leuprolide and Polycystic-Ovary-Syndrome

Hirsutism is the excessive growth of terminal hair in a typical male pattern in a female. It is often a sign of excessive androgen levels. Although many conditions can lead to hirsutism, polycystic ovary syndrome and idiopathic hyperandrogenism account for more than 85% of cases. Less common causes include idiopathic hirsutism, nonclassic congenital adrenal hyperplasia, androgen-secreting tumors, medications, hyperprolactinemia, thyroid disorders, and Cushing syndrome. Women with an abnormal hirsutism score based on the Ferriman-Gallwey scoring system should be evaluated for elevated androgen levels. Women with rapid onset of hirsutism over a few months or signs of virilization are at high risk of having an androgen-secreting tumor. Hirsutism may be treated with pharmacologic agents and/or hair removal. Recommended pharmacologic therapies include combined oral contraceptives, finasteride, spironolactone, and topical eflornithine. Because of the length of the hair growth cycle, therapies should be tried for at least six months before switching treatments. Hair removal methods such as shaving, waxing, and plucking may be effective, but their effects are temporary. Photoepilation and electrolysis are somewhat effective for long-term hair removal but are expensive.

Topics: Adrenal Hyperplasia, Congenital; Androgen Antagonists; Antineoplastic Agents, Hormonal; Contraceptives, Oral, Hormonal; Cushing Syndrome; Drug-Related Side Effects and Adverse Reactions; Eflornithine; Female; Glucocorticoids; Gonadotropin-Releasing Hormone; Hair Removal; Hirsutism; Humans; Hyperandrogenism; Hyperprolactinemia; Leuprolide; Mineralocorticoid Receptor Antagonists; Neoplasms; Ornithine Decarboxylase Inhibitors; Polycystic Ovary Syndrome; Spironolactone; Thyroid Diseases

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

To assess the efficacy of IVP-ET in infertile women with the polycystic ovary syndrome (PCOS) and to provide a comprehensive review of contemporary therapeutic options and their complications as reflected in the current literature.. Pertinent studies in medical literature identified through computerized bibliographic search and via manual review of relevant scientific publications.. In vitro fertilization and ET is an effective therapy for PCOS patients who are refractory to ovulation induction in vivo or who have coexisting infertility factors. The use of GnRH agonist (GnRH-a) is associated with significant reductions in the incidence of pregnancy loss and may improve fertilization and cleavage rates. In the PCOS patient, the use of purified FSH preparations does not appear to improve pregnancy rates nor other clinical parameters when compared with hMG. Severe ovarian hyperstimulation syndrome (OHSS) is an important consideration when PCOS patients undergo superovulation protocols. Strategies for OHSS prevention include the use of intravenous albumin immediately after oocyte retrieval, triggering of ovulation with a GnRH-a, or withholding menotropin therapy for several days before hCG administration. Cryopreservation of all embryos for future transfer in an artificial cycle has also proven to be an effective alternative in PCOS patients at high risk for severe OHSS.. Pregnancy rates for PCOS patients undergoing IVF-ET are comparable with those for women with tubal factor infertility. Therefore, IVF-ET should be offered to patients with PCOS who are refractory to conventional infertility modalities.

Topics: Embryo Transfer; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Humans; Leuprolide; Menotropins; Ovarian Hyperstimulation Syndrome; Polycystic Ovary Syndrome; Pregnancy; Triptorelin Pamoate

In the May 1993 issue of the Journal we reviewed the basic science of androgen biology in women. We now discuss the evaluation of suspected hyperandrogenism and the therapeutic modalities available.

Topics: Adrenal Hyperplasia, Congenital; Androgen Antagonists; Androgens; Contraceptives, Oral; Cushing Syndrome; Female; Hirsutism; Humans; Leuprolide; Polycystic Ovary Syndrome; Reference Values; Virilism

The use of exogenous gonadotropins for ovulation induction in anovulatory women or for superovulation in gamete intrafallopian transfer or in vitro fertilization is complicated by premature luteinization, multiple gestation and ovarian hyperstimulation. Desensitization of the pituitary gonadotrophs can be achieved with gonadotropin releasing hormone (GnRH) agonists. The adjunctive use of GnRH agonists with exogenous gonadotropins prevents premature luteinization, possibly resulting in an improvement in ovarian stimulation.

Topics: Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Ovarian Follicle; Ovulation Induction; Pituitary Hormone-Releasing Hormones; Polycystic Ovary Syndrome

In women with PCOS (polycystic ovary syndrome), hyperinsulinaemia stimulates ovarian cytochrome P450c17α activity that, in turn, stimulates ovarian androgen production. Our objective was to compare whether timed caloric intake differentially influences insulin resistance and hyperandrogenism in lean PCOS women. A total of 60 lean PCOS women [BMI (body mass index), 23.7±0.2 kg/m²] were randomized into two isocaloric (~1800 kcal; where 1 kcal≈4.184 J) maintenance diets with different meal timing distribution: a BF (breakfast diet) (980 kcal breakfast, 640 kcal lunch and 190 kcal dinner) or a D (dinner diet) group (190 kcal breakfast, 640 kcal lunch and 980 kcal dinner) for 90 days. In the BF group, a significant decrease was observed in both AUC(glucose) (glucose area under the curve) and AUC(insulin) (insulin area under the curve) by 7 and 54% respectively. In the BF group, free testosterone decreased by 50% and SHBG (sex hormone-binding globulin) increased by 105%. GnRH (gonadotropin-releasing hormone)-stimulated peak serum 17OHP (17α-hydroxyprogesterone) decreased by 39%. No change in these parameters was observed in the D group. In addition, women in the BF group had an increased ovulation rate. In lean PCOS women, a high caloric intake at breakfast with reduced intake at dinner results in improved insulin sensitivity indices and reduced cytochrome P450c17α activity, which ameliorates hyperandrogenism and improves ovulation rate. Meal timing and distribution should be considered as a therapeutic option for women with PCOS.

Topics: Adult; Blood Glucose; Breakfast; Energy Intake; Female; Humans; Hyperandrogenism; Insulin; Insulin Resistance; Leuprolide; Meals; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Steroid 17-alpha-Hydroxylase; Testosterone; Thinness; Time Factors

To determine whether there are any differences in the incidence of ovarian hyperstimulation syndrome (OHSS) and implantation rates in high-risk patients undergoing IVF using a protocol consisting of GnRH agonist trigger after cotreatment with GnRH antagonist or hCG trigger after dual pituitary suppression protocol.. Prospective randomized controlled trial.. University-based tertiary fertility center.. Sixty-six patients under 40 years of age with polycystic ovarian syndrome, polycystic ovarian morphology, or previous high response undergoing IVF.. Patients were randomized to an ovarian stimulation protocol consisting of either GnRH agonist trigger after cotreatment with GnRH antagonist (study group) or hCG trigger after dual pituitary suppression with a GnRH agonist (control group). Both groups received luteal phase and early pregnancy supplementation with IM progesterone (P), and patients in the study group also received E(2) patches and their doses were adjusted according to the serum levels.. Incidence of OHSS and implantation rate.. None of the patients in the study group developed any form of OHSS compared with 31% (10/32) of the patients in the control group. There were no significant differences in the implantation (22/61 [36.0%] vs. 20/64 [31.0%]), clinical pregnancy (17/30 [56.7%] vs. 15/29 [51.7%]), and ongoing pregnancy rates (16/30 [53.3%] vs. 14/29 [48.3%]) between the study and control groups, respectively.. The use of a protocol consisting of GnRH agonist trigger after GnRH antagonist cotreatment combined with adequate luteal phase and early pregnancy E(2) and P supplementation reduces the risk of OHSS in high-risk patients undergoing IVF without affecting implantation rate.

Topics: Adult; Contraceptives, Oral, Hormonal; Embryo Implantation; Estradiol; Female; Fertility Agents, Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Incidence; Infertility, Female; Leuprolide; Luteinizing Hormone; Odds Ratio; Oocytes; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Progesterone; Prospective Studies; Risk Assessment; Sperm Injections, Intracytoplasmic; Treatment Outcome

To compare the outcome of using gonadotropin-releasing hormone (GnRH) antagonists versus agonists in women with polycystic ovary disease (PCOD) who underwent controlled ovarian hyperstimulation (COH) for assisted reproductive techniques (ART).. A total of 129 patients with PCOD were randomly allocated to undergo COH with a GnRH antagonist (59 patients) and GnRH agonist (leuprolide acetate) (70 patients) to prevent a premature luteinizing hormone (LH) surge. Assisted fertilization following oocyte retrieval and embryo transfer was performed.. None of the cycles were cancelled due to a premature LH surge. There was no significant difference between the antagonist and agonist arms in the number of gonadotropin ampules consumed per cycle. However, in the antagonist arm a shorter duration of ovarian stimulation was recorded as compared to the agonist arm. Although similar numbers of oocytes was retrieved from both groups of patients, the quality of the oocytes, as measured by metaphase 2/total oocyte ratio, was lower in the antagonist arm as compared to the agonist arm. Pregnancy rates were 57.6% and 58.5% in the antagonist and agonist arms, respectively (p > 0.05). Implantation rates were not different (34.0% and 34.6%, respectively). The frequency of ovarian hyperstimulation syndrome also did not differ between the treatment groups (5% and 7.1%, respectively).. The size of our study, on a specific subgroup of patients, does not allow a reliable conclusion regarding ART outcomefollowing the use of a GnRH antagonist versus agonist. Nevertheless, the protocol with the antagonist gave results that were as good as those of the protocol with the agonist in this PCOD patient population.

Topics: Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fertilization in Vitro; Follow-Up Studies; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility, Female; Leuprolide; Ovulation Induction; Pilot Projects; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Probability; Prospective Studies; Risk Assessment; Statistics, Nonparametric

Women with polycystic ovary syndrome (PCOS) have chronic anovulation and hyperandrogenism and frequently have abnormalities in their lipid profiles and insulin/insulin-like growth factor axis that increase their lifetime risk for cardiovascular disease. Normal ovulatory women may have polycystic ovaries on ultrasonography and yet lack the clinical features of PCOS. To further explore whether ovulatory women without clinical/biochemical hyperandrogenism but with polycystic appearing ovaries (ov-PAO) have subclinical features of PCOS, we prospectively characterized 26 ov-PAO women and matched them by age and body mass index to 25 ovulatory women with normal appearing ovaries (ov-NAO) and to 22 women with PCOS. After an overnight fast, all women had baseline endocrine and metabolic assessments. In addition, a subset of each group of women underwent GnRH-agonist (leuprolide acetate 1 mg s.c.) testing, ACTH stimulation, and an insulin tolerance test (ITT). At baseline, ov-PAO and ov-NAO women had similar endocrine profiles (LH, LH:FSH, androstenedione, and DHEAS). Compared with ov-NAO, 31% of ov-PAO women had reduced glucose responses after insulin (K(itt)), suggesting mild insulin resistance, and 35% had high density lipoprotein levels below 35 mg/dL, a level considered to represent significant cardiovascular risk. After GnRH-agonist, ov-PAO women had response patterns in LH, total testosterone, and 17-hydroxyprogesterone (17-OHP) that were intermediate between ov-NAO and women with PCOS. Ovarian responses were above the normal range in 30-40% of women with ov-PAO. In ov-PAO, peak responses of LH after leuprolide correlated with triglyceride levels (P < 0.05) and peak responses of 17-OHP correlated inversely with Kitt values (P < 0.05). No significant differences were noted with ACTH testing. In conclusion, occult biochemical ovarian hyperandrogenism may be uncovered using GnRH-agonist in ovulatory women with ov-PAO, while adrenal responses remain normal. Subtle metabolic abnormalities may also be prevalent.

Topics: Adrenocorticotropic Hormone; Adult; Antineoplastic Agents, Hormonal; Body Mass Index; Female; Glucose Clamp Technique; Gonadotropin-Releasing Hormone; Hormones; Humans; Hyperandrogenism; Insulin Resistance; Leuprolide; Lipids; Ovary; Ovulation; Pituitary Gland; Polycystic Ovary Syndrome; Prospective Studies; Stimulation, Chemical

This prospective, randomized study included 18 polycystic ovarian syndrome (PCOS) patients with severe ovarian dysfunction, who were evaluated by standard clomiphene and FSH stimulation. In this group of patients, a 6 month down-regulation with gonadotrophin-releasing hormone (GnRH) analogues gave outcomes similar to laparoscopic ovarian laser diathermy with respect to stimulatory outcome and pregnancy rate. Clomiphene stimulation with 50 mg of clomiphene/day and FSH stimulation in a low-dose, step-up protocol with purified FSH did not result in oligofollicular development; thus patients were divided into two subgroups: one subgroup received laparoscopic laser drilling and the other received 6 months of therapy with GnRH analogues plus add-back therapy after diagnostic laparoscopy. Subsequently, three cycles of low-dose, step-up stimulation with recombinant FSH were started. In both groups, approximately 30% of cycles still remained anovulatory. In the down-regulated subgroup, this mainly happened in the first cycle. In each group, ovulation was achieved in 14 cycles, intrauterine insemination was performed, and five pregnancies were obtained. This resulted in a pregnancy rate of 36% per ovulatory cycle in both groups. Overall, 50% of the formerly unreactive patients in both groups overcame childlessness. In achieving this, long-term treatment with GnRH analogues was as successful as laparoscopic laser diathermy.

