leptin and Hypogonadism

One-third of men with obesity or type 2 diabetes have subnormal free testosterone concentrations. The lower free testosterone concentrations are observed in obese men at all ages, including adolescents at completion of puberty. The gonadotropin concentrations in these males are inappropriately normal; thus, these patients have hypogonadotropic hypogonadism (HH). The causative mechanism of diabesity-induced HH is yet to be defined but is likely multifactorial. Decreased insulin and leptin signaling in the central nervous system are probably significant contributors. Contrary to popular belief, estrogen concentrations are lower in men with HH. Men with diabesity and HH have more fat mass and are more insulin resistant than eugonadal men. In addition, they have a high prevalence of anemia and higher mortality rates than eugonadal men. Testosterone replacement therapy results in a loss of fat mass, gain in lean mass, and increase in insulin sensitivity in men with diabesity and HH. This is accompanied by an increase in insulin-signaling genes in adipose tissue and a reduction in inflammatory mediators that interfere with insulin signaling. There is also an improvement in sexual symptoms, anemia, LDL cholesterol, and lipoprotein (a). However, testosterone therapy does not consistently affect HbA

Topics: Diabetes Mellitus, Type 2; Humans; Hypogonadism; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Obesity; Prevalence; Testosterone

Patients with type 2 diabetes have lower serum testosterone levels and a higher prevalence of hypogonadism than non-diabetic patients, independently of the metabolic control of disease. The mechanisms underlying a decrease in testosterone might be related to age, obesity and insulin resistance, often present in patients with type 2 diabetes. The increase in estrogens due to higher aromatase enzyme activity in increased adipose tissue might exert negative-feedback inhibition centrally. Insulin stimulates gonadal axis activity at all three levels and therefore insulin resistance might account for the lower testosterone production. Leptin exerts a central stimulatory effect but inhibits testicular testosterone secretion. Thus, resistance to leptin in obese subjects with type 2 diabetes determines lower central effects of leptin with lower gonadotropin-releasing hormone (GnRH) secretion and, on the other hand, hyperleptinemia secondary to leptin resistance inhibits testosterone secretion at the testicular level. However, lower testosterone levels in patients with diabetes are observed independently of age, weight and body mass index, which leads to the assumption that hyperglycemia per se might play a role in the decrease in testosterone. Several studies have shown that an overload of glucose results in decreased serum testosterone levels. The aim of this review is to assess changes in the male gonadal axis that occur in patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Estrogens; Humans; Hyperglycemia; Hypogonadism; Insulin Resistance; Leptin; Male; Prevalence

Hypothalamic obesity represents a rare diagnosis applicable to only a small subset of obese patients. It is important to identify, diagnose, and treat these patients. This article reviews the physiology of the hypothalamus, focusing on its role in regulation of hunger, feeding, and metabolism. The causes of hypothalamic obesity are discussed including genetic, anatomic, and iatrogenic etiologies. The complex hormonal environment leading to obesity is explored for each etiology and treatment strategies are discussed. Reproductive consequences are also reviewed.

Topics: Appetite; Appetite Depressants; Bariatric Surgery; Craniopharyngioma; Energy Metabolism; Feeding Behavior; Humans; Hyperphagia; Hypogonadism; Hypothalamic Diseases; Hypothalamic Hormones; Hypothalamus; Iatrogenic Disease; Infertility; Leptin; Nerve Tissue Proteins; Obesity; Pituitary Neoplasms; Postoperative Complications; Pro-Opiomelanocortin; Puberty, Delayed; Receptors, Leptin; Receptors, Melanocortin; Sedentary Behavior

Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic-pituitary-gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin.

Topics: Amenorrhea; Energy Metabolism; Female; Humans; Hypogonadism; Hypothalamic Diseases; Leptin; Obesity; Reproduction

Obesity in men, particularly when central, is associated with lower total testosterone [TT], free testosterone [FT] and sex hormone-binding globulin [SHBG], and a greater decline in TT and FT with increasing age compared with lean men. Obesity-related conditions such as obstructive sleep apnea, insulin resistance and type 2 diabetes mellitus are independently associated with decreased plasma testosterone. Possible mechanisms include decreased LH pulse amplitude, inhibitory effects of oestrogen at the hypothalamus and pituitary and the effects of leptin and other peptides centrally and on Leydig cells. Obese men have reduced sperm concentration and total sperm count compared to lean men but sperm motility and morphology appear unaffected. The cause and effect relationships between low plasma androgen levels, obesity and the metabolic syndrome, and associated cardiometabolic risk remain unclear. While weight loss normalizes TT and FT in obese men, androgen replacement in the short term does not significantly improve cardiometabolic risk profile despite reducing fat mass.

Topics: Aging; Animals; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Leptin; Luteinizing Hormone; Male; Metabolic Syndrome; Obesity; Risk Factors; Signal Transduction; Sleep Apnea, Obstructive; Spermatogenesis; Testis; Testosterone; Weight Loss

The prevalence of anorexia nervosa has increased in recent years and a large proportion of patients with this disorder have low bone density at diagnosis and, therefore, an increased risk of early and late fractures. The mechanism of bone loss in anorexia nervosa is not well understood, yet it likely includes hypogonadism, alterations of the GH-IGF-1 axis and hypercortisolism. DEXA is the most effective tool for assessing and monitoring bone density in these patients, and it is important to improve or at least stabilize bone metabolism in those with low bone mass. No agent has yet been proven to be effective in improving bone density. However, sustained weight recovery and menses besides an adequate intake of calcium and vitamin D are recommended to optimize the conditions in which bone mass accrual may occur.

Topics: Adipose Tissue; Adolescent; Adult; Anorexia Nervosa; Bone and Bones; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Calcium; Cushing Syndrome; Fractures, Bone; Gonadal Steroid Hormones; Humans; Hypogonadism; Intercellular Signaling Peptides and Proteins; Leptin; Male; Minerals; Osteoporosis; Vitamin D; Young Adult

Congenital hypogonadotropic hypogonadisms (CHH) are a well-known cause of pubertal development failure in women. In a majority of patients, the clinical spectrum results from an insufficient and concomitant secretion of both pituitary gonadotropins LH and FSH that impedes a normal endocrine and exocrine cyclical ovary functioning after the age of pubertal activation of gonadotropic axis. In exceptional but interesting cases, they can result from an elective deficit of one of the gonadotropins follicle-stimulating hormone (FSH) or luteinizing hormone (LH) by genetic anomaly of their specific ss sub-unit. CHH prevalence, estimated from teaching hospital series, is considered to be two to five fold less important in women compared to men bearing the disease. This frequency is probably under-estimated in reason of under-diagnosis of forms with partial pubertal development. Isolated or apparently isolated forms (i.e., Kallmann syndrome with anosmia or hyposmia not spontaneously expressed by the patients) of these diseases are most of the time discovered during adolescence or in adulthood in reason of lacking, incomplete or even apparently complete pubertal development, but with almost constant primary amenorrhea. In a minority of cases and mainly in familial forms, genetic autosomal causes have been found. These cases are related to mutations of genes impinging the functioning of the pituitary-hypothalamic pathways involved in the normal secretion of LH and FSH (mutations of GnRHR, GnRH1, KISS1R/GPR54, TAC3, TACR3), which are always associated to isolated non syndromic CHH without anosmia. Some cases of mutations of FGFR1, and more rarely of its ligand FGF8, or of PROKR2 or its ligand PROK2 have been shown in women suffering from Kallmann syndrome or its hyposmic or normosmic variant. In complex syndromic causes (mutations of CHD7, leptin and leptin receptor anomalies, Prader-Willi syndrome, etc.), diagnosis of the CHH cause is most often suspected or set down before the age of puberty in reason of the associated clinical signs, but some rare cases of paucisymptomatic syndromic causes can initially be revealed during adolescence, like isolated non syndromic CHH or Kallmann syndrome.

Topics: Female; Fibroblast Growth Factor 8; Follicle Stimulating Hormone; Gastrointestinal Hormones; Humans; Hypogonadism; Kallmann Syndrome; Leptin; Luteinizing Hormone; Mutation; Neuropeptides; Ovarian Follicle; Ovulation; Prader-Willi Syndrome; Pregnancy; Pregnancy Complications; Puberty; Receptor, Fibroblast Growth Factor, Type 1; Receptors, G-Protein-Coupled; Receptors, Leptin; Receptors, Peptide; Theca Cells

Puberty is the developmental period during which rapid somatic changes and attainment of reproductive capacity take place. The sine qua non event for the onset of puberty is the increase in pulsatile GnRH release from GnRH neurons. GnRH neurons originate in the nasal placode and migrate, from the nasal compartment through the basal forebrain, before they attain their positions in the hypothalamus. Failure of GnRH neurons to migrate, mainly due to genetic alterations, leads to a clinical condition defined congenital hypogonadotropic hypogonadism. Other important factors demonstrated a permissive role for GnRH secretion at time of puberty, such as the kisspeptin G-protein-coupled receptor 54 (GPR54, now called KISS-1R) and its ligand, as well as neurokinin B (NKB) and the neurokinin 3 (NK3) receptor. Kisspeptin and neurokinin B colocalized in a subset of hypothalamic neurons that regulate GnRH secretion by GnRH neurons. Indeed, loss of function mutations in the above-mentioned and other genes result in hypogonadotrophic hypogonadism with absence of pubertal development. In males, pubertal increase of androgens levels seems to be required for the attainment of a normal bone density and male-specific body composition. However, also genetic variants of genes involved in bone metabolism as well as in osteoblast/osteoclast activation are associated to bone mineral density.

Topics: Androgens; Animals; Body Composition; Bone Density; Cell Movement; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Kisspeptins; Leptin; Male; Neurons; Puberty; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Tumor Suppressor Proteins

Women with mood disorders, especially bipolar disorder (BD), have been shown to have high rates of reproductive and metabolic dysfunction. The available data on the functional, anatomic, and clinical neuroendocrine abnormalities in women with BD suggest a two-tiered relationship with mood pathology. First, many of the medications commonly used in the treatment of BD can have deleterious effects on blood levels of reproductive hormones and consequently on the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. Studies that have specifically addressed the association between psychotropic medications and menstrual abnormalities, polycystic ovary syndrome, and overall reproductive endocrine function in women with BD have found high rates of HPG irregularities in women with BD. Second, there is evidence of reproductive dysfunction in women with BD prior to treatment. In addition, many of the psychotropic medications used in the treatment of BD are associated with weight gain, insulin resistance, and dyslipidemia. These metabolic side effects further compound the neuroendocrine system dysregulation in women with BD. Current understanding of the reproductive and metabolic function in women with BD points to vulnerability, which in turn increases the risk of later-life cardiovascular disease and diabetes, among other morbidities, for women with BD.

Topics: Bipolar Disorder; Dyslipidemias; Endocrine System Diseases; Female; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Leptin; Lithium Carbonate; Menstruation; Obesity; Pituitary-Adrenal System; Polycystic Ovary Syndrome; Psychotropic Drugs; Valproic Acid

Puberty is an important developmental and life stage that leads to sexual maturation and reproductive capability. Although the physiology of puberty is similar among individuals, the timing of puberty is quite variable and affected by environmental and genetic influences. Identification of the responsible genetic factors will greatly enhance the understanding of the key components and the modulation of the hypothalamic-pituitary-gonadal axis.. Genetic analyses are increasingly elucidating the genetic basis of pathological abnormalities in pubertal timing, including causes of idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Ongoing studies are also investigating the genetic control of puberty in the general population, although no definitive association between genetic variants and variations in pubertal timing has been discovered so far.. This review summarizes recent advances regarding the genetic control of pubertal timing and presents areas for future investigation.

