Mechanisms Of Testosterones Effects On Body Composition

The prevalent view that testosterone produces muscle hypertrophy by increasing fractional muscle protein synthesis (46,83) is supported by several studies. However, as discussed below, recent observations suggest that increase in muscle protein synthesis probably occurs as a secondary event and may not be the sole or the primary mechanism by which testosterone induces muscle hypertrophy (84). To determine whether testosterone-induced increase in muscle size results from muscle fiber hypertrophy...

Physiopathology of Hypogonadism

Cushing's disease is characterized by chronic glucocorticoid excess secondary to hypersecretion of adrenocorticotropic hormone (ACTH) and other proopiomelanocortin peptides. It is commonly caused by a pituitary corticotroph adenoma. Hypogonadism is common in Cushing's disease. High levels of glucocorticoids decrease serum testosterone levels in men through several mechanisms (see Fig. 3). Excessive production of glucocorticoids may produce gonadotropin deficiency by acting at the pituitary and...

Altered Estrogen Levels During Pregnancy

Another mechanism by which reproductive development of the male fetus might be adversely affected is by altered exposure to maternal placental estrogens during pregnancy (5). There is evidence that the risk of cryptorchidism and testicular germ cell cancer are both increased in twin and first pregnancies in which estrogen levels are higher and administration of the potent estrogen diethylstibestrol (DES) to pregnant women also increased risk of these disorders in the offspring (4,5,8). The...

Klinefelters Syndrome And Infertility

Previously, donated sperm or adoption were the only options for men with KS to have children, however, dramatic advances in infertility treatment for individuals with KS have recently occurred. Several reports of births resulting from intracytoplasmic sperm injection (ICSI) of sperm obtained from testicular biopsy specimens in patients with KS have been published (56-58). Although most patients with nonmosaic KS do not have sperm on testicular biopsy (59,60), this technique offers a chance at...

Diagnosis

Many patients with nonpituitary sellar and suprasellar tumors have symptoms of anterior pituitary hormone failure. The most common hormone insufficiency is gonadotropin deficiency. Hypogonadism is diagnosed by a decrease in serum FSH, LH, and testosterone levels. Hyperprolactinemia is often detected, particularly in patients with craniopharyngiomas, meningiomas, or cystic lesions (87). Visual field impairment and decreased visual acuity are frequent events, because of the proximity of the optic...

The Clinical Effect of Leydig Cell Dysfunction

A significant proportion of men have evidence of impairment of Leydig cell function after high-dose chemotherapy, procarbazine-containing chemotherapy, or radiation involving the testis. The biochemical abnormalities are usually mild and consist of a raised LH level associated with a low normal testosterone level. A deleterious effect of overt testosterone deficiency and a clear benefit of androgen replacement in such patients on bone density, body composition, and quality of life, has been...

P Michael Conn Series Editor

Male Hypogonadism Basic, Clinical, and Therapeutic Principles, edited by Stephen J. Winters, 2004 Androgens in Health and Disease, edited by Carrie Bagatell and William J. Bremner, 2003 Endocrine Replacement Therapy in Clinical Practice, edited by A. Wayne Meikle, 2003 Early Diagnosis of Endocrine Diseases, edited by Robert S. Bar, 2003 Type I Diabetes Etiology and Treatment, edited by Mark A. Sperling, 2003 Handbook of Diagnostic Endocrinology, edited by Janet E. Hall and Lynnette K. Nieman,...

Therapy

Trans-sphenoidal resection of the adenoma is the preferred and most effective treatment for symptomatic NFPA, because it may improve visual field defects and permits recovery of pituitary function (83). A two-stage procedure, craniotomy followed by trans-sphenoidal resection, is often used in patients with extremely large tumors. More than 80 of patients with microadenomas are cured by surgery. On the other hand, only 15-30 of macroadenomas are completely cured. In hypogonadism, patients with...

References

Goldsmith PC, Song T, Kim EJ, Boggan JE. Location of the neuroendocrine gonadotropin-releasing hormone neurons in the monkey hypothalamus by retrograde tracing and immunostaining. J Neu-roendocrinol 1990 2 157-168. 2. Kepa JK, Spaulding AJ, Jacobsen BM, et al. Structure of the distal human gonadotropin releasing hormone (hGnrh) gene promoter and functional analysis in Gt1-7 neuronal cells. Nucleic Acids Res 1996 24 3614-3620. 3. El Majdoubi M, Sahu A, Plant TM. Changes in hypothalamic gene...

Testicular Cancer

Testicular cancer is associated with oligospermia in more than 50 of men before treatment (11,14). Several possible causes have been suggested. First, local pathological change to the testis is apparent on biopsy of the contralateral testis, with 24-60 showing significant fibrosis of the seminiferous tubules, Sertoli cell only in 8 , and carcinoma in situ in 5-8 . Local tumor effects, including elevation of scrotal temperature, alterations in testicular blood flow, and disruption of the...

Mechanism of Actions

Anabolic steroids are believed to affect athletes by mechanisms that are both physiological and psychological (106). These proposed mechanisms include (1) activating steroid hormone receptors in skeletal muscle cells, (2) producing an anticatabolic effect in the skeletal muscle, and (3) inducing motivational psychological effects. It is presently unclear to what extent each of these mechanisms contributes to the overall physiological adaptation and performance changes found in anabolic steroid...

Regularity Analysis

Nocturnal Penile Tumescence

Homeostasis in an endocrine axis requires repeated decremental and incremental adjustments in secretion (39,82,83). (see Fig. 1). In the male gonadal axis, core home-ostatic signals include (at least) GnRH, LH, and testosterone, which enforce adaptations over a rapid (minute-by-minute) time course (108). Orderliness of the resultant subpatterns of hormone release can be quantitated objectively via a regularity statistic, approximate entropy (ApEn) (30,109-111). ApEn is calculated on a desktop...

