leuprolide and Obesity

In the 1990s, estrogens were thought to protect the aging brain. Large randomized controlled studies, however, showed that estrogens did not treat dementia symptoms and even increased risk for dementia in older women. These findings contrast with earlier positive findings, including a wealth of cell culture and animal data all suggesting that estrogens could be a prophylactic treatment for dementia. Observational data had also suggested a significantly decreased risk for dementia in women who had been treated with estrogens for menopausal symptoms in midlife. This review discusses the "Critical Window", Healthy Cell Bias' and "Limited Duration" hypotheses, and forms of bias (healthy user, recall and survivor bias) and potential mediators (e.g., body mass, genetics) to attempt to explain the differences seen between the studies. On the basis of limited data, we conclude that estrogens only have limited positive effects on some tests for a number of months regardless of age. These effects were seen in recently menopausal women, but also in women with dementia, who are at least 15 years past the average age of menopause. In addition, after a longer period of time, treatment may confer risk, especially in older women. From this it would follow that longer term treatment with estrogens to maintain cognitive function is not indicated for older women. Whether there still is a case to treat surgical menopausal women with estrogens for a longer or shorter period of time remains to be tested.

Topics: Aged; Aged, 80 and over; Animals; Brain; Cardiovascular Diseases; Cognition Disorders; Comorbidity; Confounding Factors, Epidemiologic; Dementia; Estrogen Replacement Therapy; Female; Humans; Leuprolide; Male; Menopause; Menopause, Premature; Middle Aged; Models, Biological; Obesity; Prevalence; Randomized Controlled Trials as Topic; Risk Factors; Sex Factors

Endometriosis is an invasive but benign disease of women that develops in endometrial glands outside the endometrium and uterine muscle. It affects about 15-20% of women of childbearing age. One effective way to treat endometriosis is to use GnRH agonists, which inhibit estrogen production. However, one of the possible side effects of this treatment is obesity and BMI increasing, which is a concern for some patients. This study investigated the role of leuprolide acetate in treating overweight patients (BMI≥30) and their comparison with non-overweight patients (BMI<30) for six months. Also, the effect of this medicine was evaluated on the expression of the MIF gene, which is an effective gene in obesity. For this purpose, a clinical trial was performed on 75 women with endometriosis aged 18 to 35 years. These patients were divided into two groups. The first group consisted of 38 patients with BMI<30. The second group consisted of 37 patients with BMI≥30. Both groups were treated with leuprolide acetate at a dose of 3.75 mg/month (intramuscularly) for six months. In addition to clinical evaluations, the expression of the MIF gene was assessed by the real-time PCR technique. The results showed that treatment with leuprolide acetate during six months in both groups reduced dysmenorrhea, dyspareunia, and chronic pelvic pain (P<0.05). Although this decrease was greater in the BMI <30 group, the difference was not significant. Also, after collecting the side effects of the medication, it was found that hypoestrogenism, such as cramps and spotting, was more in the first group; Endogenous complications such as oily skin, acne, and hirsutism were also more common in the second group. The results of MIF gene expression showed that the expression level before and after the start of the experiment in the second group (BMI≥ 30) is higher than the first group (BMI <30). The results also showed that the two groups increased the expression of the MIF gene after treatment with leuprolide acetate. This increase was statistically significant in the second group (P = 0.042). Generally, it was found that this medication causes more weight gain in obese people and increases the risk of obesity-related diseases among these patients. Therefore, it is recommended that this treatment be used with caution in obese patients with endometriosis.