Topics: Adolescent; Animals; Gene Expression Regulation; Genetic Variation; Humans; Hypogonadism; Kallmann Syndrome; Leptin; Puberty; Quantitative Trait Loci; Time Factors

Recent work shows a high prevalence of low testosterone and inappropriately low LH and FSH concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity, and other features of the metabolic syndrome (obesity and overweight, hypertension and hyperlipidemia) in patients with type 2 diabetes. However, the duration of diabetes or HbA1c were not related to HH. Furthermore, recent data show that HH is also observed frequently in patients with the metabolic syndrome without diabetes but is not associated with type 1 diabetes. Thus, HH appears be related to the two major conditions associated with insulin resistance: type 2 diabetes and the metabolic syndrome. CRP concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and CRP concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations in type 2 diabetic men have also been related to a significantly lower hematocrit and thus to an increased frequency of mild anemia. Low testosterone concentrations are also related to an increase in total and regional adiposity, and to lower bone density. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates symptoms related to sexual dysfunction, and features of the metabolic syndrome, insulin resistance and inflammation.

Topics: Animals; Atherosclerosis; Bone Density; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Hematocrit; Humans; Hypogonadism; Inflammation Mediators; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Models, Biological; Obesity; Prostatic Neoplasms; Sexual Dysfunction, Physiological; Testosterone

Anorexia nervosa (AN), a condition of severe undernutrition, is associated with low bone mineral density (BMD) in adults and adolescents. Whereas adult women with AN have an uncoupling of bone turnover markers with increased bone resorption and decreased bone formation markers, adolescents with AN have decreased bone turnover overall. Possible contributors to low BMD in AN include hypoestrogenism and hypoandrogenism, undernutrition with decreased lean body mass, and hypercortisolemia. IGF-I, a known bone trophic factor, is reduced despite elevated growth hormone (GH) levels, leading to an acquired GH resistant state. Elevated ghrelin and peptide YY levels may also contribute to impaired bone metabolism. Weight recovery is associated with recovery of BMD but this is often partial, and long-term and sustained weight recovery may be necessary before significant improvements are observed. Anti-resorptive therapies have been studied in AN with conflicting results. Oral estrogen does not increase BMD or prevent bone loss in AN. The combination of bone anabolic and anti-resorptive therapy (rhIGF-I with oral estrogen), however, did result in a significant increase in BMD in a study of adult women with AN. A better understanding of the pathophysiology of low BMD in AN, and development of effective therapeutic strategies is critical. This is particularly so for adolescents, who are in the process of accruing peak bone mass, and in whom a failure to attain peak bone mass may occur in AN in addition to loss of established bone.

Topics: Androgens; Anorexia Nervosa; Bone Density Conservation Agents; Calcium; Diphosphonates; Eating; Estrogen Replacement Therapy; Ghrelin; Humans; Hypogonadism; Insulin-Like Growth Factor I; Leptin; Malnutrition; Motor Activity; Osteoporosis; Peptide Hormones; Peptide YY; Recombinant Proteins; Vitamin D

Underlying causes of hypogonadotropic hypogonadism are acquired or congenital disorders of the hypothalamus or pituitary (e.g. pituitary adenoma, craniopharyngioma, prior radiotherapy, trauma, severe general diseases, extreme stress, genetic mutations). In addition to a comprehensive history and physical examination, the diagnostic work-up includes measurement of testosterone, LH and FSH, with the aim of differentiating between primary and secondary hypogonadism. Where indicated, investigation of pituitary function, the use of imaging procedures, possibly an olfactory test, a GnRH stimulation test or genetic analyses may be added. Depending upon the indication, treatment is effected with testosterone, GnRH or gonadotropines.

Topics: Adolescent; Adult; Age Factors; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Hypogonadism; Infertility, Male; Kallmann Syndrome; Leptin; Male; Mutation; Olfaction Disorders; Prader-Willi Syndrome; Pregnancy; Puberty, Delayed; Receptors, Cell Surface; Receptors, Leptin; Spermatogenesis; Testosterone; Time Factors

Hypogonadotropic hypogonadism is characterized by failure of gonadal function secondary to deficient gonadotropin secretion, resulting from either a pituitary or hypothalamic defect, and is commonly seen in association with structural lesions or functional defects affecting this region. Although the genetic basis for idiopathic hypogonadotropic hypogonadism is largely unknown, mutations in several genes involved in the hypothalamo-pituitary-gonadal axis development and function have recently been implicated in the pathogenesis of this condition. Genes currently recognized to be involved include KAL-1 (associated with X-linked Kallmann Syndrome), gonadotropin-releasing hormone (GnRH) receptor, gonadotropins, pituitary transcription factors (HESX1, LHX3, and PROP-1), orphan nuclear receptors (DAX-1, associated with X-linked adrenal hypoplasia congenital, and SF-1), and three genes also associated with obesity (leptin, leptin receptor, and prohormone convertase 1 [ PC1]). Study of these mutations provides an important contribution in the understanding of the different stages of the reproductive axis development and physiology. Treatment options currently available for puberty induction, maintenance replacement therapy, and fertility induction are considered here. Gametogenesis can be induced with either exogenous gonadotropin or pulsatile GnRH therapy, depending on the etiology.

Topics: Aspartic Acid Endopeptidases; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Humans; Hypogonadism; Leptin; Male; Mutation; Obesity; Proprotein Convertases; Receptors, Cell Surface; Receptors, Leptin; Receptors, LHRH

Anorexia nervosa is a chronic illness that involves a reduction in caloric intake, loss of weight and amenorrhoea, either primary or secondary. In addition to prolonged amenorrhoea, osteopenia and osteoporosis are the most frequent complications. Patients exhibit an alteration in the hypothalamic-pituitary-gonadal axis, which is responsible for the menstrual disorders. The increase in gonadotrophin secretion that can be observed after ponderal recuperation suggests that malnutrition could be the most important mechanism involved in the decrease in gonadotrophin secretion. The loss of fat tissue, as a consequence of the restriction of nutrients, has been associated with hypoleptinaemia, abnormal secretion of peptides implicated in food control (neuropeptide Y, melanocortins and corticotrophin-releasing hormone, among others) and diminution of the amount of total body fat. Despite oestrogen therapy, the severe loss of bone mass may progress. Other factors such as weight loss, duration of amenorrhoea and low insulin-like growth factor-I (IGF-I) levels could contribute to the loss of bone mass in women with anorexia nervosa. The recuperation of weight and, in particular, the amount of total body fat could lead to the spontaneous recuperation of menstruation.

Topics: Adipocytes; Anorexia Nervosa; Biomarkers; Bone Density; Bone Remodeling; Energy Metabolism; Female; Hormones; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Leptin; Models, Theoretical; Nutrition Disorders; Ovary

Deficiency of the adipocyte-derived hormone leptin in ob/ob mice results in severe, early-onset obesity and infertility. Administration of leptin results in complete reversal of the phenotype, suggesting that leptin is needed for the development of puberty in rodents. In humans, mutations in the genes encoding leptin and the leptin receptor result in obesity syndromes and hypogonadotropic hypogonadism. I have shown that administration of recombinant human leptin results in the onset of puberty at an appropriate developmental age in human congenital leptin deficiency. This work suggests that leptin is a metabolic gate for the onset of puberty in humans. Leptin's actions may be mediated by central pathways and by direct action on peripheral organs.

Topics: Animals; Animals, Genetically Modified; Female; Genetics; Humans; Hypogonadism; Leptin; Male; Mice; Mutation; Obesity; Puberty; Receptors, Cell Surface; Receptors, Leptin; Recombinant Proteins; Sexual Maturation

Menopause favors osteoporosis and obesity protects from it. In an attempt to decipher the molecular bases of these two well-known clinical observations, we hypothesized that they meant that bone remodeling, body weight, and reproduction are controlled by identical endocrine pathways. We used mouse genetics as a tool to translate these clinical observations into a molecular hypothesis. The ob/ob and db/db mice were valuable models, since two of the three functions thought to be co-regulated are affected in these mice: they are obese and hypogonadic. Surprisingly, given their hypogonadism, both mouse mutant strains have a high bone mass phenotype. Subsequent analysis of the mechanism leading to this high bone mass revealed that it was due to an increase of bone formation. All data collected indicate that, in vivo, leptin does not act directly on osteoblasts but rather through a central pathway following binding to its specific receptors located on hypothalamic nuclei. This result revealed that bone remodeling, like most other homeostatic functions, is under hypothalamic control. The nature of the signal downstream of the hypothalamus is unknown but current experiments are attempting to identify it.

Topics: Animals; Body Weight; Bone and Bones; Bone Development; Bone Remodeling; Humans; Hypogonadism; Leptin; Mice; Mice, Transgenic; Obesity; Phenotype; Signal Transduction

Topics: Animals; Blood Pressure; Female; Glucose; Humans; Hypertension; Hypogonadism; Leptin; Mice; Mice, Transgenic; Obesity; Sympathetic Nervous System

Humans with hypogonadotropic hypogonadism (HH) manifest irreversible pubertal delay, infertility, and low serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Although the genetic basis of this condition is largely unknown, mutations have been identified in approximately 5-10% of HH patients. Mutations in the KAL gene (Kallmann syndrome) and the AHC gene (adrenal hypoplasia congenita/HH) cause X-linked recessive HH. Autosomal recessive HH may be brought about by mutations in the gonadotropin-releasing hormone receptor, leptin, and the leptin receptor genes. Isolated deficiencies of the gonadotropins FSH and LH are due to corresponding beta-subunit genes. PROP1 gene mutations lead to combined pituitary deficiency, and HESX gene mutations result in septo-optic dysplasia, both of which include HH. These identified gene mutations advance our understanding of normal hypothalamic-pituitary-gonadal function.

Topics: DAX-1 Orphan Nuclear Receptor; DNA-Binding Proteins; Extracellular Matrix Proteins; Female; Follicle Stimulating Hormone; Genes, Homeobox; Genes, Recessive; Gonadotropins; Homeodomain Proteins; Humans; Hypogonadism; Hypothalamo-Hypophyseal System; Kallmann Syndrome; Leptin; Luteinizing Hormone; Male; Mutation; Nerve Tissue Proteins; Receptors, LHRH; Receptors, Retinoic Acid; Repressor Proteins; Transcription Factors

Hypogonadism frequently occurs in male patients with type 2 diabetes (T2DM) and is linked to insulin resistance and inflammation. Testosterone levels rise acutely in obese patients following bariatric surgery, though long-term changes have not been investigated in a randomized controlled trial. This study evaluated obese men with T2DM randomized to either bariatric surgery or medical therapy. Testosterone, gonadotropins, body composition, insulin sensitivity, and inflammatory markers were evaluated in 32 patients at baseline and at 5 years. Surgical patients had 47.4% increase in free testosterone compared to medical therapy patients who had 2.2% decrease (P = 0.013). Increase in free testosterone correlated with reduction in body weight, high-sensitivity C-reactive protein (hsCRP), and leptin levels. Prolonged improvements in testosterone levels after bariatric surgery in T2DM are found to be related to reduction in body weight and adipogenic inflammation.