Sleep Apnea

Obstructive sleep apnea can adversely affect reproductive function (106), and one study found that androgen therapy can precipitate sleep apnea (107). An observational study reported a high prevalence of obstructive sleep apnea in men on hemodialysis and examined whether testosterone ester injections are causative (108). Sleep apnea symptoms were common (12 29, 41 ), particularly in those receiving regular testosterone enanthate injections (250 mg wk) to stimulate erythropoiesis (9 12, 75 ),...

Aging of Leydig Cells

Reproductive function declines as men grow older. An age-associated decline in plasma testosterone concentration occurs even in healthy men (104,105), although there is considerable variation in the age of onset (106). The level of testosterone in the blood stream declines on average by 1.2 each year for men over 40 yr of age. Because SHBG rises, the level of free (bioavailable) testosterone in the blood decreases more with age compared to total testosterone (106,107). Because clearance of...

Hypogonadism

Male hypogonadism is characterized by low testosterone levels in serum, accompanied by androgen deficiency symptoms, which depend on the time of manifestation. When hypogonadism begins before adolescence, it results in a failure to undergo puberty, whereas postpubertal hypogonadism causes a regression of reproductive function, with impaired libido and impotence, diminished body hair, soft skin, weakness and muscle atrophy, anemia, and osteoporosis. Low testosterone levels, in combination with...

Androgen Deficiency

Men with chronic renal failure exhibit features consistent with classical androgen deficiency reproductive manifestations, including gynecomastia, impotence, testicular atrophy, impaired spermatogenesis, and infertility, as well as somatic disorders of bone, muscle, and other androgen responsive tissues (1,2). However, only a single well-controlled study has examined androgen replacement therapy in men with uremia (34). Nineteen men who were receiving regular hemodialysis were randomized to...

FSHp Subunit

Only four women and three men with a total of four different inactivating mutations of the FSHfi gene have so far been described in the literature (34-38,51) (Table 1). All four women had similar phenotypes, with slightly variable severity, including sexual infantilism, lack of follicular development, and infertility, which are readily explained by the lack of FSH action on granulosa cell estrogen production and progression of follicular maturation beyond the early stages. The phenotypes of the...

Testosterone Effects On Fat Metabolism

Percent body fat is increased in hypogonadal men (76). Induction of androgen deficiency in healthy men by administration of a GnRH agonist leads to an increase in fat mass (47). Some studies of young, hypogonadal men have reported a decrease in fat mass with testosterone replacement (46,76), whereas others (77,78) found no change. In contrast, long-term studies of testosterone supplementation of older men are consistent in demonstrating a significant decrease in fat mass (79). Epidemiological...

LHR Mutations

Testosterone Activating Receptors

In the human male, LH-R function is essential at all ages for testicular androgen production. Therefore, these mutations influence male sexual differentiation, development, and mature functions from the fetal period through adulthood. The inactivating LH-R mutations vary in completeness, and the phenotype of affected males depends on the extent of receptor inactivation (9,59,60). In the mildest forms, the phenotype is hypospadias and or micropenis, and in the completely inactivating form, the...

Congenital Hypogonadotropic Hypogonadism Caused by Genetic Defects of the Gonadotropin Subunit Genes Mutation in the

A single case report from this institution described a male who had an inactivating mutation of the LH-P subunit (99). The proband presented at the age of 17, with delayed puberty. He was from a family with several infertile male members. T levels were reduced in association with elevated LH and FSH levels. Testicular biopsy revealed spermatogenic arrest and absent Leydig cells. Long-term hCG therapy induced testicular growth and spermatogenesis. The mutant hormone had normal immunoreactivity...

Appraising Testosterone Signaling

Testosterone Levels Age

To date, the majority of clinical studies have used the total testosterone concentration to assess androgen-dependent negative feedback on the hypothalamic-pituitary unit (36,37). However, in men, total testosterone is distributed in plasma as free (approx 2 ), weakly albumin-bound (50-55 ) and tightly globulin-bound (40-45 ) steroid (116,117). Rapid dissociation of testosterone from low-affinity albumin (nominal unidirectional half-time 0.2 s at 37 C) would favor effectual tissue uptake within...

FSHContaining Gonadotropin Preparations and hMG

Because different FSH preparations are available, the question of variability in their potency to induce sperm production and paternity arises. Unfortunately, no direct comparison between hMG, highly purified preparations, and recombinant FSH in the treatment of male hypogonadism is available. Analysis of the studies that have been performed using individual preparations in the past is complicated by the fact that different therapeutic regimens were used. Both hMG and uFSH contain urinary...

Prader Willi Syndrome

Prader-Willi syndrome is a genetic disorder characterized by short stature, low lean body mass, hypotonia, mental retardation, behavioral abnormalities, dysmorphic features, excessive appetite, and progressive obesity. Most patients also present with reduced GH secretion and hypogonadism. The principal genetic mutation identified is a deletion of the paternally derived segment of chromosome 15 (15q11-15q13). Several other genetic abnormalities have been linked to the syndrome (114,115). The...

Inhibin Activin And

Inhibin And Activin Signaling Pathway

There are both similarities and differences in how FSH secretion is regulated when compared to LH. The synthesis and secretion of LH as well as FSH is stimulated by GnRH and suppressed by gonadal steroid hormones through GnRH suppression. However, two paracrine factors, pituitary activin and follistatin, and testicular inhibin-B selectively regulate FSH secretion by regulating FSH-P gene expression (67). Because of these unique control mechanisms for FSH, LH and FSH secretion are sometimes...

