leptin and Hyperandrogenism

Growth during childhood and adolescence occurs at different rates and is influenced by the interaction between genetic and environmental factors. Nutritional status plays an important role in regulating growth, and excess body weight early in life can influence growth patterns. Childhood obesity is a growing and alarming problem, associated with several short-term and long-term metabolic and cardiovascular complications. In addition, there is evidence suggesting that excess adiposity during childhood influences growth patterns and pubertal development. Several studies have shown that during prepubertal years obese children have higher height velocity and accelerated bone age compared to lean subjects. However, this prepubertal advantage in growth tends to gradually decrease during puberty, when obese children show a reduced growth spurt compared with lean subjects. Growth hormone (GH) secretion in obese children is reduced, therefore suggesting that increased growth is GH independent. Factors which have been implicated in the accelerated growth in obese children include increased leptin and insulin levels, adrenal androgens, insulin-like growth factor (IGF)-1, IGF-binding protein-1 and GH-binding proteins. Excess body weight during childhood can also influence pubertal development, through an effect on timing of pubertal onset and levels of pubertal hormonal levels. There is clear evidence indicating that obesity leads to early appearance of pubertal signs in girls. In addition, obese girls are also at increased risk of hyperandrogenism. In boys, excess adiposity has been associated with advanced puberty in some studies, whereas others have reported a delay in pubertal onset. The existing evidence on the association between childhood and adolescence obesity underlines a further reason for fighting the epidemics of childhood obesity; that is preventing abnormal growth and pubertal patterns.

Topics: Adiposity; Adolescent; Body Height; Body Weight; Child; Child Development; Child, Preschool; Female; Humans; Hyperandrogenism; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Leptin; Male; Nutritional Status; Pediatric Obesity; Puberty; Risk Factors

Abdominal adiposity, overweightness and obesity are frequently present in patients with polycystic ovary syndrome (PCOS). A large body of evidence suggests that abdominal adiposity and the resulting insulin resistance contribute to ovarian and, possibly, adrenal hyperandrogenism. However, androgen excess itself might also contribute to abdominal fat deposition in hyperandrogenic women. Recent genomic and proteomic analyses of visceral fat from PCOS patients have detected differences in gene expression and protein content compared with those of non-hyperandrogenic women. Here we review the existing evidence for a vicious circle whereby androgen excess favoring the abdominal deposition of fat further facilitates androgen secretion by the ovaries and adrenals in PCOS patients.

Topics: Abdominal Fat; Adiposity; Female; Humans; Hyperandrogenism; Hyperinsulinism; Insulin Resistance; Leptin; Models, Biological; Polycystic Ovary Syndrome

The polycystic ovary syndrome (PCOS) is one of the most common causes of infertility due to anovulation in women. The clinical features of PCOS are heterogeneous and may change throughout the lifespan, starting from adolescence to postmenopausal age. This is largely dependent on the influence of obesity and metabolic alterations, including an insulin-resistant state and the metabolic syndrome, which consistently affect most women with PCOS. Obesity does in fact have profound effects on both the pathophysiology and the clinical manifestation of PCOS, by different mechanisms leading to androgen excess and increased free androgen availability and to alterations of granulosa cell function and follicle development. Notably, simple obesity per se represents a functional hyperandrogenic state. These mechanisms involve early hormonal and metabolic factors during intrauterine life, leptin, insulin and the insulin growth factor system and, potentially, the endocannabinoid system. Compared with normal weight women with PCOS, those with obesity are characterised by a worsened hyperandrogenic and metabolic state, poorer menses and ovulatory performance and, ultimately, poorer pregnancy rates. The importance of obesity in the pathogenesis of PCOS is emphasised by the efficacy of lifestyle intervention and weight loss, not only on metabolic alterations but also on hyperandrogenism, ovulation and fertility. The increasing prevalence of obesity among adolescent and young women with PCOS may partly depend on the increasing worldwide epidemic of obesity, although this hypothesis should be supported by long-term prospective epidemiological trials. This may have great relevance in preventive medicine and offer the opportunity to expand our still limited knowledge of the genetic and environmental background favouring the development of the PCOS.

Topics: Adipose Tissue; Adult; Cannabinoid Receptor Modulators; Female; Humans; Hyperandrogenism; Infertility, Female; Insulin Resistance; Leptin; Male; Menstruation Disturbances; Obesity; Phenotype; Polycystic Ovary Syndrome; Pregnancy; Prenatal Exposure Delayed Effects

The lipodystrophies (LD) are characterized by metabolic abnormalities (insulin resistance, hypertriglyceridemia, and diabetes) and a polycystic ovarian syndrome (PCOS) phenotype. Therapeutic administration of leptin improves insulin sensitivity and the metabolic features.. The objective of the study was to investigate whether the PCOS features are corrected by increasing insulin sensitivity as a function of leptin treatment.. This was a prospective, open-label trial using leptin replacement in various forms of lipodystrophy.. The study was performed at the Clinical Center at the National Institutes of Health.. Twenty-three female patients with LD were enrolled in a leptin replacement trial from 2000 to the present. Different parameters were assessed at baseline and after 1 yr of therapy.. Patients were treated with leptin for at least 1 yr.. We evaluated free testosterone, SHBG, and IGF-I at baseline and after 1 yr of leptin.. Testosterone levels decreased from 3.05 ±0.6 ng/ml at baseline to 1.7 ±0.3 ng/ml (P = 0.02). SHBG increased from 14.5 ±2 to 25 ±3.5 nmol/liter after 1 yr of leptin therapy. There were no significant changes in the levels of gonadotropins and ovarian size as a result of leptin replacement therapy. IGF-I increased significantly after leptin therapy from 150 ±14 to 195 ±17. There was a significant decrease in triglycerides and glycosylated hemoglobin in the context of reduced insulin requirements.. In the present study, we show that LD may be a model for the common forms of PCOS and that the endocrine features are corrected by leptin therapy, which reduces insulin resistance.

