Low Testosterone Treatment

31 Day Testosterone Plan

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31 Day Testosterone Plan Overview

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My 31 Day Testosterone Plan Review

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The writer has done a thorough research even about the obscure and minor details related to the subject area. And also facts weren’t just dumped, but presented in an interesting manner.

As a whole, this book contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

Evaluation of Congenital Hypogonadotropic Hypogonadism

Hypogonadism is defined as a defect in one of the two major functions of the testes (i.e., production of T and spermatogenesis). Hypogonadism can reflect either a primary testicular defect (hypergonadotropic hypogonadism) or a disorder of the pituitary or hypothalamus (secondary or hypogonadotropic hypogonadism). Serum LH and FSH concentrations distinguish primary from secondary hypogonadotropic hypogonadism. Primary hypogonadism is diagnosed in the presence of low serum T levels, oligospermia, or azoospermia, and elevated serum gonadotropin levels. In contrast, secondary hypogonadism is defined by a low T level and a reduced sperm count in the setting of low or inappropriately normal serum LH and FSH concentrations. Given the diurnal rhythm of T secretion in normal men, T should be measured in a morning blood sample. If the initial level is low, repeat measurements should be performed. In secondary hypogonadism, the serum LH response to a single bolus of exogenous GnRH cannot...

Physiopathology of Hypogonadism

Clinically nonfunctioning pituitary adenomas (NFPAs) represent approx 25-30 of pituitary tumors and are the most commonly encountered macroadenomas (78-80). Hypogonadism is present in approximately half of the patients with NFPA, 50 of whom have mild hyperprolactinemia (31), reflecting stalk compression that might contribute to impaired gonadal function.

Adverse Consequences Of Low Testosterone Concentrations On Healthrelated Outcomes In Hivinfected Individuals

Low testosterone levels are associated with an adverse disease outcome in HIV-infected men. Serum testosterone levels are lower in HIV-infected men who have lost weight than in those whose weight has been stable (39). Longitudinal follow-up of HIV-infected homosexual men revealed a progressive decrease in serum testosterone levels (40). This decrease was much greater in HIV-infected men who progressed to AIDS than in those who did not. We do not know whether the decrease in testosterone levels is a consequence of weight loss or is a contributory factor that precedes muscle wasting. In a longitudinal study, Dobs et al. (41) measured serum testosterone levels in a cohort of HIV-infected men and reported that serum testosterone levels decline early in the course of events that culminate in wasting. Testosterone levels correlate positively with muscle mass and exercise capacity in HIV-infected men (2), leading to the speculation that hypogonadism may contribute to muscle wasting and...

Other Associations of Cancer and Hypogonadism

Cryptorchidism is associated with spermatogenesis impairment and an increased risk of neoplastic change in the testes. Tumors arising in the region of the pituitary and hypothalamus or their treatment may result in hypopituitarism and consequent hypogonadism. Hormonally active tumors elsewhere may also inhibit hypothalamic-pituitary function. Ectopic adrenocorticotropic hormone (ACTH) secretion, most commonly from lung tumors, may cause secondary hypogonadism. Androgen-secreting tumors may suppress gonadotrophin secretion, thereby causing oligospermia or azoospermia. However, with the exception of cryptorchidism, hypogonadism would be an unusual presentation for these conditions.

Hypogonadotropic Hypogonadism

GnRH and gonadotropin deficiency can be caused by various genetic or developmental defects of the hypothalamus or by destructive lesions, such as tumors, inflammatory processes, vascular lesion, or trauma. Patients with isolated gonadotropin deficiency are generally of normal height for age in the prepubertal period and contrast with boys with constitutional delay who are shorter. In patients with hypogonadotropic hypogonadism, gonadotropin responses to GnRH stimulation may be subnormal, but because of the functional hypogonadotropism in constitutional delay, the differential diagnosis between these two conditions may be difficult (54,55). Anorexia Nervosa. Anorexia nervosa, which results from a distorted body image, an obsessive fear of obesity, and avoidance of food, can be associated with severe, even fatal, weight loss. For unknown reasons, this disorder is much more common in girls than in boys. The boys' functional hypogonadotropic hypogonadism at least partly results from...

Hypogonadotropic Hypogonadism Associated With Leptin and LeptinR Mutations

Moreover, the patient's basal and stimulated gonadotropin levels increased after 1 yr of leptin therapy and a nocturnal LH secretion pattern was observed, characteristic of midpuberty (105). These findings might suggest a permissive role of leptin in the onset of puberty. In 1998, another consanguineous family with three affected obese individuals who had undetectable leptin levels was reported. Affected individuals were homozygous for a missense mutation (Arg105Try) in the leptin gene (106). Among the sibship, a 24-yr-old man failed to undergo puberty. He had low T and low gonadotropin levels, but a normal response to exogenous hCG and GnRH. Similar to the ob ob mice with leptin mutation, these patients had morbid obesity, hyperinsulinemia, and hypogonadotropic hypogonadism, but unlike the mice, these patients were not hyperglycemic, had normal glucocorticoid concentrations, and did not present with growth abnormalities. In 1998, three sisters with...

Hypogonadism Can Result From Defects at Several Levels

Male hypogonadism may result from defects in spermato-genesis, steroidogenesis, or both. It may be a primary defect in the testes or secondary to hypothalamic-pituitary dysfunction, and determining whether the onset of gonadal failure occurred before or after puberty is important in establishing the cause. However, several factors must be considered. First, normal spermatogenesis almost never occurs with defective steroidogenesis, but normal steroidogenesis can be present with defective spermatogenesis. Second, primary testicular failure removes feedback inhibition from the hypothalamic-pituitary axis, resulting in elevated plasma gonadotropins. In contrast, hypothalamic and or pituitary failure is almost always accompanied by decreased gonadotropin and steroid levels and reduced testicular size. Third, gonadal failure before puberty results in the absence of secondary sex characteristics, creating a distinctive clinical presentation called eunuchoidism. In contrast, men with a...

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 the inverse correlation between SHBG and obesity (25) and insulin resistance (50) and the propensity for obese and insulin-resistant individuals to develop type 2 diabetes. In the Massachusetts Male Aging Study (66), not only total but also free-testosterone levels were 17 lower in men who developed type 2 diabetes 7-10 yr later than in those with no diabetes. Free-testosterone levels that were 10 lower at baseline were also found in men in the Multiple Risk Factor Intervention Trials...

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 to cause hypogonadotropic hypogonadism. CHH may also be associated with impaired production of other pituitary hormones, often resulting from reduced or absent expression of transcription factors such as PROP-1 or HEXS-1. Finally, hypogonadotropic hypogonadism can be a component of complex syndromes with multiple somatic abnormalities, such as morbid obesity (Prader-Willi), cerebellar ataxia (26), cranial nerves palsies and peripheral neuropathy (27), congenital spherocy-tosis (28). CHH is...

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 fertility is desired later in life (5,7). In patients with hypogonadism that began after puberty, treatment can be initiated either with testosterone for androgen substitution or with GnRH or gonadotropins if fertility is desired immediately. Because GnRH and gonadotropins are both costly, they are justified only when fertility is desired or in the initial phase of treatment, when spermatogenesis is to be stimulated to the point of sperm production. Treatment may be required for 2 or more...

Hypogonadism

Patients with congenital hypogonadotropic hypogonadism are usually infertile, and most cases, therefore, occur sporadically, presumably as a result of de novo mutation. Because of the therapeutic use of pulsatile GnRH or gonadotropins, however, these patients may become fertile, and vertical disease transmission may increase. Segregation analysis has demonstrated X-linked, autosomal recessive and autosomal dominant inheritance patterns, suggesting the existence of several genes regulating GnRH secretion (61-63). Genes currently recognized to be involved in congenital hypogonadotropic hypogonadism include KAL (64), the GnRH receptor (13-15,65,66), DAX1 (67,68), and PROP 1 (69). Furthermore, sporadic cases of mutations in ANK 1 gene (70), SF-1 gene, LHX 3 gene (71), HESX1 gene (72) and leptin (Ob) gene (73), leptin receptor (Ob R) gene (74), and prohormone convertase 1 (PC 1) gene (75) have been reported. However, a genetic basis for IHH has been established in less than 20 of cases,...