Reproductive Endocrinology Of Chronic Renal Failure

Men with chronic renal failure have consistent reduction in circulating testosterone, accompanied by moderate elevations in luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-a (1,12). The pathophysiological interpretation of these changes is complex. Prima facie elevated blood gonadotropin and inhibin concentrations, together with moderate reduction in sperm and testosterone production, are indicative of primary (testicular) hypogonadism. Nevertheless, the modest...

Puberty In Chronic Renal Failure

Disorders of puberty commonly accompany chronic renal failure and require age-appropriate medical management. Although centrally mediated precocious puberty, which is reversed by renal transplantation, has been reported (46), the most characteristic feature of chronic renal failure in boys is delayed puberty with retarded bone age (1). The delayed puberty usually progresses slowly to completion during dialysis, whereas transplantation accelerates maturation unless complicated by poor graft...

Blood Coagulation and Fibrinolytic Proteins

Testosterone may influence the risk of cardiovascular disease by affecting hemosta-tic function and thrombosis. Fibrinogen is the primary coagulation protein, and through conversion to fibrin, it promotes thrombus formation (151). Thrombosis is a major precipitating factor in the onset of cardiovascular events, and prospective studies have shown that increased fibrinogen levels are an independent risk factor for clinical cardiovascular disease (152). The few population studies that have...

Measures Of Androgenicity In Men At Risk For Coronary Artery Disease

Because the portion of circulating testosterone that is not bound to SHBG is generally believed to represent the biologically active fraction, many laboratory methods for determining non-SHBG-bound testosterone or free testosterone have been developed. Because SHBG levels are low with obesity or hyperinsulinemia, established risk factors for the development of coronary artery disease, such methods are essential for research seeking to link testosterone to cardiovascular endpoints. Of the...

Treatment Of Patients With Hypogonadotropic Hypogonadism

In patients with hypogonadism of prepubertal onset, treatment is initiated with testosterone to induce pubertal development and to achieve normal virilization. Subsequently, spermatogenesis can be stimulated with GnRH or with gonadotropins, because exogenous testosterone will not initiate spermatogenesis 5,6 see Fig. 1 . This treatment approach is recommended, even if fertility is not initially desired, because sper-matogenesis, once driven to full maturation, can be readily restimulated when...

Hormonal Manipulation

The belief that prepubertal boys have a lower rate of permanent chemotherapy-induced gonadal damage 5 has led many investigators to propose that suppression of testicular function in adult men i.e., inducing a prepubertal state will provide a degree of protection against cytotoxic therapy. Irrespective of the validity of the hypothesis, data derived from animal models have been encouraging, but there is presently no convincing evidence of similar success in humans. Ward et al. 51 demonstrated...

Inactivating LHp Subunit Mutation

Only one totally inactivating mutation of the LHfi gene has so far been detected 27 Table 1 . The proband was a male who presented with delayed puberty at the age of 17 yr and had a family history of male infertility on the father's side, but none on the mother's side. His serum testosterone level was low and immunoreactive LH was high. A normal serum testosterone response was found on challenge with exogenous hCG, but in vitro bioassay of serum LH revealed no activity. These findings, together...

Ontogeny of Gonadotropin Releasing Hormone Secretion

The pattern of gonadotropin-releasing hormone GnRH induced gonadotropin secretion in the human changes dynamically with sexual development see Fig. 1 . Therefore, understanding the ontogeny of GnRH secretion is essential for assessing normal sexual maturation and pathologic states, such as congenital hypogonadotropic hypogonadism. GnRH neurons originate in the olfactory placode and migrate along the olfactory tract through the cribriform plate to the forebrain to reach their final destination,...

Testicular Germ Cell Cancer and Its Fetal Origins

As evident from the discussion in the section on environmental and lifestyle effects, the importance and mechanisms of male fetal induction of testicular dysfunction remains speculative. This is partly because it is still a new area and partly because of the inherent difficulties in establishing cause and effect involving the human fetus, particularly when any outcome, such as infertility low sperm counts, may not manifest for two or more decades. Nevertheless, there is a good and proven...

Descent Of The Testis

Testicular development begins at conception under complicated genetic direction 22 . This involves a cascade of sequential steps under the control of numerous genes, most of which are yet to be identified. Key to testicular differentiation is the sex-determining region Y SRY gene. Genetic components upstream from SRY that are essential for gonadal development include splicing factor 1 SF1 , Wilm's tumor 1 gene WT1 , and Double sex and MAb-3-Related Transcription Factor 1 DMRT1 . Downstream from...

Lipids and Coronary Artery Disease Risk

Supraphysiological doses of testosterone esters administered to normal men suppressed serum HDL cholesterol levels by 13 , but LDL-cholesterol LDL-C and triglyceride levels were unchanged 52 . On the other hand, in hypogonadal men administered transdermal testosterone in patches or gels, serum HDL-cholesterol HDL-C levels were not significantly changed 17,53-55 . The decrease in serum HDL-C was dependent on the dose of testosterone administered and serum testosterone achieved 43 . Thus, in...

Sexual Function

It is well known that androgen replacement restores sexual function in hypogonadal men. These include sexual desire libido , sexual fantasies, sexual enjoyment and frequency of sexual thoughts, sexual activities, and erectile function. In younger hypogo-nadal men, sexual performance, including erectile dysfunction, is improved by androgen replacement therapy 13-17 . In older men, erectile dysfunction is usually multifactorial other causes, such as vascular, neurogenic, psychogenic,...

