Male Hypogonadism. Part I: Epidemiology of Hypogonadism
Posted 03/22/2006
AD Seftel
Abstract and Introduction
Abstract
Male hypogonadism is a frequent and potentially undertreated condition. A number of longitudinal epidemiologic studies, including the Baltimore Longitudinal Study of Aging, the New Mexico Aging Process Study, and the Massachusetts Male Aging Study, have demonstrated age-related increases in the likelihood of developing hypogonadism. In addition to advancing age, increasing body mass index and/or type II diabetes mellitus may be associated with lower circulating androgen levels. Owing to the demographic trends toward increasing population age and life expectancy, together with the emerging pandemic of diabetes and recent trend toward an increasing prevalence of obesity in the United States, clinicians are likely to encounter increasing cases of hypogonadism in the near future.
Introduction
Hypogonadism affects up to 4 million American men, yet only 5% of candidates receive treatment.[1] Evidence suggests that low testosterone (T) and the attendant symptoms and signs of hypogonadism can be effectively treated using testosterone replacement therapy (TRT). This article will review the epidemiology of male hypogonadism. Subsequent articles will review (1) the etiology, pathophysiology, and diagnosis of male hypogonadism; and (2) the pharmacokinetics, efficacy, tolerability, and safety profiles of different forms of TRT, as well as required screening and monitoring tests prior to and during TRT.
Epidemiology
Demographic Trends and Potential Risk Factors Aging
Trend. The advancing median age, increased life expectancy, and rising prevalences of obesity and type II diabetes mellitus (DM2) in western industrialized societies may result in increasing numbers of male hypogonadism cases in the near future. According to US Census Bureau projections, the number of Americans ages 65 or older will rise from approximately 35 million (12.4% of all Americans) in 2000 to nearly 55 million (16.3% of total) by 2020 and nearly 87 million (20.7%) in 2050.[2] In addition to a two-fold increase in the number of elderly patients, octogenarians will comprise the fastest-growing population segment according to age.[3]
Effects of Aging on Circulating Testosterone. In healthy, young eugonadal men, serum T levels range from 300 to 1050 ng/dl, but decline with advancing age, particularly after 50 years (Figure 1).[4,5,6] Using a serum T level <325 ng/dl, the Baltimore Longitudinal Study of Aging (BLSA) reported that approximately 12, 20, 30, and 50% of men in their 50s, 60s, 70s, and 80s, respectively, are hypogonadal.
Longitudinal and cross-sectional studies have demonstrated annual T decrements of 0.5-2% with advancing age.[5,6,7,8,9] The rate of decline in serum T in men appears to be largely dependent on their ages at study entry. In the BLSA, the average decline was 3.2 ng/dl per year among men age 53 years at entry.[5] On the other hand, the New Mexico Aging Process Study of men 66-80 years at entry showed a decrease in serum T of 110 ng/dl every 10 years.[6] Although serum T levels are generally measured in the morning when at peak, this circadian rhythm is often abolished in elderly men.[10]
In healthy men, only 1-3% of biologically active steroids circulate free, with the balance being bound tightly to sex hormone binding globulin (SHBG) or loosely to albumin. The free T (FT) and the fraction bound loosely to albumin are readily available for entry into tissues. Unlike serum T, concentrations of SHBG, as well as luteinizing hormone (LH) and follicle-stimulating hormone (FSH), rise significantly with age[5,6] such that the SHBG level of a man in his 80s is about twice as high as in his 20-year-old male counterpart.[11] In the Massachusetts Male Aging Study, SHBG increased by 1.2% annually.[9] Owing to the differences in binding affinities of male and female hormones for SHBG, increases in circulating levels of this glycoprotein tend to generate a more estrogenic, rather than androgenic, milieu.[11]
Unlike the sharp, universal decreases in hormone levels observed in women with menopause, declines in circulating androgens in men with advancing age are gradual and variable. For this reason and others, the term andropause is misleading and should be avoided when discussing age-associated male hypogonadism;[12] the term partial androgen deficiency of the aging male (PADAM) is generally preferred. Waning T levels represent one facet of a larger endocrine decline in many elderly men, with frequent reductions in secretion of thyroid hormone, growth hormone, and/or insulin-like growth factor.