Neuroendocrine Mechanisms For The Differential Control Of Fsh And Lh

In addition to the selective regulation of FSH-P mRNA levels by pituitary activin and follistatin and by testicular inhibin-B, there may be other mechanisms for the differential secretion of FSH and LH. Results from studies in rats (124) and rat pituitary cell cultures (125) revealed that the frequency of GnRH pulses regulates LH-P and FSH-P mRNA levels differently, with rapid GnRH pulse frequencies (every 15-30 min) favoring LH-P over FSH-P gene expression. This difference may be partly due to upregulation of follistatin mRNA levels by rapid GnRH pulse frequencies (125), with subsequent blockade by follistatin of activin-stimulated FSH-P gene expression. Although this mechanism is applicable to rats, its importance in men is less well established. For example, in men with congenital hypogonadotropic hypogonadism

Leydig Cells as a Target for Male Contraception

Hormonal contraception targets Leydig cells, suppressing their androgenic function. How much testosterone is needed for normal spermatogenesis in humans remains to be determined. In rats, intratesticular testosterone concentrations as low as 5 of normal support the complete spermatogenic process, whereas in the nonhuman primate, testic-ular androgen levels of 30 of baseline do not prevent complete suppression of germ cell development (134,135). Therefore, testosterone levels must be reduced below a threshold for successful interruption of spermatogenesis. In primates, however, the selective suppression of Leydig cell testosterone production is not sufficient to accomplish the goal of fertility regulation, and the additional inhibition of FSH secretion is necessary (136). One effective approach may be to suppress both LH and FSH secretion and, simultaneously, supply androgen to avoid peripheral androgen deficiency (137).

Diagnosis Of Klinefelters Syndrome

KS in a prepubertal boy are verbal learning disabilities and taurodontism, the unusual enlargement of the pulp of the tooth seen roughly half of men and boys with KS (46). After puberty, individuals with KS will often exhibit tall stature (usually greater than 184 cm) with proportionally long legs and will frequently manifest an arm span that is greater than their height (51). In adults, the diagnosis of KS should be considered in men with gynecomastia, primary hypogonadism, infertility, or osteoporosis. Because serum testosterone levels may be normal, serum gonadotropins should also be measured. Peripheral blood karyotyping can be used to confirm the diagnosis, although this test can be negative in mosaic individuals, and tissue karyotype may be necessary (9).

Testosterone Effects On Healthrelated Outcomes In Men With Chronic Illness

The effects of testosterone supplementation on health-related outcomes in HIV-infected men have not been rigorously examined in adequately powered, prospective studies. However, in several placebo-controlled trials, testosterone administration has been associated with improvements in several subdomains of health-related quality of life. For example, testosterone administration has been reported to improve depression indices in HIV-infected men (72). In a recent study, Pope et al. (73) administered a replacement dose of a testosterone gel or placebo to men with refractory depression and low testosterone levels. Testosterone administration was associated with greater improvements in scores on the Hamilton depression scale than was placebo. These preliminary data suggest that testosterone administration might have a clinically important antidepressant effect. In open-label, studies of healthy, hypogonadal men, testosterone replacement also improved positive aspects of mood and reduced...

Other Potential Causes of Androgen Deficiency

Men with pre-existing testicular dysfunction (including renal failure) may be more susceptible to further impairment of steroidogenesis caused by medications or illnesses. HMG-CoA reductase inhibitors inhibit cholesterol synthesis and may, therefore, impair steroidogenesis, particularly because adverse events consistent with androgen deficiency (gynecomastia and impotence) have been reported. A prospective, open-label study of 25 nephrotic, hyperlipidemic men with moderate chronic renal failure treated for 12 mo with lovastatin (40 mg d) showed no change in baseline and GnRH-stimulated LH, FSH, and testosterone levels (38). A more discerning test of testicular steroidogenesis, such as testosterone response to submaximal hCG stimulation, was not reported. Adrenal steroidogenesis (plasma cortisol before and after adrenocor-ticotropic hormone ACTH stimulation) was comparable with age-matched healthy controls at entry and remained unchanged by lovastatin treatment. Not surprisingly,...

Treatment of Hematological Malignancy

In addition to effects on the germinal epithelium, there is also some evidence for Ley-dig cell dysfunction after chemotherapy for lymphomas. Howell et al. (22) measured testosterone and LH levels in 135 men treated with either MVPP or ChlVPP EVA hybrid. They demonstrated significantly higher LH levels in patients compared with a cohort of age-matched controls (mean LH 7.8 vs 4.1 IU L). They suggested that this raised LH level indicated a reduction in hypothalamic-pituitary negative feedback consequent to a small reduction in testosterone production. This may still result in testosterone levels that fall in the cross-sectional normal range, and they thus defined mild Leydig cell dysfunction as a raised LH level in the presence of a testosterone level that is in the lower half of the normal range or is frankly subnormal. This combination was found in 44 men (31 ) after chemotherapy with a further 10 (7 ) having a raised LH level alone. This suggests that a significant proportion of men...

Johannes D Veldhuis MD Ali Iranmanesh MD and Daniel Keenan PhD

The aging process is marked by a relatively subtle short-term decline in reproductive hormone outflow in men. However, the nominal 0.8-1.3 annual fall in systemic bioavailability of testosterone results in a reduction of 30-50 by the sixth through eighth decades of life. Low testosterone concentrations forecast relative sarcopenia, osteopenia, visceral fat accumulation, detectable cognitive impairment, and variable mood depression. Accordingly, the mechanisms driving progressive androgen deprivation are important to understand. To this end, age-associated alterations in three dominant sites of physiological control, namely the hypothalamus, pituitary gland, and testis, are highlighted. The cognate signals are gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and testosterone, which jointly determine androgen availability via feedback and feedforward adaptations. According to this emergent notion, no single gland acts in isolation to maintain homeostasis. An integrative...

Seasonal Effects on Testicular Function

Although humans are considered to be nonseasonal mammals, we are undoubtedly sensitive to photoperiod (9), as exemplified by seasonal affective disorder and by seasonal trends in the frequency of births and in the incidence of twins. Such effects are most obvious in northern Europe, where photoperiodic changes are most extreme (10). Furthermore, both longitudinal and cross-sectional studies have demonstrated that sperm counts in men are consistently approx 30 lower in summer than in winter (11,12), although not all studies have reported such effects, and they may be less apparent or absent in tropical countries (13). An alternative explanation is that it is exposure to the higher summer temperature that is responsible for lowering sperm production (see section on scrotal temperature), although temperature changes do not account for all of the seasonal trends in births, especially in northern Europe (3). If the reported seasonal changes in sperm counts are an echo from our seasonally...

Occupational Environmental Exposure to Pesticides FungicidesPCBs

The DBCP example means that in nonscientific circles, the concept that pesticide exposure results in lowered sperm counts infertility has become more or less accepted as dogma. In reality, there are relatively few studies that support this stance (32-35), and many of these are studies in developing countries, where exposure controls may be less vigorous than in developed countries. Furthermore, there are numerous studies in which occupational pesticide exposure is associated with no change in semen quality and or fertility and no effect on testosterone levels (36-40) these include comparative studies of organic and nonorganic farmers. Although it is difficult to draw firm conclusions from these conflicting studies, it is reasonable to expect that occupational exposure to current, nonpersistent pesticides is unlikely to exert major adverse effects on semen quality and fertility in most men, but effects in individuals who might be exposed to unusually high pesticide levels should still...