Historical Description Of Klinefelters Syndrome

Klinefelter, Jr., a native of Baltimore and a graduate of the Johns Hopkins Medical School, spent a year working as a traveling fellow with Dr. Fuller Albright in the Metabolic Ward of the Massachusetts General Hospital in Boston 3 . At that time, Dr. Albright was at the height of his formidable academic career and, among many other subjects, was interested in the endocrinology of sexual development and the therapeutic applications of the recently available steroid hormones....

Malnutrition and Reproduction

Normal reproductive function requires an optimal nutritional intake, and both caloric deprivation and consequent weight loss, as well as excessive food intake and obesity, are associated with impaired reproductive function 26 . Sexual maturation may be substantially delayed during food deprivation 27,28 small animals with a short life span may not even achieve puberty before death during periods of food scarcity 29 . Undernutri-tion caused by famine, eating disorders, or exercise results in...

Testicular Control Of Gonadotropin Secretion

Gonadotropin secretion, although upregulated by GnRH, is maintained at physiological levels through testicular negative feedback mechanisms summarized in Fig. 5. Accordingly, plasma LH and FSH levels decrease after testosterone or estradiol administration and rise when negative feedback is disrupted by castration. The process of negative feedback control of LH and FSH by gonadal steroids in males is partly species-specific. There is considerable evidence in primates that androgens suppress LH...

Blood Lipids and Lipoproteins

HDL is a powerful independent risk factor for atherosclerotic cardiovascular disease. HDL influences atherosclerosis, in part, by promoting the efflux of cholesterol from macrophages in the arterial wall and returning this cholesterol to the liver for excretion, a process referred to as reverse cholesterol transport 136 . In observational studies, every 1-mg dL increment in HDL cholesterol HDL-C is associated with a 2 decreased risk of coronary artery disease in men 137 . Most studies that have...

Chemotherapy

Many drugs, particularly alkylating agents, are gonadotoxic, and the agents most commonly implicated are listed in table Table 1. The germinal epithelium is far more sensitive to the effects of cytotoxic drugs than are the Leydig cells, and, although complete azoospermia is not uncommon after chemotherapy, evidence of Leydig cell dysfunction is usually limited to raised luteinizing hormone LH levels with normal or low normal testosterone levels. Most research has focused on either...

Summary

Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men. Alkylating agents, such as cyclophosphamide and procarbazine, are the most common agents implicated. The majority of men receiving procarbazine-containing regimens for the treatment of lymphomas are rendered permanently infertile. Treatment with ABVD has a significant advantage in terms of testicular function, with a return to normal fertility in the majority of patients. Cisplatin-based...

Exercise And Pituitarytesticular Function Normal Men Exercise Responses

Normal Testosterone Blood Level

It is generally accepted that short-term, maximal, and anaerobic-type exercise results in an elevation of the circulating testosterone level see Table 1 for definitions of exercise-types terminology 25,28-30 . It is still debatable whether this effect results from solely hemoconcentration and reduced metabolic clearance or whether there is also an increase in testosterone production. Unlike changes during maximal exercise, testosterone responses to submaximal exercise are more variable and are...

Effects Of Androgen Replacement On Body Composition And Muscle Function In Hiv Infection

Several different anabolic interventions have been examined as treatments for HIV-related wasting, including appetite stimulants such as dronabinol 54 and meges- terol acetate 55 , anabolic hormones such as human growth hormone 56,57 , insulin-like growth factor IGF -1 57 , and androgens 44,52,53,58-67 and immune response modulators, such as thalidomide. Dronabinol increases appetite but does not increase lean body mass. Similarly, megesterol acetate treatment produces a modest weight gain but...

Hypogonadotropic Hypogonadism

Kallmann Syndrome Pituitary Gland

Hypogonadotropic hypogonadism is a clinical syndrome resulting from a disorder of the pituitary gland, or hypothalamus, or from systemic factors that suppress GnRH production. Hypogonadotropic hypogonadism can be congenital, i.e., Kallmann syndrome, or acquired, which most often results from a pituitary tumor. Head trauma, central nervous system CNS infections, hemochromatosis, radiotherapy, and vascular disorders can also lead to pituitary insufficiency 4 . Hypogonadotropic hypogonadism can...

Normal Sex Steps Amages

Hypogonadism Klinefelter Syndrome

Cardiovascular disease is more common in men than in menstruating women, and more common in women with elevated serum androgen levels, as in polycystic ovary syndrome PCOS 1 or type 2 diabetes 2 than in normal women. Interest in the relationship between androgens and cardiovascular disease has been stimulated further by the emerging use of testosterone replacement for older men because of concern that cardiovascular risk might increase as a side effect of therapy. The relationship between...

Leydig Cell Development

Reinke Crystals Leydig

Leydig cells were first described by the German histologist Franz Leydig in 1850 1 . In all mammalian species, Leydig cells are located in the interstitial compartment of the testis, between and surrounding the seminiferous tubules 2 . Human Leydig cells are epithelioid and ovoid or polygonal. Other cytological features include eosinophilic cytoplasm, euchromatic round eccentric nuclei with a peripheral distribution of heterochro-matin, and conspicuous nucleolus. The predominant cytoplasmic...

The SHBG Gene

The human gene that encodes SHBG is found on the short arm of chromosome 17, comprises 8 exons, and spans 3 kb of genomic DNA 10 and is expressed at high levels in the liver. SHBG gene expression in testicular Sertoli cells produces androgen-binding protein ABP , with an identical AA sequence but variant glycosylation. SHBG is also expressed in placenta, endometrium, brain, and prostate. So far, not Factors That Influence Circulating Sex Hormone-Binding Globulin Levels much is known about the...