Topics: Adult; Androgen Antagonists; Chorionic Gonadotropin; Clomiphene; Cyproterone Acetate; Drug Combinations; Electrocoagulation; Ethinyl Estradiol; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Laparoscopy; Lasers; Leuprolide; Ovary; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Prospective Studies; Recombinant Proteins

To test the hypothesis that in women with polycystic ovary syndrome (PCOS), adrenal cytochrome P450c 17alpha activity is different after physiologic vs. pharmacologic ACTH stimulation and that ovarian activity promotes adrenal hyperactivity that is different after physiologic vs. pharmacologic ACTH stimulation.. Prospective controlled pilot study.. Reproductive endocrinology unit of an academic medical center.. Six women with PCOS who had adrenal hyperandrogenism were compared with four women with normal ovulation.. Adrenal dynamic blood sampling was performed before and after 6 months of GnRH agonist administration.. Comparison of physiologic and pharmacologic ACTH-stimulated levels of progesterone, 17-hydroxyprogesterone, and androgens before and after ovarian steroid modulation.. In women with PCOS, exaggerated responses of androstenedione and 11beta-hydroxyandrostenedione as well as elevated ratios of 17-hydroxyprogesterone to progesterone and of androstenedione to 17-hydroxyprogesterone after physiologic ACTH stimulation did not persist after GnRH-agonist administration. Three of the six women with PCOS had an increased response of androstenedione and a ratio of androstenedione to 17-hydroxyprogesterone that were >2 SD above the mean of those in the women with normal ovulation after pharmacologic ACTH stimulation; this finding persisted after GnRH-agonist administration.. In women with PCOS, increases in adrenal androgen sensitivity after physiologic ACTH stimulation reflected in both arms of cytochrome P450c 17alpha activity may be influenced by ovarian activity. However, 17,20-lyase hyperactivity in a subset after pharmacologic ACTH stimulation may be an intrinsic adrenal disorder.

Topics: Adrenocorticotropic Hormone; Adult; Cosyntropin; Female; Gonadotropin-Releasing Hormone; Hormones; Humans; Hyperandrogenism; Leuprolide; Ovary; Pilot Projects; Polycystic Ovary Syndrome; Steroid 17-alpha-Hydroxylase

To evaluate the possible involvement of ovarian steroids on the opioid-mediated disorders of insulin in patients affected by polycystic ovary syndrome (PCOS), we studied 40 PCOS women. All patients underwent an oral glucose tolerance test (OGTT; 75 g) and basal hormone assay; based on the insulin response to OGTT, 26 women were classified as hyperinsulinemic and continued the study protocol. Patients were randomly divided into three groups characterized by different treatments: group A (nine patients) was treated with GnRH analog (one ampule every 28 days for 2 months), group B (eight patients) was treated with naltrexone (an oral opioid antagonist, 50 mg/day, orally) for 8 weeks, and group C (nine patients) was treated with GnRH analog plus naltrexone for 2 months. After continuation of treatment, all patients repeated the basal study in a second hospitalization. Naltrexone treatment significantly reduced the insulin response to OGTT, whereas GnRH analogue administration did not significantly change the insulin secretion after the glucose load. The GnRH analog/ naltrexone cotreatment was not able to influence the insulin secretory pattern; in fact, the insulin area under the curve was superimposable before and after therapy. These data could lead to the hypothesis that the opioidergic regulation of insulin secretion requires a normal steroidogenic pattern, thus suggesting that ovarian steroids modulate opioid activity also at peripheric districts.

Topics: Adult; Androgens; Estradiol; Female; Follicle Stimulating Hormone; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin; Insulin Secretion; Kinetics; Leuprolide; Luteinizing Hormone; Naltrexone; Narcotic Antagonists; Opioid Peptides; Ovary; Polycystic Ovary Syndrome; Steroids

To compare the effect of a gonadotropin releasing hormone (GnRH) analog plus 'add-back' oral contraceptive (OC) therapy with OC therapy alone on the clinical and hormonal parameters that are characteristic of polycystic ovary syndrome (PCOS).. Prospective, randomized study.. Thirty PCOS patients were randomly assigned to treatment with leuprolide acetate for depot suspension plus a combined monophasic OC (Group I) or to OC alone (Group II).. Hormonal (luteinizing hormone (LH), follicle stimulating hormone (FSH), LH : FSH concentration ratio, estradiol, androstenedione, testosterone), clinical (Ferriman-Gallwey score), ultrasonographic (ovarian volume, number of subcapsular follicles, stromal score) and Doppler (uterine artery and ovarian intraparenchymal vessels' pulsatility index, ovarian stromal vascularization) parameters were evaluated during 6 months' therapy and 6 months' follow-up.. Significant changes in all the parameters analyzed occurred as a result of therapy and the changes were more marked in the group undergoing treatment with GnRH analog plus OC.. GnRH analog plus OC use has a more rapid and marked effect on the hormonal milieu as well as the ovarian architecture and vascularization in patients with PCOS than OC used alone. The former treatment may be a more efficient therapy for PCOS.

Topics: Adolescent; Adult; Analysis of Variance; Contraceptives, Oral; Delayed-Action Preparations; Drug Therapy, Combination; Female; Follicle Stimulating Hormone; Follow-Up Studies; Humans; Leuprolide; Linear Models; Luteinizing Hormone; Polycystic Ovary Syndrome; Prospective Studies; Sensitivity and Specificity; Treatment Outcome; Ultrasonography; Ultrasonography, Doppler, Color

The aim of this study was to evaluate the ovarian cysts appearing during GnRH-a/hMG treatment in patients with polycystic ovarian syndrome (PCOS). A total of 35 women with PCOS were included in the study. All women received 3.75 mg IM of long-acting leuprolide acetate on the first day of the menstrual cycle. On the 15th day of the menstrual cycle, transvaginal ultrasound examination (US) and determination of serum E2 were done. A total of 90 cycles were studied in this way and during these cycles, 14 (15.5%) ovarian cysts with a diameter of >/= 20 mm developed. According to the serum E2 levels, 11 cases (group A) had E2 concentrations > 35 pg/ml and 3 (group B) had serum E2 levels < 35 pg/ml. Group A patients attained a significantly larger mean size of ovarian cyst than group B patients (42 +/- 7.3 vs. 24.2 +/- 3.2 mm, p < 0.001). When the serum E2 concentrations were < 35 pg/ml, the ovarian cysts were disregarded and ovarian stimulation with gonadotropins was initiated. In case that serum E2 levels were > 35 pg/ml, the initiation of the ovarian stimulation with hMG was postponed until serum E2 levels indicated down-regulation, which was achieved after 5.8 +/- 2.9 days. In both groups the ovarian stimulation resulted in ovulatory cycles, while four pregnancies in group A and one in group B were achieved. In conclusion, our results indicate that in patients with PCOS the GnRH-a administration may cause follicular cysts at an incidence of 15.5%. These cysts do not constitute a contraindication for ovarian stimulation provided that serum E2 levels are low.

Topics: Adult; Estradiol; Female; Humans; Infertility, Female; Leuprolide; Menotropins; Ovarian Cysts; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy

To evaluate the hormonal and clinical follow-up after the suspension of a longterm therapy with GnRH-agonist (GnRH-a) plus oral contraceptive (OC) in comparison to OC alone in patients with polycystic ovary syndrome (PCOS).. Hormonal (plasma LH, FSH, sex steroid levels) and clinical (Ferriman-Gallwey score and ultrasound) parameters were monitored at various moments during the 6 months of treatment and during the 6 months after treatment suspension.. Physiopathology of Human Reproduction, University of Modena, Italy.. Thirty patients with PCOS were enrolled and randomly subdivided in two groups of 15 each.. Group A was treated with 3.75 mg IM GnRH-a plus OC. Group B was treated only with OC.. Both therapeutical regimens were effective in reducing androgenic milieu, Ferriman-Gallwey score, and ovarian volume within the 6th month of treatment. However, only patients treated with GnRH-a + OC showed a normal LH:FSH ratio, adequate plasma E2 and P levels, and ovulatory cycles during the 6 months of the after treatment follow-up. Patients treated with OC alone showed no beneficial effect after the 3rd month of the follow-up.. These data support the evidence of a higher efficacy of the combined regimen (GnRH-a + OC) than OC alone in the treatment of patients with PCOS. In addition, the former regimen is associated with recovery of normal ovulatory cycles.

Topics: Androgens; Contraceptives, Oral; Estradiol; Female; Follicle Stimulating Hormone; Follow-Up Studies; Humans; Leuprolide; Luteinizing Hormone; Luteolytic Agents; Menstrual Cycle; Ovary; Ovulation Induction; Polycystic Ovary Syndrome; Progesterone; Triptorelin Pamoate; Ultrasonography

It is unknown whether hyperinsulinemia plays a role in the pathogenesis of polycystic ovary syndrome (PCOS) in normal weight or thin women. Evidence indicates that these women are insulin resistant and hyperinsulinemic, and this study was conducted to test the hypothesis that hyperinsulinemia stimulates ovarian cytochrome P450c17 alpha activity in nonobese women with PCOS, thereby increasing serum androgen concentrations. We assessed ovarian P450c17 alpha activity (by measuring the response of 17 alpha-hydroxyprogesterone to a GnRH agonist), fasting serum steroids, and oral glucose tolerance before and after oral administration of either metformin (500 mg) or placebo three times daily for 4-6 weeks in 31 nonobese women with PCOS. In the 19 women given metformin, the mean (+/- SE) area under the serum insulin curve after oral glucose administration decreased from 44 +/- 5 to 24 +/- 3 nmol/L.min (P = 0.003). Basal serum 17 alpha-hydroxyprogesterone decreased from 3.4 +/- 0.3 to 2.5 +/- 0.4 nmol/L (P = 0.05), and GnRH-stimulated peak serum 17 alpha-hydroxyprogesterone decreased from 12.2 +/- 1.6 to 7.5 +/- 0.7 nmol/L (P = 0.005). Serum 17 alpha-hydroxyprogesterone values did not change in the placebo group. In the metformin group, serum free testosterone decreased by 70% from 18.2 +/- 3.1 to 5.5 +/- 0.7 pmol/L (P < 0.001), and serum sex hormone-binding globulin increased from 84 +/- 6 to 134 +/- 15 nmol/L (P = 0.002). None of these values changed in the placebo group. These findings suggest that hyperinsulinemia stimulates ovarian P450c17 alpha activity in nonobese women with PCOS. They also indicate that decreasing serum insulin with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates the hyperandrogenism of these women.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adult; Androgens; Anthropometry; Blood Glucose; Body Composition; Female; Gonadal Steroid Hormones; Humans; Insulin; Leuprolide; Luteinizing Hormone; Ovary; Polycystic Ovary Syndrome; Steroid 17-alpha-Hydroxylase

Insulin resistance and increased ovarian cytochrome P450c17 alpha activity are both features of the polycystic ovary syndrome. P450c17 alpha, which is involved in androgen biosynthesis, has both 17 alpha-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17 alpha-hydroxyprogesterone in response to stimulation by gonadotrophin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17 alpha activity.. We measured fasting serum steroid concentrations and the response of serum 17 alpha-hydroxyprogesterone to leuprolide, a gonadotrophin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome.. In the 11 women given metformin, the mean (+/- SE) area under the serum insulin curve after oral glucose administration decreased from 9303 +/- 1603 to 4982 +/- 911 microU per milliliter per minute (56 +/- 10 to 30 +/- 6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17 alpha-hydroxyprogesterone concentration from 135 +/- 21 to 66 +/- 7 ng per deciliter (4.1 +/- 0.6 to 2.0 +/- 0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone concentration from 455 +/- 54 to 281 +/- 52 ng per deciliter (13.7 +/- 1.6 to 8.5 +/- 1.6 nmol per liter) (P = 0.01). The serum 17 alpha-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5 +/- 2.2 to 2.8 +/- 0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34 +/- 0.07 to 0.19 +/- 0.05 ng per deciliter (12 +/- 3 to 7 +/- 2 pmol per liter) (P = 0.009), and the serum sex hormone-binding globulin concentration increased from 0.8 +/- 0.2 to 2.3 +/- 0.6 microgram per deciliter (29 +/- 7 to 80 +/- 21 nmol per liter) (P < 0.001). None of these values changed significantly in the placebo group.. In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17 alpha activity and ameliorates hyperandrogenism.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adult; Blood Glucose; Female; Humans; Hydroxyprogesterones; Hyperandrogenism; Hypoglycemic Agents; Insulin; Leuprolide; Luteinizing Hormone; Metformin; Obesity; Polycystic Ovary Syndrome; Steroid 17-alpha-Hydroxylase; Testosterone