Environmentallifestyle Effects On The Adult Testis That Arise During Fetal Development

There is growing evidence that a syndrome of interconnected disorders affecting the human male, so-called testicular dysgenesis syndrome, may have a common origin in fetal life (Fig. 1) during the period of sexual differentiation (68). Manifestations of this syndrome in adulthood can include low sperm counts reduced fertility and or testicu-lar germ cell cancer, as well as a history of cryptorchidism and or hypospadias (see Fig. 3) other potential aspects, such as lowered testosterone levels for life, remain to be clearly defined. Several of these disorders are increasing in incidence, with environmental lifestyle causes implicated in this increase (68). An integral part of this syndrome of disorders is evidence for impaired hormone production action or abnormal

Crosssectional And Prospective Studies Relating Testosterone To Cardiovascular Disease Endpoints

There has been considerable interest during the past two decades regarding the importance of endogenous testosterone to the development of cardiovascular disease in middle-aged and elderly men (71-77). Studies evaluating the relationship between endogenous testosterone and cardiovascular morbidity and mortality in men have yielded inconclusive results. Most of these studies were hospital-based, case-control studies, in which cases were either men with acute myocardial infarction or men who had survived an infarction. Of the 31 cross-sectional studies, 19 (61 ) found lower plasma total or free-testosterone levels in men with myocardial infarction or coronary artery disease compared with controls (21,78,79-95), whereas the remaining studies reported no significant difference in hormone levels between cases and controls (96-107). Cross-sectional studies have also analyzed the relationship between endogenous testosterone levels and the presence of angiographically defined coronary artery...

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). Wischusen et al. described a patient with partial 21-hydroxylase deficiency, azoospermia, small testes, normal to high serum testosterone levels, and suppressed serum levels of gonadotropins. After treatment with glucocorticoids for several months, the semen quality improved, and he fathered a child (59). The cases described illustrate that hypogonadotropic hypogonadism may occur in males with undiagnosed 21-hydroxylase deficiency or as a result of poor adrenal control. Most reports show reversible hypogonadotropism and improved fertility after increasing glucocorticoid therapy.

Measures Of Subclinical Atherosclerosis

Testosterone Levels

Numerous studies have shown that carotid intima-media wall thickness predicts coronary atherosclerosis and the incidence of clinical cardiovascular disease (116). Lower total testosterone levels were associated with greater carotid atherosclerosis in 297 elderly Dutch men independent of body mass index, WHR, hypertension, diabetes, cigarette smoking, and serum cholesterol levels in one recent report (117). A similar inverse association between testosterone and carotid artery wall thickness was observed in men with and without prevalent cardiovascular disease. More recently, Hak et al. (118) demonstrated a relationship between endogenous testosterone levels and both the prevalence and the progression of atherosclerosis in a population-based study of 504 nonsmoking men aged 55 yr and older. The extent of arterial calcification in the abdominal aorta was measured with lateral radiographs at a baseline examination and after an average of 6.5 yr. Progression of aortic atherosclerosis was...

Management Of Delayed Puberty

For boys who are hypogonadal, testosterone substitution therapy should be initiated at a low dose, because too large a dose may advance skeletal maturation disproportionately and, thus, compromise final adult height. Furthermore, large doses may cause acne, gynecomastia, or too-rapid change in libido. Doses are adjusted according to the clinical response (Tanner stage and bone age). Most commonly, long-acting testosterone preparations, which are administered intramuscularly, are used for this purpose. Esterification of testosterone with either propionic or enanthic acid at position 17 prolongs the metabolite's activity (69). Testosterone propionate is not a suitable testosterone preparation for substitution therapy, because plasma concentration show wide fluctuations, and the maximal between-injection interval is only 3 d with a 50 mg dose (70). Testosterone enanthate at a dose of 250 mg intramuscularly has a half-life of 4.5 d. Based on multiple-dose pharmacokinetics, an injection...

Factors Affecting Circulating Testosterone Hypothalamic PituitaryTesticular Axis

These factors are discussed in detail elsewhere (6,24,25). Collectively, all of the aforementioned considerations must be carefully examined when comparing the hormonal results of research studies if a valid interpretation of the endocrine system's responses to exercise is to be made. Figure 1 illustrates some of these physiological and nonphysiological factors that affect circulating testosterone levels in exercising men.

GnRh Synthesis And Secretion

Gnrh Neurons

GnRH, like most hypophysiotropic peptides, is released into the portal blood in bursts. The average GnRH concentration in hypothalamic portal blood (in rams) is approx 20 pg mL (0.02 nM), and levels in conscious sheep ranged from nadir values of less than 5 pg mL to pulse peak values of approx 30 pg ml (4). In those studies, the amplitudes of GnRH pulses in intact, castrated, and testosterone-replaced rams were roughly equivalent by contrast, GnRH pulse frequency was higher in castrates than in intact animals, and was reduced by testosterone replacement. The implication of those observations is that GnRH secretion rises with testosterone deficiency, primarily because GnRH pulse frequency is accelerated.

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 against age of orchidopexy. These data suggest lower levels in men with orchiopexy at older ages (1). recent study found an inverse relationship between testosterone levels in adulthood and age at orchiopexy (see Fig. 4), suggesting a subtle progressive detrimental consequence of a nonscrotal testis during childhood (1). In infertile men overall, there is a significant correlation between testicular volume and indices of spermatogenesis (sperm density and motility and FSH levels) (141)....

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 have cryptorchidism. Furthermore, most patients with congenital primary hypogonadism (e.g., Klinefelter's syndrome) do not have cryptorchidism. Although the absence of cryp-torchidism as a universal finding may be a consequence of the amount of gonadotropin or androgen present during differentiation, these examples are further evidence that many factors are involved in testicular descent, most of which are not yet understood. Decreased testosterone levels have been reported in cryptorchid...

Use Of Recombinant Human Growth Hormone To Stimulate Spermatogenesis

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 response to chorionic gonadotropins stimulation was increased by GH and IGF-1 treatment (54), and an effect of GH on Leydig cell function was also shown in prebu-bertal boys (57). Because testosterone secretion by Leydig cells is necessary for sper-matogenesis, a complementary or permissive role of GH in the induction of spermatogenesis by gonadotropins in patients with hypogonadotropic hypogonadism who failed gonadotropin therapy alone has been suggested. Indeed, in an open trial, in three of four patients with hypogonadotropic hypogonadism who remained azoosper-mic during treatment with hCG hMG for 12 wk, spermatogenesis was induced after GH was added for...

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 uremia. The increase in gonadotropins is less than expected in castrated men who are nonuremic or controls with a similar degree of androgen deficiency (16), indicating a defect in neuroendocrine regulation leading to reduced LH secretion. Indeed, the increase in gonadotropins is largely explained by the substantial ( 70 ) reduction in renal filtration and whole-body clearance rate of LH, which, in the presence of decreased testosterone secretion, indicates significantly reduced LH secretion....

Clinical Features Of Klinefelters Syndrome

Klinefelter Syndrome

Hormonally, the majority of affected men have decreased total testosterone levels, and those with normal total testosterone levels may, in fact have decreased free testosterone, because serum sex hormone-binding globulin (SHBG) levels are elevated in KS (18). More than 90 of men have increased levels of serum gonadotropins, particularly FSH, because inhibin-B levels are low in individuals with KS (5). Because of low androgen levels, individuals with KS can have low bone mineral density and are at increased risk of developing osteoporosis, despite seemingly adequate androgen Low testosterone levels 65-85

Testosterone Shbg And Obesity

Determine whether visceral fat is more closely linked to low testosterone than is total body fat, but results have been conflicting (26). Glass et al. (25) also first noted that low testosterone levels in obese men could be partly explained by a decrease in SHBG, but whether SHBG is more highly correlated with abdominal obesity or with body mass index remains controversial. A summary of several studies reporting cross-sectional correlations between SHBG and body mass index and waist-to-hip ratio (WHR) is found in Table 2. In massively obese men, weight loss after bariatric surgery can reverse the SHBG abnormalities when near-normal body weight is achieved (27). Whereas a low level of SHBG is the major reason for low testosterone levels in mild to moderately obese men, free and non-SHBG-bound testosterone levels are also reduced in massive obesity (28,29) and correlate inversely with body mass index (30). The testosterone response to human chorionic gonadotropin (hCG) stimulation is...