Congenital Hypogonadotropic Hypogonadism

Congenital abnormalities leading to hypogonadotropic hypogonadism are rare but are well described Table 1 . Congenital hypogonadotropic hypogonadism CHH is usually the consequence of deficient GnRH secretion or function. CHH can occur by itself normosmic CHH or can be associated with anosmia and other midline defects and is termed Kallmann syndrome. Mutations in both LH-P and FSH-P subunits have been reported to cause CHH. Recently, leptin and leptin-R gene mutations have also been demonstrated...

Introduction

Athletes who compete in endurance-based events are swimming, running, cycling, and skating faster than ever before, and, thus, world records in many events are being broken on a nearly annual basis 1 . There are many factors that contribute to this improvement in human exercise performance. First, the coaches working with these athletes have improved scientific knowledge because of advances in the fields of sports medicine and exercise physiology. Second, sporting equipment changes have allowed...

Effect Of Androgens On Renal Function

The androgen responsiveness of the kidney has led to speculation that androgen therapy in patients with chronic renal failure or nephrotic syndrome might improve or slow deterioration in underlying renal function. This hypothesis arose from animal experiments showing androgen-induced renal hypertrophy and protection against certain nephrotoxins 40 . Clinical evidence for renotrophic effects of androgen therapy has been comprehensively reviewed 40,41 but remains ambiguous because of the lack of...

Testosterone Shbg And Insulin

The mechanism for the association between obesity and low testosterone and SHBG has received considerable attention. Many studies have shown that testosterone levels are inversely correlated with insulin and c-peptide concentrations 50,51 . This association is partly through SHBG, because fasting insulin likewise correlates negatively with SHBG levels 52 , and insulin infusion lowered circulating SHBG, albeit slighty 53 . Moreover, lowering circulating insulin levels with diazoxide increased...

Therapy of Adrenal Rest Tumors

Intensified glucocorticoid-mineralocorticoid therapy is the preferred treatment for testicular tumors in CAH. By increasing the glucocorticoid dose, ACTH secretion is suppressed and the adrenal rest tissue is no longer stimulated. The need for tumor shrinkage and the side effects of increasing glucocorticoid therapy must be carefully balanced, especially in asymptomatic cases 55 . In 1988, Rutgers et al. reported tumor shrinkage in 75 of 16 patients after increasing the glucocorticoid dose 28 ....

Shalender Bhasin MD

High Prevalence of Androgen Deficiency in HIV-Infected Men and Women Pathophysiology of HIV-Infection in the Reproductive Tract and Potential Mechanisms of Gonadal Dysfunction Adverse Consequences of Low Testosterone Concentrations on Health-Related Outcomes in HIV-Infected Individuals Evidence That Testosterone Has Anabolic Effects on Muscle Effects of Androgen Replacement on Body Composition and Muscle Function in HIV Infection Testosterone Effects on Health-Related Outcomes in Men With...

Low Testosterone Shbg And Diabetes Mellitus

Total testosterone levels are lower than normal in men with type 2 diabetes even when controlling for body mass index 2,61-63 . Much of this difference may result from lower SHBG, because the calculated value for free testosterone was not different from controls 2 , although another study found lower levels of free testosterone using an analog assay 63 . Several prospective studies found that low SHBG levels predict the development of type 2 diabetes 64-66 . This finding follows logically from...

Who Should Receive Androgen Replacement Therapy

Total Testosterone Reference Range

Men with androgen deficiency may have symptoms that include decreased libido, impaired erectile function, decreased body and facial hair, easy fatigability, decreased muscle mass and strength, increased body fat, bone pain or fractures resulting from low From Male Hypogonadism Basic, Clinical, and Therapeutic Principles Edited by S. J. Winters Humana Press Inc., Totowa, NJ aBased on a reference range of serum T levels of between 300 to 1000 ng dL Fig. 1. Who should be treated with androgen...

Pulsatile Gonadotropin Secretion

Diurnal Variation Testosterone

Experiments in ovariectomized rhesus monkeys rendered gonadotropin deficient with hypothalamic lesions led to the proposal that an intermittent pattern of GnRH secretion was necessary for normal LH secretion 28 . In those animals, GnRH administered in pulses stimulated LH secretion, but GnRH administered continuously was much less effective. The pulsatile nature of LH secretion was subsequently established in all species, including man 29 . Accordingly, LH secretion is stimulated when GnRH is...

Differential Diagnosis Of Delayed Puberty

The cutoff age for boys who need an evaluation for delayed puberty may vary in different ethnic groups, but in most populations, early signs of secondary sexual development should be present by age 14 yr. A thorough medical history should note the symptoms and signs of anorexia nervosa, the intensity of athletic training, and the timing of puberty of both parents see Fig. 5 . In boys with constitutional delay of puberty, one parent often developed late as well. A history of chronic illness,...

Secular Trends in Pubertal Development

Prepuberty Puberty Gnrh

Current trends in the timing of puberty have been reported recently in both sexes. In North American boys, recent data indicate earlier genital growth 3 . However, that study has elicited significant criticism, because the boys were not investigated thoroughly, although strong conclusions were drawn from the data. European studies do not support the American experience of strikingly earlier onset of puberty, e.g., in the Netherlands, a halt in the trend toward earlier puberty has been found...

Pathophysiology Of Hivinfection In The Reproductive Tract And Potential Mechanisms Of Gonadal Dysfunction

Testicular atrophy is a common finding in autopsy series of patients infected with HIV 8-11 . Histological examination of the testes reveals a spectrum of abnormalities, including hypospermatogenesis, spermatogenic arrest, and Sertoli cell-only pheno-types 11 . In addition to the loss of germ cells and atrophy, the seminiferous tubules exhibit basement membrane thickening and peritubular fibrosis 8,9 . Common abnormalities in semen include leukocytospermia, lower ejaculation volume and total...