Topics: Adolescent; Adult; Child; Female; Follow-Up Studies; Hormone Replacement Therapy; Humans; Hyperandrogenism; Insulin Resistance; Leptin; Lipodystrophy; Polycystic Ovary Syndrome; Time Factors; Young Adult

The aim was to compare the effects of a traditional therapy (an oral estroprogestagen) to those of a novel treatment (a low-dose combination of generics) in adolescent girls with androgen excess.. In an open-label trial over 1 yr, 34 adolescents (age, 16 yr; body mass index, 23 kg/m2) with hyperinsulinemic androgen excess and without pregnancy risk were randomized to receive daily ethinyl estradiol-cyproterone acetate (EE-CA; Diane 35 Diario) or a low-dose combination of pioglitazone 7.5 mg/d, flutamide 62.5 mg/d, and metformin 850 mg/d (PioFluMet). Markers of androgen excess, C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, body composition (absorptiometry), abdominal fat partitioning (magnetic resonance imaging), and gene expression in longitudinal biopsies of sc adipose tissue at the abdominal level (RT-PCR) were assessed at baseline and after 1 yr.. EE-CA and low-dose PioFluMet reduced androgen excess comparably, but had divergent effects on C-reactive protein, high molecular weight adiponectin, lipids, carotid intima media thickness, lean mass, abdominal and visceral fat, and on the expression of CD163, leptin, TNF-like weak inducer of apoptosis receptor, and angiopoietin-like protein 4, respectively, related to macrophage activation, fat accretion, inflammation, and lipoprotein metabolism in adipose tissue. All these divergences pointed to a healthier condition on low-dose PioFluMet.. EE-CA and PioFluMet are similarly effective in reversing androgen excess over 1 yr, but low-dose PioFluMet is superior in reversing inflammatory, metabolic, and cardiovascular anomalies that are often associated with androgen excess.

Topics: Abdominal Fat; Adolescent; Androgen Antagonists; Angiopoietin-Like Protein 4; Angiopoietins; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Body Composition; Cyproterone Acetate; Dose-Response Relationship, Drug; Drug Combinations; Ethinyl Estradiol; Female; Flutamide; Gene Expression; Humans; Hyperandrogenism; Hypoglycemic Agents; Leptin; Metformin; Pioglitazone; Receptors, Cell Surface; Receptors, Tumor Necrosis Factor; Subcutaneous Fat; Thiazolidinediones; TWEAK Receptor

Lipodystrophy patients are hypoleptinemic and insulin resistant. Women have enlarged polycystic ovaries, hyperandrogenism, and amenorrhea. We have determined the role of correction of hypoleptinemia on these metabolic and neuroendocrine parameters. Ten females and 4 males with generalized lipodystrophy were treated with recombinant methionyl human leptin (r-metHuLeptin) in physiologic doses in an open-labeled study for a period of 12 and 8 months, respectively. In the female group, serum free testosterone decreased from 39.6 +/- 11 to 18.9 +/- 4.5 ng/dL (P < 0.01) and serum sex hormone binding globulin increased from 14 +/- 2.5 to 25 +/- 4.8 nmol/L (P < 0.02). Luteinizing hormone (LH) responses to LH releasing hormone were more robust after therapy and significantly changed in the youngest group of 3 female patients (P < 0.01). Ovarian ultrasound showed a polycystic ovarian disease pattern in all patients and did not change after therapy. Eight of the 10 patients had amenorrhea prior to therapy and all 8 developed normal menses after therapy. In the male group, serum testosterone tended to increase from 433 +/- 110 to 725 +/- 184 ng/dL (P = 0.1) and sex hormone binding globulin also increased from 18.25 +/- 2.6 to 27 +/- 1.7 nmol/L (P < 0.04) following r-metHuLeptin therapy. Serum LH response to LH releasing hormone did not show significant changes. Five additional hypoleptinemic male subjects with minimal metabolic abnormalities underwent normal pubertal development without receiving r-metHuLeptin therapy. In both genders, insulin-like growth factor increased significantly and there were no differences in growth hormone, thyroid, or adrenal hormone levels following r-metHuLeptin therapy. Glycemic parameters significantly improved after r-metHuLeptin therapy in both groups. Hypoglycemic medications were discontinued in 7 of 12 patients and dramatically reduced in 5 patients. r-metHuLeptin therapy plays an important role in insulin sensitivity. In females, it plays an additional role in normalizing menstrual function. This is likely to occur both from increasing insulin sensitivity and from restoring LH pulsatility. The persistent hypoleptinemic state in these subjects did not inhibit pubertal development.

Topics: Adolescent; Adult; Aged; Amenorrhea; Androgens; Blood Glucose; Child; Female; Human Growth Hormone; Humans; Hyperandrogenism; Insulin-Like Growth Factor I; Leptin; Lipodystrophy; Luteinizing Hormone; Male; Menstruation; Pituitary Function Tests; Pituitary Gland; Polycystic Ovary Syndrome; Puberty; Recombinant Proteins; Sex Hormone-Binding Globulin; Testosterone; Thyroid Gland