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 positive. The huge variation in individuals can be explained by the diversity of hypogonadotropic hypogonadism and depends on whether spermatogenesis previously progressed to full maturation. There are several other factors that influence the success of stimulation therapy in patients with hypogonadotropic hypogonadism which are discussed later in this chapter. dose of GnRH that is required to achieve testosterone levels in the normal adult male range and to stimulate spermatogenesis varies...

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 prospectively measured serum total and free-testosterone and dihydrotestosterone (DHT) levels in 148 consecutive HIV-infected men and compared the results to 42 healthy men. Thirty-one percent of HIV-infected men had serum testosterone levels less than 275 ng dL, the lower limit of the normal male range (5). Overall, serum testosterone, free-testosterone, and DHT levels were lower in HIV-infected men than in healthy men, but serum DHT-to-testosterone ratios were not significantly different...

Other Lifestyle Dietary Factors Affecting the Adult Male

Cryptorchidism Human Males

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 quality. However, obesity in men is clearly associated with a fall in total testosterone levels, and this may be severe in massively obese individuals (57-60). One large study found no clear relationship between dietary factors and testosterone levels (60), but one smaller study showed a positive relationship to carbohydrate intake (59). Protein and fiber intake may also affect testosterone bioavailability via effects on sex hormone-binding globulin (SHBG) (61). There is a well-established relationship between obesity, insulin resistance, and SHBG secretion (62,63), but probably the most important pathways by which obesity affects testosterone levels are at the hypothalamic-pituitary level (57) and or at the testicular level (64). The latter study, as well as animal studies, have indicated a role...

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 this finding suffered from small sample sizes. However, recent work with larger numbers of subjects has substantiated the findings (59,60). These low resting testosterone levels are highly reproducible and are not just an aberration of the athletes' seasonal training regime (60). Prospective studies have also been conducted in which blood samples have been collected for weeks or months during endurance training regimens. Findings thus far from such studies have been inconsistent. Some reports...

How Do We Monitor Androgen Replacement Therapy

In hypogonadal men, most of the symptoms of androgen deficiency are alleviated with androgen replacement. To determine the dose of testosterone to be administered, serum testosterone levels should be measured at appropriate times after drug administration, based on the PK characteristics of the specific preparation. For example, serum testosterone levels peak 12-16 h after application of testosterone patches and return toward baseline by 24 h. Monitoring is thus done approx 12 h after application, and levels should be in the mid-normal range. Because serum T levels are maintained in a steady state by the transdermal gels (see Fig. 2), serum testosterone can be measured at any time. Because the injectable testosterone preparations, such as testosterone enan-thate and cypionate, result in early peaks (i.e., 2-3 d) and troughs (10-14 + d), serum testosterone is measured at day 7 to ensure that serum testosterone levels are within normal limits. Once a stable dose of testosterone...

Neonatal Leydig Cells

Just after birth, the number of Leydig cells again increases to a peak at 2 to 3 mo of age, contributing to a second surge in plasma testosterone levels. At this stage, Leydig cells contain abundant SER membranes and mitochondria, as well as varying amounts of lipid droplets (4,24-27). In the neonatal testis, fetal Leydig cells persist through at least 3 mo after birth. Postnatal increase in the number of these cells most likely results from recruitment of interstitial precursor cells. After this increase, neonatal Leydig cell numbers regress rapidly to a nadir by the end of the first year. The neonatal period is relatively brief, extending only through the first year of life (28,29).

Secular Trends in Pubertal Development

Prepuberty Puberty Gnrh

With the onset of puberty, LH secretion is augmented, first only during the night (see Fig. 2). In boys, this increase in LH is associated with an increase in plasma testosterone levels during the morning hours. With progression of puberty, LH secretion increases through an increase in both LH pulse frequency and amplitude. The day-night rhythm of gonadotropin secretion is evident during puberty, but it disappears in adulthood (7,8).

Pulsatile Gonadotropin Secretion

Testosterone Secretion

In addition to moment-to-moment pulsatile pattern of LH secretion, there is a diurnal rhythm in circulating LH, as well as testosterone levels, in pubertal boys with increased LH pulsatile amplitude during sleep and increased testosterone levels in the early morning hours (35). Although there is a diurnal variation in plasma testosterone in adults, there is no clear diurnal rhythm for LH in most adult men (36), implying that the diurnal variation in testosterone levels in men is only partly

Who Should Receive Androgen Replacement Therapy

Total Testosterone Reference Range

From Male Hypogonadism Basic, Clinical, and Therapeutic Principles Edited by S. J. Winters Humana Press Inc., Totowa, NJ For confirmation of the diagnosis of male hypogonadism, the total serum testosterone testosterone level should be measured, preferably in the morning, because of the known diurnal variation of serum testosterone concentrations. It should be noted that some clinical laboratories use testosterone assays with testosterone or a testosterone analog as the assay standard, using chemiluminence methods on automated platforms (5). These newer assays might give a testosterone reference range for adult men, which is quite different from those obtained using traditional radioimmunoassays. The clinician must carefully review the reference range quoted by each laboratory to accurately diagnose hypogonadism (5). The reference range generally is based on serum values from healthy young adult men. Serum total testosterone assays in which the reference ranges differ from approx...

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 plasma SHBG in men (54) and in obese women with PCOS (55). The regulation of SHBG expression by insulin has been studied directly using cultures of HepG2 hepatoma cells that express the SHBG gene (56). In these cells, adding insulin reduced SHBG mRNA levels (13) and protein secretion (12). As noted in the section on the SHBG gene, this insulin effect may be mediated by the liver-enriched transcription factor HNF-4 (hepa-tocyte nuclear factor-4) that transactivates the SHBG promoter (57)....

Leydig Cell Development

Reinke Crystals Leydig

From Male Hypogonadism Basic, Clinical, and Therapeutic Principles Edited by S. J. Winters Humana Press Inc., Totowa, NJ In humans, blood levels of testosterone peak three times during development (8). The first peak occurs at 12-14 wk of gestation, during the fetal differentiation of Ley-dig cells (9). Testosterone levels then decline and are low for the remainder of gestation

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 circulating androgens and the cardiovascular syndrome is intimately related to sex hormone-binding globulin (SHBG) and its downregulation in obesity and by insulin. In fact, SHBG is an indicator of the association between sex hormones and plasma lipids, and low levels of SHBG predict the development of type 2 diabetes. Thus, low testosterone and low SHBG are a part of the metabolic cardiovascular syndrome, and, therefore, testosterone replacement has been advocated in these men to reduce their...

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

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 no significant change in lean body mass. Importantly, this progestational agent decreases serum testosterone levels and may produce androgen deficiency symptoms. Of the five placebo-controlled studies of testosterone replacement in HIV-infected men with weight loss, three (see Table 1) (52,60,68) demonstrated an increase in fat-free mass, and two (59,62) did not. The three studies (60,68,69) that showed gains in fat-free mass selected patients with low testosterone levels. Coodley et al. (59) examined the effects of 200-mg testosterone cypionate given every 2 wk for 3 mo to 40 HIVseropositive patients with weight loss of greater than 5 of usual...

Exercise And Pituitarytesticular Function Normal Men Exercise Responses

Normal Testosterone Blood Level

Unlike changes during maximal exercise, testosterone responses to submaximal exercise are more variable and are dependent on the duration and intensity of exercise. Progressive increases in testosterone levels during moderate intensity exercise lasting 45 to 90 min have been found (25,31,32). However, 90 min of submaximal moderate intensity exercise has also been reported to produce no change or a slight decrease in testosterone concentrations (25,31). Exercise of a moderate or hard intensity until exhaustion, of more than approx 2 h duration typically lowers testosterone concentrations (25,31,32). Several explanations for these dissimilar changes during short-term submaximal exercise have been proposed. Initially, hemoconcentration may increase the testosterone concentration but as exercise continues, testicular testosterone production declines. The latter change may partly result from reduced testicular blood flow (26,27). Hepatic blood flow may also decline, reducing hepatic...