Hypogonadotropic Hypogonadism Associated With Leptin and LeptinR Mutations

The adipocyte-specific hormone, leptin, the product of the obese ob gene, acts on the hypothalamus to control appetite and energy expenditure 102 . Leptin acts through the leptin receptor leptin-R , a single transmembrane-domain receptor of the cytokine-receptor family 103 . In 1997, Montague reported the first consanguineous family with two very obese prepubertal children who had congenital leptin deficiency 104 . The two cousins were homozygous for a frameshift mutation in the leptin gene....

Sexual Dysfunction

Sexual function is frequently impaired by chronic renal failure 55 and is only partly reversed by transplantation, although few well-controlled studies are available. Contributory factors include vascular failure, pelvic autonomic neuropathy, antihypertensives particularly centrally acting agents and beta blockers , and other medications, together with additive effects of age, depression, and general debility. Uremic sexual function is not consistently improved with androgen therapy 200-400 mg...

Role Of Intrinsic GnRh Deficiency In Mediating Lowamplitude Lh Secretion

Elderly Body Cells

Experiments in the male mouse and rat support an important, but not exclusive, role of GnRH-deficient hypogonadotropism in the hypoandrogenemia of aging 41-44 . Evidence to this end includes 1 decreased castration-, naloxone-, and restraint stress-induced LH release in the older rodent 24,42,45-47 2 diminished in vivo LH pulse amplitude in senescent animals 43,48 3 reduced in vitro hypothalamic GnRH secretion 49,50 4 altered GnRH neuronal synaptology 51 5 preservation of the stimulatory...

Factors Regulating GnRH secretion

The current view is that central inhibition of GnRH release results in a prepubertal quiescence of gonadotropin secretion, and the onset of puberty results from the removal of this central restraint 28 . Mechanisms related to the control of the onset of puberty have been extensively studied in various rodent models. However, in rodents, the interval between infancy and puberty is condensed, and these two developmental phases cannot be separated by a clearly demarcated juvenile phase of...

Fertility In Men With Other Enzymatic Deficiencies In Steroid Synthesis

CAH can also be caused by enzyme deficiencies other than 21-hydroxylase deficiency see Fig. 1 . The first two enzymes in steroid synthesis 30-hydroxysteroid dehydrogenase and 17a-hydroxylase 17,20-lyase and the intracellular cholesterol transport protein StAR , are present in both adrenals and gonads. A deficiency of these enzymes or in the StAR protein leads to cortisol and aldosterone deficiency and insufficient gonadal production of sex steroids. In the male patient, this results in prenatal...

Injectables

Testosterone Cypionate Levels

Testosterone enanthate TE and cypionate are testosterone esters administered by biweekly or triweekly deep im injection. The usual recommended dose for hypogo-nadal men is 200 mg in 1 mL oil administered every 2 wk. The pharmacokinetics PK of injectable testosterone preparations have been carefully studied 73,74 , and the PK of TE is shown in Fig. 2. Serum testosterone levels peak within 1 to 3 d after administration, and gradually decline to a trough after 2 to 3 wk. In many subjects, the peak...

Exercise Hypogonadal Males Basal Hormonal Responses

Testosterone Levels

Retrospective comparative studies examining isolated, single blood samples have found lower testosterone levels in chronically endurance-trained males. The subjects in those studies were typically distance runners who had been involved with the physical-training aspects of their sport for 1 to 15 yr. In those studies, total and free-testosterone levels in the endurance-trained men were only 60-85 of the levels of matched sedentary controls 7,35,54,56-58 . Many of the early studies reporting...

Other Lifestyle Dietary Factors Affecting the Adult Male

Cryptorchidism Human Males

The preceding section dealing with scrotal temperature obviously applies as much to sedentary lifestyles outside, as well as inside, of the workplace. Probably the most important other factors are dietary habits, particularly obesity and alcohol intake, smoking, stress, and recreational sporting drug use. Unlike the well-established relationship between caloric intake and maintenance of menstrual cycles in women, there is no such clear relationship in men regarding sperm production and semen...

Anemia

The anemia of end-stage renal failure has multiple contributory factors, including EPO deficiency, toxic inhibitors of EPO action, androgen deficiency, micronutrient deficiency iron, folate, and pyridoxine , blood loss, and hemolysis 81 . Although the balance between these remains conjectural, EPO deficiency is a major factor 82 , and androgen therapy has consistent effects on EPO secretion and hemoglobin concentrations 83 . Endogenous testosterone is an important physiological determinant of...

GnRH Deficient

Testosterone Levels Puberty

Schematic drawing of the hypothalamic-pituitary-gonadal axis in a normal adult male and in congenital hypogonadotropic hypogonadism. Biochemical Studies. Despite variation in the clinical phenotype of CIHH men, their biochemical findings are similar. By definition, all patients have T levels in the hypogonadal range. Gonadotropins are low normal in all subjects, which, in the setting of low T levels, indicate hypogonadotropic hypogonadism see Figs. 5 and 6 . Interestingly, mean LH and...

High Prevalence Of Androgen Deficiency In Hivinfected Men And Women

Early studies 1-4 suggested that as many as 30-50 of HIV-infected men have serum testosterone levels that are below the lower limit of the normal range for healthy, young men. For instance, Dobs et al. 1 reported that 50 of HIV-infected men had low testosterone concentrations. Grinspoon et al. 2 described a reduction in free testosterone levels in 49 of HIV-infected men with AIDS wasting. In a prospective survey 5 conducted in 1998 during the early days of protease inhibitor therapy, we...