To evaluate the effect of rosiglitazone on insulin resistance and hyperandrogenism in polycystic ovary syndrome (PCOS).. Rosiglitazone was given 4 mg daily to 30 patients with PCOS for 12 weeks. Before and after treatment, body mass index (BMI), plasma glucose, insulin, levels insulin resistance index (HOMA IR), blood lipid spectrum, leptin, neuropeptide Y, and sex hormone concentrations and ovulation rate were determined and compared.. After 12 weeks of treatment, basal insulin level decreased from (18 +/- 8) to (12 +/- 7) mIU/L (P < 0.01), HOMA IR decreased from 4.3 +/- 1.2 to 2.6 +/- 0.7 (P < 0.01). Luteinizing hormone, free testosterone and androstenedione levels decreased [(15.4 +/- 4.4) versus (7.9 +/- 2.1) U/L, (12.5 +/- 1.9) versus (8.9 +/- 1.4) pmol/L, (9.8 +/- 1.7) versus (7.4 +/- 1.2) nmol/L respectively, P < 0.01]; Dehydroepiandrosterone sulfate level also decreased [(8.7 +/- 3.5) versus (6.9 +/- 2.1) micromol/L, P < 0.05]; Sex hormone binding globulin level increased [(39 +/- 3) versus (58 +/- 5) nmol/L, P < 0.01]. Plasma leptin level was decreased [(18 +/- 4) versus (13 +/- 3) microg/L, P < 0.01]. Ovulation rate increased to 50%.. Rosiglitazone might decrease plasma leptin level and improve insulin sensitivity, which led to alleviation of hyperandrogenism and resumption of ovulation and menses in patients with PCOS.

Topics: Administration, Oral; Adult; Androstenedione; Blood Glucose; Body Weight; Female; Follicle Stimulating Hormone; Humans; Hyperandrogenism; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Lipids; Luteinizing Hormone; Menstruation; Neuropeptide Y; Ovulation; Polycystic Ovary Syndrome; Rosiglitazone; Testosterone; Thiazoles; Thiazolidinediones; Treatment Outcome

Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder characterized by high androgen levels. The aim of this study was to evaluate the effects of hyperandrogenism on the hypothalamus and subsequently on the food intake and obesity in females.. A dihydroxy testosterone (DHT)-induced rat model was established to recapitulate the hyperandrogenism features of PCOS patients. Body weight and food intake of the rats were recorded. The food intake of DHT-induced rats was restricted by pair feeding to exclude possible effects of weight gain on the hypothalamus. The expression levels of relevant proteins and mRNAs in the hypothalamus and primary hypothalamic neurons exposed to DHT were analyzed by Western blotting and RT-PCR, respectively. The leptin levels in the serum and cerebrospinal fluid (CSF) were measured, and leptin was injected via the intracerebroventricular (ICV) route to test the leptin sensitivity of the hypothalamus.. The excessive prepuberty androgen levels in the DHT-induced rats markedly elevated food intake prior to weight gain. Consistent with this, the expression of neuropeptide Y and agouti-related peptide mRNAs was upregulated, which occurred prior to obesity and even with restricted food intake. In addition, the hypothalamic sensitivity to insulin and leptin was also impaired in the DHT-induced rats before obesity and with restricted food intake. DHT significantly reduced the leptin levels in the CSF, and ICV injection of leptin inhibited the DHT-induced increase in food intake.. Androgen excess increased food intake in rats and promoted obesity by downregulating insulin and leptin signaling in the hypothalamus, most likely by suppressing leptin levels in the CSF.

Topics: Androgens; Animals; Body Weight; Eating; Female; Humans; Hyperandrogenism; Hypothalamus; Insulin; Leptin; Neuropeptide Y; Obesity; Polycystic Ovary Syndrome; Rats; RNA, Messenger; Signal Transduction; Testosterone; Weight Gain

Whether HAIR-AN syndrome and polycystic ovarian syndrome (PCOS) are distinct entities or represent a phenotypic spectrum of the same syndrome is still unclear. HAIR-AN syndrome is characterized by high insulin resistance, obesity, and hyperinsulinemia as compared to PCOS and could represent adipose tissue dysfunction as the primary pathophysiologic trigger. This study was undertaken to study the role of adipose tissue dysfunction in HAIR-AN syndrome and PCOS using adipocytokines as surrogate markers of "adiposopathy.". A cross-sectional observational study was conducted at a tertiary care hospital over a period of 1 year. Serum adiponectin, leptin, IL-6, and TNF-α levels were measured in 30 women with HAIR-AN syndrome and in 30 women with PCOS. Correlations between adipocytokines, inflammatory markers, serum testosterone, and serum insulin were determined. Data analysis was performed using the SPSS version 23.0 (IBM SPSS Statistics Inc., Chicago, IL, USA) software program.. Women with HAIR-AN syndrome had significantly higher hyperandrogenemia, hyperinsulinemia, and insulin resistance as compared to PCOS women. They also had high leptin levels and lower adiponectin levels (p < 0.001). However, the levels of inflammatory markers (TNF-α and IL-6) were similar in both the groups (p > 0.05). Serum adiponectin showed a negative correlation with HOMA-IR and testosterone levels, while leptin showed a positive correlation with both in HAIR-AN patients while no such correlation was found in the PCOS group.. The significantly raised adipocytokines in HAIR-AN syndrome patients as compared to PCOS patients indicates the primary role of adipose tissue dysfunction ("adiposopathy") in the pathogenesis of HAIR-AN syndrome while only a minor role, if any, in PCOS. Both these syndromes stand as distinct entities pathogenically with an overlapping phenotype.

Topics: Acanthosis Nigricans; Adiponectin; Adipose Tissue; Adolescent; Adult; Asian People; Cross-Sectional Studies; Female; Humans; Hyperandrogenism; India; Insulin Resistance; Interleukin-6; Leptin; Polycystic Ovary Syndrome; Tumor Necrosis Factor-alpha; Young Adult