Advancing age independently lowers T levels even after controlling for chronic conditions associated with aging. Conditions associated with reduced T and/or higher SHBG levels include obesity; diabetes mellitus (DM);[13] use of certain medications; hyperthyroidism, which elevates hepatic SHBG output; as well as alcoholism (daily intake >40 g[14]) and/or alcoholic liver disease.[11]
Diabetes Mellitus
Trend. Approximately 5% of persons ages 20-79 years have DM, according to data from the International Diabetes Federation.[15] This includes 48 million Europeans and 43 million residents of the Western Pacific. Diabetes rates are highest in the United States (7.9%) and Europe (7.8%). With population aging, as well as unhealthful diets, sedentary lifestyles, and/or attendant obesity, the number of people with DM has increased from 30 million in 1985 to more than 150 million in 2000. The number is projected to escalate to nearly 333 million by the year 2025.[15]
Effects of DM on Circulating Testosterone. In a recent study, hypogonadism (low FT) was observed overall in 33% of men with DM2, who had a mean body mass index (BMI) of 33.4 kg/m2 and a hemoglobin A1c of 8.4%.[13] Figure 2 shows the distribution of hypogonadism (defined as low FT or calculated FT (cFT)) across different age groups in men with DM2.[13] A total of 58% of massively obese individuals with DM2 (BMI>40 kg/m2) had hypogonadism as defined by low FT.[13] According to the authors, FT should be measured before designating any DM2 patient as hypogonadal. Using only a low T (<300 ng/dl) to define hypogonadism resulted in 36% false positives and 12% false negatives compared with low FT or cFT.[13]
Trend. In the United States, visits to physicians for obesity-related maladies rose 90% from 1988 through 1994.[16] In addition, about one in four American adults has metabolic syndrome, a condition indicative of insulin resistance that includes overweight, central (upper-body) adiposity, hypertension, low levels of high-density lipoprotein cholesterol, and high levels of small dense low-density lipoprotein cholesterol, which is considered to be highly atherogenic. According to the third National Health and Nutrition Examination Survey,[17] 47 million Americans have metabolic syndrome, including approximately 44% of those ages 60 years or more.[18]
Potential Effects of Obesity on Circulating Testosterone. In the aforementioned study on hypogonadism in men with DM2, values for T, FT, and cFT were all significantly lower in hypogonadal compared with eugonadal men, while SHBG was not significantly different between the two groups. Testosterone (r=-0.327; P<0.01) and FT (r=-0.382; P<0.01) were inversely correlated with BMI. The study demonstrated that BMI was an independent predictor of hypogonadism.[13]
On the other hand, 31.3% of lean men (normal BMI) with DM2 were also hypogonadal, suggesting that factors other than adiposity may play a role in the hypogonadism associated with insulin-resistant states.[13] A recent study involving men without DM showed that age-adjusted bioavailable T (BT), FT, and T correlated inversely with fasting insulin (P≤0.03 for each), and both SHBG and T correlated inversely with fasting glucose (P≤0.003 for each).[19]
Epidemiologic relationships between obesity and hypogonadism are complex. In a large-scale longitudinal study, T decreased by 10 ng/dl per 1 kg/m2 increment in BMI.[5] Other studies have also shown reduced T and FT in men with increasing total or abdominal adiposity.[20,21] The direction of causality between abdominal adiposity and low T levels is not clear.[8]
In one cross-sectional study of 400 community-dwelling men ages 40-80 years, increases in both BMI and central adiposity (waist circumference) were associated with low levels of T, BT, and dehydroepiandrosterone sulfate, whereas both current smoking and greater physical activity were associated with higher T concentrations.[14]
Some grossly obese patients have reduced total T and SHBG levels, as well as diminished T-SHBG binding, such that FT levels remain normal.[11,22] Obesity may lower circulating androgens or reduce T-SHBG binding via (1) excessive metabolic clearance of androgens in adipose tissues;[11] (2) aromatization of androgens in adipose tissues; or (3) increased formation of inflammatory cytokines (eg tumor necrosis factor-α, interleukin-1β), which may also blunt secretion of LH and gonadotropin-releasing hormone (GnRH).[23,24] Conversely, T has potential anti-inflammatory (and antiatherogenic) properties in animal models and humans.[25]
Controversies in Diagnosis
Diagnostic issues in hypogonadism will be covered at greater length in part II of this three-part review. The diagnosis of male hypogonadism, particularly PADAM, is fraught with controversy. Frequently debated topics include threshold hormone levels for determining PADAM; whether low T levels in the presence of normal LH levels warrant further workup to detect underlying hypothalamic-pituitary axis disorders; the optimal manner in which to measure these hormone levels, particularly total testosterone (TT); and the ideal hormone fraction to identify patients with hypogonadism: TT, bioavailable testosterone (BT), or free testosterone (FT).