Topics: Adult; Bariatric Surgery; Blood Glucose; Body Composition; C-Reactive Protein; Diabetes Mellitus, Type 2; Follow-Up Studies; Humans; Hypogonadism; Insulin Resistance; Leptin; Male; Middle Aged; Obesity; Testosterone

One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH.. A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks.. Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (-3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all).. Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.

Topics: Adult; Body Composition; C-Reactive Protein; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Hormone Replacement Therapy; Humans; Hypogonadism; Inflammation; Insulin; Insulin Resistance; Interleukin-1beta; Intra-Abdominal Fat; Leptin; Male; Middle Aged; Subcutaneous Fat; Testosterone; Tumor Necrosis Factor-alpha

Hypopituitarism, often characterized by hypogonadism, is associated with central obesity, increased cardiovascular and endocrine morbidity and mortality. In Turner syndrome, which is also characterized by hypogonadism liver enzymes are often elevated, but readily suppressed by a short course of hormone replacement therapy (HRT). We investigated the effect of HRT on liver enzymes, lipid levels and measures of insulin sensitivity 26 in hypopituitary women.. We studied 26 hypopituitary women (age 38.8+/-11.0 (mean+/-SD years), BMI 27.4+/-5.1kg/m(2)) during HRT and 28days off therapy.. We measured liver enzymes, fasting levels of lipids, insulin and glucose as well as adiponectin and leptin levels. Body composition was assessed by means of anthropometry and bioimpedance.. Alanine transaminase (ALT) and aspartate transaminase (AST) increased after discontinuation of HRT (ALT; treated: 22.3+/-11.5 vs. untreated: 27.1+/-11.1 (U/L) (P<0.02); AST; treated: 20.4+/-6.1 vs. untreated: 24.6+/-8.9 (U/L) (P<0.002)), whereas other liver function tests remained unchanged. Measures of insulin sensitivity and fasting lipids were also unaffected by HRT, whereas leptin levels decreased with cessation of HRT (leptin; treated: 23 (8-71) vs. untreated: 20 (8-64) (mug/L) (P<0.0005)).. Short time discontinuation of HRT in young hypopituitary women increased liver enzymes, whereas measures of insulin sensitivity and lipid levels remained unchanged. We speculate that the estrogen component of HRT has beneficial effects on hepatic metabolism through various pathways. Further studies including liver imaging and with a time-dependent design are needed to clarify the role of HRT on liver enzyme levels, metabolic variables and liver fat content.

Topics: Adiponectin; Adult; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Body Mass Index; Female; Hormone Replacement Therapy; Human Growth Hormone; Humans; Hypogonadism; Hypopituitarism; Insulin; Insulin Resistance; Leptin; Lipids; Liver; Obesity; Withholding Treatment

Men with the metabolic syndrome (MetS) have low plasma testosterone (T) levels. The aim of this study was to establish whether the normalization of plasma T improves the features of the MetS.. A randomized, placebo-controlled, double-blinded, phase III trial of 184 men suffering from both the MetS and hypogonadism.. One hundred and eighty-four men, aged 35-70, with the MetS and hypogonadism (baseline total T level <12·0 nm or calculated free T level <225 pm.), recruited in the outpatient andrology and urology clinic, Research Center for Endocrinology in Moscow, Russia.. Treatment for 30 weeks with either parenteral T undecanoate (n = 113; TU; 1000 mg IM) or placebo (n = 71), administered at baseline, and after 6 and 18 weeks. One hundred and five (92·9%) men receiving TU and 65 (91·5%) receiving placebo completed the trial.. Body weight, body mass index (BMI), waist circumference (WC), hip circumference, waist-to-hip ratio, insulin, leptin, glucose, cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein (CRP), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-α).. There were significant decreases in weight, BMI and WC in the TU vs placebo group. Levels of leptin and insulin also decreased, but there were no changes in serum glucose or lipid profile. Of the inflammatory markers, IL-1β, TNF-α and CRP decreased, while IL-6 and IL-10 did not change significantly.. Thirty weeks of T administration normalizing plasma T in hypogonadal men with the MetS improved some components of the MetS and a number of inflammatory markers.

Topics: Adult; Aged; Body Mass Index; C-Reactive Protein; Humans; Hypogonadism; Inflammation; Insulin; Interleukin-10; Interleukin-6; Leptin; Lipids; Male; Metabolic Syndrome; Middle Aged; Testosterone; Tumor Necrosis Factor-alpha; Waist Circumference; Waist-Hip Ratio

To assess the efficacy and safety of a novel long-acting im testosterone undecanoate (TU) formulation in comparison with testosterone enanthate (TE).. An open-label, randomized, prospective clinical trial in 40 hypogonadal men (baseline serum testosterone levels <5 nmol/l), randomly assigned to 250 mg TE/3 weeks (no.=20) or 1000 mg TU im every 6 to 9 weeks for 30 weeks (no.=20). Subsequently, 32/40 men continued the study for another 114 weeks, now receiving TU 1000 mg/12 weeks.. TU and TE produced no statistically significant improvements in grip strength over the first 30 weeks, which only occurred after approximately 90 weeks when all subjects received TU. There were no changes in body mass index with TU and TE, neither in the follow-up period when all patients received TU. But ratios of waist to hip circumferences declined in the longer term. Total serum cholesterol, LDL cholesterol, and triglycerides declined over the first 30 weeks, while plasma HDL also declined. Plasma LDL decreased further under long-term TU therapy, while HDL then increased. Hemoglobin and hematocrit values significantly increased over the first 30 weeks in both treatment groups and then no further increase was observed. Levels did not exceed the upper limit of normal. In both treatment groups, serum prostate specific antigen levels rose slightly after 30 weeks, with no further increase over the first 12 months, remaining stable within the normal range. Plasma T before the following TU injection was above the lower limit of reference values. Four injections per year are adequate.. Administration of TU every 12 weeks is at least as safe and efficacious for treatment of hypogonadal men as TE, with a substantially lower frequency of administration. Follow-up over 114 weeks, when all subjects received TU, showed an excellent profile of efficacy and safety.

Topics: Adolescent; Adult; Aged; Body Mass Index; Chemistry, Pharmaceutical; Delayed-Action Preparations; Hand Strength; Humans; Hypogonadism; Injections, Intramuscular; Leptin; Lipids; Male; Middle Aged; Testosterone; Waist-Hip Ratio; Young Adult

Leptin replacement rescues the phenotype of morbid obesity and hypogonadism in leptin-deficient adults. However, leptin's effects on insulin resistance are not well understood. Our objective was to evaluate the effects of leptin on insulin resistance. Three leptin-deficient adults (male, 32 yr old, BMI 23.5 kg/m(2); female, 42 yr old, BMI 25.1 kg/m(2); female, 46 yr old, BMI 31.7 kg/m(2)) with a missense mutation of the leptin gene were evaluated during treatment with recombinant methionyl human leptin (r-metHuLeptin). Insulin resistance was determined by euglycemic hyperinsulinemic clamps and by oral glucose tolerance tests (OGTTs), whereas patients were on r-metHuLeptin and after treatment was interrupted for 2-4 wk in the 4th, 5th, and 6th years of treatment. At baseline, all patients had normal insulin levels, C-peptide, and homeostatic model assessment of insulin resistance index, except for one female diagnosed with type 2 diabetes. The glucose infusion rate was significantly lower with r-metHuLeptin (12.03 +/- 3.27 vs. 8.16 +/- 2.77 mg.kg(-1).min(-1), P = 0.0016) but did not differ in the 4th, 5th, and 6th years of treatment when all results were analyzed by a mixed model [F(1,4) = 0.57 and P = 0.5951]. The female patient with type 2 diabetes became euglycemic after treatment with r-metHuLeptin and subsequent weight loss. The OGTT suggested that two patients showed decreased insulin resistance while off treatment. During an off-leptin OGTT, one of the patients developed a moderate hypoglycemic reaction attributed to increased posthepatic insulin delivery and sensitivity. We conclude that, in leptin-deficient adults, the interruption of r-metHuLeptin decreases insulin resistance in the context of rapid weight gain. Our results suggest that hyperleptinemia may contribute to mediate the increased insulin resistance of obesity.

Topics: Adult; Blood Glucose; Female; Follow-Up Studies; Glucose; Glucose Tolerance Test; Hormone Replacement Therapy; Humans; Hypogonadism; Infusion Pumps; Insulin; Insulin Resistance; Leptin; Life Style; Male; Middle Aged; Obesity, Morbid

Serum testosterone levels are known to inversely correlate with insulin sensitivity and obesity in men. Furthermore, there is evidence to suggest that testosterone replacement therapy reduces insulin resistance and visceral adiposity in type 2 diabetic men. Adipocytokines are hormones secreted by adipose tissue and contribute to insulin resistance. We examined the effects of testosterone replacement treatment on various adipocytokines and C-reactive protein (CRP) in type 2 diabetic men.. Double-blinded placebo-controlled crossover study in 20 hypogonadal type 2 diabetic men. Patients were treated with testosterone (sustanon 200 mg) or placebo intramuscularly every 2 weeks for 3 months in random order followed by a washout period of 1 month before the alternate treatment phase.. Leptin, adiponectin, resistin, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and CRP levels were measured before and after each treatment phase. Body mass index (BMI) and waist circumference were also recorded.. At baseline, leptin levels significantly correlated with BMI and waist circumference. There was a significant inverse correlation between baseline IL-6 and total testosterone (r=-0.68; P=0.002) and bioavailable testosterone levels (r=-0.73; P=0.007). CRP levels also correlated significantly with total testosterone levels (r=-0.59; P=0.01). Testosterone treatment reduced leptin (-7141.9 +/- 1461.8 pg/ml; P=0.0001) and adiponectin levels (-2075.8 +/- 852.3 ng/ml; P=0.02). There was a significant reduction in waist circumference. No significant effects of testosterone therapy on resistin, TNF-alpha, IL-6 or CRP levels were observed.. Testosterone replacement treatment decreases leptin and adiponectin levels in type 2 diabetic men. Moreover, low levels of testosterone in men are associated with pro-inflammatory profile, though testosterone treatment over 3 months had no effect on inflammatory markers.