To determine if continuous oral contraceptive (OC) therapy was superior to a cyclic regimen in achieving persistent pituitary suppression of LH in patients with polycystic ovary syndrome (PCOS).. Fourteen women (ages 16 to 41 years) with PCOS received one of three treatment groups: continuous OC therapy (30 micrograms ethinyl E2 plus 150 micrograms desogestrel), cyclic OC therapy, or monthly injections of a GnRH agonist (GnRH-a, leuprolide acetate depot 3.75 mg) for 3 months. Basal hormone levels were obtained before initiating therapy, on days 15 to 17 of the 3rd month of treatment (study 1) and again on days 26 to 28 of the 3rd month (study 2). A GnRH stimulation test was also performed during study 1 and study 2.. After 3 months of treatment, LH levels were decreased significantly in all groups with less effective suppression observed in the cyclic OC group compared with the continuous OC or GnRH-a groups. A significant rise in LH was found only in the cyclic OC group after 5 to 7 days of placebo treatment (study 1 versus study 2). An increase in T was also observed in the cyclic OC group during study 2, whereas the continuous OC and GnRH-a groups showed continued inhibition of T levels. Although there was no significant difference in LH area under the curve (AUC) measurements after GnRH stimulation in study 1 versus study 2, the LH AUC was significantly greater in both studies in the cyclic OC group compared with the continuous OC or GnRH-a groups.. Increased LH secretion during the week of placebo in the cyclic OC group was associated with a concomitant increase in T. The striking rise in LH secretion after GnRH stimulation in the cyclic OC group may represent increased pituitary sensitivity in patients receiving cyclic OCs regardless of the phase of the treatment cycle, perhaps secondary to increased pituitary stores of LH in these women.. Clinical researchers recruited 16 women aged 16-41 diagnosed with polycystic ovary syndrome (PCOS) for a study designed to compare their pituitary responsiveness to exogenous gonadotropin releasing hormone (GnRH) stimulation after three months of therapy with either the continuous or cyclic regimen of combined oral contraceptives (OCs). The three treatments included six women on continuous therapy (i.e., every day for 3 months) with an OC containing 30 mcg ethinyl estradiol and 150 mcg desogestrel, six women on cyclic therapy (i.e., 21 days of OC therapy with 7 days of placebo over 3 months) with the same OC formulation, and four women on therapy with a GnRH agonist (GnRH-a), Lupron depot (3.75 mg leuprolide acetate). Luteinizing hormone (LH) levels fell significantly in all groups between baseline and three months treatment (p 0.001). Cyclic OCs exerted a less effective LH suppression than the continuous OC and the GnRH-a, however (88% vs. 99%; p 0.05). Only the cyclic OC group experienced a significant increase in LH after 5-7 days of placebo treatment (126% increase; p 0.008). The percent change in LH levels was significantly different between the cyclic and continuous OC groups (p 0.03) and between the cyclic OC and GnRH-a groups (p 0.01). Similarly, the cyclic OC group had an increase in testosterone levels after 5-7 days of placebo treatment (86% increase), while the other two groups had no change. When both the cyclic and continuous OC groups received their first GnRH stimulation test on days 15-17 of the third 28-day cycle and on days 26-28 (5-7 days of placebo in the OC cyclic group), the LH area under the curve (AUC) measurements were much greater in the cyclic OC group than the continuous OC and the GnRH-a groups (p 0.004). This event suggests increased pituitary sensitivity in patients receiving cyclic OCs regardless of the phase of the treatment cycle; which may be secondary to increased pituitary stores of LH in women with PCOS. These findings support the theory that LH contributes greatly to ovarian testosterone secretion in women with PCOS.

Topics: Adolescent; Adult; Contraceptives, Oral; Drug Administration Schedule; Female; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Menstrual Cycle; Pituitary Gland; Polycystic Ovary Syndrome

To study the beneficial effects of oral contraceptive (OC) therapy following gonadotropin-releasing hormone agonist (GnRH-a) administration in women with polycystic ovary disease (PCOD).. Twenty-three hyperandrogenic women (aged 15-39) were randomized into two groups; GnRH-a (depot every 28 days) for six months or combination therapy (GnRH-a plus OC "addback") for six months. Following six months of treatment with either therapy, all patients received OC therapy for at least six months. The hormonal state was evaluated at three-month intervals.. Hormone levels of luteinizing hormone (LH), testosterone (T) and free T remained suppressed within the normal range in 11 of 17 patients (65%) during the six months of OC only therapy, while the other six patients showed "escape" from suppression, with the LH, T and free T concentrations rising to pre-GnRH-a treatment levels. Use of OC addback therapy did not potentiate the long-acting therapeutic effect of GnRH-a pretreatment; three of six patients in the escape group were pretreated with combination therapy and three with GnRH-a only.. In the majority of women with PCOD, OC therapy following GnRH-a administration was effective in maintaining ovarian androgen suppression. Failure to maintain ovarian suppression in this patient population was associated with higher elevations of baseline free T concentrations.. Clinical investigators randomly allocated 24 hirsute women aged 15-39 years with polycystic ovary disease (PCOD) to either the treatment program offering an injection of leuprolide acetate (a highly potent gonadotropin-releasing hormone agonist [GnRH-a]) for depot suspension (3.75 mg) at 28-day intervals for six months or the treatment program offering both the same injection and a combined oral contraceptive (OC) as add-back for six months. At three months, one woman moved out of state and withdrew from the study. After six months of either GnRH-a treatment regimen, all remaining 23 women received only OCs for six more months. Six women did not successfully complete the OC therapy and were excluded from the statistical analyses. The investigators aimed to examine the benefits of OC use in the management of women with PCOD after six months of pretreatment with the GnRH-a. During the OC-only treatment period, 11 (65%) of 17 patients still had suppressed levels of luteinizing hormone (LH), testosterone (T), and free T within the normal range. These levels increased to pre-GnRH-a treatment levels in the remaining six women, indicating escape from ovarian suppression. Three of six women in the escape group received combination therapy for pretreatment, while the other three received only GnRH-a. The women in the escape group had a higher baseline free T concentration than the suppressed group (5.1 vs. 3.3 ng/dl; p = 0.02). The findings revealed that OC therapy following GnRH-a administration effectively maintained ovarian androgen suppression in most women with PCOD. They also indicated that failure to maintain this suppression had a significant association with higher baseline free T concentrations.

Topics: Adolescent; Adult; Contraceptives, Oral; Drug Therapy, Combination; Female; Humans; Hyperandrogenism; Leuprolide; Luteinizing Hormone; Polycystic Ovary Syndrome; Testosterone; Time Factors

Women with polycystic ovary syndrome (PCOS: hyperandrogenism and oligomenorrhea) have been shown to have exaggerated ovarian 17-hydroxyprogesterone (17-OHP) responses after GnRH agonist stimulation, suggestive of disordered ovarian cytochrome P450c17 alpha activity. However, most hyperandrogenic women also have an exaggerated LH response to both native GnRH and GnRH agonists. To assess whether the known LH hyperresponsiveness in PCOS patients mediates their exaggerated 17-OHP response to GnRH agonist challenge or whether the 17-OHP response can be duplicated by direct stimulation of the ovary with a fixed amount of hCG, 25 PCOS women [age, 20.6 +/- 1.1 yr; body mass index (BMI), 24.9 +/- 1.3 kg/m2] and 5 controls (age, 29.4 +/- 2.3 yr; BMI, 29.2 +/- 3.0) underwent both GnRH agonist (leuprolide acetate) and hCG testing. In addition, 23 normal women (age, 26.5 +/- 1.5 yr; BMI, 27.2 +/- 1.7 kg/m2) underwent hCG testing, and 21 other normal women (age, 19.3 +/- 0.5 yr; BMI, 23.0 +/- 0.8 kg/m2) underwent leuprolide acetate challenge. Blood was sampled before and 24 h after (the previously determined time of the peak response) leuprolide acetate (500 micrograms, sc) and hCG (5000 IU, im) stimulation tests. The tests were administered during the early follicular phase in women who were ovulatory and in randomized order in the subjects receiving both stimuli. Peak serum 17-OHP levels did not differ between leuprolide acetate or hCG stimulation in PCOS patients or controls when measured at 24 h (324.9 +/- 41.9 vs. 360.4 +/- 54.0 in PCOS; 183.2 +/- 19.6 vs. 141.2 +/- 11 ng/dL in controls). Peak 17-OHP levels after hCG challenge and GnRH agonist stimulation were highly correlated (r = 0.82; P < 0.001) in the subjects receiving both stimuli. Although leuprolide acetate elicited a higher estradiol (E2) response than hCG in all subjects, serum E2 levels increased significantly after hCG treatment in both patients and controls (P < 0.001 and P < 0.0001). The small, but significant, increase in serum E2 after hCG stimulation suggests that a rigid two-cell model of ovarian steroidogenesis may be an oversimplification of in vivo physiology. Our results suggest that exaggerated 17-OHP responses to GnRH agonist stimulation in hyperandrogenic women are not mediated by the known hyperresponsiveness of LH in these patients, but are due to increased ovarian androgen sensitivity to LH stimulation.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adult; Case-Control Studies; Chorionic Gonadotropin; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Ovary; Polycystic Ovary Syndrome

To determine the efficacy of treatment of significant hirsutism with a GnRH agonist (GnRH-a) and estrogen and progestin replacement therapy.. Clinical series.. Ambulatory gynecology clinic in a community hospital.. Ten women with significant hirsutism caused by polycystic ovarian disease.. The patients were treated with leuprolide acetate 20 micrograms/kg per day in combination with E2 (2 mg) and medroxyprogesterone acetate (5 mg) for 6 months.. Hirsutism scores and hair growth rates determined before and upon completion of treatment protocol.. Hirsutism scores and hair growth rates significantly decreased by 23% and 26%, respectively. The duration of hirsutism was the only significant covariate for hirsutism scores and hair growth rates. Only two patients had minimal, irregular bleeding that was corrected by increasing the estrogen dose.. The combination of a GnRH-a and estrogen replacement therapy was an effective and well-tolerated treatment in a small group of women with significant hirsutism caused by PCOD.

Topics: Adolescent; Adult; Estrogen Replacement Therapy; Female; Hair; Hirsutism; Humans; Leuprolide; Medroxyprogesterone Acetate; Polycystic Ovary Syndrome; Testosterone

To compare the therapeutic effects of a GnRH-agonist (GnRH-a), leuprolide acetate (LA) depot, versus LA plus and oral contraceptive (OC) containing cyproterone acetate in the treatment of hirsutism.. Randomized study.. Women addressed to the Department of Gynecological Endocrinology, University of Brescia, Brescia, Italy.. Thirty-two patients suffering from moderate and severe hirsutism secondary to polycystic ovary syndrome (PCOS) or idiopathic causes were selected.. Leuprolide acetate was injected IM every 28 days in all patients; 16 women, randomly allocated, received LA plus OC. At the beginning and at the end of treatment hirsutism score and hair diameters were evaluated.. Both treatment arms resulted in a decrease of hirsutism score and hair diameter, both in idiopathic hirsutism (16% to 31% versus 24% to 32%) and in hirsutism secondary to PCOS (23% to 33% versus 24% to 36%).. Gonadotropin-releasing hormone agonist can improve moderate and severe hirsutism effectively. It is necessary to add an OC.

