leuprolide and Insulin-Resistance

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

The purpose of this study was to determine (1) the influence of estrogen deficiency induced by gonadotropin-releasing hormone (GnRH) agonist administration on insulin sensitivity as well as hormones and factors related to insulin resistance and (2) the differences in the influence for these parameters by the degree of basal insulin sensitivity.. Thirty-five women diagnosed with leiomyoma were enrolled in this study. Serum levels of fasting glucose, insulin, sex steroid hormones, sex hormone-binding globulin (SHBG), vascular inflammatory markers and cytokines before and at 6months after commencement of GnRH agonist administration were examined.. In all women, levels of insulin, glucose and homeostasis model assessment of insulin resistance (HOMA-IR) were not significantly changed. However, in women who had a low HOMA-IR before treatment, levels of insulin, glucose and HOMA-IR showed significant increases and total testosterone level showed a significant decrease. In women who had a high HOMA-IR, levels of insulin, HOMA-IR and SHBG were significantly decreased and levels of highly sensitive C-reactive protein, soluble intercellular adhesion molecule-1, E-selectin and monocyte chemoattractant protein-1 were significantly increased.. Change in insulin sensitivity caused by GnRH agonist administration for premenopausal women with leiomyoma differs depending on baseline insulin sensitivity before treatment.

Topics: Adult; Antineoplastic Agents, Hormonal; Blood Glucose; Body Mass Index; C-Reactive Protein; Chemokine CCL2; Cytokines; E-Selectin; Female; Gonadotropin-Releasing Hormone; Humans; Insulin; Insulin Resistance; Intercellular Adhesion Molecule-1; Leiomyoma; Leuprolide; Middle Aged; Premenopause; Sex Hormone-Binding Globulin; Testosterone; Uterine Neoplasms

GnRH analogue (GnRHa) combined with GH treatment has been proposed to increase adult height. Effect on metabolic profile and GH, IGF1, and IGFBP3 levels in short small for gestational age (SGA) children is unknown.. To assess fat mass and lean body mass SDS, percentage trunk fat, blood pressure (BP), insulin sensitivity (Si), beta-cell function (disposition index, DI), lipid profile, and GH, IGF1, and IGFBP3 levels during 2 years of combined treatment.. Forty-one pubertal short SGA children with a mean (+/-S.D.) age of 12.1 (+/-1.0) years.. Children received 3.75 mg of leuprolide acetate depot subcutaneously every 4 weeks, and they were randomly assigned to receive 1 mg (group A) or 2 mg (group B) of GH/m(2) per day.. Percentage trunk fat increased in both groups, but to a lower extent in group B. Lean body mass SDS increased only in group B. Changes in BP, Si, DI, and lipids were similar in both groups. Si significantly decreased, but DI remained unchanged. Lipids remained normal. GH and IGF1 levels were significantly higher in group B.. Our study is the first to report that 2 years of combined treatment with a GnRHa and either 1 or 2 mg GH/m(2) per day does not adversely affect body composition and metabolic profile of short SGA children who come under medical attention at the onset of puberty. There was a dose-dependent effect on fat mass SDS(height), percentage trunk fat, lean body mass SDS(height), and GH and IGF1 levels in favor of treatment with GnRHa and the higher GH dose of 2 mg/m(2) per day.

Topics: Adipose Tissue; Adolescent; Blood Pressure; Body Composition; Child; Female; Growth Disorders; Human Growth Hormone; Humans; Infant, Newborn; Infant, Small for Gestational Age; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Leuprolide; Male