Topics: Adiponectin; Aged; Body Composition; C-Reactive Protein; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Hormone Replacement Therapy; Humans; Hypogonadism; Interleukin-6; Leptin; Male; Middle Aged; Peptide Hormones; Resistin; Statistics, Nonparametric; Testosterone; Tumor Necrosis Factor-alpha

Testosterone (T) therapy in older men with low serum T levels increases lean body mass and decreases fat mass. These changes might improve physical performance and strength; however, it has not been established whether T therapy improves functional outcome in older men. Moreover, concerns exist about the impact of T therapy on the prostate in older men. The administration of finasteride (F), which partially blocks the conversion of T to the more potent androgen, dihydrotestosterone, attenuates the impact of T replacement on prostate size and prostate-specific antigen. We hypothesized that T replacement in older, hypogonadal men would improve physical function and that the addition of F to this regimen would continue to provide the T-induced improvements in physical performance, strength, and body composition. Seventy men with low serum T (<350 ng/dl), age 65 yr and older, were randomly assigned to receive one of three regimens for 36 months: 1) T enanthate, 200 mg im every 2 wk, with placebo pills daily (T-only); 2) T enanthate, 200 mg every 2 wk, with 5 mg F daily (T + F); or 3) placebo injections and pills (placebo). We obtained serial measurements of timed physical performance, grip strength, lower extremity strength, body composition (by dual-energy x-ray absorptiometry), fasting cholesterol profiles, and hormones. Fifty men completed the 36-month protocol. After 36 months, T therapy significantly improved performance in a timed functional test when compared with baseline and placebo [4.3 +/- 1.6% (mean +/- sem, T-only) and 3.8 +/- 1.0% (T + F) vs. -5.6 +/- 1.9% for placebo (P < 0.002 for both T and T + F vs. placebo)] and increased handgrip strength compared with baseline and placebo (P < 0.05). T therapy increased lean body mass [3.77 +/- 0.55 kg (T-only) and 3.64 +/- 0.56 kg (T + F) vs. -0.21 +/- 0.55 kg for placebo (P < 0.0001)], decreased fat mass, and significantly decreased total cholesterol, low-density lipoprotein, and leptin, without affecting high-density lipoprotein, adiponectin, or fasting insulin levels. These results demonstrate that T therapy in older men with low serum T improves physical performance and strength over 36 months, when administered alone or when combined with F, and suggest that high serum levels of dihydrotestosterone are not essential for these beneficial effects of T in men.

Topics: Adiponectin; Aged; Aged, 80 and over; Aging; Androgens; Body Composition; Body Mass Index; Double-Blind Method; Drug Therapy, Combination; Enzyme Inhibitors; Finasteride; Hand Strength; Humans; Hypogonadism; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Lipids; Male; Motor Activity; Testosterone

A decline in testicular function is recognized as a common occurrence in older men. However data are sparse regarding the effects of hypogonadism on age-associated physical and cognitive declines. This study was undertaken to examine the year-long effects of testosterone administration in this patient population. Fifteen hypogonadal men (mean age 68 +/- 6 yr) were randomly assigned to receive a placebo, and 17 hypogonadal men (mean age 65 +/- 7 yr) were randomly assigned to receive testosterone. Hypogonadism was defined as a bioavailable testosterone <60 ng/dL. The men received injections of placebo or 200 mg testosterone cypionate biweekly for 12 months. The main outcomes measured included grip strength, hemoglobin, prostate-specific antigen, leptin, and memory. Testosterone improved bilateral grip strength (P < 0.05 by ANOVA) and increased hemoglobin (P < 0.001 by ANOVA). The men assigned to testosterone had greater decreases in leptin than those assigned to the control group (mean +/- SEM: -2.0 +/- 0.9 ng/dL vs. 0.8 +/- 0.7 ng/dL; P < 0.02). There were no significant changes in prostate-specific antigen or memory. Three subjects receiving placebo and seven subjects receiving testosterone withdrew from the study. Three of those seven withdrew because of an abnormal elevation in hematocrit. Testosterone supplementation improved strength, increased hemoglobin, and lowered leptin levels in older hypogonadal men. Testosterone may have a role in the treatment of frailty in males with hypogonadism; however, older men receiving testosterone must be carefully monitored because of its potential risks.

Topics: Aged; Cognition; Hand Strength; Hemoglobins; Humans; Hypogonadism; Leptin; Male; Middle Aged; Prostate-Specific Antigen; Proteins; Testosterone; Time Factors

The ob gene product leptin (OB) is a feedback signal from the adipocyte to the hypothalamus and is involved in regulation of food intake and energy expenditure in rodents. A major determinant of serum OB levels is fat mass. Several studies suggest that men have lower OB levels than women even after adjustment for percent body fat. We, therefore, investigated the influence of testosterone (T) substitution in hypogonadal men on serum OB levels. Hypogonadal men with T levels of 3.6 nmol/L or less and off substitution therapy for at least 3 months were assigned to two treatment groups: testosterone enanthate (TE; 250 mg, i.m., every 21 days; n = 10) or a single s.c. implantation of 1200 mg crystalline T (TPEL; n = 12). Blood samples for determination of T, 5 alpha-dihydrotestosterone (DHT), sex hormone-binding globulin, and 17 beta-estradiol were obtained before therapy and then every 21 days until day 189 and at follow-up visits on days 246 and 300. Serum OB levels were assessed on days 0, 42, 84, 126, 168, and 300. OB levels were referred to a normal range for men based on the analysis of OB levels in 393 adult men. Substitution with T led to a large rise in T and DHT in both groups compared to baseline values (average T, days 21-189: TE, 14.33 +/- 2.63 nmol/L; TPEL, 24.98 +/- 1.64; average DHT, days 21-189: TE, 4.20 +/- 0.57 nmol/L; TPEL, 5.11 +/- 0.56; P < or = 0.05). Concomitantly, 17 beta-estradiol increased in both groups, and sex hormone-binding globulin levels were significantly decreased. At baseline, serum OB levels in hypogonadal men were 3-fold elevated compared to those in normal men (12.39 +/- 2.93 micrograms/L vs. 4.28 +/- 0.52; P < 0.01) and not different between groups (TE, 13.7 +/- 5.6; TPEL, 11.3 +/- 2.9 micrograms/L). This elevation was retained after adjustment for body mass index in the normal control group [TE, 1.45 +/- 0.51 SD score (P < 0.0001); TPEL, 0.98 +/- 0.35 SD score (P < 0.0008)]. During T substitution serum OB was completely normalized (trough levels: TE, 4.6 +/- 1.0 micrograms/L; TPEL 4.3 +/- 0.9 micrograms/L). In multiple regression analysis, the androgen (T plus DHT)/estrogen ratio was the only significant determinant of OB levels (r = -0.32; P < 0.01). At baseline, OB levels did not correlate with body mass index, but during substitution, the correlation was considerably improved. We conclude that hypogonadal men exhibit elevated OB levels that are normalized by substitution with T. The only determinant of OB levels was

Topics: Adult; Body Mass Index; Dihydrotestosterone; Estradiol; Humans; Hypogonadism; Leptin; Male; Proteins; Regression Analysis; Sex Hormone-Binding Globulin; Testosterone

With this case report we support our medical hypothesis that metreleptin treatment ameliorates starvation related emotional, cognitive and behavioral symptomatology of anorexia nervosa (AN) and show for the first time strong effects in a male patient with AN. A 15.9 year old adolescent with severe AN of eight-month duration was treated off-label with metreleptin. Hyperactivity was assessed with accelerometry. Visual analogue scales (VAS), validated self- and clinician rating scales and lab results tracked changes from baseline to end of the 24-day dosing period and a five-month follow-up. Substantial improvements of mood and eating disorder related cognitions and hyperactivity set in after two days of treatment. During dosing, sub-physiological testosterone and TT3 levels normalized; clinically libido reemerged. Weight did not increase substantially during the dosing period. During follow-up target weight was attained; mood did not deteriorate; hyperactivity ceased. The results substantiate the strong effects seen in female cases and underscore the need for a double-blind placebo-controlled trial to confirm the observed strong, multiple and rapid onset beneficial effects of metreleptin in AN.

Topics: Adolescent; Anorexia Nervosa; Feeding and Eating Disorders; Female; Humans; Hypogonadism; Leptin; Male; Testosterone

Energy balance is closely related to reproductive function, wherein hypothalamic kisspeptin mediates regulation of the energy balance. However, the central mechanism of kisspeptin in the regulation of male reproductive function under different energy balance states is unclear. Here, high-fat diet (HFD) and exercise were used to change the energy balance to explore the role of leptin and inflammation in the regulation of kisspeptin and the hypothalamic-pituitary-testis (HPT) axis.. Four-week-old male C57BL/6 J mice were randomly assigned to a normal control group (n = 16) or an HFD (n = 49) group. After 10 weeks of HFD feeding, obese mice were randomly divided into obesity control (n = 16), obesity moderate-load exercise (n = 16), or obesity high-load exercise (n = 17) groups. The obesity moderate-load exercise and obesity high-load exercise groups performed exercise (swimming) for 120 min/day and 120 min × 2 times/day (6 h interval), 5 days/week for 8 weeks, respectively.. Compared to the mice in the normal group, in obese mice, the mRNA and protein expression of the leptin receptor, kiss, interleukin-10 (IL-10), and gonadotropin-releasing hormone (GnRH) decreased in the hypothalamus; serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels and sperm quality decreased; and serum leptin, estradiol, and tumor necrosis factor-α (TNF-α) levels and sperm apoptosis increased. Moderate- and high-load exercise effectively reduced body fat and serum leptin levels but had the opposite effects on the hypothalamus and serum IL-10 and TNF-α levels. Moderate-load exercise had anti-inflammatory effects accompanied by increased mRNA and protein expression of kiss and GnRH in the hypothalamus and increased serum FSH, LH, and testosterone levels and improved sperm quality. High-load exercise also promoted inflammation, with no significant effect on the mRNA and protein expression of kiss and GnRH in the hypothalamus, serum sex hormone level, or sperm quality. Moderate-load exercise improved leptin resistance and inflammation and reduced the inhibition of kisspeptin and the HPT axis in obese mice. The inflammatory response induced by high-load exercise may counteract the positive effect of improving leptin resistance on kisspeptin and HPT.. During changes in energy balance, leptin and inflammation jointly regulate kisspeptin expression on the HPT axis.

Topics: Animals; Energy Metabolism; Hypogonadism; Hypothalamus; Infertility, Male; Inflammation; Inflammation Mediators; Kisspeptins; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Reproduction; Signal Transduction

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Diabetes Mellitus; Dyslipidemias; Fatty Liver; Glycated Hemoglobin; Humans; Hypogonadism; Lamin Type A; Leptin; Lipase; Lipodystrophy, Congenital Generalized; Male; Progeria; Treatment Outcome

Age-related hypogonadism in men leads to abnormal body composition development and overproduction of inflammatory cytokines, and thus has atherogenic and potentially cancer promoting effects. The aim of the study was to assess the effect of agedependent testosterone deficiency replacement in men on body composition, serum leptin, adiponectin, and C-reactive protein levels.. Men aged 50-65 years (56.0 ± 5.7, average ± SD), with total testosterone levels < 4 ng/mL, and clinical symptoms of hypogonadism were divided into two groups of 20 men and treated with testosterone (200 mg/two weeks intramuscularly) or placebo during 12 months.. Twelve months of treatment with testosterone led to body mass index (BMI) and fat mass (FM) decrease from 26.6 ± 2.1 to 26.1 ± 1.8 kg/m², p < 0.05, and from 17.0 ± 4.4 to 15.6 ± 4.0 kg, p < 0.05, respectively. Body mass index and FM did not change in placebo-receiving subjects. Serum leptin and highly selective C-reactive protein (hsCRP) levels in testosterone group decreased from 6.2 ± 1.4 to 4.0 ± 1.2 μg/L, p < 0.05, and from 1.4 ± 1.2 to 1.0 ± 1.0 mg/L, p < 0.05 after 12 months, respectively. Adiponectin increased from 7.6 ± 2.5 μg/mL to 9.4 ± 2.8 μg/mL, p < 0.05 in the same time. In the placebo group serum leptin, adiponectin, and hsCRP levels did not change significantly.. Testosterone replacement in men with age-related hypogonadism causes a decrease in body mass index, fat mass, serum leptin, and C-reactive protein levels and increases serum adiponectin levels.