Topics: Adolescent; Adult; Endometriosis; Female; Humans; Intramolecular Oxidoreductases; Leuprolide; Macrophage Migration-Inhibitory Factors; Obesity; Treatment Outcome; Young Adult

To determine whether recombinant follicle-stimulating hormone (rFSH) should be administered intramuscularly (i.m.) or subcutaneously (s.c.) to obese women.. Randomized, single-center, two-way crossover study.. Academic clinical research center.. Nineteen healthy women of reproductive age with body mass indices of 19.9 kg/m(2)-42.8 kg/m(2).. Leuprolide acetate 3.75 mg i.m. to achieve pituitary down-regulation as determined by serum E(2) levels. Subjects were then given a single dose of 300 IU rFSH either i.m. or s.c.. Multiple blood sampling was performed over the next two weeks, and after retreatment with leuprolide, a second 300 IU rFSH dose was given via the other administration route.. Serum samples were analyzed in duplicate for follicle-stimulating hormone (FSH) using a standard radioimmunoassay in a single run. Maximum concentrations (C(max)), times to C(max) (T(max)), and extent of absorption (area under curve [AUC]) with i.m. vs. s.c. administration were compared using paired analysis.. Maximal concentrations were achieved within 24 hours with both s.c. and i.m. routes. No significant differences were found in C(max), T(max), or AUC with s.c. vs. i.m. administration. A decline of AUC occurred among subjects of higher body mass index (BMI) with rFSH given either s.c. or i.m.. Subcutaneous administration achieved AUCs comparable to i.m. administration in both normal-weight and obese subjects.. Our data indicate that the s.c. administration of rFSH is appropriate for women regardless of body mass.

Topics: Adult; Area Under Curve; Body Mass Index; Cross-Over Studies; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Humans; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Obesity; Ovulation Induction

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

A total of 413 consecutive infertile patients (572 cycles) with a body mass index (BMI) of ≥ 25 kg/m(2) were enrolled into the study. The luteal-long GnRH agonist group (Group I) constituted 211 patients (300 cycles) and the flexible-multidose GnRH antagonist group (Group II) constituted 202 patients (272 cycles). The duration of stimulation (d) (10.1 ± 2.5 vs. 9.2 ± 2.0; p < 0.01); the total dose of gonadotrophin used (IU) (3,099.4 ± 2,885.0 vs. 2,684.0 ± 1,046.4; p < 0.05) and the E2 level on the day of hCG (pg/ml) (2,375.8 ± 1,554.6 vs. 1,905.6 ± 1,598.8; p < 0.01) were significantly lower in Group II when compared with Group I. However, the ongoing pregnancy per embryo transfer (37.0% vs. 25.7%; p < 0.05) and the implantation rate (25.7% vs. 15.6%; p < 0.01) were significantly lower in Group II when compared with Group I. In conclusion, we noted that the luteal-long GnRH agonist protocol produced higher implantation rates and higher clinical-ongoing pregnancy rates in overweight and obese patients when compared with the flexible-multidose GnRH antagonist protocol.

Topics: Adult; Clinical Protocols; Contraceptives, Oral, Hormonal; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Infertility; Leuprolide; Luteal Phase; Obesity; Overweight; Pregnancy; Pregnancy Rate; Reproductive Techniques, Assisted; Retrospective Studies; Time Factors

The objective of this study was to assess the relationship between BMI and oocyte number and maturity in participants who underwent minimal stimulation (mini-) or conventional IVF.. Participants who underwent their first autologous cycle of either conventional (n = 219) or mini-IVF (n = 220) were divided according to their BMI to analyze IVF outcome parameters. The main outcome measure was the number of oocytes in metaphase II (MII). Secondary outcomes included the number of total oocytes retrieved, fertilized (2PN) oocytes, cleavage and blastocyst stage embryos, clinical pregnancy (CP), and live birth (LB) rates.. In conventional IVF, but not in mini-IVF, the number of total oocytes retrieved (14.5  ±  0.8 versus 8.8  ±  1.3) and MII oocytes (11.2 ± 0.7 versus 7.1 ± 1.1) were significantly lower in obese compared with normal BMI women. Multivariable linear regression adjusting for age, day 3 FSH, days of stimulation, and total gonadotropin dose demonstrated that BMI was an independent predictor of the number of MII oocytes in conventional IVF (p = 0.0004). Additionally, only in conventional IVF, BMI was negatively correlated with the total number of 2PN oocytes, as well as the number of cleavage stage embryos.. Female adiposity might impair oocyte number and maturity in conventional IVF but not in mini-IVF. These data suggest that mild ovarian stimulation might yield healthier oocytes in obese women.