Topics: Adult; Contraceptives, Oral; Cyproterone Acetate; Delayed-Action Preparations; Drug Therapy, Combination; Female; Follicle Stimulating Hormone; Hirsutism; Humans; Injections, Intramuscular; Leuprolide; Luteinizing Hormone; Polycystic Ovary Syndrome; Severity of Illness Index; Sex Hormone-Binding Globulin

Little data exist on the effects of adjunctive therapy with leuprolide acetate (LA) in the luteal phase of women with polycystic ovary syndrome (PCOS) undergoing ovulation induction with human menopausal gonadotropin (hMG). Additionally, it is not known whether gonadal steroid concentrations in the luteal phase of induced cycles in PCOS are predictive of pregnancy. In this prospective, randomized study comparing cycles using hMG alone (n = 26) with cycles using hMG with LA (n = 33), no differences were noted between treatment groups in progesterone (P), estradiol (E2), and P:E2 ratios on luteal days 3, 6, and 9. When all treatment cycles were pooled, there were no differences in P, E2, or P:E2 ratios, comparing conception and nonconception cycles. We conclude that adjunctive therapy with LA in PCOS patients undergoing ovulation induction with hMG does not alter the luteal phase concentrations of P, E2, and P:E2. Furthermore, no correlation was found between the serum concentrations of these luteal phase steroids and cycle fecundity.

Topics: Drug Therapy, Combination; Estradiol; Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Leuprolide; Luteal Phase; Menotropins; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Progesterone; Prospective Studies; Random Allocation

Ten hirsute women with polycystic ovarian syndrome (PCO) and nine with idiopathic hirsutism (IH) underwent selective ovarian suppression with leuprolide for 5-6 months and then were randomized to receive, in addition, dexamethasone or placebo for 4 more months. Serum hormone levels and hair growth rates were determined before and after each treatment period. During the initial treatment period with leuprolide alone, testosterone decreased by 54 +/- 6% (mean +/- SEM) in PCO and by 36 +/- 3% in IH (P = 0.02). Androstenedione decreased by 53 +/- 6% in PCO and by 31 +/- 7% in IH (P = 0.02). Androstanediol glucuronide (Adiol-G) decreased by 14 +/- 6% in PCO and by 7 +/- 3% in IH. There was no change in dehydroepiandrosterone sulfate (DHEAS). While initial serum androgen levels were higher in PCO than in IH, they were similar after ovarian suppression in the two groups. After ovarian suppression, Adiol-G was more consistently correlated with testosterone and androstenedione than was DHEAS, suggesting that Adiol-G may be a better marker than DHEAS of adrenal androgen secretion. Hair growth rates decreased by 37 +/- 6% in PCO and by 14 +/- 10% in IH (P = 0.07). The change in hair growth correlated with the change in androstenedione (r = 0.66; P = 0.002), but not significantly with the change in testosterone (r = 0.29; P = 0.2). After the addition of dexamethasone therapy (0.5 mg daily), testosterone, androstenedione, and DHEAS levels fell to near or below assay detection limits, while Adiol-G decreased by 80 +/- 3%. Hair growth rates decreased slightly more in women during dexamethasone (46 +/- 6%) than during placebo (26 +/- 9%; P = 0.18). In summary, the ovary was the major source of circulating testosterone and androstenedione in PCO. The adrenal contributed a substantial minority of these hormones in PCO and was the major source of androgen secretion in IH. Adrenal hyperandrogenism was common in both IH and PCO. Hair growth rates correlated best with changes in serum androstenedione levels. Adiol-G, which was derived primarily from adrenal precursors, was a better marker of adrenal androgen secretion than was DHEAS in these subjects.

Topics: Adolescent; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Androgens; Androstenedione; Bone Density; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Dexamethasone; Female; Follicle Stimulating Hormone; Follow-Up Studies; Gonadotropin-Releasing Hormone; Hair; Hirsutism; Humans; Leuprolide; Luteinizing Hormone; Ovary; Polycystic Ovary Syndrome; Random Allocation; Testosterone

The use of exogenous gonadotropins for treatment of clomiphene-resistant chronic anovulation in women with the polycystic ovary syndrome (PCO) is hazardous and often ineffective, possibly because of the abnormal endogenous gonadotropin secretion characteristic of PCO. We evaluated the effect of leuprolide acetate, a long-acting GnRH agonist, on serum gonadotropin and sex steroid concentrations before and during human menopausal gonadotropin (hMG) induction of ovulation in women with PCO. In this controlled prospective randomized study, leuprolide was administered daily for 4 weeks, followed by concomitant hMG administration. Gonadotropin and steroid hormone concentrations were compared with those during ovulation induction cycles in women with PCO receiving hMG only. Daily administration of leuprolide for 4 weeks resulted in significantly decreased serum LH, estradiol, and testosterone concentrations, but no change in serum progesterone, FSH, and dehydroepiandrosterone sulfate. Compared to ovulation induction using hMG alone, leuprolide administration before and during hMG treatment prevented preovulatory rises in serum LH and P concentrations, while having no effect on serum FSH, testosterone, estradiol, and dehydroepiandrosterone sulfate. We conclude that leuprolide administered to women with PCO decreases gonadal steroid production and is capable of preventing premature luteinization during hMG induction of ovulation.

Topics: Adult; Anovulation; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Menotropins; Ovulation Induction; Polycystic Ovary Syndrome; Progesterone; Testosterone

Hypothalamic inflammation is a pathophysiological basis of polycystic ovarian syndrome (PCOS), while overactivated and/or excess M1 polarized microglia are considered to be the main reason for the occurrence of hypothalamic inflammation. Therefore,

Topics: Animals; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Microglia; Polycystic Ovary Syndrome; Rats; Receptors, LHRH

Ovarian hyperandrogenism from polycystic ovary syndrome (PCOS) and hyperinsulinemia from insulin resistance are modulators of ovarian follicle development. We report on a woman with PCOS and hyperandrogenism and severe insulin resistance from metabolic syndrome who received long-term GnRH analogue therapy preceding bilateral salpingo-oophorectomy for massive ovarian enlargement. Ovarian histological examination showed proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas, demonstrating a unique link between hyperinsulinemia and granulosa cell mitogenesis.. A 30-year-old woman with PCOS with hyperandrogenism, severe insulin resistance from metabolic syndrome, and nonalcoholic steatohepatitis experienced abdominal pain from bilaterally enlarged ovaries. She had previously experienced a pulmonary embolism while taking oral contraceptives and hepatotoxicity from metformin and spironolactone therapies. Long-term GnRH analogue therapy to induce pituitary desensitization to GnRH successfully decreased gonadotropin-dependent steroidogenesis without improving insulin resistance. Despite GnRH analogue therapy, progressive ovarian enlargement in the presence of hyperinsulinemia from worsening metabolic function eventually required bilateral salpingo-oophorectomy for removal of massively enlarged ovaries. Histological examination showed both ovaries contained proliferating granulosa cells within antral follicles coexistent with serous cystadenofibromas.. In women with PCOS and hyperinsulinemia from severe insulin resistance due to metabolic syndrome, granulosa cell proliferation within antral follicles can occur despite long-term GnRH analogue therapy, implicating hyperinsulinemia as a granulosa cell mitogen in the absence of gonadotropin-dependent ovarian function.

Topics: Abdominal Pain; Adult; Cell Proliferation; Cystadenofibroma; Female; Fertility Agents, Female; Granulosa Cells; Humans; Hyperandrogenism; Hyperinsulinism; Insulin Resistance; Leuprolide; Organ Size; Ovarian Follicle; Ovarian Neoplasms; Polycystic Ovary Syndrome; Salpingo-oophorectomy; Severity of Illness Index; Tomography, X-Ray Computed; Ultrasonography

Gonadotropin-releasing hormone (GnRH) modulators are widely used in numerous reproductive conditions including infertility. Several clinical studies showed mixed results regarding the efficacy of GnRH modulators in patients with polycystic ovary syndrome (PCOS). Along with this, few preclinical studies focus on the effect of GnRH modulators in PCOS-induced animals. Therefore, the present study was designed to study the effect of leuprolide and cetrorelix on hormonal, metabolic, and menstrual dysfunction PCOS rats. Prepubertal female rats were divided into four groups: Group I received a normal pellet diet and Groups II, III, and IV received 40% high-fat diet for 105 days. Similarly, adult female rats were divided into four groups: Group I received 1% carboxymethylcellulose (CMC) and Groups II, III, and IV received letrozole (1 mg/kg, per oral [p.o.] in 1% CMC) for 21 days. Thereafter, leuprolide (2.5 µg/rat, s.c.) and cetrorelix (10 µg/kg, subcutaneous [s.c.]) treatment were given to Group III and Group IV animals, respectively, for 21 days. Oral glucose tolerance test, lipid profile, fasting glucose, insulin, estrus cycle, hormonal profile, ovary weight, ovarian histopathological changes, and LHR and FSHR expressions were measured. Treatment with leuprolide and cetrorelix did not improve glucose intolerance, insulin level, insulin sensitivity indices, sex hormone levels, lipid profile, and estrus cycle. Only testosterone level, total cholesterol level, and follicular development were improved. Therefore, it was concluded that both leuprolide and cetrorelix showed improvement in follicular development, which could be helpful for improving fertility in PCOS.

Topics: Animals; Blood Glucose; Disease Models, Animal; Drug Evaluation, Preclinical; Estrous Cycle; Female; Gonadotropin-Releasing Hormone; Insulin; Leuprolide; Lipids; Ovary; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley

Polycystic ovary syndrome (PCOS), affecting more than 5-10% of woman at reproductive childbearing age, is characterized by anovulation and hyperandrogenism. Frozen-thawed embryo transfer (ET) has been widely used for PCOS women to minimize the risk of ovarian hyperstimulation syndrome. However, the hyperandrogenic status of PCOS women deteriorates endometrial function, which has subsequently increased miscarriage rates in PCOS women. Therefore, we conducted this retrospective study to compare the pregnancy outcomes of hyperandrogenic PCOS women with (n = 29) and without (n = 31, controls) pretreatment of gonadotropin-releasing hormone (GnRH) agonist before frozen-thawed ET. We found that pretreatment with GnRH agonist before frozen-thawed ETs could not significantly improve the clinical pregnancy rate in these hyperandrogenic PCOS women. However, the ongoing pregnancy rate was significantly increased in women with GnRH agonist pretreatment (odds ratio: 3.98, 95% confidence interval: 1.12-14.20, p = 0.033). We concluded that androgen deprivation status due to pretreatment with GnRH agonist might improve the ongoing pregnancy rate in hyperandrogenic PCOS women. Additional large, well-designed prospective studies are worthwhile and necessary.

Topics: Adult; Embryo Transfer; Female; Fertility Agents, Female; Humans; Hyperandrogenism; Infertility, Female; Leuprolide; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Retrospective Studies; Treatment Outcome

In this study, a GnRH agonist, leuprolide acetate (LA), was given as a single depot injection before 48 h of life to Wistar female rats allotted to prenatal (E16-18) and postnatal androgenization (day 5 of life) by the use of testosterone propionate, looking for reproductive endpoints. Remarkably, a single injection of LA increased the estrus cycles in the postnatal group (PostN) from 0% to 25% of the estrus cycles in the postnatal LA treated group (PostN L). LA also reduced the serum testosterone levels and cysts and atretic follicles in PostN L in contrast with rats (>100 days) from the PostN group (p = 0.04). Prenatally androgenized rats (PreN) exhibited significant modifications in the hypothalamic genes, such as Gnrh. To the best of our knowledge, this is the first study to show that blockage of the GnRH axis with leuprolide acetate depot prevented the development of typical features (anovulation, cysts, atretic follicles) in a postnatal testosterone propionate rat model of PCOS.

Topics: Animals; Anovulation; Estrous Cycle; Female; Gonadotropin-Releasing Hormone; Leuprolide; Male; Ovarian Follicle; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Reproduction; Testosterone; Virilism

To evaluate the effects of a gonadotropin-releasing hormone (GnRH) antagonist protocol, with or without oral contraceptive pill (OCP) pretreatment, in patients with polycystic ovary syndrome (PCOS) undergoing intracytoplasmic sperm injection (ICSI).. In this retrospective cohort study, 410 infertile patients with PCOS were assessed in their first ICSI cycles between January 2006 and June 2013. In Group A (n=208), patients underwent a long luteal GnRH agonist protocol, and in Groups B (n=143) and C (n=59), patients underwent a GnRH antagonist protocol. The patients in Group C also received OCPs containing 30mg of ethinyl oestradiol and 3mg of drospirenone prior to treatment. The main outcome measures were pregnancy and ovarian hyperstimulation syndrome (OHSS) rates.. Demographic features, body mass index, duration of infertility, serum baseline hormone levels, cycle outcomes, multiple pregnancy rates, miscarriage rates, OHSS rates, total number of Grade A embryos and total number of transferred embryos were comparable between the groups. Clinical pregnancy rates were 27.4%, 26.6% and 23.7% in Groups A, B and C, respectively (p=0.853).. OCP pretreatment was found to have no beneficial or adverse effects in patients with PCOS undergoing a GnRH antagonist protocol for ICSI, but can be used for cycle scheduling.