Topics: Adiponectin; Aged; Body Mass Index; C-Reactive Protein; Case-Control Studies; Hormone Replacement Therapy; Humans; Hypogonadism; Leptin; Male; Middle Aged; Testosterone

Even though obesity surgery normalizes circulating testosterone concentrations in males with obesity-associated secondary hypogonadism, its impact on spermatogenesis remains controversial. We aimed to evaluate sperm characteristics in obese men after bariatric surgery as well as changes in reproductive hormones.. Twenty severely obese men (body mass index (BMI) ≥ 35 kg/m. After surgery, serum total testosterone, calculated free testosterone, inhibin B, and kisspeptin increased, whereas fasting insulin, HOMA-IR, and leptin concentrations decreased. Despite these improvements, sperm volume showed a small decrease after surgery, while the rest of sperm characteristics remained mostly unchanged. Abnormal sperm concentration persisted in 60% of the patients.. Sperm characteristics may not improve after bariatric surgery despite the beneficial changes of reproductive hormones.

Topics: Adult; Bariatric Surgery; Body Mass Index; Follow-Up Studies; Gonadal Steroid Hormones; Humans; Hypogonadism; Infertility, Male; Inhibins; Insulin; Leptin; Male; Middle Aged; Obesity, Morbid; Postoperative Period; Prognosis; Semen Analysis; Spermatozoa; Testosterone; Treatment Outcome

Obesity may lead to male hypogonadism, the underlying mechanism of which remains unclear. In the present study, we established a murine model of male hypogonadism caused by high-fat diet-induced obesity to verify the following hypotheses: 1) an increased leptin level may be related to decreased secretion of GnRH in obese males, and 2) repression of kisspeptin/GPR54 in the hypothalamus, which is associated with increased leptin levels, may account for the decreased secretion of GnRH and be involved in secondary hypogonadism (SH) in obese males.. Male mice were fed high-fat diet for 19 weeks and divided by body weight gain into diet-induced obesity (DIO) and diet-induced obesity resistant (DIO-R) group. The effect of obesity on the reproductive organs in male mice was observed by measuring sperm count and spermatozoid motility, relative to testis and epididymis weight, testosterone levels, and pathologic changes. Leptin, testosterone, estrogen, and LH in serum were detected by ELISA method. Leptin receptor (Ob-R), Kiss1, GPR54, and GnRH mRNA were measured by real-time PCR in the hypothalamus. Expression of kisspeptin and Ob-R protein was determined by Western blotting. Expression of GnRH and GPR54 protein was determined by immunohistochemical analysis.. We found that diet-induced obesity decreased spermatozoid motility, testis and epididymis relative coefficients, and plasma testosterone and luteinizing hormone levels. An increased number and volume of lipid droplets in Leydig cells were observed in the DIO group compared to the control group. Significantly, higher serum leptin levels were found in the DIO and DIO-R groups. The DIO and DIO-R groups showed significant downregulation of the GnRH, Kiss1, GPR54, and Ob-R genes. We also found decreased levels of GnRH, kisspeptin, GPR54, and Ob-R protein in the DIO and DIO-R groups.. These lines of evidence suggest that downregulation of Ob-R and kisspeptin/GPR54 in the murine hypothalamus may contribute to male hypogonadism caused by high-fat diet-induced obesity.

Topics: Animals; Body Weight; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Gonadotropin-Releasing Hormone; Hypogonadism; Hypothalamus; Kisspeptins; Leptin; Male; Mice; Obesity; Receptors, Kisspeptin-1; Receptors, Leptin; Sperm Motility; Testis

Hypogonadism is a common endocrine disorder in men with chronic kidney disease (CKD), but its pathophysiology is poorly understood. We here explore the plausible contribution of abdominal adiposity and leptin hyperproduction to testosterone deficiency in this patient population.. Cross-sectional analysis with all men included the Malnutrition, Inflammation and Vascular Calcification cohort, which enrolled consecutive nondialyzed patients with CKD stages 3-5.. A total of 172 men with CKD stages 3-5 nondialysis (median age 61 [45-75] years, median glomerular filtration rate 24 [9-45] mL/min/1.73 m. None, observational study.. Total testosterone, hypogonadism.. The median level of total testosterone was 11.7 (7.3-18.4) nmol/L, with hypogonadism (<10 nmol/L) present in 52 (30%) patients. Testosterone-deficient patients presented with significantly higher body mass index, waist circumference, and VAT. An inverse correlation between testosterone and VAT (rho = -0.25, P = .001) or waist circumference (rho = -0.20, P = .008) was found, also after multivariate adjustment including sex hormone binding globulin and estrogen. Total testosterone was inversely correlated with serum leptin (rho = -0.22, P = .003), and the ratio of leptin/VAT, an index of leptin hyperproduction, was strongly and independently associated with the prevalence of hypogonadism in multivariable regression analyses.. Visceral adiposity independently associated with lower testosterone levels among men with CKD stage 3-5 nondialysis. The observed link between hyperleptinemia and hypogonadism is in line with previous evidence on direct effects of leptin on testosterone production.

Topics: Adiposity; Aged; Body Mass Index; C-Reactive Protein; Cholesterol; Cross-Sectional Studies; Estrogens; Glomerular Filtration Rate; Hand Strength; Humans; Hypogonadism; Intra-Abdominal Fat; Leptin; Logistic Models; Male; Middle Aged; Prevalence; Renal Insufficiency, Chronic; Sex Hormone-Binding Globulin; Testosterone; Waist Circumference

We evaluated the body composition and its association with hypogonadism in adult male long-term acute lymphoblastic leukemia (ALL) survivors.. The cohort included 49 long-term male ALL survivors and 55 age-matched healthy controls. Fat and lean mass was assessed by dual-energy X-ray absorptiometry; blood biochemistry was obtained for adipokines and testicular endocrine markers.. As compared with controls, the ALL survivors (median age 29 years, range 25-38), assessed 10-28 years after ALL diagnosis, had higher percentages of body (p < 0.05) and trunk fat mass (p < 0.05), and a lower body lean mass (p < 0.001). Survivors had significantly higher levels of leptin and adiponectin and lower levels of insulin-like growth factor-binding protein 3. Body fat mass and percent fat mass correlated with serum leptin and sex hormone-binding globulin (SHBG) levels. Altogether, 15% of the ALL survivors and 9% of age-matched controls were obese (BMI ≥ 30). Obese survivors more often had hypogonadism, had received testicular irradiation, and needed testosterone replacement therapy compared to nonobese survivors.. At young adulthood, long-term male ALL survivors have significantly increased body adiposity despite normal weight and BMI. Potential indicators of increased adiposity included high leptin and low SHBG levels. Serum testicular endocrine markers did not correlate with body adiposity.

Topics: Absorptiometry, Photon; Adipokines; Adiponectin; Adiposity; Adult; Child; Cohort Studies; Hormone Replacement Therapy; Humans; Hypogonadism; Insulin-Like Growth Factor Binding Protein 3; Leptin; Male; Obesity; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Radiotherapy; Survivors; Testis; Testosterone

This study evaluated the effects of obesity on the function of reproductive organs in male mice and the possible mechanism of male secondary hypogonadism (SH) in obesity.. Ninety-six mice were randomly assigned to three groups: the control group, diet-induced obesity group, and diet-induced obesity resistant group for 8 weeks and 19 weeks. The effects of short- and long-term high-fat diet on the reproductive organs were determined by measuring sperm count and motility, relative testis weight, testosterone level, pathological changes and apoptosis of Leydig cells. Oxidative stress was evaluated by determining malondialdehyde, H2O2, NO levels, and GSH in testis tissues. CAT, SOD, GSH-Px and Nrf2 mRNA were measured by real-time PCR.. Short- and long-term high-fat diet decreased sperm count and motility, relative testis weight, testosterone level; decreased CAT, SOD, GSH-Px and Nrf2 mRNA expression; increased MDA, H2O2, NO and leptin levels; inhibited the activity of CAT and GSH-Px enzymes. Pathological injury and apoptosis of Leydig cells were found in testis tissue.. Pathological damage of Leydig cells, oxidative stress in testis tissue, and high level of leptin may provide some evidence to clarify the mechanisms of male SH in obesity.

Topics: Animals; Apoptosis; Body Weight; Diet, High-Fat; Hypogonadism; Leptin; Leydig Cells; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidative Stress; Oxidoreductases; Reactive Oxygen Species; RNA, Messenger; Spermatozoa; Testis; Testosterone

Several studies have shown that estrogens mimic leptin's effects on energy balance regulation. However, the findings regarding the consequences of reduced sex hormone levels on leptin sensitivity are divergent. In the present study, we employed different experimental paradigms to elucidate the interaction between estrogens, leptin, and energy balance regulation. We confirmed previous reports showing that ovariectomy caused a reduction in locomotor activity and energy expenditure leading mice to obesity and glucose intolerance. However, the acute and chronic anorexigenic effects of leptin were preserved in ovariectomized (OVX) mice despite their increased serum leptin levels. We studied hypothalamic gene expression at different time points after ovariectomy and observed that changes in the expression of genes involved in leptin resistance (suppressors of cytokine signaling and protein-tyrosine phosphatases) did not precede the early onset of obesity in OVX mice. On the contrary, reduced sex hormone levels caused an up-regulation of the long form of the leptin receptor (LepR), resulting in increased activation of leptin signaling pathways in OVX leptin-treated animals. The up-regulation of the LepR was observed in long-term OVX mice (30 d or 24 wk after ovariectomy) but not 7 days after the surgery. In addition, we observed a progressive decrease in the coexpression of LepR and estrogen receptor-α in the hypothalamus after the ovariectomy, resulting in a low percentage of dual-labeled cells in OVX mice. Taken together, our findings suggest that the weight gain caused by reduced sex hormone levels is not primarily caused by induction of a leptin-resistance state.

Topics: Animals; Appetite Depressants; Drug Resistance; Energy Metabolism; Female; Glucose; Gonadal Steroid Hormones; Hypogonadism; Leptin; Mice; Mice, Inbred C57BL; Obesity; Ovariectomy; Sex Factors; Weight Gain

Hypogonadism has major effects on the urogenital system, in addition to other systems, the cardiovascular system in particular. There have been few studies conducted on markers of atherosclerosis, such as flow mediated dilatation (% FMD), carotid intima-media thickness (CIMT) and adipocytokine levels in idiopatic hypogonadotropic hypogonadal (IHH) males mostly in adult patients. The aim of this study was to evaluate the relationship between androgens and adipocytokines and parameters of vascular functions in hypogonadal men.. The study population consisted of 11 treatment naive IHH patients (group 1) and 15 age-matched healthy control males (group 2). A fasting blood sample was obtained for leptin, adiponectin and resistin. The endothelial functions were evaluated by studying % FMD and CIMT by high resolution B-mode ultrasound.. No significant differences in age, body mass index, systolic and diastolic blood pressure were recorded between the two groups. The leptin level was significantly higher in group 1, whereas adiponectin and resistin levels were same between two groups. There was a negative correlation between total testosterone and carotid intima-media thickness (r=-0.656, p=0.008), and a negative correlation between total testosterone and leptin level (r=-0.794, p<0.001). No correlation was found between leptin and CIMT (p=0.184).. Testosterone deficiency in hypogonadal men is associated with vascular parameters of atherosclerosis. The findings may establish indications for testosterone replacement therapy in hypogonadal men.