Blood Lipids and Lipoproteins

Most studies that have included 100 or more adult men have found a positive association between testosterone or SHBG and HDL-C levels (14,87,138-147). Although it has been less well studied, there is evidence that the age-related decline in testosterone may be associated with decreases in HDL-C in middle-aged men (148). The relationship between endogenous testosterone and HDL-C has been observed in different ethnic groups (142,143) and is linear throughout the physiologic range of testosterone concentrations, such that HDL-C increases by 1-mg dL with every 100 ng dL increase in total testosterone (143). Low HDL-C is often found in individual patients in association with other metabolic risk factors, including elevated very low-density lipoprotein (VLDL) and small, dense low-density lipoprotein (LDL), hypertriglyceridemia, and glucose intolerance (136). Insulin resistance may underlie this clustering of metabolic abnormalities, which has been referred to as the metabolic syndrome...

Leydig Cell Toxicology

Toxicants, such as ethanol, interfere with Leydig cell steroidogenesis by interfering with LH secretion, LH receptor binding, intracellular signal transduction pathways, and steroidogenic enzyme activities. Ethanol, for example, decreases LH secretion and reduces LH receptor binding and intracellular cyclic guanosine 5'-monophosphate (GMP) levels. Hence, chronic alcohol abuse causes declines in testosterone levels (138-140). Tumor formation and cell death are also observed after toxicant exposures. Carcinogenesis is considered to be a consequence of multiple insults to the genome. Necrosis and apoptosis have both been implicated in the process of toxicant-related Leydig cell death, with ethylene dimethanesulfonate exposure as the experimental paradigm (141).

Testicular Control Of Gonadotropin Secretion

Estradiol also plays an important physiological role in the negative feedback control of gonadotropin secretion in men. This control mechanism was suggested by pharmacological studies using the estrogen antagonist clomiphene (60) or the aromatase inhibitor testolactone (61). When those drugs were administered to normal men, circulating LH and FSH levels rose, together with plasma testosterone concentrations. More recently, as shown in Table 1, gonadotropin and testosterone levels increased in a man with an inactivating mutation of the estrogen receptor-a (62) and in two men with mutations in the aromatase gene (63,64). In these models, even though androgen levels were increased, estrogen blockade or deficiency was associated with increased gonadotropin secretion. Moreover, in one man with aromatase deficiency, estrogen treatment suppressed serum gonadotropin levels. The finding that clomiphene increased LH pulse frequency (60) indicated that the negative feedback action of estradiol...

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 weight loss and changes in body composition and the endocrine milieu that can impair reproductive function (30). As a general rule, weight loss and body composition changes resulting from undernutri-tion are associated with reduced GnRH secretion, and the decrease in follicle-stimulating hormone (FSH) and LH levels correlates with the amount of weight loss (30). However, both hypogonadotropic and hypergonadotropic hypogonadism have been described in cachexia associated with certain chronic...

Historical Description Of Klinefelters Syndrome

Klinefelter and his colleagues were uncertain of the cause of the syndrome. They excluded testicular inflammation, infection, or obstruction of the vas deferens and noted on testicular biopsy specimens that the lesion involved the seminiferous tubules without dramatically affecting the histology of the Leydig cells, testicular interstitium, or epididymis. They recommended testosterone therapy (available since the late 1930s) for those men with signs or symptoms of hypogonadism but noted that this therapy did not improve the gynecomastia or infertility.

Lipids and Coronary Artery Disease Risk

As discussed more thoroughly in Chapter 17, epidemiological studies have shown that men with lower serum total testosterone levels are at higher risk for cardiovascular events (56,57). In men undergoing coronary angiograms, those with evidence for coronary artery disease had significantly lower serum free androgen index and bioavailable testosterone levels than did those without apparent coronary artery disease (58,59). Older studies described a lessening of ST segment depression and

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. From Male Hypogonadism Basic, Clinical, and Therapeutic Principles Edited by S. J. Winters Humana Press Inc., Totowa, NJ Fig. 1. Schematic drawing of the activity of the hypothalamic-pituitary-gonadal axis across the life cycle. During the neonatal window, pulsatile gonadotropin-releasing hormone (GnRH) stimulates luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion, which induce adult levels of testosterone, estradiol, and inhibin B. Childhood is marked by a low-amplitude LH secretion and low testosterone levels. Pubertal reactivation of the hypothalamic-pituitary-gonadal axis subsequently triggers the onset of sexual maturation,...

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 methods available, there is a high positive correlation between the level of free testosterone by equilibrium dialysis, the gold-standard, non-SHBG testosterone (bioavailable testosterone), and the free-testosterone level calculated from the levels of total testosterone and SHBG (171,172). The direct free-testosterone assay was developed as a single-step, nonextraction method (125) in which an I125-labeled testosterone analog competes with free testosterone in plasma for binding to a...

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 examined the relationship between endogenous testosterone and hemostatic factors have produced inconsistent results. Lower levels of total testosterone were associated with higher concentrations of fibrinogen independent of obesity and other cardiovascular risk factors in one small cross-sectional study of middle-aged and elderly men (153,154) but not in another (155). Bonithon-Kopp et al. (156) examined the cross-sectional relationships between endogenous testosterone and hemostatic factors in 251...

Puberty In Chronic Renal Failure

Cystinosis is a rare autosomal recessive disease characterized by defective extrusion of cystine from lysosomes, causing lysosomal storage and crystal formation that can lead to early renal failure, with the need for dialysis and or transplantation before puberty. Cross-sectional studies have shown marked delay in growth and pubertal development, which improves after transplantation (52) but that remains more severe than other patients matched for age, gender, puberty, and renal status (53). This suggests that toxic cystine accumulation in the testis can lead to hypergonadotrophic hypogonadism when life is prolonged by transplantation. If chelation therapy does not prevent progression to renal failure with attendant growth and pubertal delay, therapeutic trials of androgen therapy could be useful.

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 elevations in peptide hormones, despite markedly impaired peptide clearance, together with direct evidence of hypothalamic dysregulation of pulsatile LH and FSH secretion (13), suggest important defects in hypothalamic-pituitary regulation of gonadotropin secretion

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. Nevertheless, all of the gonadotropin preparations have a good safety record without evidence of contamination, and there is no need to change current prescribing habits (47). A pharmacokinetic-pharmacodynamic study with rhFSH in patients with hypogo-nadotropic hypogonadism showed dose linear serum FSH levels (48), and the pharmacokinetics of recombinant and urinary FSH are similar (49).

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 a brief (2 to 10 s) capillary transit time, so long as reassociation is minimized (118). On the other hand, slow release of testosterone from high-affinity SHBG (half-time 3.3 s at 37 C) would putatively restrict access to cells, at least when reassociation is limited. Protein-binding effects are important, because SHBG concentrations increase as much as twofold and bioavailable (non-SHBG-bound) testosterone concentrations fall by 30-50 in older individuals (20,119-122) (see Fig. 10A). Dynamic...

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 studies (80,81) have found lower serum testosterone levels in middle-aged men with visceral obesity. Serum testosterone levels correlate inversely with visceral fat area and directly with plasma high-density lipoprotein (HDL) levels. Testosterone replacement of middle-aged men with visceral obesity improved insulin sensitivity and decreased blood glucose and blood pressure (82). Testosterone is an important determinant of regional fat distribution and metabolism in men (82). In our dose-response...

