Humans; Insulin; Insulin Resistance; Lipoproteins; Lipoproteins, LDL; Nafarelin; Ovary; Polycystic Ovary Syndrome; Testosterone; Triglycerides

To evaluate the clinical relevance of testing pituitary-ovarian responses in patients suffering from polycystic ovary syndrome (PCOS) with the GnRH agonist nafarelin, a 1.2-mg dose of nafarelin was given intranasally to 19 women with PCOS and 15 healthy premenopausal women. The subsequent analysis of steroids in both serum and urine during the test was carried out at several time points for up to 24 h. Serum levels of 17 alpha-hydroxyprogesterone were elevated at all time points of the test in PCOS patients vs. controls [at baseline, 3.5 +/- 0.2 vs. 1.8 +/- 0.1 nmol/L (P < 0.001); at 24 h, 9.9 +/- 0.9 vs. 4.9 +/- 0.3 nmol/L (P < 0.001)]. Basal levels of androstenedione were higher in the patient group, but there was no significant change during the test in either group. Serum testosterone levels were also found to differ in PCOS patients compared with the control values at baseline (2.2 +/- 0.2 vs. 1.5 +/- 0.1 nmol/L; P < 0.05) and after nafarelin treatment (at 24 h, 3.2 +/- 0.4 vs. 1.8 +/- 0.2 nmol/L; P < 0.05). Serum estradiol levels rose significantly in both groups during the test; the posttest levels were significantly higher in PCOS than in controls. The PCOS patients displayed a significant increase in androgen and gestagen metabolites as well as in glucocorticoid metabolites excreted in the urine during the 24 h. In the control subjects, except for 17 alpha-hydroxypregnanolone, which rose significantly, none of the urinary steroids investigated showed relevant changes during the nafarelin test. The posttest excretion of allo-tetrahydrocortisol (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) and the increase in 17 alpha-hydroxypregnanolone excretion (1.4 +/- 0.2 vs. 0.3 +/- 0.1 mumol/g creatinine; P < 0.001) were distinctly higher in PCOS patients than in the controls; the diagnostic sensitivity of the combination of both parameters was 89% at a 93% specificity. Thus, measurements of 17 alpha-hydroxyprogesterone levels in serum and of urinary allo-tetrahydrocortisol and 17 alpha-hydroxypregnanolone after nafarelin treatment make this stimulation test a valuable diagnostic tool for identifying PCOS patients. The significant changes in the excretion of urinary androgen and gestagen metabolites, unmasked by GnRH agonist stimulation, suggest a functional alteration of the pituitary-ovarian axis. The reason for the increased excretion of glucocorticoid metabolites after nafarelin stimulation remains to be clarified.

Topics: Administration, Intranasal; Adult; Circadian Rhythm; Female; Glucocorticoids; Gonadotropins; Hormones; Humans; Nafarelin; Polycystic Ovary Syndrome; Steroids

Distinguishing between ovarian and adrenal causes of androgen excess may be difficult. We have found that women with the polycystic ovary syndrome have supranormal plasma 17-hydroxyprogesterone responses to the gonadotropin-releasing hormone agonist nafarelin. We determined the usefulness of testing with nafarelin to distinguish ovarian causes of hyperandrogenism in women.. We studied 40 consecutive women with hyperandrogenism who had oligomenorrhea, hirsutism, or acne. All 40 underwent testing with nafarelin, dexamethasone, and corticotropin with measurement of circulating concentrations of gonadotropins and steroid hormones, and 19 underwent ovarian ultrasonography.. The plasma 17-hydroxyprogesterone response to nafarelin was supranormal in 23 of the 40 women (58 percent), and the plasma androgen response to corticotropin was elevated in 23; 13 women had both abnormalities. Only one woman had conclusive evidence of a steroidogenic block; she had nonclassic adrenal 21-hydroxylase deficiency. Of the 23 women with abnormal responses to nafarelin, only 11 (48 percent) had elevated base-line serum luteinizing hormone concentrations. Of the 13 women with abnormal responses to nafarelin who underwent ultrasonography, 7 (54 percent) had polycystic ovaries. Peak plasma 17-hydroxyprogesterone concentrations after nafarelin administration correlated closely with plasma free testosterone concentrations after dexamethasone administration (r = 0.75, P less than 0.001).. Approximately half of women with oligomenorrhea, hirsutism, or acne have an abnormal response to the gonadotropin-releasing hormone agonist nafarelin, suggesting an ovarian cause of their androgen excess.