Topics: Adiponectin; Adult; Blood Pressure; Blood Vessels; Brachial Artery; Humans; Hyperemia; Hypogonadism; Leptin; Male; Resistin; Testosterone; Young Adult

Leptin deficiency leads to midluteal-phase defect or reduced testicular volume in adults, despite normal gonadotropin levels. All children documented to date with leptin deficiency were prepubertal with physiologically low gonadotropins prior to therapy. A direct effect of leptin on pubertal development in a leptin-naive adolescent has not yet been shown.. In 2010, we reported the first connatal leptin-deficient adolescent girl with clinically and chemically proven hypogonadotropic hypogonadism. In this study, we evaluated the effect of recombinant methionyl human leptin substitution.. Initially, the patient had prepubertal basal and stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, low growth hormone and insulin-like growth factor 1 (IGF1) levels and no pulsatile secretion of LH and FSH. After 11 weeks of therapy, basal and stimulated LH and FSH levels rose to pubertal values and nocturnal pulsatility was initiated. After 76 weeks of therapy, menstruation occurred at the age of 16.3 years. Pulsatile nocturnal growth hormone secretion, stimulated growth hormone secretion and IGF1 values also normalized.. We describe here the first adolescent with hypogonadotropic hypogonadism due to connatal leptin deficiency. Leptin substitution led to a rapid induction of gonadotropin secretion and menarche. These data are further proof of the concept that leptin is needed for a timely maturation of the hypothalamic/pituitary/gonadal axis.

Topics: Adolescent; Body Mass Index; Female; Humans; Hypogonadism; Leptin; Menarche; Obesity; Puberty, Delayed; Treatment Outcome

Leptin restores gonadotropic function in lean hypogonadotropic animals by an unknown mechanism. We aimed to test the hypothesis that restoration of gonadotropic function is a result of an upregulation of central acetylated melanocortin production.. Lean ovariectomised (OVX) ewes received intracerebroventricular (i.c.v.) infusions of leptin (or vehicle) for 3 days, which upregulated proopiomelanocortin (POMC) mRNA and restored pulsatile luteinizing hormone (LH) secretion. A melanocortin agonist (MTII), but not naloxone treatment, reinstated pulsatile LH secretion in lean OVX ewes. We treated (i.c.v.) lean OVX ewes with leptin (or vehicle) and measured peptide levels and post-translational modification in the arcuate nucleus (ARC). Levels of beta-endorphin (beta-END) were lower in lean animals, with no effect of leptin treatment. Desacetyl-alpha-MSH was the predominant form of alpha-melanocyte-stimulating hormone (alpha-MSH) in the ARC and levels were similar in all groups. In another group of lean and normal-weight OVX ewes, we measured the different forms of alpha-MSH in ARC, hypothalamus (ARC-removed) and the preoptic area (POA). Acetylated alpha-MSH levels were lower in lean animals in the terminal beds of the hypothalamus and POA but not the ARC.. Leptin corrects the hypogonadotropic state in the lean condition by upregulation of POMC gene expression, and may increase transport and acetylation of melanocortins to target cells in the brain. Melanocortin treatment restores LH secretion in lean animals.

Topics: alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; beta-Endorphin; Central Nervous System Agents; Female; Hormone Replacement Therapy; Hypogonadism; Hypothalamus; Leptin; Luteinizing Hormone; Melanocortins; Ovariectomy; Preoptic Area; Pro-Opiomelanocortin; Reproduction; RNA, Messenger; Sheep; Thinness

Leptin, a protein product of adipocytes, plays a critical role in the regulation of body weight, immune function, pubertal development, and fertility. So far, only three homozygous mutations in the leptin gene in a total of 13 individuals have been found leading to a phenotype of extreme obesity with marked hyperphagia and impaired immune function.. Serum leptin was measured by ELISA. The leptin gene (OB) was sequenced in patient DNA. The effect of the identified novel mutation was assessed using HEK293 cells.. We describe a 14-yr-old child of nonobese Austrian parents without known consanguinity. She had a body mass index of 31.5 kg/m(2) (+2.46 SD score) and undetectable leptin serum levels. Sequencing of the leptin gene revealed a hitherto unknown homozygous transition (TTA to TCA) in exon 3 of the LEP gene resulting in a L72S replacement in the leptin protein. RT-PCR, Western blot, and immunohistochemical analysis indicated that the mutant leptin was expressed in the patient's adipose tissue but retained within the cell. Using a heterologous cell system, we confirmed this finding and demonstrated that the side chain of Leu72 is crucial for intracellular leptin trafficking. Our patient showed signs of a hypogonadotropic hypogonadism. However, in contrast to the literature, she showed only mild obesity and a normal T cell responsiveness.. These findings shed a new light on the clinical consequences of leptin deficiency. Congenital leptin deficiency should be considered possible in pediatric patients with mild obesity even if parents are lean and unrelated.

Topics: Adiposity; Adolescent; Blotting, Western; Calorimetry, Indirect; Cell Proliferation; Cloning, Molecular; Cold Temperature; Cytokines; DNA, Complementary; Eating; Energy Intake; Energy Metabolism; Female; Humans; Hypogonadism; Immunohistochemistry; Leptin; Motor Activity; Mutation, Missense; Obesity; Pressure; T-Lymphocytes; Transfection

Hypogonadotropic hypogonadism (HH) secondary to hypothalamic gonadotropin-releasing hormone deficiency is a notable feature of a number of rare syndromes, where unlike idiopathic (isolated) HH, other endocrinopathies may also be apparent. The presence of a particular spectrum of clinical features in addition to HH may suggest a particular underlying diagnosis. Placing the diagnosis of HH into that context will then have important implications in terms of management and predicting long-term functional outcome. In some instances, establishing the genetic basis of a particular syndrome or disorder has advanced the understanding of normal hypothalamo-pituitary-gonadal function (e.g. LEP deficiency, DAX-1 and CHARGE syndrome) whilst in other disorders much has still to be learnt (e.g. Bardet-Biedl and Prader-Willi syndrome). In this chapter the above syndromes, where HH is a feature in most or all affected individuals, will be discussed. Recent advances in our understanding of the pathophysiology of the HH will be highlighted and management options presented. Longer term therapy with sex steroid replacement is becoming even more important if improvements in life expectancy are to be matched by improvements in quality of life.

Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Animals; Bardet-Biedl Syndrome; CHARGE Syndrome; DAX-1 Orphan Nuclear Receptor; Female; Genetic Diseases, X-Linked; Hormone Replacement Therapy; Humans; Hypoadrenocorticism, Familial; Hypogonadism; Leptin; Male; Mice; Prader-Willi Syndrome; Proprotein Convertase 1

Hypogonadotropic hypogonadism (HH) is defined by the absence of sex steroid synthesis associated with the lack of appropriate gonadotrophin secretion. This leads to a variable degree of impuberism, often diagnosed during childhood or adolescence. Genetics of HH involve many genes. However, molecular defects have been identified in only 30 % of patients. Kallmann syndrome (KS) is defined by the association of HH and anosmia. Six genes are involved in KS (KAL1, FGFR1, FGF8, PROK2, PROKR2 and CHD7). However, genetics of KS is complex, because of the variability of the phenotype for a similar molecular defect. Otherwise, heterozygous anomalies are frequently described. Identification in the same patient of several mutations in some of these genes (digenism) could account for this variability. Autosomal recessive transmission is frequently observed in familial cases of HH without anosmia. Molecular alterations have been identified for several neuropeptides or their corresponding receptors, which are involved in the physiology of the gonadotropic axis : GNRHR, KISS1R/GPR54, neurokinin B (TAC3), TACR3 and GNRH1 (and PROK2, PROKR2 and CHD7). Anomalies of leptin or its receptor are also involved in HH cases. A new negative regulating element has been recently identified in humans : RFRP3, which is ortholog of the avian GnIH (gonadotrophin inhibitory hormone). Recent progress about these neuropeptides leads to a new model of comprehension of the gonadotropic axis physiology, from a linear model to a network model, which regulates the central element of regulation of the gonadotropic axis, represented by the GnRH neurons.

Topics: DNA Helicases; DNA-Binding Proteins; Extracellular Matrix Proteins; Female; Fibroblast Growth Factor 8; Gastrointestinal Hormones; Gonads; Humans; Hypogonadism; Hypothalamus; Kallmann Syndrome; Leptin; Male; Nerve Tissue Proteins; Neuropeptides; Olfaction Disorders; Pituitary Gland; Pituitary Hormone Release Inhibiting Hormones; Receptor, Fibroblast Growth Factor, Type 1; Receptors, G-Protein-Coupled; Receptors, Leptin; Receptors, Peptide

To describe our 10-year experience in treating leptin-deficient humans. Three adults and one boy presented with childhood-onset morbid obesity, hypogonadism and family history of obesity and early death. Serum leptin was inappropriately low. A recessive C105T leptin gene mutation was identified. Metabolic and endocrine assessments were conducted, before and while on and off leptin. The adults' body mass index decreased from 51.2 ± 2.5 to 29.5 ± 2.8 kg/m(2). Serum lipids normalized, insulin resistance decreased, and one of the initially diabetic females became normoglycemic. Hypogonadotropic hypogonadism was reversed, and other changes were observed in the adrenal, sympathetic, somatotropic and thyroid functions. Leptin replacement therapy reverses endocrine and metabolic alterations associated with leptin deficiency. Some of these results may be extrapolated to other diseases.

Topics: Adult; Body Mass Index; Child; Energy Metabolism; Female; Hormone Replacement Therapy; Humans; Hypogonadism; Leptin; Lipid Metabolism; Male; Phenotype; Young Adult

Topics: Adult; Feeding and Eating Disorders; Humans; Hypogonadism; Leptin; Male; Osteoporosis

A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined.. We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives.. Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency.. The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

Topics: Adult; Age of Onset; Basal Metabolism; Body Composition; Child; Diagnosis, Differential; Female; Genotype; Humans; Hyperphagia; Hypogonadism; Immunologic Deficiency Syndromes; Leptin; Lymphocyte Count; Male; Metabolism, Inborn Errors; Mutation; Obesity; Pedigree; Phenotype; Receptors, Cell Surface; Receptors, Leptin

Leptin-deficient ob/ob mice have reduced gonadotropin-releasing hormone (GnRH) secretion, leading to gonadotropin deficiencies, hypogonadism, and anovulation, which are completely reversed following leptin administration. To determine whether the role of leptin in ovulation is mediated exclusively through GnRH, we studied leptin's action in GnRH-deficient (hpg) mice, as well as ob/ob mice and normal, prepubertal mice in which the GnRH axis was blocked with antide. Following pretreatment with pregnant mare serum gonadotropin, leptin induced ovulation in all three mouse models. Unlike mature normal mice, these ovulations were not triggered by a luteinizing hormone (LH) surge, as demonstrated by lack of increase in its surrogate marker progesterone. Rather, leptin induced hyperemia and leakage in the follicle, as well as the proteinase ADAMTS-1 (a disintegrin and metalloproteinase with a thrombospondin-like motif), which facilitates extrusion of the follicular content. These data show that on top of its role as an inducer of GnRH secretion, leptin may elicit an LH-independent ovulation.