Selective Androgen Receptor Modulators SARMs

SARMs act via androgen receptor signaling and may be androgen agonists or antagonists, depending on the target tissues and their modulating effects on the coactivators or coinhibitors of the androgen receptor. An example of a steroid SARM is 7a-methyl 19 nor-testosterone (MENT). MENT is believed to be aromatized to an active estrogen but is not converted to a 5-a-reduced product. In rodents and monkeys, MENT has a greater stimulatory effect on skeletal muscle relative to the prostate (103-104). A clinical study showed that MENT could maintain sexual function and muscle mass in hypogonadal men. MENT is being developed as a long-acting implant (105). Other nonsteroidal orally active SARMs, which have potent actions on muscle and brain but little or substantially lower stimulatory effect on the prostate, are being developed by several pharmaceutical companies (106,107). SARMs may inhibit the synthesis and secretion of the gonadotropins, and, thereby, testosterone production will be...

Lh Control Of Testosterone Synthesis

The blood production rate of testosterone in normal adult men has been estimated to range from 5000 to 7500 g 24 h (45), and levels of total testosterone in normal men range from 250 to 1000 ng dL (10-40 nmol L) in most assays. The testosterone level in adult men declines by more than 95 if the testes are removed. The remainder of the testosterone is derived from androstenedione and DHEA production by the adrenal cortex.

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 testosterone does not rise with age, it is reasonable to deduce that the age-related decreases in androgen concentrations result from decreased Leydig cell androgen production (108,109). Age-related declines in testosterone could be caused by decreased Leydig cell numbers and atrophy of their structure and or reduced steroidogenic ability. Leydig cell numbers are inversely correlated with age, decreasing 44 by age 58 compared to 32-yr-old men (34). Leydig cell numbers decline because of degeneration...

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 well demonstrated. However, there are few data concerning the effect of milder forms of testosterone deficiency.

Sex Hormonebinding Globulin

Of the circulating testosterone in adult men, approx 45 is bound with high affinity to SHBG, 50 is loosely bound to albumin (Alb), 1-2 is bound to cortisol-binding globulin, and less than 4 is free (not protein bound) (3). SHBG is a carbohydrate-rich P-globulin produced by hepatocytes. It is a 100,000-kDA dimer, with protomers of 48-52 kDA that convert to a single 39 kDA species when deglycosylated and fractionated on a polyacrylamide gel (4). SHBG binds testosterone and other steroids with high affinity and prolongs their metabolic clearance (5). Because of SHBG's role as a plasma testosterone binding protein, there is a positive correlation between its level and the level of testosterone in human adult male plasma, such that total testosterone levels are low when SHBG levels are low (see Fig. 1). The general view is that SHBG reduces the cellular uptake of androgens from the plasma compartment (6) and negatively regulates availability to target cells (7). On the other hand, the...

Definition

Approximately 99.6 of white boys have at least early signs of secondary sexual development by the age of 14, but the cutoff age for identifying boys who need to be evaluated for delayed puberty may vary in different ethnic groups. The most common reason for delayed puberty is constitutional (idiopathic), which is usually accompanied by a delay in height growth. Various endocrine disorders, causing hypogo-nadotropic or hypergonadotropic hypogonadism, must also be considered in boys with pubertal delay.

FSHR Mutations

Several inactivating mutations have been detected in the FSH-R gene, most of them in women with hypergonadotropic hypogonadism (9) (see Fig. 3). The complete form of FSH-R mutation in women causes the total arrest of follicular development (57), a process which is dependent on FSH action. The incomplete forms cause a partial phe-notype that is responsive to high-dose gonadotropin treatment (74,75). In addition to the Finnish-type FSHR inactivation (C T transition, causing Ala189Val mutation), which has been found in multiple families (57), all other FSH-R mutations detected have been sporadic (9,74-77). Five men with totally inactivating mutation of FSH-R have been described from Finland (53). These men were identified because they were homozygous brothers of women with hypergonadotropic hypogonadism caused by FSH-R mutation. The men were normally masculinized, with normal puberty and virilization. Their testes were mildly or severely reduced in size, and all had pathological semen...

Diagnosis

The symptoms of hypogonadism in men with acromegaly are similar to those of men with prolactinomas, including oligospermia and reduced sperm motility. These manifestations, like the specific acromegalic clinical features (see Table 2), progress slowly. Therefore, the diagnosis of acromegaly is often delayed for as many as 5 to 15 yr (22).

Conclusions

Endurance exercise training does have significant effects on the major male reproductive hormone, testosterone, and the hypothalamic-pituitary-axis that regulates testicular function. A growing body of evidence suggests that testosterone is chronically lowered in endurance exercise-trained men, and we have referred to this condition as exercise hypogonadism. Although the mechanism of this testosterone lowering is currently unclear, it may be related to a dysfunction or a readjustment in the hypothala-mic-pituitary-testicular regulatory axis brought about by years of endurance training. Currently, the time course of these changes, including their reversibility, remains unresolved and is in need of further scientific investigation (137). The lowered testosterone levels of the exercise-hypogonadal male could potentially disrupt anabolic or androgenic testosterone-dependent processes. Conversely, the alterations in testosterone levels

Bone Mineral Density

Androgens are required to achieve peak bone mass in adolescence and are responsible for the higher BMD in men compared to women. Hypogonadism is associated with a decrease in bone mass and is one cause of osteoporosis in men. With aging, progressive loss of BMD is associated with increased fracture rates. Interestingly, the BMD in older men is more significantly correlated with serum free estradiol than with serum free testosterone levels (44,45). The few case reports of estrogen-receptor mutations and aromatase deficiency in males were all associated with severe osteoporosis (46-48). Thus, the current hypothesis is that estrogens are required for maintaining peak BMD in men. The concentration of serum E2, or the level of estrogen activity in the target tissues, that is required to maintain BMD is not known. Although it is apparent that some estrogenic action is required for normal BMD, it is probable that testosterone also directly effects bone mass through androgen receptors.

Prostate Disease

Most urologists believe that androgens do not induce BPH, but androgens should not be used in subjects with lower urinary tract obstructive symptoms until these symptoms have been treated. There is no direct evidence in hypogonadal young or older men that androgen replacement will induce the formation of prostate cancer or convert a latent, histological prostate cancer to a clinically significant or metastatic cancer (68). However, androgens should not be used in a hypogonadal man who has had prostate cancer. There are possible rare exceptions, e.g., a patient with a distant completely resected intraprostatic cancer and long-standing near-undetectable PSA levels who is suffering from severe symptoms and signs of testosterone deficiency. Treatment of such a patient may be justified but only with careful surveillance and well-documented informed consent. It is not known whether testosterone treatment, together with the 5-a reductase inhibitor finasteride or an androgen that cannot be...

Hormonal Treatment

Cryptorchidism Testosterone

Diagnostic test is limited to the situation in which neither testis is palpated. In the boy with bilateral nonpalpable testes that may be either absent or abdominal, hCG stimulation is useful during the childhood years (120). Testes may become palpable, or testosterone levels may rise. Because testes will respond to brief stimulation by hCG during childhood with increased testosterone secretion, this test is useful in determining the presence of testicular tissue containing responsive Leydig cells. This test does not differentiate between unilateral anorchia and a unilateral undescended testis, and an increase in testosterone does not ensure a normal testis. Because of the transient physiological increase in gonadotropin secretion, an infant male with absent testes will likely have markedly elevated LH levels consistent with primary hypogonadism. However, gonadotropin levels are low beyond infancy until the peripubertal period. It has also been reported that inhibin-B levels rise in...

Infertility

Cryptorchidism Testosterone

It has been hypothesized that earlier treatment decreases the risk of infertility, but this has not been demonstrated convincingly. A 1975 report of 79 men found that fertility was greater when patients were younger at the time of orchiopexy (152). Another study of men with bilateral cryptorchidism also reported an inverse correlation between age at orchiopexy and sperm concentration (148). However, a meta-analysis (113) found no difference in the percentage of men with azoospermia or oligospermia with unilateral or bilateral cryptorchidism who were treated before vs. after 9 yr of age. Unfortunately, no patients in the meta-analysis were treated during the first few years of life. Efficacy of early therapy has been questioned, particularly for unilateral cryptorchidism. The percentage of men with azoospermia or oligospermia in the uni-laterals was similar after surgical, hormonal, both treatments, or no treatment. A study of 329 men, including 66 married men, also failed to show a...