Topics: Adult; Androstenes; Cohort Studies; Contraceptives, Oral, Combined; Contraceptives, Oral, Hormonal; Drug Administration Schedule; Drug Therapy, Combination; Embryo Transfer; Ethinyl Estradiol; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Leuprolide; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Retrospective Studies; Sperm Injections, Intracytoplasmic; Treatment Outcome

Prenatal exposure to excess testosterone induces reproductive disturbances in both female and male sheep. In females, it alters the hypothalamus-pituitary-ovarian axis. In males, prenatal testosterone excess reduces sperm count and motility. Focusing on males, this study tested whether pituitary LH responsiveness to GNRH is increased in prenatal testosterone-exposed males and whether testicular function is compromised in the testosterone-exposed males. Control males (n=6) and males born to ewes exposed to twice weekly injections of 30  mg testosterone propionate from days 30 to 90 and of 40  mg testosterone propionate from days 90 to 120 of gestation (n=6) were studied at 20 and 30 weeks of age. Pituitary and testicular responsiveness was tested by administering a GNRH analog (leuprolide acetate). To complement the analyses, the mRNA expression of LH receptor (LHR) and that of steroidogenic enzymes were determined in testicular tissue. Basal LH and testosterone concentrations were higher in the testosterone-exposed-males. While LH response to the GNRH analog was higher in the testosterone-exposed males than in the control males, testosterone responses did not differ between the treatment groups. The testosterone:LH ratio was higher in the control males than in the testosterone-exposed males of 30 weeks of age, suggestive of reduced Leydig cell sensitivity to LH in the testosterone-exposed males. The expression of LHR mRNA was lower in the testosterone-exposed males, but the mRNA expression of steroidogenic enzymes did not differ between the groups. These findings indicate that prenatal testosterone excess has opposing effects at the pituitary and testicular levels, namely increased pituitary sensitivity to GNRH at the level of pituitary and decreased sensitivity of the testes to LH.

Topics: Adrenal Hyperplasia, Congenital; Animals; Animals, Inbred Strains; Disease Models, Animal; Female; Gene Expression Regulation, Developmental; Gonadotropin-Releasing Hormone; Leuprolide; Luteinizing Hormone; Male; Pituitary Gland; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Complications; Random Allocation; Receptors, LH; Sexual Maturation; Sheep, Domestic; Steroids; Testis; Testosterone; Testosterone Propionate

To evaluate the ovarian function during early infancy in daughters of women with polycystic ovary syndrome (PCOS) treated with metformin throughout pregnancy (PCOSd+M), as a means to reduce androgen and insulin levels, compared with daughters of nontreated PCOS women (PCOSd-M) and daughters of women who belong to a healthy comparison group (HCd).. Descriptive and analytic study.. Unit of endocrinology and reproductive medicine.. Fifteen PCOSd+M, 23 PCOSd-M, and 35 HCd were studied at 2-3 months of age.. A GnRH analogue test was performed with determinations of gonadotropins, sex steroids, SHBG, and anti-Müllerian hormone (AMH).. Differences in AMH levels between PCOSd+M, PCOSd-M and HCd.. AMH and peak E(2) concentrations were significantly higher in PCOSd-M compared with HCd, whereas PCOSd+M exhibited AMH concentrations and peak E(2) levels similar to those observed in HCd.. The improvement of the altered endocrine-metabolic environment of PCOS mothers reduces AMH levels in their daughters, which might reflect a decrease in their follicular mass.

Topics: Adult; Anti-Mullerian Hormone; Birth Weight; Diabetes, Gestational; Female; Fertility Agents, Female; Humans; Hyperandrogenism; Hyperinsulinism; Hypoglycemic Agents; Infant, Low Birth Weight; Infant, Newborn; Insulin; Leuprolide; Metformin; Ovarian Follicle; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects; Testosterone; Young Adult

This study evaluated women with a high body mass index (BMI) (>40 kg/m(2)) and low BMI (<18 kg/m(2)) undergoing assisted reproduction treatment and determined whether the type of gonadotrophin-releasing hormone (GnRH) analogue used has an impact on cycle parameters and outcome. The study analysed 65 women with high BMI and 118 with low BMI. In the former group, polycystic ovarian syndrome was significantly more prevalent in the agonist long protocol (ALP) group (P=0.01) and gonadotrophin consumption was lower, peak oestradiol concentrations and total number of oocytes retrieved were higher in the ALP group compared with the antagonist (ANT) group. Implantation rate (IR), pregnancy rate (PR) per embryo transfer and early pregnancy loss rate (EPLR) were similar in both stimulation groups, with overall rates of 21.6%, 55.4% and 44.4%, respectively. In women with low BMI, peak oestradiol concentrations, total oocytes retrieved, mature oocytes and transferred embryos were higher in the ALP group compared with ANT group. IR, PR/embryo transfer and EPLR were similar in both groups, with overall rates of 24.3%, 52.5% and 16.1%, respectively. In all patients, no difference was found between ALP and ANT protocols concerning treatment outcome. Contrary to the reasonable EPLR observed in women with low BMI, the high rate found in women with high BMI is remarkable.

Topics: Abortion, Spontaneous; Adult; Body Mass Index; Embryo Implantation; Embryo Transfer; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Retrospective Studies

Several drugs, shown to be safe for other uses, have proven to be highly effective adjuncts for ovarian stimulation. The authors evaluate these "orphan" indications and make recommendations so that more patients will benefit from their use.

Topics: Androgens; Aspirin; Contraceptives, Oral; Dopamine Agonists; Estrogens; Female; Fertilization in Vitro; Human Growth Hormone; Humans; Leuprolide; Metformin; Orphan Drug Production; Ovulation Induction; Polycystic Ovary Syndrome

Topics: 17-Hydroxysteroid Dehydrogenases; 3-Hydroxysteroid Dehydrogenases; Adenosine Triphosphate; Aldo-Keto Reductase Family 1 Member C3; Androstenedione; CCAAT-Enhancer-Binding Protein-beta; Diazoxide; Female; Gene Expression Regulation, Enzymologic; Humans; Hydroxyprostaglandin Dehydrogenases; Hyperandrogenism; Hyperinsulinism; Insulin; Leuprolide; Polycystic Ovary Syndrome; Testosterone; Thinness

Two previous reports have reported myocardial infarction during ovarian hyperstimulation syndrome, a complication of controlled ovarian stimulation characterized by ascites, pleural effusion, hemoconcentration and an increased thromboembolic risk, but no association with the initial phase (before treatment with human chorionic gonadotropin) of a normal ovarian stimulation protocol for infertility has ever been described. We report the first case, to our knowledge, of acute myocardial infarction occurring during the initial phase of an otherwise uncomplicated ovarian stimulation protocol. A young woman with infertility associated to polycystic ovary syndrome was treated with leuprolide acetate and recombinant follicle stimulating hormone to induce ovarian stimulation for in vitro fertilization and embryo transfer. After 12 days the patient presented a non-ST elevation myocardial infarction, which was treated with aspirin, clopidogrel, enoxaparin, intravenous nitrates and beta blockers. Cardiac catheterization showed angiographically normal coronary arteries. Echocardiography showed a circumscribed akinesis of the inferior apical segment of the left ventricle and right ventricular apex, which was confirmed by cardiac magnetic resonance. A screening for thrombophilic diathesis was negative. The patient was discharged and remained asymptomatic at 1 and 3 months follow up. Further ovarian stimulations were excluded and a trial of oocyte retrieval on spontaneous cycle was planned. Myocardial infarction can complicate ovarian stimulation protocols for infertility even in their early phase without any sign of ovarian hyperstimulation syndrome.

Topics: Adult; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Humans; Infertility, Female; Leuprolide; Myocardial Infarction; Obesity; Ovulation Induction; Polycystic Ovary Syndrome

To determine the effect of reducing insulin secretion on hyperandrogenemia in lean normoinsulinemic women with polycystic ovary syndrome (PCOS) and normal metabolic insulin sensitivity.. Transversal assessment at baseline and prospective follow-up of lean PCOS group after 8 days of diazoxide, which reduces insulin secretion, and 1 month of leuprolide, which suppresses LH.. Clinical research center of an academic hospital.. Nine lean women (body mass index

Topics: Adolescent; Adult; Androgens; Androstenedione; Diazoxide; Female; Humans; Insulin; Leuprolide; Luteinizing Hormone; Polycystic Ovary Syndrome; Prospective Studies; Sex Hormone-Binding Globulin; Testosterone; Thinness

Polycystic ovary syndrome (PCOS) is a reproductive disorder of ovarian hyperandrogenism and insulin resistance characterized by abnormal luteinization of small follicles. After exposure to GnRH analog/FSH stimulation for in vitro fertilization (IVF), however, it is unclear whether such PCOS follicles remain abnormally luteinized during the resumption of oocyte maturation in vivo.. The aim of this study was to determine whether PCOS follicles exposed to GnRH analog/FSH stimulation for IVF show abnormal luteinization.. This study was a prospective cohort.. The setting was an institutional practice.. Eleven PCOS and 30 normoandrogenic ovulatory women were included.. All subjects received GnRH analog/FSH therapy after basal serum hormone determinations.. Follicle fluid aspirated at oocyte retrieval from the first follicle of each ovary was assayed for gonadotropins, steroids, insulin, and glucose. LH receptor mRNA expression was determined in granulosa cells of the same follicle.. In PCOS patients with basal hyperandrogenemia and hyperinsulinemia, total oocyte number was increased and follicle diameter was decreased, despite normal maximal serum estradiol levels. Within PCOS follicles, progesterone levels were reduced (P < 0.01), despite comparable bioactive LH and insulin levels and granulosa cell LH receptor mRNA expression; estradiol levels were normal, despite diminished FSH availability (P < 0.004). Elevated androstenedione (P < 0.01), testosterone (P < 0.001), and glucose (P < 0.01) levels also occurred. In PCOS follicles containing mature oocytes, however, elevated androgen levels were accompanied by both normal progesterone concentrations and a normal inverse relationship between glucose depletion and lactate accumulation.. Hyperandrogenic follicles with mature oocytes from PCOS women receiving GnRH analog/recombinant human FSH therapy for IVF show sufficient glucose utilization for normal luteinization.

Topics: Adult; Body Mass Index; Female; Fertilization in Vitro; Humans; Hyperandrogenism; Leuprolide; Luteinization; Ovarian Follicle; Polycystic Ovary Syndrome; Prospective Studies; Receptors, LH; RNA, Messenger

The aim of this study was to evaluate the effect of a single dose of leuprolide acetate on gonadotrophin and gonadal steroid secretion in brothers of women with polycystic ovary syndrome (PCOS), in order to assess P450c17alpha activity. An oral glucose tolerance test (OGTT) and a lipid profile were also performed.. Twenty-two unrelated brothers of women with PCOS (PCOS(b)) and 14 brothers of normal cycling women (C(b)), matched for age, underwent a leuprolide acetate test (10 microg/kg s.c.) and an OGTT with measurement of circulating concentrations of gonadotrophins, steroid hormones, glucose, insulin and lipids.. Clinical and basal hormonal parameters were similar in both groups. After leuprolide administration, PCOS(b) exhibited a significant increase of 17alpha-hydroxyprogesterone (17-OHP) compared to C(b) (P<0.05). However, only 45% of PCOS(b) showed a supranormal increase of 17-OHP (2 SD above the respective control group mean values, P<0.003) with a normal gonadotrophin response (group 1). The other 55% of the PCOS(b) exhibited a normal 17-OHP response to the analogue (group 2). However, in group 2, basal steroid concentrations did not show a uniform pattern: six of the PCOS(b) exhibited high basal androstenedione (2 SD above the respective control group mean values), three were very similar to C(b), and the other three presented lower basal testosterone concentrations (2 SD below the respective control group mean values) than those observed in C(b).. This study shows that different responses to leuprolide in PCOS brothers make evident the heterogeneity of this syndrome in which P450c17alpha activity could be involved.