TIME minutes

Men With High Testosterone Levels

Frequent blood sampling every 10 min for 24 h for luteinizing hormone LH in a normal man and a man with idiopathic hypogonadotropic hypogonadism IHH . A Normal adult male pattern of gonadotropin-releasing hormone GnRH secretion with high amplitude LH pulsations 10 pulses in 24 h , normal serum testosterone levels, and normal testicular volume B Apulsatile pattern of GnRH secretion in an IHH male as assessed by a complete absence of endogenous LH pulsations, low serum testosterone...

Spermatogenesis Stimulation

Testosterone And Prenatal Development

The induction of spermatogenesis in patients with hypogonadotropic hypogonadism requires testicular stimulation with GnRH or gonadotropins. Various preparations are available see Table 1 to reach this goal, each with advantages and disadvantages. Because the maturation of spermatogonia to mature sperm takes approx 70 d, the first sperm usually do not appear in the ejaculate for at least 3 mo, but it may take 2 yr for patients with congenital hypogonadotropic hypogonadism to become sperm...

Hematocrit Hemoglobin and Liver Function Tests

Androgens increase erythropoiesis EPO by acting directly on stem cell proliferation and through its action on the kidneys to stimulate EPO production 69 . Androgen therapy in hypogonadal and eugonadal men results in elevation of hematocrit and hemoglobin 17,40,55 . The increases in hemoglobin and hematocrit occur within 3 mo, but progressive increases are uncommon, unless the dose of testosterone is adjusted upward or another cause for polycythemia is also present. Direct dose-response...

Testosterone Shbg And Obesity

Correlations Between Sex Hormone-Binding Globulin and Measures of Adiposity in Men Relation Between Sex Hormone-Binding Globulin and Author No. of Men Body Mass Index Waist-to-Hip Ratio Correlations Between Sex Hormone-Binding Globulin and Measures of Adiposity in Men Relation Between Sex Hormone-Binding Globulin and Author No. of Men Body Mass Index Waist-to-Hip Ratio determine whether visceral fat is more closely linked to low testosterone than is total body fat, but results have been...

Pathophysiology Of Klinefelters Syndrome

Testicular Biopsy Klinefelter

Most cases of KS occur through sporadic chromosomal nondisjunction during parental gametogenesis in either the sperm or the egg. A seminal study using DNA probes to X chromosome restriction-site polymorphisms demonstrated that in one series of 32 individuals with KS the additional X chromosome was of paternal origin in 17 53 of cases and of maternal origin in 14 44 of cases and resulted from a postzygotic mitotic error in 1 3 case see Table 1 10 . Because these are sporadic errors in...

Clinical Features Of Klinefelters Syndrome

Klinefelter Syndrome

The clinical manifestations of KS are those of prepubertal androgen deficiency and infertility. Because testicular failure occurs before puberty, the developmental changes Fig. 2. An individual with Klinefelter's syndrome. Note tall body proportions, gynecomastia, relative paucity of facial and body hair, and small testis. Photos courtesy of Dr. C. Alvin Paulsen. Fig. 2. An individual with Klinefelter's syndrome. Note tall body proportions, gynecomastia, relative paucity of facial and body...

Functional Gonadotropin Deficiency

Pulse Frequency

Men with chronic renal failure have reduced circulating total and free testosterone concentrations, unchanged sex hormone-binding globulin SHBG and elevated immunoreactive LH, FSH, and inhibin-a however, these changes are largely reversed after successful transplantation 1 . Although this pattern is consistent with a primarily defect in testicular function, there is also strong evidence for defective neuroendocrine regulation as an important functional aspect of the reproductive dysfunction in...

Use Of Recombinant Human Growth Hormone To Stimulate Spermatogenesis

Various direct or indirect effects of growth hormone GH and other growth factors on the process of sexual maturation have been postulated because deprivation of GH during maturation leads to impaired or absent spermatogenesis in male rats 53 . Furthermore, GH and growth factors, such as insulin-like growth factor-1 IGF-1 , epidermal growth factor EGF , and transforming growth factor TGF , influence testicular steroid production and secretion 54-56 . In mice, the testicular steroidogenic...

Hormonal Regulation Of Spermatogenesis

Regulation Spermatogenesis

The central role of the pituitary to stimulate spermatogenesis5 in adult primates was established nearly 60 yr ago 5 . Surgical removal of the pituitary gland in rhesus 5 In the context of this discussion, spermatogenesis is defined as the production of testicular spermatozoa whether one or many. Fig. 2. A schematic representation of the two mechanisms of stem cell renewal in higher primates. The top two diagrams illustrate the scheme that is common to rhesus monkey Macaca mulatta , African...

Endocrine Aspects Of Testicular Descent

Fsh Testosterone

A role for hormones in testicular descent was demonstrated more than 70 yr ago when a urinary extract from pregnant monkeys containing hCG was used to treat monkeys with cryptorchidism 54 . It remains unclear whether that was a direct gonadotropin effect or an indirect effect from increased testosterone production. The factors controlling testicular descent are clearly more complicated than hormone insufficiency alone, because only a portion of hypogonadotropic patients with Kallmann syndrome...

Hormone Production Sexual Development and Activity Hormone Production

Cryptorchid Testicular Volume

Testosterone levels are generally normal in men with cryptorchidism, even those who were not treated 73,130 . Although testosterone levels are within the normal range in men who were formerly cryptorchid see Fig. 3 without other problems, a Fig. 4. Testosterone levels ng dL in men who were formerly cryptorchid plotted against age of orchidopexy. These data suggest lower levels in men with orchiopexy at older ages 1 . Fig. 4. Testosterone levels ng dL in men who were formerly cryptorchid plotted...