To determine whether insulin sensitizers lower androgen levels and whether androgen suppression improves insulin resistance in nondiabetic postmenopausal women.. Randomized, double-blind, placebo-controlled study.. Clinical and Translational Research Center of a university hospital.. Thirty-five postmenopausal women aged 50-79 years with insulin resistance and higher T levels.. Subjects were randomized to metformin plus leuprolide acetate (LA) placebo, LA plus metformin placebo, or LA placebo plus metformin placebo in a 1:1:1 fashion during a 12-week period.. Insulin sensitivity (M) assessed by euglycemic-hyperinsulinemic clamp and free T by equilibrium dialysis.. In those randomized to metformin, free T decreased by 19% compared with placebo, along with an expected improvement in M. Total T also decreased significantly, whereas sex hormone-binding globulin (SHBG) did not change. In those randomized to LA, the percent change in M was not different from placebo, despite a 48% relative decrease in free T levels.. These data are the first to establish a causal link between insulin resistance and T in postmenopausal women. They confirm that treatment of insulin resistance decreases T production in this population and demonstrate that pharmacologic lowering of T does not affect insulin resistance.

Topics: Aged; Double-Blind Method; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Humans; Hypoglycemic Agents; Insulin Resistance; Leuprolide; Longitudinal Studies; Luteinizing Hormone; Metformin; Middle Aged; Placebos; Postmenopause; Testosterone

To evaluate the influence of two medical treatments for endometriosis on insulin sensitivity.. After surgery, 26 women with endometriosis were randomly allocated to a 6-month treatment with a GnRH agonist (Leuprorelin 3.75 mg/28 days) or a subdermal progestin implant (etonogestrel 68 mg). Insulin sensitivity (SI) and glucose utilization independent of insulin (Sg) were investigated at baseline and after 6 months by a frequently sampled intravenous glucose tolerance test (FSIGT) associated with the minimal model method.. Both therapies tended to decrease SI, but the effect did not reach statistical significance in the GnRH agonist group (5.43+/-1.29 vs. 3.99+/-0.8) and was significant in the etonogestrel group (5.74+/-1.12 vs. 3.95+/-0,78; p=.046). Sg, fasting glucose, insulin, C-peptide and C-peptide/insulin were not modified by either treatment.. The modifications of glucose-insulin metabolism induced by the GnRH agonist are of no relevance for the short-term use of this molecule. Even if the modification induced by the etonogestrel implant is subtle and of no major impact, it should be taken into consideration for the long-term treatment of individuals with abnormalities of glucose-insulin metabolism.

Topics: Blood Glucose; C-Peptide; Desogestrel; Drug Implants; Endometriosis; Fasting; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leuprolide

Although GnRH analogues are widely used to treat a variety of sex hormone-related diseases, little is known about their effect on metabolism. Therefore, we have evaluated the effect of a GnRH analogue, administered with or without raloxifene, on serum levels of lipoproteins, glucose, insulin and homocysteine (Hcy).. One hundred premenopausal women with symptomatic uterine leiomyomas were initially enrolled and randomized to receive 3.75 mg/28 days leuprolide acetate depot associated with 60 mg/day raloxifene hydrochloride (group A) or 1 placebo tablet/day (group B) for six cycles of 28 days. At entry and at cycle 6, subjects underwent anthropometric measurements, including body mass index and waist-to-hip ratio measurements, and blood chemistry assays for serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), glucose, insulin, Hcy, vitamin B(12) and folate concentrations. Insulin resistance was evaluated with the homeostasis model assessment (HOMA) score.. Baseline parameters were similar in the two groups. At cycle 6, TC, HDL-C, LDL-C and TG levels were significantly increased (P < 0.05) in group B. In group A, LDL-C levels were unchanged, and TC, HDL-C and TG levels were increased (P < 0.05). Serum TC and LDL-C levels differed (P < 0.05) between the groups. Glucose levels were unchanged between and within groups, whereas insulin levels and HOMA scores increased (P < 0.05) versus baseline in group B. Post-treatment Hcy levels were higher (P < 0.05) versus baseline in group B; they were unchanged in group A. Serum vitamin B(12) and folate concentrations were unchanged in both groups.. GnRH analogues alter serum lipoprotein and Hcy levels and increase insulin resistance. These acute metabolic changes may be prevented or reduced by raloxifene.