Topics: 17-alpha-Hydroxyprogesterone; Adult; Alopecia; Androstenedione; Case-Control Studies; Dehydroepiandrosterone Sulfate; Female; Follicle Stimulating Hormone; Genetic Heterogeneity; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Male; Menstrual Cycle; Polycystic Ovary Syndrome; Reference Values; Siblings; Testosterone

Hirsute women with normal ovulatory menstrual function are often diagnosed as having idiopathic hirsutism. We prospectively evaluated 62 hirsute ovulatory women to determine if they had a subtle form of polycystic ovary syndrome, and if they exhibited any of the metabolic abnormalities commonly associated with classic polycystic ovary syndrome.. Baseline hormonal profiles, ovarian responses to gonadotropin-releasing hormone agonist, and ovarian morphology by ultrasound were compared in the hirsute women and two groups of ovulatory controls.. Among 62 women, only 8 (13%) had normal androgen levels and were considered to have idiopathic hirsutism. Twenty-four (39%) had characteristic polycystic ovaries on ultrasound, an exaggerated response of 17-hydroxyprogesterone to leuprolide, or both, suggesting ovarian hyperandrogenism and the diagnosis of mild polycystic ovary syndrome. The remaining 30 women (48%) were considered to have unspecified hyperandrogenism. Age, body weight, and androgen level were similar among the hyperandrogenic subgroups. However, when compared with both normal and overweight controls and with patients with idiopathic hirsutism, the women who had mild polycystic ovary syndrome had higher fasting insulin levels [P < 0.01, mean (+/- SD) increase of 7 +/- 3 microU/mL], lower glucose-insulin ratios (P < 0.01, mean reduction of 3 +/- 1.5), higher low-density lipoprotein cholesterol levels (P < 0.05, mean increase of 26 +/- 10 mg/dL), and lower high-density lipoprotein (HDL) cholesterol levels (P < 0.01, mean reduction of 10 +/- 4 mg/dL). Compared with patients who had unspecified hyperandrogenism, these women also had higher fasting insulin levels (P < 0.05), lower glucose-insulin ratios (P < 0.05), and lower HDL cholesterol levels (P < 0.05).. These data suggest that mild polycystic ovary syndrome is more common than idiopathic hirsutism, and it is also associated with subtle metabolic abnormalities.

Topics: Adult; Analysis of Variance; Androgens; Blood Glucose; Body Mass Index; Cholesterol; Female; Fertility Agents, Female; Gonadal Steroid Hormones; Hirsutism; Humans; Insulin; Leuprolide; Menstrual Cycle; Polycystic Ovary Syndrome; Prospective Studies; Triglycerides; Ultrasonography

Topics: Adipose Tissue; Adult; Anthropometry; Body Composition; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Polycystic Ovary Syndrome

To investigate serum and follicular fluid (FF) insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) behavior in superstimulated cycles in patients with polycystic ovary syndrome (PCOS).. Controlled clinical study.. Department of Obstetrics and Gynecology, University of Naples.. Thirty-two patients with regular menses and tubal and/or male factor infertility and 21 patients with PCOS undergoing IVF.. The IVF program used leuprolide acetate suppression followed by sequential hMG in the subsequent cycle. After follicular development, hCG administration was followed 34-36 hours later by oocyte retrieval.. E2, GH, IGF-I, and IGFBP-3 assayed by RIA and immunoradiometric assay.. The controls and patients with PCOS showed similar increases in E2 and GH titers in response to FSH stimulation. Serum IGF-I did not change in either group and was equivalent in the FF. Patients with PCOS had a higher FF IGFBP-3 titer and did not show the decrease in serum IGFBP-3 levels of the control group after FSH stimulation.. The apparent failure of IGFBP-3 reduction in patients with PCOS alters IGF-I bioavailability. Increased sequestration of IGF-I affects ovarian steroidogenesis and may explain the poor response to gonadotropin stimulation.

Topics: Adult; Chorionic Gonadotropin; Estradiol; Female; Follicle Stimulating Hormone; Human Growth Hormone; Humans; Infertility, Female; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leuprolide; Male; Menotropins; Polycystic Ovary Syndrome

Insulin resistance and increased ovarian cytochrome P450c17 alpha activity (i.e. increased 17 alpha-hydroxylase and, to a lesser extent, increased 17,20-lyase) are both features of the polycystic ovary syndrome (PCOS). Evidence suggests that hyperinsulinemia may stimulate ovarian P450c17 alpha activity in obese women with PCOS. We hypothesized that weight loss would decrease serum insulin and P450c17 alpha activity in PCOS. Therefore, we measured serum steroid concentrations and 17 alpha-hydroxyprogesterone responses to leuprolide administration and performed oral glucose tolerance tests before and after 8 weeks of a hypocaloric diet in 12 obese women with PCOS (PCOS group) and 11 obese women with normal menses (control group). Serum insulin decreased in both groups. In the PCOS group, basal serum 17 alpha-hydroxyprogesterone decreased from 4.2 +/- 0.6 to 3.0 +/- 0.5 nmol/L (P < 0.05), and leuprolide-stimulated peak serum 17 alpha-hydroxyprogesterone decreased from 14.9 +/- 2.6 to 8.9 +/- 0.8 nmol/L (P < 0.025). Serum testosterone decreased from 2.47 +/- 0.52 to 1.56 +/- 0.33 nmol/L (P < 0.05), and free testosterone decreased from 9.03 +/- 1.39 to 5.95 +/- 0.50 pmol/L (P < 0.02). None of these values changed in the control group. Serum sex hormone-binding globulin increased by 4.5- and 3-fold in the PCOS (P < 0.003) and control (P < 0.007) groups, respectively. We conclude that dietary weight loss decreases ovarian P450c17 alpha activity and reduces serum free testosterone concentrations in obese women with PCOS, but not in obese ovulatory women. The changes in women with PCOS may be related to a reduction in serum insulin.

Topics: 17-alpha-Hydroxyprogesterone; Adult; Androgens; Blood Glucose; Female; Gonadal Steroid Hormones; Humans; Insulin; Leuprolide; Luteinizing Hormone; Obesity; Polycystic Ovary Syndrome; Weight Loss

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the beta-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator]. There was no change in body mass index (39.9 +/- 1.4 vs. 40.2 +/- 1.4 kg/m2) or body fat distribution after treatment. Both the fasting (91 +/- 3 vs. 103 +/- 3 mg/dL; P < 0.001) and 2 h (146 +/- 8 vs. 171 +/- 6 mg/dL; P < 0.02) plasma glucose concentrations during the oral glucose tolerance test declined significantly. There was a concordant reduction in glycosylated hemoglobin to 5.7 +/- 0.1 from a pretreatment level of 6.1 +/- 0.1% (P < 0.03). Insulin sensitivity increased from 0.58 +/- 0.14 to 0.95 +/- 0.26 10(-5) min-1/pmol.L (P < 0.01) after treatment as did the disposition index (745 +/- 135 vs. 381 +/- 96; P < 0.05). The ability of the beta-cell to appropriately detect and respond to an oscillatory glucose infusion improved significantly after troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 +/- 1.1 from 4.3 +/- 0.8 (P < 0.05). Basal levels of total testosterone (109.3 +/- 15.2 vs. 79.4 +/- 9.8 ng/dL; P < 0.05) and free testosterone (33.3 +/- 4.0 vs. 21.2 +/- 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment. Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 +/- 2.8 to 6.3 +/- 1.4 AU/mL P < 0.05) wa

Topics: Adult; Androgens; Chromans; Female; Fibrinolysis; Glucose; Glucose Tolerance Test; Gonadotropins; Humans; Insulin; Insulin Resistance; Leuprolide; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome; Thiazoles; Thiazolidinediones; Troglitazone

Certain patients have a tendency for high response to gonadotrophin therapy which is often not ameliorated with prior gonadotrophin-releasing hormone agonist (GnRHa) suppression. As a result, these patients are frequently cancelled and often experience ovarian hyperstimulation syndrome (OHSS) episodes during in-vitro fertilization (IVF)-embryo transfer cycles. Patients with polycystic ovarian syndrome (PCOS) have been noted to be particularly sensitive to exogenous gonadotrophin therapy. We have developed a protocol which is effective in improving IVF outcome in high responder patients, including those with PCOS. Oral contraceptive pills (OCP) are taken for 25 days followed by s.c. leuprolide acetate, 1 mg/day, which is overlapped with the final 5 days of oral contraceptive administration. Low-dose gonadotrophin stimulation is then initiated on the third day of withdrawal bleeding in the form of either human menopausal gonadotrophins or purified urinary follicle-stimulating hormone at a dosage of 150 IU/day. Over a 5 year period, we reviewed our experience utilizing this dual method of suppression in 99 cycles obtained in 73 high responder patients. There were only 13 cancellations prior to embryo transfer (13.1%). The clinical and ongoing pregnancy rates per initiated cycle were 46.5 and 40.4% respectively. Only eight patients experienced mild-moderate OHSS following treatment. For those patients who had undergone previous IVF-embryo transfer cycles at our centre, significant improvements were noted in oocyte fertilization rates, embryo implantation rates and clinical/ongoing pregnancy rates with this protocol. Hormonal analyses revealed that the chief mechanism may be through an improved luteinizing hormone/follicle-stimulating hormone ratio following dual suppression. An additional feature of this dual method of suppression is significantly lower serum androgen concentrations, particularly dehydroepiandrosterone sulphate.. Presented is a protocol that is effective in improving in vitro fertilization (IVF) outcome in women with a tendency for a high response to gonadotrophin therapy. High responders to exogenous gonadotrophin therapy show recruitment of large numbers of follicles, rapid estradiol responses, and a significant cycle cancellation rate due to the potential risk of hyperstimulation during IVF-embryo transfer attempts. Women with polycystic ovarian syndrome are especially sensitive to exogenous gonadotrophin therapy. The protocol entails 25 days of oral contraceptive (OC) use, followed by 1 mg/day of subcutaneous leuprolide acetate overlapped with the final 5 days of OC therapy. On the third day of withdrawal bleeding, gonadotrophin stimulation is initiated through either human menopausal gonadotrophins or purified urinary follicle-stimulating hormone (150 IU/day). This approach permits normalization of the luteinizing hormone/follicle-stimulating hormone ratio and reduces ovarian androgen concentrations, while circumventing the initial gonadotrophin flare response. This protocol was tested in a retrospective review (1990-94) of 99 cycles from 73 high-responder women treated at a US infertility center. There were only 13 cancellations (13.1%) prior to embryo transfer. The clinical and ongoing pregnancy rates per initiated cycle were 46.5% and 40.4%, respectively. Only 8 women experienced ovarian hyperstimulation syndrome after treatment. Among women who had undergone previous IVF embryo transfer cycles at the center, the present regimen was associated with significant improvements in oocyte fertilization rates, embryo implantation rates, and pregnancy rates.

Topics: Adult; Contraceptives, Oral; Embryo Transfer; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Ovulation; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome

To evaluate the therapeutic effects of a GnRH agonist (GnRH-a), leuprolide acetate (LA) plus a pill containing ethinyl E2 plus cyproterone acetate (CPA) in a group of women with severe hirsutism who were unresponsive to oral contraceptive (OC) therapy.. Twenty-four patients suffering from severe hirsutism secondary to polycystic ovary disease (PCOD) were treated for 12 months with 3.75 mg IM LA every 28 days in association with 0.035 mg/d ethinyl E2 plus 2 mg/d CPA (Diane; Schering, Berlin, Germany) for 21 d/mo.. Patients were recruited in the Institute of Obstetrics and Gynecology, St. Bambino Hospital, University of Catania, Catania, Italy. Hormonal assays were performed in the Hormone Laboratories of St. Bambino Hospital, University of Catania, Catania, Italy.. Every 3 months the hirsutism score was evaluated. Mean serum concentrations of LH, FSH, E2, total and free T, androstenedione (A), sex hormone-binding globulin (SHBG), and DHEAS were determined. Every 6 months a vaginal ultrasound examination was performed.. In all patients after 6 and 12 months of treatment with LA plus OC, the hirsutism score improved significantly. Serum levels of LH, FSH, E2, total and free T, A, and DHEAS decreased significantly, whereas SHBG showed a marked increase. A significant reduction in the ovarian size was observed.. Gonadotropin-releasing hormone agonist, associated with a pill containing CPA, reduced the hirsutism in severely affected women with PCOD who are unresponsive to OC treatment alone.

Topics: Adult; Contraceptives, Oral; Cyproterone Acetate; Drug Therapy, Combination; Ethinyl Estradiol; Female; Hirsutism; Humans; Leuprolide; Polycystic Ovary Syndrome

To reevaluate the clinical significance of elevations of adrenal androgens in polycystic ovary syndrome (PCOS).. Thirty women with PCOS and ten ovulatory controls were evaluated. Serum dehydroepiandrosterone (DHEA) sulfate and 11 beta-hydroxyandrostenedione were measured before and after 3 and 6 months of GnRH agonist (GnRH-A) therapy. All controls and 15 women with PCOS received intravenous ACTH before and after GnRH-A therapy.. Twenty-one (70%) of the women with PCOS had elevations of DHEA sulfate, and 16 (53%) had elevations in 11 beta-hydroxyandrostenedione. Only two women with PCOS had normal values of both adrenal androgens. After GnRH-A therapy, only 11 subjects (37%) had elevated values of DHEA sulfate. Four of 16 women had reductions in 11 beta-hydroxyandrostenedione. Only those with elevated baseline DHEA sulfate levels had reductions after GnRH-A therapy. The reduction of DHEA sulfate with GnRH-A correlated with the reduction in androstenedione. Of the subjects who had reductions in DHEA sulfate with GnRH-A therapy, there was a blunted response of DHEA to ACTH after treatment.. Our findings suggest that the ovary may influence the prevalence and magnitude of adrenal androgen excess in PCOS.