The present study was designed to elucidate the underlying mechanisms of Bao Gui capsule (BGC) against hyperandrogenism, insulin resistance and leptin resistance of PCOS. Letrozole was used to induce a PCOS model in rats, which were then randomly divided into four groups (n=9): Control, Model, high‑dose BGC (BGC‑H) and low‑dose BGC (BGC‑L) group. Serum levels of follicle‑stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2), insulin, leptin, and interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α (TNF‑α) in the hypothalamus were determined by ELISA. Protein levels of cytochrome P450c17α and cytochrome P450 aromatase (P450arom) in ovaries were determined by immunohistochemistry and western blot analysis. Additionally, the expression of GLUT4 in uterus and muscle tissue, and NF‑κB, IKKβ and SOCS3 mRNA levels in the hypothalamus were evaluated. BGC significantly reduced body weight gain and decreased serum levels of LH/FSH, T, log T/E2, insulin and leptin compared with the PCOS model rats. Furthermore, BGC markedly reduced the expression of P450c17α and significantly increased the expression of P450arom in ovaries, and increased the expression of GLUT4 in uterus and muscle tissues. BGC also effectively reduced the level of IL‑6 and TNF‑α, and the expression of IKKβ, NF‑κB and SOCS3 in the hypothalamus of PCOS model rats. These results suggest that BGC may effectively improve hyperandrogenism, insulin resistance, endometrial receptivity and the low‑grade chronic inflammation in the hypothalamus.

Topics: Animals; Cytokines; Drugs, Chinese Herbal; Endometrium; Estradiol; Female; Follicle Stimulating Hormone; Glucose Transporter Type 4; Hyperandrogenism; Hypothalamus; Insulin; Insulin Resistance; Leptin; Luteinizing Hormone; Phytotherapy; Plant Preparations; Polycystic Ovary Syndrome; Rats; Testosterone; Uterus

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.

Topics: Animals; Blood Pressure; Body Composition; Body Weight; Disease Models, Animal; Drug Evaluation, Preclinical; Eating; Female; Glucagon-Like Peptide-1 Receptor; Heart Rate; Hyperandrogenism; Insulin Resistance; Leptin; Lipids; Liraglutide; Metabolic Syndrome; Polycystic Ovary Syndrome; Postmenopause; Random Allocation; Rats, Sprague-Dawley; Renin-Angiotensin System

Polycystic ovary syndrome (PCOS) is an androgen excess disorder associated with obesity and adipose tissue disturbances. Our aim was to evaluate gene expression of adipocytokines and adipocyte characteristics in abdominal subcutaneous adipose tissue (SAT) of PCOS women.. Twelve PCOS (PCOSw) and 12 control (Cw) premenopausal women (BMI 20-35 kg/m. Both groups were comparable in age and BMI. Trunk fat mass amount (p = .043), serum and SAT leptin/adiponectin ratio (p = .034 and p = .028, respectively) and adipocyte area (p = .015) were higher in PCOSw compared to Cw. Interestingly, trunk fat mass was positively correlated with adipocyte area in PCOSw (r = 0.821, p = .023), while the inverse correlation was found in Cw (r = -0.786, p = .021). Only in PCOSw, adipocyte area was positively correlated with serum testosterone (r = 0.857, p = .014) and visceral adipose tissue volume (r = 0.857, p = .014).. Our results indicate that PCOS women present adipose tissue dysfunction in the subcutaneous compartment, characterized by an alteration in adipocyte size and leptin/adiponectin expression and secretion, probably associated with higher androgen concentrations.

Topics: Adipocytes; Adipokines; Adiponectin; Adult; Body Composition; Female; Humans; Hyperandrogenism; Intra-Abdominal Fat; Leptin; Polycystic Ovary Syndrome; Subcutaneous Fat

Hyperandrogenic state in females is accompanied with metabolic syndrome, insulin resistance and vascular pathologies. A total of 67%-85% of hyperandrogenic women suffer also from vitamin D deficiency. We aimed to check a potential interplay between hyperandrogenism and vitamin D deficiency in producing insulin resistance and effects on coronary resistance arteries. Adolescent female rats were divided into four groups, 11-12 animals in each. Transdermal testosterone-treated and vehicle-treated animals were kept either on vitamin D-deficient or on vitamin D-supplemented diet for 8 weeks. Plasma sexual steroid, insulin, leptin and vitamin D plasma levels were measured, and oral glucose tolerance test was performed. In coronary arterioles, insulin receptor and vitamin D receptor expressions were tested by immunohistochemistry, and insulin-induced relaxation was measured in vitro on isolated coronary resistance artery segments. Testosterone impaired glucose tolerance, and it diminished insulin relaxation but did not affect the expression of insulin and vitamin D receptors in vascular tissue. Vitamin D deficiency elevated postprandial insulin levels and homeostatic model assessment insulin resistance. It also diminished insulin-induced coronary arteriole relaxation, while it raised the expression of vitamin D and insulin receptors in the endothelial and medial layers. Our conclusion is that both hyperandrogenism and vitamin D deficiency reduce sensitivity of coronary vascular tissue to insulin, but they do it with different mechanisms.

Topics: Animals; Arterioles; Biomarkers; Blood Glucose; Coronary Artery Disease; Coronary Vessels; Disease Models, Animal; Female; Glucose Tolerance Test; Gonadal Steroid Hormones; Hyperandrogenism; Insulin; Insulin Resistance; Leptin; Polycystic Ovary Syndrome; Rats, Wistar; Time Factors; Vascular Resistance; Vasodilation; Vitamin D; Vitamin D Deficiency