Topics: ADAM Proteins; ADAMTS1 Protein; Animals; Corpus Luteum; Disintegrins; Enzyme Activation; Female; Gonadotropin-Releasing Hormone; Gonadotropins, Equine; Hypogonadism; Leptin; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Oocytes; Ovarian Follicle; Ovulation; Progesterone

Topics: Animals; Brain; Circadian Rhythm; Female; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Kisspeptins; Leptin; Male; Mutation; Neurons; Proteins; Puberty; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Receptors, Leptin; Receptors, Neuropeptide; Reproduction; Signal Transduction; Tumor Suppressor Proteins

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 +/- 2.5 (mean +/- SEM) at baseline to 26.9 +/- 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.

Topics: Adult; Behavior; Body Composition; Body Mass Index; Circadian Rhythm; Diabetes Mellitus, Type 2; Female; Humans; Hypogonadism; Leptin; Phenotype; Weight Loss

Leptin seems to play a role in both food intake and energy balance as well as in the regulation of reproductive features. In order to investigate the regulation of testicular functions by leptin we analysed leptin concentrations in the semen of men with different andrological diseases. It was demonstrated that semen leptin concentrations were inversely correlated with serum testosterone levels and directly with serum leptin concentrations. Furthermore, semen leptin concentrations display only a fraction of serum leptin levels. Semen leptin levels of patients with azoospermia due to hypergonadotrophic hypogonadism, associated with increased follicle-stimulating hormone levels and of high-grade oligozoospermia, were significantly elevated (1.19 +/- 0.46 and 1.09 +/- 0.54 microg l(-1), respectively), while semen levels of leptin in patients with obstructive azoospermia (0.54 +/- 0.41 microg l(-1)) and low-grade oligozoospermia (0.54 +/- 0.34 microg ml(-1)) were comparable with those of normozoospermic men (0.21 +/- 0.21 microg l(-1)). Our data suggest that dysfunction of testicular epithelia as found in hypergonadotrophic hypogonadism and high-grade oligozoospermia with decreased testosterone levels causes elevated spermal leptin concentrations. However, the correlation of semen with serum leptin concentrations indicates that leptin is not actively transported but rather leaks through the blood-testis barrier.

Topics: Adult; Humans; Hypogonadism; Leptin; Male; Oligospermia; Semen

Neonatal L-monosodium glutamate (MSG) administration in rats induces several neuroendocrine and metabolic disruptions. Leptin, the adipocyte product, modulates several neuroendocrine systems including the hypothalamic-pituitary-gonadal (HPG) axis in mammals. The aim of the present study was to determine whether MSG-induced chronic hyperleptinemia could play any relevant role in the hypogonadism developed by male rats when examined in adulthood. We found that 120-day-old MSG male rats displayed significant hyperleptinemia, hypogonadism, and undisturbed basic testis structure and spermatogenesis. In vitro studies in purified Leydig cells from normal (CTR) and MSG-damaged rats revealed that basal and human chorionic gonadotropin (hCG)-stimulated 17-hydroxy-progesterone (17-HO-P(4)), Delta(4)-androstenedione (Delta(4)A) and testosterone (T) secretions were significantly lower in MSG than in CTR cells. Exposure to murine leptin (Mleptin, 10(-8)M) significantly inhibited hCG-elicited T secretion by CTR cells after 180 min incubation. While Mleptin significantly inhibited hCG-stimulated Delta(4)A output and the Delta(4)A:17-OH-P(4) ratio of secretion, conversely, it failed to modify the ratio T:Delta(4)A release by CTR Leydig cells. Interestingly, the effects of Mleptin found on CTR Leydig cells were absent in MSG Leydig cells. Finally, endogenous hyperleptinemia was associated with a significant decrease in Leydig cell expression of Ob-Rb mRNA in MSG rats. In summary, this study demonstrates that: (1) Mleptin inhibited testicular steroidogenesis in CTR rats; (2) MSG-treated rats showed lower in vitro 17-OH-P(4), Delta(4)A and T production under basal and post-hCG stimulation conditions; (3) purified Leydig cells from MSG-treated rats displayed resistance to the inhibitory action of Mleptin on T release, and (4) endogenous leptin exerts a modulatory effect on Leydig cell Ob-Rb mRNA expression. The inhibitory effect of leptin on testicular function is thus abrogated in MSG-damaged rats. The testicular leptin-resistance developed by MSG rats seems to be due to early chronic exposure of Leydig cells to high leptin circulating levels, which in turn down-regulate testicular Ob-Rb expression. It remains to be determined whether the testicular dysfunction of MSG rats can be reversed after correction of hyperleptinemia or whether it is an irreversible effect of the hypothalamic lesion.

Topics: Analysis of Variance; Androstenols; Animals; Animals, Newborn; Blotting, Northern; Body Weight; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Follicle Stimulating Hormone; Hypogonadism; Leptin; Leydig Cells; Luteinizing Hormone; Male; Mice; Organ Size; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sodium Glutamate; Testis; Testosterone; Thyroxine

The aim of the study was to investigate the association of leptin with hematological parameters in beta-thalassemia patients in Greece. We measured plasma levels of soluble transferrin receptor (sTfR) and leptin by enzyme-linked immunosorbent assay (ELISA) in 40 beta-thalassemia patients (21 transfusion dependent and 19 not transfused or sporadically transfused), in 20 beta-thalassemia carriers, and in 30 healthy individuals (HI). The percentage of reticulocytes (RET) was measured by the NE 9500 Sysmex automated method. Body mass index (BMI) was calculated by dividing body weight (kg) by square height (m). Endocrine measurements including sex hormones were also determined. sTfR concentrations were significantly higher in both transfusion-dependent (females 10.5+/-2.9, males 9.1+/-3.1) and non-transfusion-dependent patients (females 15.8+/-5.4, males 19.8+/-13.7) as compared to carriers (females 3.1+/-2.5, males 3.8+/-1.8) and to HI (females 1.5+/-1.2, males 2.5+/-2.1). Leptin levels were lower both in female and in male transfusion-dependent patients (0.5+/-0.3 and 1.2+/-1, respectively) and in non-transfused males (1.9+/-2) compared to carriers (females 7.9+/-2.7, males 13.1+/-9.1) and HI (females 14.6+/-6, males 7.5+/-3). There was a negative correlation between leptin and sTfR levels in transfused patients (R=-0.61, p<0.05). A stronger negative correlation (R=-0.7, p=0.006) was found in hypogonadic men and women with beta-thalassemia. These findings enhance previous results indicating that leptin may play some role in hematopoiesis and could associate the pathophysiology of thalassemic patients with the triggering effect of leptin in reproductive ability.

Topics: Adult; beta-Thalassemia; Case-Control Studies; Female; Greece; Heterozygote; Homozygote; Humans; Hypogonadism; Leptin; Male; Middle Aged; Receptors, Leptin; Receptors, Transferrin; Solubility; Statistics, Nonparametric

Circulating leptin shows a pulsatile secretory pattern along with a nocturnal rise. We have previously shown that circulating leptin concentrations are high in males with untreated idiopathic hypogonadotropic hypogonadism (IHH). However, circadian leptin secretion in IHH before and after gonadotropin treatment is not known. Thus, we studied 14 adult males with IHH who had no history of previous hormonal therapy, and 12 age- and body mass index-matched healthy men. Plasma leptin concentrations were measured with 1-h intervals for 24 h before and 6 months after gonadotropin treatment. The 24-h mean leptin concentration showed a significant decrease, from 11.78 +/- 1.908 microg/liter at baseline to 10.85 +/- 1.939 microg/liter after 6 months of therapy (z = 3.107; P = 0.002). Before and after treatment, 24-h mean leptin concentrations were also significantly higher in the patient group when compared with controls (4.275 +/- 0.711 microg/liter) (z = 5.938; P = 0.0001). Hourly leptin levels demonstrated a diurnal pattern in hypogonadal patients, a surge in the midday, and a peak just after midnight, and this pattern did not differ before and after treatment. We observed a similar diurnal pattern in the control subjects too. Leptin levels were negatively and significantly correlated with free testosterone and total testosterone levels both before (r = -0.656, P = 0.011; and r = -0.639, P = 0.014, respectively) and after (r = -0.537, P = 0.048; and r = -0.563, P = 0.036, respectively) gonadotropin administration. Our observations suggest that the diurnal rhythm of leptin is intact in males with IHH, and short-term gonadotropin treatment does not effect its diurnal rhythm. Moreover, testosterone produced under the influence of the gonadotropin treatment led to decreases in the leptin levels.

Topics: Adult; Chorionic Gonadotropin; Circadian Rhythm; Gonadotropins; Hormone Replacement Therapy; Humans; Hypogonadism; Leptin; Male; Menotropins; Testosterone

In healthy men, body weight and total fat content increase with advancing age, while serum testosterone levels decrease. In order to elucidate whether a causal relationship between these phenomena exists, we investigated the influence of testosterone or human chorionic gonadotrophin substitution on body mass index (BMI), total fat mass and serum leptin in testosterone-treated and untreated hypogonadal patients in comparison with ageing eugonadal men.. In a cross-sectional study, the inter-relationships of body weight, total fat mass, serum sex hormones and leptin were analysed in untreated hypogonadal men (n=24; age 19-65 years), treated hypogonadal men (n=61; age 20-67 years) and healthy eugonadal men (n=60; age 24-78 years). Total fat mass was assessed by bioimpedance measurement. Univariate and multiple linear regression analysis was used to detect possible differences.. In eugonadal men, serum testosterone levels decreased with advancing age (correlation coefficients: r=-0.71; P<0.0001), while BMI (r=0.39; P=0.002), total fat content (r=0.51; P<0.0001) and leptin (r=0.48; P<0.0001) increased significantly. In untreated hypogonadal patients, an increase in BMI (r=0.50; P=0.013) and total fat mass (r=0.41; P=0.044) was also observed with advancing age. However, in substituted hypogonadal patients, no age-dependent change in BMI (r=0.067; P=0.606), body fat content (r=-0.083; P=0.522), serum testosterone (r=-0,071; P=0.59) or serum leptin (r=-0.23; P=0.176) was found.. Since testosterone-substituted older hypogonadal men show BMI and fat mass similar to those of younger eugonadal men and since non-treated hypogonadal men are similar to normal ageing men, testosterone appears to be an important factor contributing to these changes. Thus ageing men should benefit from testosterone substitution as far as body composition is concerned.