GnRh Synthesis And Secretion

Gnrh Neurons

GnRH is the proximate regulator of reproduction. GnRH, a C-terminal amidated decapeptide is found in a small number of neurons that are located diffusely throughout the anterior hypothalamus in primates 1 . GnRH neurons send axons through subventricular and periventricular pathways to terminate in the capillary space within the median eminence. GnRH from these axons enters the capillaries and is transported in the hypothalamic portal blood to the cells of the anterior pituitary. Many factors...

Congenital Idiopathic Hypogonadotropic Hypogonadism CIHH Definition

Delayed Adolescence

CIHH is characterized by an isolated defect in GnRH secretion or function. Criteria for the diagnosis of CIHH include 1 decreased T levels in the hypogonadal range e.g., lt 3.5 nmol L , 2 low normal gonadotropin levels representing absent or reduced GnRH secretion, 3 otherwise normal hormonal testing of the anterior pituitary, 4 a normal ferritin level, and, 5 normal radiographic imaging of the hypothalamic-pitu-itary region. Familial CIHH was reported in 1944, in association with anosmia and...

Infertility

Testicular Size Age

Cryptorchidism may be a prominent cause of male infertility. Although there are no truly accurate indicators of male infertility, this number has been inferred from the portion of infertile couples whose infertility is believed to result from a male factor. It is estimated that 13 to 14 of couples in which the female partner is less than 45 yr of age are infertile excluding those who are surgically sterile 143 . In US studies, it is not possible to estimate what portion of these cases result...

Hormonal Treatment

Cryptorchidism Testosterone

Human chorionic gonadotropin hCG and gonadotropin-releasing hormone GnRH are being used in patients with cryptorchidism for both diagnostic and therapeutic purposes. No uniform regimen for hCG is superior for either purpose, and it is likely that most regimens provide maximal stimulation. Treatment for 3 to 4 d is practical and provides a reliable assessment of testicular responsiveness 119 . The use of the diagnostic test is limited to the situation in which neither testis is palpated. In the...

Hypotheses on Control of the Onset of Puberty

Onset Puberty Factors

In 1931, Hohlweg presented a so-called gonadostat theory of puberty, which was based on the concept of a changing sensitivity of the gonadotropin-regulating system to the negative feedback effect of gonadal steroids 20 . This theory was further developed by Grumbach and colleagues 21 . Hohlweg and Junkmann observed that Fig. 3. The gonadostat hypothesis for puberty, i.e., a developmental change in the sensitivity of the gonadotropin-releasing hormone GnRH system in the regulation of...

Occupational Lifestyle Effects on Scrotal Temperature

Scrotal Hyperthermia

Another situation in which occupational effects on male reproductive function might become apparent is if the occupational effect applies to a large proportion of men. It is possible that scrotal heating may be one such example. Scrotal, and therefore testicular, temperature has to be maintained some 3-4 C lower than core body temperature if normal spermatogenesis is to occur see Fig. 2 , and interference with the normal scrotal cooling process can profoundly affect sperm production, quality,...

Kinetics Of Spermatogenesis And Cycle Of The Seminiferous Epithelium

Seminiferous Stages

The kinetics of spermatogenesis are the temporal relationships among the various germ cells within the seminiferous epithelium as they proceed through mitosis, meiosis, and spermiogenesis 13,16,17,20,21 . The Sertoli cells, the only somatic cells found in the seminiferous epithelium, provide nourishment, growth factors, and organization to the germ cells 14 . These somatic cells span the entire seminiferous epithelium, sitting on the basement membrane and stretching to the lumen of the...

Measures Of Subclinical Atherosclerosis

Testosterone Levels

Research in the field of atherosclerosis and cardiovascular disease has changed substantially in recent years because of the development of noninvasive methods of measuring the extent of atherosclerosis, including ultrasound measures of carotid intima-media wall thickness, CT measures of coronary artery and aortic calcification, ankle-brachial blood pressure assessments of lower extremity peripheral arterial disease, and measures of vascular stiffness, compliance, and pulse characteristics and...

Leydig Cell Tumors

Leydig Cell Testosterone

Testicular tumors occur at a rate of 2 cases per 100,000 men and constitute 1 of all tumors in men. Leydig cell tumors LCTs account for 1 to 3 of testicular tumors 119 . LCTs were first identified by Sacchi in 1895 120 . Although they are rare gonadal stromal tumors, LCTs may occur at any age and represent approx 40 of all non-germ cell testicular tumors 121 . Most LCTs are unilateral only 3 are bilateral 121 . LCTs are found at all ages from 2 to 90 yr, with a peak occurrence in the fifth...

Secondary Hypogonadotropism

In male patients with 21-hydroxylase deficiency, as in affected females, adrenal androgens may suppress the hypothalamic-pituitary-gonadal axis, both directly and after conversion to estrogens, thereby leading to hypogonadotropic hypogonadism 12-14 . Augarten et al. described a patient who was referred for secondary infertility and was diagnosed with nonclassic 21-hydroxylase deficiency, as was his daughter 58 . Serum FSH and LH levels were decreased and unresponsive to GnRH stimulation....

Gonadotrophs And GnRh Receptors

Testosterone Gonadotroph

Gonadotrophs account for 6-10 of the cells of the normal anterior pituitary 14 . Gonadotrophs may be small and round or larger and ovoid and are difficult to identify by morphological criteria. Instead, immunostaining, using specific antibodies for LH-P and FSH-P proteins, is used to identify gonadotrophs. In primates 15 , as in rodents 14 , the majority of gonadotrophs are bihormonal, i.e., they express both LH-P and FSH-P subunit genes. A small fraction of cells express LH or FSH selectively,...