Hyperandrogenemia in females may be associated with sympathetic nervous system (SNS) activation and increased blood pressure (BP). However the importance of hyperandrogenemia in causing hypertension in females and the mechanisms involved are still unclear. We tested whether chronic hyperandrogenemia exacerbates hypertension in young female spontaneously hypertensive rats (SHR) and whether endogenous melanocortin-3/4 receptor (MC3/4R) activation contributes to the elevated BP.. Cardiovascular and metabolic effects of chronic MC3/4R antagonism were assessed in female SHR treated with dihydrotestosterone (DHT, beginning at 5 weeks of age) and placebo-treated female SHR. BP and heart rate (HR) were measured by telemetry and an intracerebroventricular (ICV) cannula was placed in the lateral ventricle for infusions. After control measurements, the MC3/4R antagonist (SHU-9119) was infused for 10 days (1 nmol/hour, ICV, at 15 weeks of age) followed by a 5-day recovery period.. MC3/4R antagonism increased food intake and body weight in DHT-treated SHR (14±1 to 35±1g/day and 244±3 to 298±8g) and controls (14±1 to 34±2g/day and 207±4 to 269±8g). Compared to untreated SHR, DHT-treated SHR had similar BP but lower HR (146±3 vs. 142±4mm Hg and 316±2 vs. 363±4 bpm). Chronic SHU-9119 infusion reduced BP and HR in DHT-treated SHR (-12±2mm Hg and -14±4 bpm) and control female SHR (-19±2mm Hg and -21±6 bpm).. These results indicate that hyperandrogenemia does not exacerbate hypertension in female SHR. MC3/4R antagonism reduces BP and HR despite marked increases in food intake and body weight in hyperandrogenemic and control female SHR.

Topics: Animals; Appetite; Blood Glucose; Blood Pressure; Body Weight; Central Nervous System; Dihydrotestosterone; Eating; Female; Hyperandrogenism; Insulin; Leptin; Rats, Inbred SHR; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Respiration

Almost 50% of the women with polycystic ovary syndrome (PCOS) are obese. Obesity in PCOS affects reproduction via various mechanisms. Hyperandrogenism, increased luteinizing hormone (LH) and insulin resistance play a pivotal role. Several substances produced by the adipose tissue including leptin, adiponectin, resistin and visfatin may play a role in the pathophysiology of PCOS. Infertility in PCOS is related to anovulation. For induction of ovulation, clomiphene citrate and human gonadotrophins are first- and second-line treatments, respectively. Other treatment modalities include the use of insulin sensitizers, such as metformin as well as aromatase inhibitors and laparoscopic ovarian drilling, while in vitro fertilization is the last resort. Obesity can adversely affect infertility treatment in PCOS. Diet and lifestyle changes are recommended for the obese women before they attempt conception. The use of anti-obesity drugs and bariatric surgery in PCOS require further evaluation.

Topics: Adipokines; Adiponectin; Female; Humans; Hyperandrogenism; Hyperinsulinism; Hypoglycemic Agents; Infertility, Female; Insulin Resistance; Leptin; Life Style; Luteinizing Hormone; Metformin; Nicotinamide Phosphoribosyltransferase; Obesity; Ovulation Induction; Polycystic Ovary Syndrome; Resistin

Five to ten percent of women of reproductive age suffer from polycystic ovary syndrome (PCOS). Leptin, NPY, galanin, cholecystokinin (CCK) are involved in the regulation of eating behavior. PPARγ are receptors that are probably involved in hyperandrogenism. This study was designed to assess associations between the Pro12Ala PPARγ2 gene polymorphism and satiety factors in PCOS. Fifty-four PCOS women and 51 healthy women were studied. Leptin, NPY, galanin, CCK levels, and genetic studies to detect Pro12Ala PPARγ2 gene polymorphism were assessed. The leptin levels in the PCOS women carrying Pro12Ala genotype were higher than in those with Pro12Pro and Ala12Ala. The PCOS women had higher leptin and NPY levels and lower galanin levels. Obese PCOS patients had lower CCK levels.. In the PCOS women, a single Ala allele may have a protective role as far as hyperleptinemia is concerned. The PCOS women may reveal a disrupted central leptin/NPY feedback loop with some shifts in food intake.

Topics: Adult; Body Mass Index; Cholecystokinin; Female; Galanin; Genotype; Humans; Hyperandrogenism; Insulin Resistance; Leptin; Neuropeptide Y; Obesity; Polycystic Ovary Syndrome; Polymorphism, Genetic; PPAR gamma; Satiation

The objective was to investigate whether the associations between leptin, adiponectin, andadiposity reported in classic polycystic ovary syndrome (PCOS) are also observed in elderly women with a novel putative postmenopausal PCOS phenotype. We studied 713 postmenopausal community-dwelling women. Diagnosis of the novel phenotype required the presence of ≥3 diagnostic features including: 1) a personal history of oligomenorrhea; 2) history of infertility or miscarriage; 3) current or past clinical or hormonal evidence of hyperandrogenism; 4) central obesity; 5) biochemical evidence of insulin resistance. Women in the control group had ≤2 of these components. Mean age (±SD) was 74±8 years for the study cohort. Sixty-six women (9.3%) had the putative PCOS phenotype. Serum leptin was higher (mean 25.70±15.67 vs 14.94+9.89 ng/mL, P<.01) and adiponectin lower (mean 11.72±4.80 vs 17.31±7.45 μg/mL, P<.01) in cases vs controls. Leptin was positively, and adiponectin inversely, associated with an increasing number of phenotype features (P<.01 for linearity). In age-adjusted regression analysis, adjustment for waist circumference eliminated the association between leptin and the PCOS phenotype, but not the association between adiponectin and the PCOS phenotype. In this novel postmenopausal PCOS phenotype, adipocytokine profiles and their associations with adiposity parallel those reported in younger women with classic PCOS. These results support our hypothesis that a putative phenotype analogous to PCOS can be identified in postmenopausal women using clinical and biochemical criteria. Use of this novel phenotype could provide a basis for studies of the delayed consequences of PCOS in older women.