Topics: Adult; Blood Glucose; Body Constitution; Body Mass Index; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Delayed-Action Preparations; Female; Folic Acid; Homeostasis; Homocysteine; Humans; Insulin; Insulin Resistance; Leiomyoma; Leuprolide; Lipids; Middle Aged; Placebos; Premenopause; Raloxifene Hydrochloride; Triglycerides; Uterine Neoplasms; Vitamin B 12

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

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

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

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

Hyperinsulinemia can lead to pathologic ovarian growth and androgen production.. A 29-year-old woman developed an autoantibody to the insulin receptor (type B insulin resistance), causing extreme insulin resistance and hyperinsulinemia. Testosterone levels were elevated to the adult male range. Treatment with gonadotropin-releasing hormone (GnRH) analog led to normalization of testosterone, despite persistent extreme insulin resistance.. This case demonstrates that gonadotropins are necessary for insulin to cause pathologic ovarian androgen production. Suppression of gonadotropins with GnRH analogs may be a useful therapeutic option in patients with severe hyperandrogenism or ovarian enlargement because of hyperinsulinemia.

Topics: Adult; Antineoplastic Agents, Hormonal; Autoantibodies; Cyclophosphamide; Dexamethasone; Diagnosis, Differential; Female; Gonadotropin-Releasing Hormone; Humans; Hyperandrogenism; Hyperinsulinism; Immunosuppressive Agents; Insulin Resistance; Leuprolide; Ovarian Diseases; Receptor, Insulin; Rituximab; Testosterone

Androgen deprivation therapy (ADT) for prostate cancer causes an increase in fasting insulin and adverse changes in body composition and serum lipid profile. It is unknown what other metabolic alterations are caused by ADT. To better characterize the metabolic effects of ADT, we measured changes in plasma metabolomic profile at baseline and after the first 3 months of therapy.. Fasting plasma samples were drawn from 36 subjects at baseline and after 3 months of gonadotropin releasing hormone (GnRH) agonist therapy. Extracted samples were split into equal parts for analysis on the gas chromatography-mass spectrometry and liquid chromatography/tandem mass spectrometry platforms.. Of the 292 identified metabolites, 56 changed significantly (P < 0.05) from baseline to 3 months. Notable changes were grouped as follows: (i) Multiple steroids were lower at 3 months, consistent with the effect of therapy on gonadal androgen synthesis. (ii) Most bile acids and their metabolites were higher during treatment. Cholesterol levels changed very little. (iii) Markers of lipid beta-oxidation (acetyl-carnitines and ketone bodies) and omega-oxidation were lower at 3 months. (iv) Two previously identified biomarkers of insulin resistance (2-hydroxybutyrate and branch chain keto-acid dehydrogenase complex products) were stable to lower at 3 months.. Unbiased metabolomic analyses revealed expected, novel, and unexpected results. Steroid levels fell, consistent with the effects of ADT. Most bile acids and their metabolites increased during ADT, a novel finding. Biomarkers of lipid metabolism and insulin resistance fell, unexpected given that ADT has been shown to increase fasting insulin.

Topics: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Adenocarcinoma; Antineoplastic Agents, Hormonal; Bile Acids and Salts; Gonadotropin-Releasing Hormone; Humans; Hydroxybutyrates; Insulin Resistance; Leuprolide; Lipid Metabolism; Male; Metabolome; Oxidation-Reduction; Prospective Studies; Prostatic Neoplasms; Steroids