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 levels, and prepubertal sized testis.

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 level of serum testosterone achieved in the first few days after an injection may reach a concentration that is higher than the normal adult male reference range. In some patients, the high peaks and low troughs of serum testosterone levels may result in mood swings and acne. In such patients, the dose may be decreased and frequency of the injections increased, for example, testosterone enanthate may be administered at a dose of 100 mg every 7 to 10 d. Most patients can be taught to...

Sexual Dysfunction

General debility (including anemia) may have a significant role in causation of uremic sexual dysfunction, because recombinant human EPO therapy improves reproductive function. Menstrual and male sexual function were significantly improved and blood prolactin concentrations lowered in a study that randomized 44 patients on dialysis to standard treatment with EPO (180 U kg wk) or no treatment (63). Other cross-sectional (64) and uncontrolled studies (65-67) corroborate these findings. Nevertheless, EPO does not improve the sexual dysfunction of men with impaired renal function who do not requiring dialysis (65). EPO administration reduces the endocrine abnormalities in men with uremia with lowering of the exaggerated basal and GnRH-stimulated LH and FSH concentrations and increases in blood testosterone concentrations (67-69). Whether this is a specific effect of EPO or is mediated via general effects, such as improvement in anemia and nutritional status, remains to be clarified.

Therapy

Secreting Pituitary Macroadenoma

The treatment goals for men with hypogonadism secondary to acromegaly are the normalization of serum GH, IGF-1, and PRL levels when hyperprolactinemia is present, and the preservation and restoration of gonadotropin secretion and testicular function. Whereas somatostatin analogs and dopamine agonists bind to specific tumor receptors and inhibit GH secretion, a new drug, pegvisomant, blocks the ability of GH to stimulate IGF-1 production, the main mediator of the somatotropic actions of GH. Pegvisomant is a genetically manipulated analog of human GH that functions as a highly selective GH receptor antagonist, normalizing IGF-1 levels in approx 90 of patients with acromegaly (55-57). However, there are no studies reporting the effects of GH antagonists on hypogonadism secondary to acromegaly at this time. Radiation therapy should be considered for patients with contraindications to pituitary surgery or whose operation and or medical treatment has failed. Radiotherapy induces a slow...

Oral Androgens

The oral 17 alkylated testosterone derivates, methyltestosterone and fluoxymes-terone, are not recommended for long-term androgen replacement because of potential adverse effects on liver function and lipid levels. Testosterone undecanoate is a testosterone ester with a long fatty acid side chain. When administered by mouth, testosterone is absorbed by lymphatics and must be administered after ingestion of food. Serum testosterone levels rose to peak levels 4 to 5 h after administration and remained in low normal range 8 to 12 h after oral administration (80,81). When testosterone undecanoate is administered in the fasting state, serum testosterone levels remained low. Testosterone undecanoate has long-term safety data (82). There are marked inter-subject as well as intrasubject variations in the peak serum testosterone levels achieved after oral administration. The usual dose is testosterone undecanoate 80 mg bid or 40 mg tid. This oral preparation is not available in the United...

Shalender Bhasin MD

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 Human immunodeficiency virus (HIV)-1 produces a complex, multisystem syndrome that results from the combined effects of the virus infection, progressive immunosuppression, malignancies and opportunistic infections, poor nutrition, and the complications of antiretroviral therapy. Androgen deficiency is only one facet of this highly heterogeneous syndrome. Therefore, androgen supplementation should only be viewed as an adjunctive therapy within the context of a multicompo-nent therapeutic strategy. Although there is increasing evidence that androgen deficiency, defined solely in terms of low testosterone levels, is highly prevalent in HIV-infected men and women and that low testosterone levels are...

Tcg Testosterone

The treatment goals in this group of patients with hypogonadism are as follow (1) reduce or eliminate the mass effects of the lesion (2) correct hormonal deficiencies, including those that impair gonadal function and (3) preserve residual pituitary function. The specific treatments for the various diseases discussed are beyond the scope of this chapter. However, most lesions are initially treated surgically to eliminate the mass effects. Androgen replacement therapy is used to correct hypogonadism. When fertility is desired, treatment with exogenous gonadotropins (hCG hFSH) is generally successful. Finally, when panhypopituarism is present, hormonal replacement therapy is mandatory.

The Male Life Span

Human testicular function is maintained through old age. However, mean testosterone levels and spermatogenesis decline with aging (25). This phenomenon of andropause and the effect of testosterone replacement therapy, have recently received a great deal of attention (see Chapter 14).

The SHBG Gene

Glass et al. (25) first reported that circulating testosterone levels are reduced in obese men, and many subsequent studies have confirmed that total testosterone levels decrease as body mass index increases. Because men and women who are hyperandro-genic gain weight predominantly in the abdomen, it is mechanistically interesting to

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 cyclophosphamide given alone for immunologically mediated disease or combination chemotherapy used in the treatment of hematological malignancies and testicular cancer.

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, medication-induced, and cavernosal problems may predominate. Improvement in erectile function by testosterone treatment of androgen-deficient older men may be minimal or not as significant as in younger subjects (18-20). Although objective data are limited, it is possible that in androgen-deficient older men whose erectile dysfunction has been improved by phosphodiesterase V inhibitors (e.g., Sildenafil, Vardenafil, and Tadalfil) sexual performance may benefit by cotreatment with testosterone through...

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 majority of individuals with Prader-Willi syndrome present with delayed or partial pubertal development. There are no detailed studies of the neonatal or childhood period in children with Prader-Willi syndrome. Decreased gonadotropin levels, consistent with hypogonadotropic hypogonadism, have been found in some patients, whereas others have hypergonadotropic hypogonadism secondary to cryptorchidism (116). In those with hypogonadotropic hypogonadism, the localization of the defect is unclear,...

LHR Mutations

Testosterone Activating Receptors

A third type of testicular tumor that has occurred in one 36-yr-old patient with FMPP due to a germ-line Asp578Gly mutation is testicular seminoma (69). Although no causative relationship was established for the LH-R mutation and seminoma, the possibility remains that a prolonged high intratesticular testosterone concentration resulting from LH-R stimulation could be oncogenic. However, transgenic (TG) mice that overexpressed hCG and produced high intratesticular testosterone levels showed no signs of testicular tumors beyond mild LCH (S. Rulli, M. Poutanen, & I. Huh-taniemi, unpublished data).

Leydig Cell Function

Leydig cells are more resistant to damage from radiotherapy than is the germinal epithelium. Significant rises in LH have been demonstrated after single dose radiation doses of above 0.75 Gy (6) and fractionated doses above 2 Gy (40). However, no change in testosterone level was seen at these doses, and LH values gradually return to normal levels during 30 mo. Higher testicular radiation doses do, however, result in more marked Leydig cell insufficiency. Giwercman et al. (41) studied 20 men who were previously treated with unilateral orchidectomy for testicular cancer, who received direct testicular irradiation at a dose of 20 Gy, in 10 fractions, for carcinoma in situ in the remaining testis. A significant increase in mean LH levels was observed in the first 3 mo (10.4 to 15.6 IU L), with a decrease in mean serum testosterone level (13.3 to 10.8 nmol L). Similar results were observed by Shalet et al. (7) in adults treated with highdose (30 Gy) testicular irradiation after unilateral...

Transdermals

Steady serum testosterone levels in the low normal range mimicking circadian variation are attained after testosterone transdermal patch application (Fig. 2). The scrotal testosterone patch was the first to become available in the early 1990s, but this patch has been superseded by other transdermals. The scrotal testosterone patch is 60 cm in diameter and requires shaving or clipping of scrotal skin hair (86,87). There are two nonscrotal skin patches available in the United States. The smaller permeation-enhanced patch (Androderm) delivers 5 mg testosterone per day and produces serum testosterone in the low normal range (86-90). This smaller testosterone patch has a major side effect of causing skin irritation in up to 60 of subjects, leading to discontinuation in up to 10 to 15 of subjects (86-90). Preapplication of corticosteroid cream may reduce the skin irritation. The larger non-scrotal testosterone patches (Testoderm TTS) produce much less skin irritation but may not adhere well...