Topics: Adipose Tissue; Adult; Aged; Aging; Body Mass Index; Chorionic Gonadotropin; Cross-Sectional Studies; Gonadal Steroid Hormones; Humans; Hypogonadism; Kallmann Syndrome; Leptin; Male; Middle Aged; Reference Values; Testosterone

Topics: Adult; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Leptin; Male; Periodicity

Neuropeptide Y (NPY) is involved in the central regulation of appetite, sexual behavior, and reproductive function. We have previously shown that chronic infusion of NPY into the lateral ventricle of normal rats produced an obesity syndrome characterized by hyperphagia, hyperinsulinism and collapse of reproductive function. We further demonstrated that acute inhibition of LH secretion in castrated rats was preferentially mediated by the NPY receptor subtype 5 (Y(5)). In the present study, the effects of chronic, central infusion of NPY, or the mixed Y2-Y5 agonist PYY(3-36), were evaluated both in normal male C57BL/6J mice and Sprague-Dawley rats. After a 7-day infusion to male mice, both NPY and PYY(3-36) at 5 nmol per day, induced marked hyperphagia leading to significant increases in body and fat pad weights. Furthermore, both compounds markedly reduced several markers of the reproductive axis. In the rat study, PYY(3-36) was more active than NPY to inhibit the pituitary-testicular axis, confirming the importance of the Y5 subtype for such effects. In the mouse, chronic NPY infusion induced a sustained increase in corticosterone and insulin secretion. Plasma leptin levels were also markedly increased possibly explaining the observed reduction in gene expression for hypothalamic NPY. Gene expression for hypothalamic POMC was reduced in the NPY- or PYY(3-36)-infused mice, suggesting that NPY exacerbated food intake by both acting through its own receptor(s), and reducing the satiety signal driven by the POMC-derived alpha-MSH. The present study in the mouse suggests in analogy with available rat data, that constant exposure to elevated NPY in the hypothalamic area unabatedly enhances food intake leading to an obesity syndrome including increased adiposity, insulin resistance, hypercorticism, and hypogonadism, reminiscent of the phenotype of the ob/ob mouse, that displays elevated hypothalamic NPY secondary to lack of leptin negative feedback action.

Topics: Animals; Hyperphagia; Hypogonadism; Insulin Resistance; Lateral Ventricles; Leptin; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Obesity; Peptide Fragments; Peptide YY; Rats; Rats, Sprague-Dawley; Syndrome

In this study, the authors assessed the endocrine system and glucose tolerance in obese and non-obese women chronically treated with typical antipsychotic drugs (AP). In particular, we tested the hypotheses that these subjects display hypogonadism and increased insulin resistance compared to healthy weight-matched controls, as these abnormalities create a tendency towards excessive body weight gain. Twenty-six AP-treated women were matched with 26 healthy women by age, body mass index and day of the menstrual cycle. The following serum variables were evaluated in each subject: glucose tolerance after an oral glucose overload, insulin, leptin, beta-endorphin, reproductive hormones, adrenal steroids and lipids. Compared to controls, AP-treated women displayed significantly higher levels of basal glucose, insulin after 60 min of the glucose overload, prolactin, thyroid stimulating hormone and beta-endorphin, with lower levels of C-Peptide, progesterone, 17-OH progesterone, androstenedione and high-density lipoprotein cholesterol. The levels of estradiol, estrone and leptin did not differ between the groups. Thus, women treated with typical AP appeared to display more insulin resistance than healthy controls, predisposing them to excessive weight gain. Insulin sensitivity might be further impaired when the subject switches to atypical AP administration. Metformin and related agents may reduce body weight in these subjects. The high levels of the opiate beta-endorphin suggest that opiate antagonists such as naloxone and naltrexone might be useful as well. Even though the luteal phase of the menstrual cycle appears to be severely disturbed, the normal serum levels of estradiol and estrone do not support the proposal derived from animal experimental studies about the use of estrogens or tamoxifen to counteract AP-induced obesity.

Topics: Adrenal Glands; Adult; Antipsychotic Agents; beta-Endorphin; Blood Glucose; C-Peptide; Endocrine System; Female; Gonadal Steroid Hormones; Humans; Hypogonadism; Insulin; Insulin Resistance; Leptin; Lipids; Multivariate Analysis; Obesity; Prolactin; Sex Hormone-Binding Globulin; Thyroid Hormones

Excess or loss of body fat can be associated with infertility, suggesting that adequate fat mass is essential for proper reproductive function. Leptin is an adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure, and its synthesis and secretion are markedly increased in obesity. Short-term administration of leptin accelerates the onset of puberty in normal mice and corrects the sterility of leptin-deficient ob/ob mice. These findings suggest a role for leptin as an endocrine signal between fat depots and the reproductive axis, but the effect of hyperleptinemia on the initiation and maintenance of reproductive function has not been elucidated. To address this issue, we examined the reproductive phenotypes of female transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. With no apparent adipose tissue, female transgenic skinny mice exhibit accelerated puberty and intact fertility at younger ages followed by successful delivery of healthy pups. However, at older ages, they develop hypothalamic hypogonadism characterized by prolonged menstrual cycles, atrophic ovary, reduced hypothalamic gonadotropin releasing hormone contents, and poor pituitary luteinizing hormone secretion. This study has demonstrated for the first time to our knowledge that accelerated puberty and late-onset hypothalamic hypogonadism are associated with chronic hyperleptinemia, thereby leading to a better understanding of the pathophysiological and therapeutic implication of leptin.

Topics: Adipose Tissue; Age Factors; Animals; Atrophy; Female; Fertility; Gene Expression Regulation; Gonadotropin-Releasing Hormone; Hypogonadism; Hypothalamic Diseases; Leptin; Luteinizing Hormone; Male; Mice; Mice, Mutant Strains; Organ Size; Ovary; Pituitary Gland, Anterior; Promoter Regions, Genetic; Recombinant Fusion Proteins; Serum Amyloid P-Component; Sexual Maturation

Serial measurements of body mass index (BMI), serum concentrations of testosterone (T), estradiol (E) and leptin (L) were performed before and after gonadotropin (Gn) therapy in an 18-year-old male subject (BMI 25.4 kg/m2) with idiopathic hypothalamic hypogonadism (IHH). We also measured the BMI and serum concentrations of L in 99 age-matched healthy subjects. Serum L correlated significantly with BMI in control subjects (r=0.84, p<0.0001). Baseline serum concentrations of L in our case were markedly high and both T and E were very low, but Gn therapy resulted in a gradual decrease in L and improvement in T and E, finally reaching the control levels of BMI-matched subjects. Our results demonstrate that T is a powerful negative modulator of serum L independent of BMI in conditions associated with low T levels, such as IHH.

Topics: Adolescent; Body Composition; Body Mass Index; Chorionic Gonadotropin; Estradiol; Gonadotropin-Releasing Hormone; Humans; Hypogonadism; Hypothalamic Diseases; Leptin; Male; Menotropins; Testosterone

Neuropeptide Y (NPY) is a powerful orexigenic factor, and alphaMSH is a melanocortin (MC) peptide that induces satiety by activating the MC4 receptor subtype. Genetic models with disruption of MC4 receptor signaling are associated with obesity. In the present study, a 7-day intracerebroventricular infusion to male rats of either the MC receptor antagonist SHU9119 or porcine NPY (10 nmol/day) was shown to strongly stimulate food and water intake and to markedly increase fat pad mass. Very high plasma leptin levels were found in NPY-treated rats (27.1 +/- 1.8 ng/ml compared with 9.9 +/- 0.9 ng/ml in SHU9119-treated animals and 2.1 +/- 0.2 ng/ml in controls). As expected, NPY infusion induced hypogonadism, characterized by an impressive decrease in seminal vesicle and prostate weights. No such effects were seen with the SHU9119 infusion. Similarly, whereas the somatotropic axis of NPY-treated rats was fully inhibited, this axis was normally activated in the obese SHU9119-treated rats. Chronic infusion of SHU9119 strikingly reduced hypothalamic gene expression for NPY (65.2 +/- 3.6% of controls), whereas gene expression for POMC was increased (170 +/- 19%). NPY infusion decreased hypothalamic gene expression for both POMC and NPY (70 +/- 9% and 75.4 +/- 9.5%, respectively). In summary, blockade of the MC4 receptor subtype by SHU9119 was able to generate an obesity syndrome with no apparent side-effects on the reproductive and somatotropic axes. In this situation, it is unlikely that hyperphagia was driven by increased NPY release, because hypothalamic NPY gene expression was markedly reduced, suggesting that hyperphagia mainly resulted from loss of the satiety signal driven by MC peptides. NPY infusion produced hypogonadism and hyposomatotropism in the face of markedly elevated plasma leptin levels and an important reduction in hypothalamic POMC synthesis. In this situation NPY probably acted both by exacerbating food intake through Y receptors and by reducing the satiety signal driven by MC peptides.

Topics: Adipose Tissue; alpha-MSH; Animals; Body Composition; Drinking; Eating; Gene Expression; Gonadotropins; Growth Hormone; Hypogonadism; Hypothalamus; Leptin; Male; Melanocyte-Stimulating Hormones; Neuropeptide Y; Obesity; Organ Size; Pituitary Gland; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, LHRH; Satiation; Signal Transduction

Topics: Case-Control Studies; Female; Humans; Hypogonadism; Leptin; Male; Obesity; Prader-Willi Syndrome; Testosterone

Topics: Adolescent; Adult; Animals; Child; Chorionic Gonadotropin; COS Cells; Female; Homozygote; Humans; Hydrocortisone; Hypogonadism; Insulin; Karyotyping; Leptin; Male; Middle Aged; Mutation; Obesity, Morbid; Pedigree; Proteins; Puberty; Transfection

Leptin serves as a hormonal signal linking food intake and energy expenditure to fat mass. As significant effects of testosterone administration on body composition and adipose tissue have been described recently, we examined a possible association between serum levels of leptin and testosterone which has not been reported so far.. Three groups comprising a total of 58 adult age-matched males were included in this cross-sectional analysis by computer-assisted clinical database selection. Group 1 (n = 22) consisted of untreated hypogonadal patients with testosterone serum levels lower than 7 nmol/l. The inclusion criterion for Groups II (n = 20) and III (n = 16) was a serum testosterone level higher than 30 nmol/l. Group II involved hypogonadal patients under effective androgen substitution therapy; Group III comprised males without any endocrine disorder attending our clinic.. Morning blood samples were taken for determination of serum levels of leptin, testosterone, oestradiol and sex-hormone binding globulin (SHBG). Serum levels of leptin were measured by homologous radioimmunoassay, the other hormones by standard immunoassays.. No significant differences in serum leptin, serum testosterone, and body mass index (BMI) were detected between Group II (3.7 +/- 1.5 micrograms/l, 40.3 +/- 7.6 nmol/ l, 24.4 +/- 4.9 kg/m2, respectively (mean +/- SD)), and Group III (4.0 +/- 2.0 micrograms/l, 35.9 +/- 6.5 nmol/l, 24.8 +/- 2.6 kg/m2, respectively). However, hypogonadal patients of Group I who were selected for low testosterone serum levels (4.3 +/- 1.7 nmol/l) had significantly higher leptin serum levels of 18.8 +/- 9.7 micrograms/l (P < 0.001) and significantly higher BMI of 30.0 +/- 6.6 kg/m2 (P < 0.001). Multiple linear regression analysis revealed a significant independent association of leptin with testosterone serum levels (partial correlation coefficient = -0.84; P < 0.001) and with BMI (partial correlation coefficient = 0.44; P = 0.001), whereas serum levels of oestradiol and SHBG had no additional influence.. This study demonstrates a close association between serum levels of testosterone and leptin in males which has not been described previously. Serum testosterone levels could be an important contributor to the known gender difference in serum leptin levels which can be found even after correction for body composition. These findings might be of clinical relevance for testosterone substitution therapy of hypogonadal as well as ageing men.

Topics: Adult; Analysis of Variance; Body Mass Index; Cross-Sectional Studies; Humans; Hypogonadism; Leptin; Male; Proteins; Regression Analysis; Testosterone