Leuprorelin acetate is an agonist of gonadotropin-releasing hormone, used as a first choice treatment in patients with prostate carcinoma. The impact of leuprorelin therapy in liver function and metabolism is largely unknown. We report about a patient who had been treated for 32 months with leuprorelin acetate, who developed a nonalcoholic fatty liver disease (NAFLD), associated with a focal lesion at the IV hepatic segment where histologic features appeared to be more severe. The patient, in addition to NAFLD, presented a marked iatrogenic hypotestosteronemia and full-criteria meeting the diagnosis of metabolic syndrome, including insulin resistance. The radiologic and clinical findings, the histopathologic features, and the absence of any hepatic abnormalities before treatment, support a causal role of leuprorelin in inducing metabolic derangement that, most likely secondary to androgen-deprivation, were, in turn, responsible for the development of NAFLD. In conclusion, this is the first case report of NAFLD with focal fatty liver associated with leuprorelin therapy. Patients in leuprorelin should be carefully monitored for the development of liver disease.

Topics: Aged; Antineoplastic Agents, Hormonal; Carcinoma; Fatty Liver; Humans; Hypogonadism; Insulin Resistance; Leuprolide; Liver; Male; Prostatic Neoplasms; Testosterone

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

In men with prostate cancer, gonadotropin-releasing hormone (GnRH) agonists increase fat mass, decrease insulin sensitivity, and increase triglycerides, features that are shared with metabolic syndrome. To the authors' knowledge, however, less is known regarding the effects of GnRH agonists on other attributes of the metabolic syndrome.. In an open-label prospective study, 26 men with recurrent or locally advanced prostate cancer were treated with leuprolide for 12 months. Outcomes included changes in blood pressure, body composition, lipids, adipocytokines, and C-reactive protein.. The mean weight, body mass index, and waist circumference increased significantly from baseline to Month 12 (P < .001 for each comparison). Fat mass increased by 11.2% +/- 1.5% (P < .001) and the percentage lean body mass decreased by 3.6% +/- 0.5% (P < .001). The total abdominal fat area increased by 16.5% +/- 2.6% (P < .001), with the accumulation of subcutaneous fat accounting for 94% of the observed increase. The waist-to-hip ratio and blood pressure did not change significantly. Serum high-density lipoprotein (HDL) cholesterol concentrations increased significantly (P = .002). Serum adiponectin levels increased by 36.4 +/- 5.9% from baseline to Month 3 and remained significantly elevated through Month 12 (P < .001). Resistin and C-reactive protein levels did not change significantly.. The term metabolic syndrome does not appear to adequately describe the effects of GnRH agonists in men with prostate cancer. In contrast to the metabolic syndrome, GnRH agonists increase subcutaneous fat mass, HDL cholesterol, and adiponectin, and do not alter the waist-to-hip ratio, blood pressure, or C-reactive protein level.

Topics: Adiponectin; Aged; Antineoplastic Agents, Hormonal; Blood Pressure; Body Composition; Body Mass Index; C-Reactive Protein; Gonadotropin-Releasing Hormone; Humans; Insulin Resistance; Leuprolide; Lipids; Male; Metabolic Syndrome; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Syndrome

Topics: Adenocarcinoma; Aged; Androgen Antagonists; Anilides; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Humans; Insulin Resistance; Leuprolide; Male; Nitriles; Prostatic Neoplasms; Tosyl Compounds

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

To determine whether 3-month GnRH analogue (GnRH-a) administration to hyperandrogenic anovulatory patients and healthy women affects glucose utilization or endogenous glucose production (EGP) in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions.. Prospective, nonrandomized study.. Academic research environment.. Twelve hyperandrogenic anovulatory patients and 11 healthy women matched by body mass index and waist to hip circumference ratio.. Variable hyperglycemic-hyperinsulinemic infusions replicated physiological increases in circulating glucose and insulin levels before and after 3-month GnRH-a administration.. Glucose utilization and EGP.. In the postabsorptive state, plasma glucose and insulin levels, glucose utilization, and EGP were similar in hyperandrogenic patients and healthy women. During variable hyperglycemic-hyperinsulinemic infusions, glucose use increased and EGP decreased to similar degrees in both groups of women. Three-month GnRH-a administration to hyperandrogenic patients and healthy women did not affect plasma glucose and insulin levels, glucose utilization and EGP in the postabsorptive state, or glucose utilization and EGP during variable hyperglycemic-hyperinsulinemic infusions.. Glucose use and EGP in the postabsorptive state and during variable hyperglycemic-hyperinsulinemic infusions are similar in hyperandrogenic anovulatory patients and healthy women of similar body fat distribution and are unaffected by 3-month GnRH-a administration.