Topics: Adrenocorticotropic Hormone; Adult; Androstenedione; Case-Control Studies; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Humans; Leuprolide; Polycystic Ovary Syndrome; Triptorelin Pamoate

While no single biochemical test is diagnostic of polycystic ovary syndrome (PCOS), most patients show a characteristic ovarian ultrasonographic appearance. It has been proposed that a dysfunction of cytochrome P-450c17 alpha in PCOS leads to an increased 17-hydroxyprogesterone (17-OHP) response to a gonadotrophin-releasing hormone (GnRH) agonist-induced gonadotrophin rise. We postulated that this abnormality of steroid metabolism might influence the ovarian response during assisted reproduction treatment. We investigated 106 patients undergoing a short 'boost' stimulation regimen for assisted reproduction treatment, including in-vitro fertilization and gamete intra-Fallopian transfers. The ovarian ultrasound pattern was correlated with serum testosterone, 17-OHP, androstenedione and oestradiol responses, and with the clinical outcome. Polycystic ovaries, defined ultrasonographically as the presence of > or = 10 follicles between 2 and 10 mm diameter in either ovary, were found in 48% of the whole study population. Dexamethasone was given to suppress adrenal androgen secretion. Functional ovarian hyperandrogenism (FOH) was defined as serum testosterone > 0.5 nmol/l after dexamethasone. There was a significantly (P < 0.001) higher prevalence of FOH in patients with polycystic ovaries (23%) compared with normal ovaries (7%). Patients with polycystic ovaries had approximately double the 17-OHP, androstenedione and oestradiol responses to a GnRH agonist as patients with non-polycystic ovaries. Exaggerated 17-OHP and oestradiol responses to GnRH agonist were found in 89% of patients with clinically diagnosed PCOS. The number of oocytes retrieved was positively correlated (r = 0.51, P < 0.001) with the oestradiol responses in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 17-alpha-Hydroxyprogesterone; Adult; Androgens; Androstenedione; Estradiol; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Gamete Intrafallopian Transfer; Humans; Hydroxyprogesterones; Infertility, Female; Leuprolide; Ovary; Polycystic Ovary Syndrome; Testosterone; Ultrasonography

Adrenal hyperandrogenism is a common feature of patients with polycystic ovary syndrome (PCO). This may be due to enhanced adrenal sensitivity to ACTH. Because enhanced ovarian androgen secretion does not appear to explain this phenomenon, we explored the role of estrogen in inducing enhanced adrenal sensitivity, in that a state of relative hyperestrogenism exists in PCO. Eight patients with PCO and seven matched controls received ovine corticotropin-releasing hormone (oCRH; 0.1 micrograms/kg) iv before and after hypoestrogenism was induced by leuprolide acetate (LA; 1 mg, sc, each day). In patients with PCO, a third oCRH test was repeated after transdermal estradiol (E2; 0.1 mg) had been applied for a week, during which time LA was continued. At baseline, patients with PCO had increased responses of 11 beta-hydroxyandrostenedione and dehydroepiandrosterone (P < 0.03 and P < 0.02) and increased delta maximal ratios of androstenedione (A4)/ACTH and dehydroepiandrosterone/ACTH (P < 0.01) after oCRH treatment. After LA administration to patients with PCO, these ratios were significantly suppressed (P < 0.01) and returned to baseline after E2 was added. There were no changes in controls. Steroid ratio responses to oCRH suggested that 17,20-desmolase activity (delta maximum change in the ratio of A4/17-hydroxyprogesterone) was lowered with estrogen suppression and increased again after transdermal E2 administration. There was a significant positive correlation between changes in E2 levels and delta maximum change in the ratios of A4/17-OHP after oCRH treatment, signifying 17,20-desmolase activity (r = 0.58, P < 0.02). In conclusion, these data provide evidence that estrogen is at least one factor that influences adrenal androgen sensitivity in PCO and may help explain the frequent finding of adrenal hyperandrogenism in this syndrome.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Androgens; Androstenedione; Animals; Corticotropin-Releasing Hormone; Estradiol; Female; Humans; Hydroxyprogesterones; Leuprolide; Polycystic Ovary Syndrome; Sheep

The aim of this study was to investigate the relationship between plasma insulin levels, peripheral insulin sensitivity and androgen secretion in ten patients with polycystic ovary syndrome and in six obese women as compared with six normal-weight control subjects. During a euglycemic-hyper-insulinemic clamp no significant change of testosterone, androstenedione or dehydroepiandrosterone sulfate plasma levels was observed in the two groups of patients or in the control subjects; insulin sensitivity was clearly reduced and was similar in polycystic ovary patients and in obese women, in spite of the different plasma androgen levels. A long-term (5 months) androgen suppression with the gonadotropin-releasing hormone agonist leuprolide was not able to improve significantly the insulin sensitivity. These results demonstrate that the short-term hyperinsulinemia achieved with the clamp technique does not affect androgen secretion and that insulin resistance, measured with the same technique, is not influenced by long-term suppression of plasma androgen levels in polycystic ovary syndrome.

Topics: Adult; Androgens; Androstenedione; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Follicle Stimulating Hormone; Glucose Clamp Technique; Gonadotropin-Releasing Hormone; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Leuprolide; Luteinizing Hormone; Obesity; Polycystic Ovary Syndrome; Testosterone

Functional ovarian hyperandrogenism (FOH) is characterized by an abnormal ovarian response to challenge with the GnRH analogs nafarelin and leuprolide acetate, similar to that observed in women with well defined polycystic ovary syndrome, regardless of whether elevated LH levels or polycystic ovaries are present. We studied an unselected group of 42 hyperandrogenic adolescents (age range, 14-22 yr; mean, 18.1 +/- 2.5 yr) 1) to determine FOH incidence through the assessment of ovarian-steroidogenic response to a single dose of leuprolide acetate, 2) to assess the clinical characteristics of patients according to their responses to GnRH analog stimulation, and 3) to evaluate adrenal steroidogenic function and its relation to ovarian hyperandrogenism in patients with either normal or abnormal responses to leuprolide acetate challenge. All patients underwent leuprolide acetate and ACTH testing, dexamethasone and ovarian suppression tests, and pelvic ultrasonography. Twenty-four (58%) patients had supranormal plasma 17-hydroxyprogesterone (17-OHP) responses to leuprolide acetate characteristic of FOH, and in 18, the 17-OHP response was similar to that of controls (n = 24; age, 17.1 +/- 2.3 yr). Seven patients (5 with FOH and 2 with normal responses to leuprolide acetate) had an abnormal response to ACTH, but only 1 had conclusive evidence of 21-hydroxylase deficiency. In 16 patients, the response to both stimulation tests was normal. Only 13 (54%) of the 24 FOH patients had polycystic ovaries on ultrasonography, and in 11 (46%), basal plasma LH levels were elevated. In FOH patients, reduction in testosterone and androstenedione plasma levels was significantly greater after ovarian suppression than after dexamethasone challenge (P < 0.0005 and P < 0.02, respectively). Peak plasma 17-OHP levels postleoprolide acetate simulation correlated with dexamethasone-suppressed plasma testosterone concentrations, dexamethasone-suppressed plasma androstenedione levels, and the free androgen index postdexamethasone treatment (r = 0.4, P = 0.01; r+ 0.4, P < 0.05; and r = 0.41, P = 0.007, respectively), Plasma sex hormone-binding globulin levels after dexamethasone administration correlated negatively with the baseline free androgen index (r = -.0.67; P < 0.0001). Considering our diagnostic criteria, 26 (62%) of our collective of 42 patients had abnormal responses to one or both stimulation tests, whereas 16 (37%) had normal response. FOH is the most common cause in (58%) of

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenocorticotropic Hormone; Adult; Androstenedione; Dexamethasone; Female; Humans; Hydroxyprogesterones; Hyperandrogenism; Leuprolide; Luteinizing Hormone; Ovarian Diseases; Ovary; Polycystic Ovary Syndrome; Testosterone; Ultrasonography

Severe ovarian hyperstimulation syndrome occurred after the administration of LA to suppress multicystic ovaries. It is possible that this patient with multiple ovarian cysts, each 2 to 3 cm in size, is at increased risk for a paradoxical stimulatory rather than inhibitory response to GnRH-a.

Topics: Adult; Estradiol; Female; Humans; Leuprolide; Ovarian Hyperstimulation Syndrome; Polycystic Ovary Syndrome; Testolactone

To assess the impact of ovarian hormone deprivation on serum concentrations of GH and insulin-like growth factor I (IGF-I) in women with polycystic ovarian syndrome (PCOS).. Growth hormone and IGF-I levels were measured before, during, and at the end of a 6-month period of treatment with leuprolide acetate (LA) depot. Normal cycling and ovariectomized women served as controls.. The Clinical Research Center of Northwestern University Medical School.. Six women with PCOS, seven normal cycling women, and six ovariectomized women.. The PCOS and normal cycling subjects were treated with six consecutive monthly injections of LA depot 3.75 mg IM.. Circulating concentrations of GH and IGF-I.. After 3 months of treatment, GH levels decreased modestly in the PCOS group; however, these changes were not significant. No further decline was observed at 6 months. Growth hormone levels were unaffected in the normal cycling group. Levels of IGF-I remained unchanged in both groups. Mean baseline levels of both GH and IGF-I in the ovariectomized group were lower than those of the normal cycling and PCOS groups at all time points, but not significantly so.. Medical castration fails to significantly alter serum GH and IGF-I levels in either normal cycling or women with PCOS. These data indicate that GH secretion is not modulated by hormones of ovarian origin in either group, at least over the period of time studied.

Topics: Adult; Estradiol; Female; Growth Hormone; Humans; Insulin-Like Growth Factor I; Leuprolide; Menstrual Cycle; Ovariectomy; Polycystic Ovary Syndrome; Reference Values

To examine if changes in insulin sensitivity and glucose effectiveness in women with polycystic ovarian disease (PCOD) occurred after ovarian androgen suppression with a GnRH agonist, leuprolide acetate (LA, Lupron; TAP Pharmaceuticals, Deerfield, IL) using the minimal model method.. Twelve patients with PCOD were tested in the untreated state (baseline) and after 6 weeks of LA treatment. Subjects were divided into two groups based on the degree of impairment of their baseline insulin sensitivity index (SI; (min-1) (microU/mL-1): mild insulin resistance (SI > 1) or severe insulin resistance (SI < 1).. In all patients, serum T was significantly decreased from elevated baseline levels to normal female concentrations after 6 weeks of LA therapy. Insulin sensitivity in PCOD patients with mild insulin resistance significantly improved from baseline after 6 weeks of LA therapy, whereas no change in SI on LA therapy was seen in PCOD women with severe insulin resistance. Glucose utilization independent of increased insulin secretion did not change as a function of LA treatment in either group.. These findings indicate a significant improvement in SI in mildly insulin-resistant women with PCOD after suppression of ovarian function with LA treatment.

Topics: Adult; Female; Glucose Tolerance Test; Humans; Hyperandrogenism; Injections, Intravenous; Insulin; Insulin Resistance; Leuprolide; Polycystic Ovary Syndrome; Testosterone

To determine if fluoroimmunoassay (FIA) of serum luteinizing hormone (LH) is more useful clinically than a conventional radioimmunoassay (RIA) because it has been suggested that FIA closely reflects biological activity.. Comparison of serum LH measurements by RIA and FIA during various perturbations in normal ovulatory women and in women with polycystic ovarian syndrome (PCOS).. Normal ovulatory subjects were healthy volunteers and women with PCOS were untreated and newly diagnosed outpatients in our Reproductive Endocrinology/Infertility Clinic, Women's Hospital, at the Los Angeles County+University of Southern California Medical Center.. Fifty-three normal ovulatory women, ages 20 to 35, and 27 women with PCOS, ages 21 to 35. All were in good health and received no other medications during the study period.. Fluoroimmunoassay of serum LH reflected status of known altered bioactivity better than with a conventional RIA. This was most evident during conditions of gonadotropin suppression and in patients with PCOS. An excellent correlation was found between values of FIA and RIA.. The measurement of LH by FIA is clinically useful, specifically when a change in biological activity of LH is sought.