Topics: Adult; Chorionic Gonadotropin; Clomiphene; Female; Fertility Agents, Female; Fertilization in Vitro; Humans; Infertility; Leuprolide; Linear Models; Menotropins; Metaphase; Obesity; Oocytes; Ovulation Induction; Pregnancy; Pregnancy Rate

The most frequent cause of virilization in postmenopausal women is excessive androgen production of ovarian origin. Bilateral oophorectomy is usually performed, even in cases of benign tumors or hyperthecosis. This is the first report of a case series of long-term GnRH-agonist treatment of hyperandrogenism in postmenopausal women.. We present three women with postmenopausal hyperandrogenism of ovarian origin who were treated with GnRH agonists.. We describe three cases of postmenopausal women with virilization and hyperandrogenism of presumed ovarian origin, all with slight enlargement of the ovaries but without visualization of a tumor, who had long-term treatment with GnRH agonists. No histological diagnosis was available, and therefore all patients received careful follow-up, including periodic testing of androgen levels and ovarian imaging by computed tomography scans. The three patients responded in different ways to treatment with GnRH agonists.. Long-term GnRH agonist treatment is an acceptable choice for treatment of postmenopausal hyperandrogenism in patients where ovarian origin of androgen excess is ascertained, and especially in those patients who have an increased risk for surgery due to comorbidities or who are unwilling to undergo bilateral oophorectomy.

Topics: Aged; Alopecia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Hirsutism; Humans; Hyperandrogenism; Hypertension; Leuprolide; Liver Cirrhosis, Alcoholic; Magnetic Resonance Imaging; Middle Aged; Obesity; Ovary; Postmenopause; Tomography, X-Ray Computed

Gonadotropin-releasing hormone agonists increase fat mass, decrease insulin sensitivity, and increase serum triglycerides. To better characterize the metabolic effects of gonadotropin-releasing hormone agonist treatment, we prospectively evaluated the changes in body composition, insulin sensitivity, and levels of adiponectin, resistin, C-reactive protein (CRP), and plasminogen activator inhibitor type 1 (PAI-1). We also assessed the relationships among changes in adipocytokines, body composition, and insulin sensitivity.. In this prospective, 12-week study, 25 nondiabetic men with locally advanced or recurrent prostate cancer and no radiographic evidence of metastases were treated with leuprolide depot and bicalutamide. The outcomes studied included changes from baseline to week 12 in body composition, insulin sensitivity, and levels of adiponectin, resistin, CRP, and PAI-1.. The mean +/- standard error percentage of fat body mass increased by 4.3% +/- 1.3% from baseline to week 12 (P = 0.002). The insulin sensitivity index decreased by 12.9% +/- 7.6% (P = 0.02). The serum adiponectin levels increased by 37.4% +/- 7.2% from baseline to week 12 (P <0.001). In contrast, the resistin, CRP, and PAI-1 levels did not change significantly. Changes in body composition tended to be associated with changes in adiponectin, but not insulin sensitivity.. Combined androgen blockade with leuprolide and bicalutamide significantly increased fat mass and adiponectin levels and decreased insulin sensitivity but did not alter the resistin, CRP, or PAI-1 levels. This pattern of metabolic changes appears distinct from the classic metabolic syndrome.

Topics: Adipokines; Aged; Androgen Antagonists; Anilides; Antineoplastic Agents, Hormonal; Body Composition; Drug Therapy, Combination; Humans; Insulin Resistance; Leuprolide; Male; Nitriles; Obesity; Prospective Studies; Prostatic Neoplasms; Tosyl Compounds