Topics: 17-alpha-Hydroxyprogesterone; Acne Vulgaris; Adolescent; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Androgens; Dexamethasone; Female; Gonadotropin-Releasing Hormone; Hirsutism; Humans; Hydroxyprogesterones; Luteinizing Hormone; Nafarelin; Oligomenorrhea; Ovary; Polycystic Ovary Syndrome; Testosterone; Ultrasonography

We investigated the mechanisms of desensitization induced by gonadotropin-releasing hormone agonist in the pituitary.. Effects of gonadotropin-releasing hormone agonist on the pituitary were studied in vitro and in vivo in the rat. In the clinical study serum luteinizing hormone was measured by radioimmunoassay with a polyclonal luteinizing hormone antibody (luteinizing hormone-radioimmunoassay) and by immunoradiometric assay with monoclonal luteinizing hormone antibodies (luteinizing hormone-immunoradiometric assay) during gonadotropin-releasing hormone agonist treatment.. In the in vitro study bead-attached pituitary cells that were desensitized with a continuous infusion of 10(-7)mol/L gonadotropin-releasing hormone responded to 50 mmol/L K+. In the in vivo study gonadotropin-releasing hormone binding sites and rat luteinizing hormone beta-messenger ribonucleic acid in the pituitary decreased during gonadotropin-releasing hormone agonist treatment, but serum levels of rat luteinizing hormone did not decrease. In addition, a disparity between luteinizing hormone-radioimmunoassay and luteinizing hormone-immunoradiometric assay was demonstrated during gonadotropin-releasing hormone agonist treatment.. Pituitary desensitization in response to gonadotropin-releasing hormone agonist may not be wholly receptor mediated and a nonreceptor process may be involved.

Topics: Animals; Buserelin; Cells, Cultured; Endometriosis; Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Leuprolide; Luteinizing Hormone; Male; Nafarelin; Pituitary Gland; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, LHRH; RNA, Messenger

Topics: Adrenal Hyperplasia, Congenital; Androgens; Female; Gonadotropin-Releasing Hormone; Hirsutism; Humans; Nafarelin; Ovarian Diseases; Ovary; Polycystic Ovary Syndrome; Reference Values; Testosterone

To investigate the basis of polycystic ovary syndrome, we examined the responses of patients to nafarelin, a specific gonadotropin-releasing-hormone agonist, given to stimulate pituitary and gonadal secretion. We compared 16 normal women in the follicular phase, 5 normal men, 8 women with polycystic ovary syndrome, and 1 woman with polycystic ovary syndrome caused by a 3 beta-hydroxysteroid dehydrogenase deficiency. After 100 micrograms of nafarelin was given subcutaneously, serum follicle-stimulating hormone and luteinizing hormone increased rapidly to peak levels within four hours. The women with polycystic ovary syndrome had a pattern similar to that of the men, with greater early luteinizing-hormone responses (30 minutes to 1 hour) and lower peak follicle-stimulating-hormone responses than normal women (P less than 0.05). Patients with polycystic ovary syndrome responded to gonadotropin stimulation with normal to increased production of plasma estrogens and increased levels of androstenedione at 16 to 24 hours (P less than 0.05). Elevated production of 17 alpha-hydroxyprogesterone was found in all the women with polycystic ovary syndrome and in the men. These abnormal responses were unchanged by pretreatment with dexamethasone to suppress adrenal function. In the patient with the 3 beta-hydroxysteroid dehydrogenase deficiency, both basal and stimulated plasma levels of delta 5-3 beta-hydroxysteroids before the enzymatic block were elevated, whereas plasma levels of 17 alpha-hydroxyprogesterone and androstenedione--the steroids immediately beyond the block--were low. We conclude that women with polycystic ovary syndrome have masculinized pituitary and ovarian responses to stimulation by nafarelin. Our findings suggest that the regulation of the ovarian 17-hydroxylase and C-17,20-lyase activities is abnormal in such women.

Topics: 3-Hydroxysteroid Dehydrogenases; Adolescent; Adult; Androstenedione; Dexamethasone; Estrogens; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hydroxyprogesterones; Luteinizing Hormone; Male; Nafarelin; Ovary; Pituitary Gland, Anterior; Polycystic Ovary Syndrome; Stimulation, Chemical

Although gonadotropin releasing hormone analog therapy successfully suppresses gonadotropin secretion and excess ovarian androgen production, it does not break the cycle of disordered hormonal patterns that perpetuates the syndrome.

Topics: Female; Gonadotropin-Releasing Hormone; Hirsutism; Humans; Nafarelin; Polycystic Ovary Syndrome

We know that there is a wide range of clinical applications for GnRH analogues in the field of benign gynaecological disorders. As we understand more of the physiology and mechanism of these GnRH agonists, and there appear more varied and perhaps efficient delivery systems, and antagonists become available, it may be possible to develop a graded approach in suppression of the hypothalamic pituitary axis. The true potential of these agents is then yet to be fully realized. There can be no doubt they are going to influence practice dramatically over the next decade. The potency of these agents, perhaps specifically their effects of oestrogen deficiency and calcium bone metabolism, suggests that limitation of duration of use and timing of recurrent administration to individuals is likely to be necessary.

Topics: Buserelin; Danazol; Endometriosis; Estradiol; Female; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leiomyoma; Nafarelin; Osteolysis; Polycystic Ovary Syndrome; Uterine Neoplasms