Topics: Adult; Evaluation Studies as Topic; Female; Fluoroimmunoassay; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Norethindrone; Polycystic Ovary Syndrome; Pulsatile Flow; Radioimmunoassay; Reference Values; Time Factors

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

While serum markers of peripheral androgen metabolism, such as 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide (3 alpha-diolG) and androsterone glucuronide (AoG), have been highly correlated with adrenal androgen production, the relative ovarian contribution to the pool of various C19 conjugates has not been fully investigated. Our hypothesis was that whereas the ovary may not produce C19 conjugates directly, ovarian androgens, such as testosterone (T) and androstenedione (A), may be used as substrate for peripheral production of these conjugates. To determine whether the ovary contributes directly to the pool of C19 conjugates, blood was obtained from the ovarian and peripheral veins of eight normal women (NW) at hysterectomy. To assess the indirect ovarian contribution to C19 conjugate production, the effect of ovarian suppression and stimulation on circulating 3 alpha-diol and Ao conjugate levels was examined in 10 NW and 10 anovulatory nonhirsute patients with PCO (NH-PCO). Ovarian suppression was carried out with leuprolide acetate (1 mg, sc) daily until the serum estradiol level was 30 pg/mL and was continued thereafter during ovarian stimulation with im human menopausal gonadotropin or FSH. Blood samples were taken before, during, and after GnRH agonist suppression and just before hCG stimulation. Both unconjugated and conjugated androgens were quantified in serum by specific RIAs. No peripheral-ovarian gradients were found for 3 alpha-diol or Ao sulfates (3 alpha-diolS or AoS) or glucuronides. In the NH-PCO group, both T and A levels were elevated, and they were suppressed significantly to levels similar those in NW. With stimulation, T and A levels rose significantly to higher levels than those observed in NW. Both AoS and 3 alpha-diolS, but not AoG and 3 alpha-diolG, decreased significantly with agonist suppression in the two groups; the decrease in levels of AoS and T correlated significantly in the NH-PCO group. With stimulation, the Ao and 3 alpha-diol conjugate levels increased significantly in NH-PCO and were most marked for Ao S and 3 alpha-diol S, which were previously suppressed; the increase in AoG and A correlated highly. Our data suggest that while there is no evidence for the direct ovarian production of C19 conjugates, these markers of peripheral androgen action are influenced by precursors from the ovary, principally A and T.

Topics: Adult; Androgens; Androstenedione; Biomarkers; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Glucuronates; Gonadotropins; Humans; Leuprolide; Middle Aged; Ovary; Polycystic Ovary Syndrome; Reference Values; Testosterone

Topics: Female; Hirsutism; Humans; Leuprolide; Polycystic Ovary Syndrome

We examined androgen responses in hyperandrogenic (polycystic ovarian disease [PCOD]) and normal women after an acute endogenous insulin elevation. Standard intravenous glucose tolerance tests (IVGTTs), modified to include a tolbutamide injection 20 minutes after IVGTTs, were performed. Polycystic ovarian disease patients were studied in the untreated state, after 6 weeks of ovarian androgen suppression with leuprolide acetate, after a 6-week rest period, and after 6 weeks of antiandrogen therapy with spironolactone. Normal menstruating women were studied during the early follicular, midcycle, and luteal phases of a single cycle. An acute rise in insulin did not alter serum testosterone or androstenedione levels in PCOD or normal women. A significant rise in dehydroepiandrosterone sulfate after modified IVGTTs was found in both hyperandrogenic and normal cycling women. Although these results are not supportive of the theory that insulin acts on the ovary to stimulate androgen production, they may be because of the short time course of insulin elevation that occurs during an IVGTT.

Topics: Adrenal Glands; Adult; Androgens; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Follicular Phase; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Hormones; Humans; Hydrocortisone; Insulin; Leuprolide; Luteal Phase; Ovary; Ovulation; Polycystic Ovary Syndrome; Spironolactone; Testosterone

It has been postulated that in polycystic ovary syndrome ovarian steroids can influence adrenal steroidogenesis. To test this hypothesis, basal and dexamethasone-suppressed-corticotropin-stimulated steroid hormone responses were compared among three groups of women before, during, and after gonadotropin-releasing hormone agonist treatment for 3 months. The groups were characterized as follows: (1) women with polycystic ovary syndrome with high dehydroepiandrosterone sulfate levels (greater than 400 micrograms/dl), (2) women with polycystic ovary syndrome with normal dehydroepiandrosterone sulfate levels (less than 300 micrograms/dl), and (3) normal ovulatory women. In response to gonadotropin-releasing hormone agonist, basal serum luteinizing hormone, follicle-stimulating hormone, estradiol, estrone, 17-hydroxyprogesterone, androstenedione, and testosterone in all three groups were suppressed to similar levels. Basal serum dehydroepiandrosterone sulfate levels in the group with high levels declined, but they did not reach the normal, unaltered concentrations in the other two groups. Two subjects with polycystic ovary syndrome in this group with high levels, who showed the greatest declines in basal serum dehydroepiandrosterone sulfate levels (34%, 40%), also had evidence of 3 beta-hydroxysteroid dehydrogenase deficiency before treatment, which was resolved by the end of treatment. In both groups with polycystic ovary syndrome, the increase in maximum incremental rise of dehydroepiandrosterone and dehydroepiandrosterone sulfate levels in response to a pharmacologic dose of corticotropin from a dexamethasone-suppressed baseline (adrenal androgen capacity) remained unaltered during gonadotropin-releasing hormone agonist administration. We conclude that ovarian steroids may promote excessive adrenal androgen secretion in women with polycystic ovary syndrome, may induce 3 beta-hydroxysteroid dehydrogenase deficiency as a mechanism for adrenal involvement in some women with polycystic ovary syndrome, and do not influence adrenal androgen capacity.

Topics: 3-Hydroxysteroid Dehydrogenases; Adolescent; Adrenal Glands; Adult; Androgens; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Humans; Hydrocortisone; Leuprolide; Luteinizing Hormone; Polycystic Ovary Syndrome; Progestins

To determine whether hyperinsulinemia can directly reduce serum sex hormone-binding globulin (SHBG) levels in obese women with the polycystic ovary syndrome, six obese women with this disorder were studied. Before study, ovarian steroid production was suppressed in each woman by the administration of 7.5 mg of a long-acting GnRH agonist, leuprolide depot, im, on days -56, -28, and 0. This resulted in substantial reductions in serum concentrations of testosterone (from 1.72 +/- 0.29 nmol/L on day -56 to 0.32 +/- 0.09 nmol/L on day 0), non-SHBG-bound testosterone (from 104 +/- 16 pmol/L on day -56 to 19 +/- 5 pmol/L on day 0), androstenedione (from 7.25 +/- 1.65 nmol/L on day -56 to 2.78 +/- 0.94 nmol/L on day 0), estrone (from 371 +/- 71 pmol/L on day -56 to 156 +/- 29 pmol/L on day 0), estradiol (from 235 +/- 26 pmol/L on day -56 to 90 +/- 24 pmol/L on day 0), and progesterone (from 0.28 +/- 0.12 nmol/L on day -56 to 0.08 +/- 0.02 nmol/L on day 0). Serum SHBG levels, however, did not change (18.8 +/- 2.8 nmol/L on day -56 vs. 17.8 +/- 2.6 nmol/L on day 0). While continuing leuprolide treatment, the women were administered oral diazoxide (300 mg/day) for 10 days to suppress serum insulin levels. Diazoxide treatment resulted in suppressed insulin release during a 100-g oral glucose tolerance test (insulin area under the curve, 262 +/- 55 nmol/min.L on day 0 vs. 102 +/- 33 nmol/min.L on day 10; P less than 0.05) and deterioration of glucose tolerance. Serum testosterone, androstenedione, estrone, estradiol, and progesterone levels did not change during combined diazoxide and leuprolide treatment. In contrast, serum SHBG levels rose by 32% from 17.8 +/- 2.6 nmol/L on day 0 to 23.5 +/- 2.0 nmol/L on day 10 (P less than 0.003). Due primarily to the rise in serum SHBG levels, serum non-SHBG-bound testosterone levels fell by 43% from 19 +/- 5 pmol/L on day 0 to 11 +/- 4 pmol/L on day 10 (P = 0.05). These observations suggest that hyperinsulinemia directly reduces serum SHBG levels in obese women with the polycystic ovary syndrome independently of any effect on serum sex steroids.

Topics: Adult; Androstane-3,17-diol; Androstenedione; Diazoxide; Estradiol; Estrone; Female; Glucose Tolerance Test; Gonadotropin-Releasing Hormone; Humans; Insulin; Insulin Resistance; Leuprolide; Obesity; Polycystic Ovary Syndrome; Progesterone; Sex Hormone-Binding Globulin; Testosterone

Androsterone glucuronide (Andros-G), a dihydrotestosterone metabolite, is present in serum at concentrations at least tenfold greater than those of androstanediol glucuronide. To investigate the significance of serum androsterone glucuronide, we developed a direct radioimmunoassay for this compound and measured its levels in normal women, women with mild or severe idiopathic hirsutism (IH), hirsute women with polycystic ovarian syndrome (PCO), and non-hirsute obese women. To determine the source of Andros-G precursors, serum levels were measured before and after selective ovarian suppression with leuprolide, combined ovarian and adrenal suppression with leuprolide and dexamethasone, and adrenal stimulation with ACTH. Androsterone glucuronide levels (nmol/l; mean +/- SD) were significantly higher (P less than 0.025) in women with mild idiopathic hirsutism (IH) (185 +/- 91), severe IH (173 +/- 97), and hirsute women with polycystic ovarian syndrome (PCO) (178 +/- 102) than in normal women (110 +/- 26). Levels in non-hirsute obese women (64 +/- 19) were lower than in normal women (P less than 0.01). Baseline levels (mean +/- SEM) in hirsute women given 20 micrograms/kg/day leuprolide for 5-9 months (171 +/- 15) were not significantly changed after leuprolide alone (153 +/- 18), and were decreased after adding dexamethasone (19 +/- 6; P less than 0.001). Andros-G levels did not increase significantly in normal women 60 min after i.v. ACTH (112 +/- 14 to 126 +/- 19), but rose in IH (170 +/- 24 to 216 +/- 26; P less than 0.001) and in PCO (179 +/- 26 to 238 +/- 31; P = 0.002). We conclude that Andros-G in women arises primarily from adrenal gland precursors and is elevated in hirsute women as a group. Its levels do not correlate with the severity of hirsutism, or the presence or absence of PCO, but reflect an increased production of adrenal androgens in both IH and PCO.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Adult; Androgens; Androsterone; Biomarkers; Dexamethasone; Female; Gonadotropin-Releasing Hormone; Hirsutism; Hormones; Humans; Leuprolide; Middle Aged; Ovary; Polycystic Ovary Syndrome; Radioimmunoassay

Continuous exposure to GnRH eliminates the pituitary as a source of gonadotropins and may have direct suppressive effects on the ovary. A woman with PCO syndrome received leuprolide acetate (1 mg/d SC) for 4 weeks before and simultaneously with hMG stimulation. Human chorionic gonadotropin (5,000 IU) was administered IM on the 8th day of hMG therapy. There were 10 follicles greater than 15 mm and a polycystic appearance to the ovaries with 25 follicles measuring less than 10 mm. The serum E2 concentration was 2,280 pg/mL. She developed severe ovarian hyperstimulation and required hospitalization for 12 days for fluid management. A viable intrauterine pregnancy was present. Four weeks of pretreatment with leuprolide did not prevent hyperstimulation in the presence of an intrauterine pregnancy.

Topics: Adult; Anovulation; Chorionic Gonadotropin; Female; Gonadotropin-Releasing Hormone; Hormones; Humans; Leuprolide; Menotropins; Ovary; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Stimulation, Chemical

A patient with PCO and primary infertility had undergone numerous failed attempts of ovulation induction. She then was treated with GnRHa leuprolide 500 micrograms subcutaneously daily for 4 weeks, later combined with hMG 225 IU IM daily for 8 days and hCG 5000 IU IM. Six oocytes were retrieved for IVF, four fertilized and two were replaced. Twin pregnancy was established and delivered at term. Hyperstimulation syndrome was managed conservatively.

Topics: Adult; Chorionic Gonadotropin; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Hormones; Humans; Infertility, Female; Leuprolide; Menotropins; Ovulation Induction; Polycystic Ovary Syndrome

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