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 evaluate effects of obesity on sex steroid levels during treatment with a gonadotropin-releasing hormone agonist in men with prostate cancer.. Forty-nine hormone-naïve men with recurrent or locally advanced prostate cancer were included in the analyses. All subjects were treated with leuprolide 3-month depot for 48 weeks. Serum levels of estradiol, sex hormone-binding globulin, total testosterone, and free testosterone were assessed at baseline, 24 weeks, and 48 weeks. Subjects were categorized by body mass index (BMI) and percent body fat.. Pretreatment serum sex hormone-binding globulin and total testosterone levels were significantly lower in overweight and obese men than in men with normal BMI. In the overall study population, mean serum testosterone concentrations decreased from 372 +/- 18 ng/dL at baseline to 13 +/- 1 ng/dL at week 48 (P < 0.001). Free testosterone decreased from 6.75 +/- 0.33 ng/dL at baseline to 0.21 +/- 0.02 ng/dL at week 48 (P < 0.001). During treatment with leuprolide, obese men had significantly higher total and free testosterone levels than men with normal BMI. Compared with normal men, total and free testosterone levels during treatment were 1.8-fold and 2.3-fold higher in obese men. Similar results were observed when subjects were categorized by body fat.. Despite lower pretreatment serum testosterone levels, obese men have higher total and free testosterone levels during leuprolide treatment than men with normal BMI. These differences may contribute to the association between obesity and increased prostate cancer mortality.

Topics: Aged; Body Mass Index; Estradiol; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Middle Aged; Obesity; Prospective Studies; Prostatic Neoplasms; Sex Hormone-Binding Globulin; Steroids; Testosterone; Time Factors; Treatment Outcome

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

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

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

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

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

Androsterone sulfate (Andros-S) is the most abundant 5 alpha-reduced androgen metabolite in serum. To determine whether this steroid could serve as a marker of 5 alpha-reductase activity, we developed a specific RIA, using tritiated Andros-S to assess procedural losses. Baseline serum Andros-S levels (mumol/L; mean +/- SEM) in 14 hirsute women (3.0 +/- 0.4) were not reduced by ovarian suppression with leuprolide (3.0 +/- 0.3), but were decreased by 79% with combined ovarian and adrenal suppression with leuprolide and dexamethasone. The mean Andros-S level in polycystic ovarian syndrome (3.2 +/- 0.4) and in idiopathic hirsutism (3.5 +/- 0.5) was not significantly different from levels in normal women (3.0 +/- 0.5), but were significantly greater than levels in obese women (1.7 +/- 0.3; P < 0.05). The serum concentrations of Andros-S were about 10-fold greater than those of androsterone glucuronide and 100-fold greater than those of androstanediol glucuronide. Serum Andros-S concentrations correlated strongly with dehydroepiandrosterone sulfate (R = 0.59; P < 0.001) and to a lesser degree with androstanediol glucuronide and androsterone glucuronide (R = 0.28 and 0.49, respectively). There was a weak correlation with androstenedione levels and the androstenedione response to ACTH (R = 0.38 and 0.34, respectively), and no significant correlation with serum testosterone (R = 0.19). The ratio of any of the 5 alpha-reduced products (Andros-S, androstanediol glucuronide, and androsterone glucuronide) to precursors (androstenedione and testosterone) was not increased in hirsute women, suggesting that these women did not have a generalized increase in 5 alpha-reductase activity. In conclusion, these results confirm that Andros-S is the most abundant 5 alpha-reduced androgen metabolite in serum. It is primarily, if not exclusively, of adrenal origin in hirsute women. The fact that its levels were not elevated in hirsutism, although those of other adrenal androgens and androgen metabolites (androstanediol glucuronide and androsterone glucuronide) were, suggests that variations in sulfotransferase activity or metabolic clearance of Andros-S may be important determinants of serum Andros-S levels. Although Andros-S may be a marker of systemic 5 alpha-reductase activity, there was no evidence of a generalized increase in 5 alpha-reductase activity in hirsute women. Andros-S is therefore not recommended as a marker of either adrenal androgen production or of hirsutism.

Topics: 17-alpha-Hydroxyprogesterone; Adrenocorticotropic Hormone; Adult; Androstenedione; Androsterone; Biomarkers; Body Mass Index; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Dexamethasone; Female; Follicle Stimulating Hormone; Glucuronates; Hirsutism; Humans; Hydrocortisone; Hydroxyprogesterones; Leuprolide; Luteinizing Hormone; Obesity; Reference Values; Testosterone

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