FSHp Subunit

The second male, reported from Israel (35), was an 18-yr-old with slight delay of puberty, small testes, azoospermia, and a plasma FSH concentration below 0.5 IU L. Total testosterone was low (4.5 nmol L), and LH was increased (24.5 IU L), indicating a defect in testosterone biosysthesis. DNA sequencing revealed the same homozygous 2 bp deletion in codon 61 that was found previously in the female patients (34,36,38). The mutation gave rise to a completely altered amino acid sequence between codons 61 and 86 of the FSH3 chain, which was followed by a premature stop codon, and lack of translation of amino acids 87 to 111. Consequently, the translated FSH3 protein was truncated and unable to associate with common -subunit to form bioactive or immunoreactive a 3 dimers.

Overview

Androgen deficiency in men is associated with reduced physical stamina, relative sarcopenia, osteopenia, visceral obesity, sexual dysfunction, depressed mood, reduced sense of well-being, and detectable cognitive impairment (1-10). Impoverished testosterone production in the older male has been affirmed by (1) direct sampling of the human spermatic vein, (2) meta-analysis of cross-sectional epidemiological data (11), and (3) longitudinal investigations in healthy populations (12-15). For example, the European SENIEUR and Massachusetts Male Aging Cohort studies inferred that bioavailable (non-sex hormone-binding globulin SHBG -bound) testosterone concentrations decline by 0.8-1.3 annually (13,16), and, a 15-yr prospective analysis in New Mexico observed that total testosterone concentrations fall by 110 ng dL per decade in men after age 60 (14,17). Surgery, trauma, stress, systemic illness, medication use, and chronic institutionalization exacerbate androgen depletion in elderly...

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 ), compared with those not receiving testosterone (6 17, 35 ). However, withdrawal of testosterone did not alter the signs or symptoms of sleep apnea in the five men studied both during and 2 mo after cessation of testosterone treatment. Further surveillance has shown that sleep apnea is common in patients with chronic renal failure even before commencement of dialysis or testosterone treatment (109). Hence, the contribution of pharmacological androgen therapy to breathing while asleep (and...

Mechanism of Actions

Anabolic steroids activate androgen receptors in skeletal muscle cells, which stimulate the promoters of specific genes and induce protein synthesis (105,106). Of these proteins, one that is important in increased muscle mass and strength is IGF-1 (109). IGF-1 mRNA in skeletal muscle is increased by testosterone treatment in older men (110) and is reduced in testosterone deficiency (111). In certain cells, most notably prostate epithelium, testosterone's action is amplified by its irreversible bioconversion

Implants

Used to treat hypogonadal men (100,101). Four 200-mg implants maintain testosterone levels for 16 to 20 wk. Insertion of the pellets requires a minor surgical procedure under local anesthesia. Extrusion of the testosterone pellets is observed in approx 8 to 11 of subjects (102), although our experience with insertion by a skilled operative is much lower. This method has not been widely used and is not routinely offered by physicians as androgen-replacement modality in the United States.

Obstructive Sleep Apnea

Obese women with PCOS are at increased risk for obstructive sleep apnea (OSA) (56). Based on the increased prevalence of OSA in men, and recent evidence that androgens may play a role in the male predominance, overnight polysomnog-raphy was performed in obese women with PCOS and age weight-matched controls (56). Women with PCOS had a significantly higher apnea-hypopnea index (AHI), and were more likely to suffer from symptomatic OSA syndrome. The AHI correlated with waist-hip ratio, as well as total and free testosterone levels. g Vgontzas et al. (57) also reported that sleep-disordered breathing (SDB) and ex- < j cessive daytime sleepiness are more frequent in women with PCOS than in pre-menopausal controls. Insulin resistance appeared to be a risk factor for SDB in J women with PCOS. Q Whether there is a causal relationship between OSA and cardiovascular

Fetal Hormones Affecting Adult Behavior

Scientists have shown that pregnant rhesus monkeys treated with testosterone produced offspring that showed rougher play and more threat behavior than usual. Male rhesus monkeys experience a decrease in blood testosterone levels within six hours after losing a fight to another male and are more submissive. These studies indicate that hormones play an important role in determining male-female behavioral differences. When the male white-crown arrives at his breeding grounds in central Alaska, he chooses a nesting territory, attacks any male territorial intruders, and attempts to attract a mate with his constant singing. Each female chooses a mate and helps him defend the nesting site. In the next few days she feeds to gain nutrients for egg production, and her estrogen levels rise rapidly, stimulating her to solicit mating. Once the eggs are laid, the gonads of both birds begin to atrophy, estrogen and testosterone levels decline, and prolactin levels increase and stimulate feeding of...

Endocrine Deficiencies

Men with low testosterone, women after menopause and both men and women with growth hormone deficiency without involvement of HPA axis perturbations tend to have abdominal obesity (49). These hormones prevent accumulation of body fat in intra-abdominal depots, and deficiency would then be expected to be followed by enlargement of these depots. The mechanisms whereby this occurs have been largely elucidated, and substitution with the deficient hormone is followed by a specific decrease of visceral fat as well as improvement of the factors included in the metabolic syndrome (6). The prevalence of such conditions seem to be in the order of 10 in the middle-aged male population (56).

Subgrouping Of Visceral Obesity With The Metabolic Syndrome

Visceral obesity is associated with other endocrine abnormalities than that of cortisol. Indeed, visceral obese individuals with the metabolic syndrome may have all the hormonal abnormalities of the elderly, suggesting that this condition may be a sign of premature ageing (58). The most common deficiencies are those of growth hormone (GH) and sex steroids (59). Whereas men have low testosterone levels (60), women have irregular menstrual cycles (61). Functionally, the growth axis and the reproductive axis are influenced at many levels by the HPA axis. Prolonged activation of the HPA axis thus leads to suppression of GH secretion as well as inhibition of sex steroids (23,62). This issue was addressed in a recently performed cohort study of middle-aged men (44). Subgroups were constructed based on the current clinical definition of low testosterone and insulin-like growth factor I (IGF-I), a mediator of the major actions of GH (63), and the dexamethasone suppression test as a...

The Brain and Reproduction

In addition to the chain leading from the brain to the pituitary to the testes, information is sent back to the brain from the testes, a checks-and-balances system using principles of negative feedback to ensure that the hormones are produced in the appropriate quantities. If, for example, the hormone system gets slightly out of balance, leading to too much testosterone being produced, this excess of testosterone will be sensed by the hypothalamus. It will cause a temporary shutdown of GnRH production, leading to the system's correcting itself, because then a little less testosterone will be produced. If testosterone levels fall too low, the opposite will happen GnRH, and then FSH and LH, and then finally testosterone, will all increase, again resulting in a correction of the original aberration. The hormonal system is a delicately balanced network that ensures the proper functioning of the testes.

Male Pseudohermaphroditism Often Results From Resistance to Androgens

A pseudohermaphrodite is an individual with the gonads of one sex and the genitalia of the other. One of the most interesting causes of male reproductive abnormalities is an end organ insensitivity to androgens. The best characterized syndrome is testicular feminization, an X-linked recessive disorder caused by a defect in the testosterone receptor. In the classical form, patients are male pseudohermaphrodites with a female phenotype and an XY male genotype. They have abdominal testes that secrete testosterone but no other internal genitalia of either sex (see Chapter 39). They commonly have female external genitalia, but with a short vagina ending in a blind pouch. Breast development is typical of a female (as a result of peripheral aromatization of testosterone), but axillary and pubic hair, which are androgen-dependent, are scarce or absent. Testosterone levels are normal or elevated, estradiol levels are above the normal male range, and circulating go-nadotropin levels are high....

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