Topics: Adolescent; Adrenal Glands; Adult; Anovulation; Blood Glucose; Body Composition; C-Peptide; Female; Glucagon; Human Growth Hormone; Humans; Hyperandrogenism; Insulin; Insulin Resistance; Leuprolide; Middle Aged; Ovary; Prospective Studies; Steroids

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

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

The hyperandrogenic-insulin-resistant acanthosis nigricans syndrome affects between 2% and 5% of hirsute women and is characterized by INS resistance, elevated INS levels, acanthosis nigricans, and androgen excess. These patients' response to therapy is unclear, although long-acting GnRH-a suppression has been proposed. The objective of this study was to determine the success of OC in suppressing the hyperandrogenemia of five patients with the hyperandrogenic-insulin-resistant acanthosis nigricans syndrome and the subsequent response to GnRH-a suppression of those women failing initial therapy. After 6 months of OC and SPA therapy, four patients experienced adequate suppression of free T, an increase in SHBG levels, and a subjective improvement in hair growth rate. Two also reported an improvement in hair texture. The total and free T levels in the fifth patient did not suppress after 8 months of OC therapy. Nevertheless, in this patient the administration of a GnRH-a along with hormonal replacement and SPA adequately suppressed free and total T, increased SHBG, and dramatically decreased the shaving interval. In conclusion, although GnRH-a suppression and hormonal replacement can be helpful in patients not responding to standard therapy, the majority of patients with the hyperandrogenic-insulin-resistant acanthosis nigricans syndrome will respond favorably to OC treatment. It is also clear that although hyperinsulinemia augments LH-stimulated androgen biosynthesis in vivo, it does not appear to be able to initiate or maintain androgen production in the absence of adequate gonadotropin stimulation.

Topics: Acanthosis Nigricans; Adolescent; Contraceptives, Oral; Drug Therapy, Combination; Female; Humans; Hyperandrogenism; Insulin Resistance; Leuprolide; Medroxyprogesterone Acetate; Spironolactone

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 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

In the syndrome of familial virilization, insulin resistance, and acanthosis nigricans, the interrelationships are not understood. Twin sisters were studied, along with a lesser affected sister and mother. They manifested amenorrhea, hirsutism, masculinization, hypertension, hyperinsulinemia, hypertriglyceridemia, and hyperprolactinemia. Medical therapy with a gonadotropin-releasing hormone agonist plus an antiandrogen resulted in reversal of the hirsutism, yet with preservation of potential fertility. In response to luteinizing hormone (LH) and follicle-stimulating hormone suppression, there was normalization of the serum androgens, but not of the hyperinsulinemia, hypertriglyceridemia, hyperprolactinemia, hypertension, or acanthosis nigricans.. (1) This syndrome may be familial. (2) Medical therapy for the virilization is successful. (3) The hyperandrogenemia is primarily LH dependent and not primarily insulin dependent, although insulin may have an amplification effect. (4) Hyperinsulinemia, hypertriglyceridemia, hyperprolactinemia, and the hypertension are not androgen dependent.

Topics: Acanthosis Nigricans; Adult; Androgen Antagonists; Antineoplastic Agents; Cyproterone; Cyproterone Acetate; Dexamethasone; Diseases in Twins; Family Health; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hirsutism; Humans; Hyperinsulinism; Hyperlipidemias; Hyperprolactinemia; Hypertension; Insulin Resistance; Leuprolide; Luteinizing Hormone; Male; Pituitary Hormone-Releasing Hormones; Syndrome; Virilism