Topics: Abortion, Spontaneous; Adiponectin; Aged; Biomarkers; Body Mass Index; Female; Humans; Hyperandrogenism; Infertility, Female; Insulin Resistance; Leptin; Medical History Taking; Middle Aged; Obesity; Obesity, Abdominal; Oligomenorrhea; Phenotype; Polycystic Ovary Syndrome; Postmenopause; Premenopause

To assess the effects of weight loss on serum adipokine levels in polycystic ovary syndrome (PCOS).. We determined serum leptin, adiponectin, resistin, and visfatin levels in 60 overweight/obese women with PCOS and 48 BMI-matched female volunteers. Measurements were repeated after 24 weeks of treatment with orlistat 120 mg 3 times per day along with an energy-restricted diet.. At baseline, serum visfatin concentration was higher in patients with PCOS than in controls (p = 0.036); serum levels of leptin, adiponectin, and resistin did not differ between the two groups. After 24 weeks, a significant reduction in BMI and waist circumference was observed in both patients with PCOS and controls (p < 0.001 vs. baseline in both groups). Also serum leptin levels decreased in both patients with PCOS and controls (p < 0.001 vs. baseline in both groups). The reduction in serum leptin levels did not differ between groups. Serum adiponectin, resistin, and visfatin levels did not change in either group.. Leptin, adiponectin, and resistin do not appear to play major pathogenetic roles in overweight/obese patients with PCOS. In contrast, visfatin emerges as a potentially important mediator of the endocrine abnormalities of these patients. However, serum visfatin levels are not substantially affected by weight loss.

Topics: Adipokines; Adiponectin; Adult; Anti-Obesity Agents; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Female; Humans; Hyperandrogenism; Insulin Resistance; Lactones; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Orlistat; Polycystic Ovary Syndrome; Resistin; Waist Circumference; Weight Loss; Young Adult

Hyperandrogenemia predisposes an organism toward developing impaired insulin sensitivity. The aim of our study was to evaluate endocrine and metabolic effects during early allostasis induced by a fructose-rich diet (FRD) in normal (control; CT) and neonatal-androgenized (testosterone propionate; TP) female adult rats. CT and TP rats were fed either a normal diet (ND) or an FRD for 3 weeks immediately before the day of study, which was at age 100 days. Energy intake, body weight (BW), parametrial (PM) fat characteristics, and endocrine/metabolic biomarkers were then evaluated. Daily energy intake was similar in CT and TP rats regardless of the differences in diet. When compared with CT-ND rats, the TP-ND rats were heavier, had larger PM fat, and were characterized by basal hypoadiponectinemia and enhanced plasma levels of non-esterified fatty acid (NEFA), plasminogen activator inhibitor-1 (PAI-1), and leptin. FRD-fed CT rats, when compared with CT-ND rats, had high plasma levels of NEFA, triglyceride (TG), PAI-1, leptin, and adiponectin. The TP-FRD rats, when compared with TP-ND rats, displayed enhanced leptinemia and triglyceridemia, and were hyperinsulinemic, with glucose intolerance. The PM fat taken from TP rats displayed increase in the size of adipocytes, decrease in adiponectin (protein/gene), and a greater abundance of the leptin gene. PM adipocyte response to insulin was impaired in CT-FRD, TP-ND, and TP-FRD rats. A very short duration of isocaloric FRD intake in TP rats induced severe metabolic dysfunction at the reproductive age. Our study supports the hypothesis that the early-androgenized female rat phenotype is highly susceptible to developing endocrine/metabolic dysfunction. In turn, these abnormalities enhance the risk of metabolic syndrome, obesity, type 2 diabetes, and cardiovascular disease.

Topics: Adipocytes; Adipokines; Adiponectin; Adipose Tissue; Adiposity; Androgens; Animals; Body Weight; Dietary Sucrose; Disease Models, Animal; Energy Intake; Fatty Acids, Nonesterified; Female; Fructose; Genitalia, Female; Glucose Metabolism Disorders; Hyperandrogenism; Insulin; Leptin; Obesity; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; Risk Factors; Testosterone Propionate; Triglycerides

Topics: Abdominal Fat; Acanthosis Nigricans; Adolescent; Atherosclerosis; Bone Diseases, Endocrine; Child; Fatty Liver; Ghrelin; Humans; Hyperandrogenism; Hypertension; Insulin; Insulin Resistance; Leptin; Obesity; Peptide Hormones; Phenotype; Satiation; Sleep Apnea Syndromes

Hyperandrogenism in postmenopausal women is due to ovarian hyperthecosis or an androgen-secreting ovarian/adrenal tumor. Making the correct diagnosis might be complicated due to the possible existence of an adrenal neoplasm secreting testosterone only, ectopic ovarian tissue or ectopic luteinizing hormone/human chorionic gonadotropin receptors in the adrenals, as well as the relatively low sensitivity of imaging techniques (computed tomography, magnetic resonance imaging) and vein catheterization for this type of pathology. We present the case of an obese postmenopausal woman with metabolic syndrome, hyperandrogenism (high testosterone levels, suppressed gonadotropins), adrenal macronodular hyperplasia and Leydig-cell ovarian tumor. At presentation she had low leptin levels despite high body fat content. After a catheter study left adrenalectomy was carried out but hyperandrogenism persisted. Then, bilateral oophorectomy with hysterectomy was performed and a small Leydig-cell tumor was found in the left ovary. Postoperatively, testosterone and gonadotropin levels were normal (postmenopausal) and leptin level became elevated without change in body mass index or body fat content. In conclusion, we speculate that low leptin levels in obese hyperandrogenic women might be a marker for androgen-secreting tumors.

Topics: Adrenal Glands; Alopecia; Biomarkers; Female; Hirsutism; Humans; Hyperandrogenism; Hyperplasia; Leptin; Leydig Cell Tumor; Metabolic Syndrome; Middle Aged; Obesity; Ovarian Neoplasms

Polycystic ovary syndrome is considered to originate during puberty. The aim of this study was to investigate hormonal status in relationship to anthropometric data in girls with premature adrenarche and adolescent girls with hyperandrogenism, as these conditions are related to polycystic ovary syndrome in adulthood.. 20 girls with premature adrenarche (aged 4.9-10.2 years), 21 postmenarcheal girls with hirsutism (aged 13.3-17.8 years), 2 groups (n=13 in each) of healthy volunteers of similar age and body mass index participated in the study.. Serum testosterone and dehydroepiandrosterone sulphate levels were significantly higher in all patients than in controls. Free androgen index and leptin levels were significantly higher, and sex-hormone-binding globulin lower in hirsute adolescents vs. controls. Birth weight standard deviation scores were comparable in all 4 groups. Serum dehydroepiandrosterone sulphate negatively correlated with birth weight standard deviation scores in the group of girls with premature adrenarche (r=-0.57, p<0.001). By linear regression, 76% in variation of serum leptin levels could be explained by subscapular skinfold thickness standard deviation scores, and by serum sex-hormone-binding globulin, insulin, and dehydroepiandrosterone sulphate levels in all participants. Mean age of onset of menarche was younger in hirsute girls vs. controls (12.1+/-1.3 vs. 13.5+/-1.3 years, p=0.004).. Inverse correlation of dehydroepiandrosterone sulphate levels and weight at birth indicates relationship between premature adrenarche in girls and fetal growth. Higher leptin levels in adolescents with hyperandrogenism than in healthy girls show possible involvement of leptin in pathogenesis of hyperandrogenism.

Topics: Adolescent; Age Factors; Birth Weight; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Dehydroepiandrosterone Sulfate; Female; Hirsutism; Humans; Hyperandrogenism; Insulin; Leptin; Linear Models; Menarche; Polycystic Ovary Syndrome; Puberty, Precocious; Risk Factors; Testosterone

Hyperandrogenism is a multifactoral chronic disease, characterised by an androgen excess, often connected with obesity, hirsutism, polycystic ovaries, hyperinsulinemia, insulin resistance and hyperleptynemia. Peroxisome proliferator activated receptors (PPARgamma) are one of the factors influencing insulin sensitivity. As a transcriptional factor it plays a crucial role in the regulation of genes involved in insulin action. The aim of this study was to evaluate the frequency of PPARgamma Pro12Ala and Pro115Gln polymorphisms in hyperandrogenic women. The additional aim was to investigate differences in leptin levels in healthy and FOH (functional ovarian hyperandrogenism) women (non-obese and obese).. we investigated 90 women: 72 healthy women (37 nonobese and 35 obese)--control group, and 18 women with FOH (9 nonobese and 9 obese)--FOH group. We performed anthropological examination: BMI, WHR and total-body densytomery, biochemical and hormonal estimations in the whole group. PPARgamma polymorphism was studied using PCR and RFLP.. in the control group Pro12Pro ("wild" type) was observed in 45 women (26 obese and 19 nonobese) - 62.5% of the group. Heterozygosity Pro12Ala was observed in 15 women (20.8%): 4 obese and 11 with BMI < 30 kg/m2, homozygosity Ala12Ala was seen in 12 women (16.6%): 5 obese i 7 nonobese. In FOH group "wild" type was discovered in 9 women (4 obese and 5 nonobese) - 50% of FOH group, heterozygosity Pro12Ala was seen in 5 women (27.7%): 2 obese and 3 with BMI < 30 kg/m2, homozygosityAla12Ala was observed in 4 women (22.2%): 3 obese and in 1 non-obese. Ala allel frequency in control group was 28%. (37% in non-obese and 20% in obese). In FOH group Ala allel frequency was 36% (nonobese - 28%, obese - 44%). In the studied group we did not find Pro115Gln polymorphism. Leptin level in control group was 19.92 +/- 14.3 ng/ml, and in FOH group - 23.41 +/- 19.47 ng/ml. Depending on BMI leptin level in non-obese healthy group was 7.45 +/- 3.76 ng/ml, in non-obese FOH women - 18.33 +/- 16.54 ng/ml, p < 0.005. In obese controls leptin level was 43.6 +/- 17.28 ng/ml, and in obese FOH women - 45.72 +/- 14.89 ng/ml.. Leptin level in non-obese FOH women is significantly higher than in lean healthy controls. This difference was not observed in obese women. However the Pro12Ala polymorphism is quite common; it does not seem to be directly related to the obesity connected with hyperandrogenism. Higher frequency of Ala allele In FOH women compared to healthy controls (36% vs 28%) may at least partially explain the beneficial effect of tiazolidinediones in the treatment of hyperandrogenism.

Topics: Adult; Alleles; Female; Gene Expression; Humans; Hyperandrogenism; Leptin; Middle Aged; Obesity; Polymerase Chain Reaction; Polymorphism, Genetic; PPAR gamma

The relationship between leptin and insulin sensitivity, sexual steroids and insulin concentrations in women with polycystic ovary syndrome is still controversial. The objective of this study was to assess the relationship between insulin levels, insulin resistance parameters and serum leptin concentrations in healthy and polycystic ovary syndrome women.. 33 hyperandrogenic polycystic ovary syndrome women (GHA) and 27 healthy women (GS) were included in this study. Leptin, insulin, sex-hormone binding globulin (SHBG), testosterone and estradiol concentrations were determined in a basal sample. Body mass index, waist diameter and waist to hip ratio were recorded. Insulin sensitivity was calculated by means of insulin tolerance test and glycemia/insulinemia ratio.. The leptin concentration was not different between GHA and GS. Insulin levels and free testosterona index (FTI) were higher in GHA than GS (p < 0.01). The glycemia/insulinemia ratio, SHBG levels, and insulin sensitivity were lower in GHA (p < 0.01). In both groups positive correlations between leptin concentration and body mass index (p < 0.01), waist diameter (p < 0.01), insulin levels (p < 0.01) and glycemia/insulinemia ratio (p < 0.01) were observed. Only GHA showed correlation between insulin sensitivity and leptin concentration (p < 0.02). SHBG and leptin levels were not correlated.. The leptin concentration was not different between GHA and healthy women, although they are metabolically different. This phenomenon could be due to the fact that in hyperandrogenic women the effects of insulin resistance and hyperandrogenemia counteract each other.

Topics: Adolescent; Adult; Blood Glucose; Estradiol; Female; Humans; Hyperandrogenism; Insulin Resistance; Leptin; Polycystic Ovary Syndrome; Sex Hormone-Binding Globulin; Testosterone

To determine whether the opioidergic system is involved in the modulation of leptin secretion in healthy and amenorrheic subjects.. Prospective study.. Department of Obstetrics and Gynecology, University of Modena, Modena, Italy.. Healthy subjects (n = 8) and patients with hypothalamic amenorrhea (n = 17) or hyperandrogenism (n = 7) and low body mass index (BMI).. Acute infusion of naloxone (4-mg bolus) and blood sampling 15 minutes before infusion; at time of infusion; and 15, 30, 45, 60, 75, 90, and 120 minutes after infusion.. Plasma leptin, LH, FSH, E2, and cortisol concentrations.. Plasma leptin concentrations were lower (P <.01) in both hypothalamic and hyperandrogenic amenorrheic subjects than in healthy controls. In all groups of subjects, no significant changes in leptin levels were observed after infusion of naloxone. A significant correlation was found between leptin concentrations and BMI when all subjects were considered together (P <.05) but was not found in the single groups.. The present data do not support the hypothesis that opioidergic receptors are involved acutely in the modulation of leptin release in healthy and amenorrheic women.

Topics: Amenorrhea; Body Mass Index; Case-Control Studies; Female; Humans; Hyperandrogenism; Hypothalamic Diseases; Infusions, Intravenous; Leptin; Naloxone; Narcotic Antagonists; Proteins; Secretory Rate

To investigate the relationship between leptin levels and IDDM with and without microalbuminuria, fasting serum levels of leptin, insulin, insulin-like growth factor-1 (IGF-1), sex hormone-binding globulin (SHBG), testosterone (SHBG) ratio, blood pressure and body mass index (BMI) were measured in 18 normo- and 11 microalbuminuric females with >5 years of IDDM, and 24 healthy controls in late puberty. Leptin levels were higher in micro- than normoalbuminuric IDDM patients, and lower in healthy controls than in both IDDM groups (p < 0.05, respectively). In multiple regression analysis, presence of IDDM and BMI independently contributed to increased leptin values (R2 = 0.34, p < 0.001). Including IDDM females only, solely low IGF-1 and high testosterone/SHBG were associated with leptin (R2 = 0.39, p = 0.009). Albumin excretion rate (AER) was correlated to leptin (r = 0.48, p = 0.01). With AER as the dependent variable only serum leptin and diastolic blood pressure added to the regression (R2 = 0.59, p < 0.001). In conclusion, serum leptin, independently of BMI, is: (1) increased in IDDM females of late puberty; (2) associated with low IGF-1 and hyperandrogenemia, and (3) related to increased albumin excretion rate in IDDM females.

Topics: 3-Hydroxybutyric Acid; Adolescent; Adult; Albuminuria; Blood Pressure; Body Mass Index; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Fluoroimmunoassay; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hyperandrogenism; Insulin; Insulin-Like Growth Factor I; Leptin; Proteins; Puberty; Radioimmunoassay; Regression Analysis; Sex Hormone-Binding Globulin; Testosterone

Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, glucose intolerance, and obesity. High levels of the lipostatic hormone, leptin, have also been reported in this condition. The purpose of the present study was to examine the effect of an oral contraceptive (OC) of low androgenicity containing desogestrel on glucose tolerance in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on leptin concentrations. Sixteen nondiabetic hyperandrogenic women, aged 29 +/- 1 yr with a body mass index (BMI) of 36.8 +/- 1.8 kg/m2, underwent an oral glucose tolerance test before and after 6 months of therapy with the OC. Free testosterone decreased and sex hormone-binding globulin increased after therapy (P < 0.001). Glucose tolerance deteriorated significantly, and two women developed diabetes. Body weight, BMI, and leptin did not change significantly. Leptin correlated with BMI before (r = 0.56; P = 0.02) and after (r = 0.51; P = 0.04) treatment, but not with glucose, insulin, total and free testosterone, or sex hormone-binding globulin before or after treatment. In conclusion, 1) glucose tolerance should be monitored in hyperandrogenic women using OC, even those of low androgenicity; and 2) changes in androgenic/estrogenic status had no effect on the leptin concentration, suggesting that its sexual dimorphism is not related to sex steroids.. Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, and glucose intolerance--all of which, in turn, have been linked to high levels of the lipostatic hormone, leptin. This study investigated the effect of an oral contraceptive (OC) containing a progestin of low androgenicity on glucose tolerance and insulinemia in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on plasma leptin levels. 16 nondiabetic hyperandrogenic US women (mean age, 29 years) with a mean body mass index of 36.8 kg/sq. m underwent oral glucose tolerance testing before and after 6 months of treatment with an OC containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel. Treatment was associated with significant decreases in free testosterone and increased sex hormone-binding globulin (p 0.001). Glucose tolerance deteriorated moderately but significantly. After 6 months of treatment, 5 women had normal glucose tolerance, 9 had impaired glucose tolerance, and 2 developed non-insulin-dependent diabetes mellitus. There were no significant changes in serum insulin concentrations, body weight, body mass index, or leptin, but leptin levels were highly correlated with body mass index both before and after treatment. The data suggest that the sexual dimorphism of leptin is not caused by differences in sex hormones. Even when OCs containing low androgenic progestins are prescribed, women at high risk for diabetes should receive regular glucose tolerance tests.

Topics: Adult; Body Mass Index; Contraceptives, Oral; Desogestrel; Estradiol; Estrone; Female; Glucose Intolerance; Humans; Hyperandrogenism; Insulin; Leptin; Osmolar Concentration; Proteins; Reference Values