According to the preponderance of literature from the past 30 years based on traditional radioimmunoassay (RIA) methods with or without chromatography, the reference range for TT is 300-1000 ng/dl.[26,27] Another way to determine the threshold for ‘low TT’ is statistical, that is, 2.5 standard deviations (s.d.'s) below the mean for healthy young men. In a recent study on the clinical utility of GnRH testing in the differential diagnosis of PADAM and secondary hypogonadism, a Swiss group used a threshold TT of <337 ng/dl, which was 2.5 s.d.'s lower than the mean for a group of 13 young healthy controls (mean age=33.9 years): approximately 625 ng/dl.[28]
One argument for using 300 ng/dl as the threshold for diagnosing male hypogonadism is that there is a functional correlation with erectile dysfunction (ED). Studying 162 elderly (mean age=64.1 years) men with ED (mean duration=45.6 months), a Korean group reported that hypogonadism (serum TT <300 ng/dl) was among the strongest independent predictors of a poor response to sildenafil 25-100 mg for 8 weeks. Only poor pretreatment erectile function (International Index of Erectile Function (IIEF) erectile function domain score <17) was a stronger independent prognostic factor (OR=2.2; 95% CI=1.45-7.33).[29]
Another consideration in the diagnosis of male hypogonadism is that measurements of TT may vary during different times of the day or year and from laboratory to laboratory. In a recent study, coefficients of variation between laboratories using the same methods/instruments ranged from 5.1 to 22.7%.[26] The median value of the quality control sample across all laboratories was 297 ng/dl, with results as low as 160 ng/dl (hypogonadal) and as high as 508 ng/dl (eugonadal). Certain manufacturers of automated assay platforms also provide normal male reference ranges that are much lower than the reference TT range of 300-1000 ng/dl cited above, with lower limits ranging from 170 to 200 ng/dl and upper limits ranging from 700 to 800 ng/dl.
Total T levels show marked circadian and circannual variation. Owing to the circadian variation, the Second International Consultation on Erectile Dysfunction of the World Health Organization (WHO)[30] recommended that a blood sample for serum T determination should be obtained between 0800 and 1100, when T levels typically peak in healthy young men. This circadian rhythmicity may be abolished or blunted in men with advancing age[10] or during certain forms of TRT.
The method of choice for determining serum TT levels is liquid chromatography-tandem mass spectrometry (LC-MS-MS). However, this methodology is not available to many hospitals and office practices. A recent study determined that commercially available automated and manual methods are capable of discriminating eugonadal from hypogonadal TT values in the presence of adult male reference ranges established by each laboratory.[26] More than 60% of serum samples from men with TT within the adult male range were within ?20% of values determined by LC-MS-MS. Certain methods (eg DPC Immulite) were biased toward lower values, while others were biased toward higher values (eg Bayer ADVIA Centaur) across a wide range of serum TT concentrations.
The chief problem with the commercially available immunoassays was in determining very low serum TT (<100 ng/dl): in specimens with such low TT values typical of prepubertal males (and females), 56-90% of values generated by commercially available assays fell outside the ?20% window around LC-MS-MS values.[26] As mentioned above, values obtained with the DPC Immulite were systematically lower and those obtained by the Bayer ADVIA Centaur systematically higher than the values provided by LC-MS-MS. Other assays (DPC-RIA and Roche Elecys) exhibited large percent differences in both directions. None of these assays is considered reliable enough to investigate serum TT levels in children and women.[26,31]
A morning T level ≤300 ng/dl should be confirmed by a repeated measurement at the same time of day. However, neither a low TT nor clinical symptoms are sufficient to discriminate PADAM from secondary, hypogonadotropic hypogonadism attributed to hypothalamic-pituitary axis disorders. In a recent study,[28] lack of libido was present in approximately 54% of men with PADAM and 67% of those with secondary hypogonadism; ED in 58 and 53%, respectively; fatigue in 38 and 58%; depressive mood in 25 and 21%; and osteopenia or osteoporosis in 17 and 29%.
According to guidelines from the American Association of Clinical Endocrinologists (AACE), exceedingly low T levels (≤150 ng/dl) warrant pituitary imaging even in the absence of other signs or symptoms.[32] Others use a threshold of <200 ng/dl to trigger magnetic resonance imaging (MRI).[33,34] Some authorities recommend sellar MRI with thyroxine, cortisol, and prolactin assessments when secondary hypogonadism is considered likely.[33]
Based on extensive hormonal evaluation of elderly men with normal and low levels of T, as compared with those with primary and secondary hypogonadism and young, healthy volunteers, a Swiss group[28] recently developed an algorithm for the use of GnRH testing to discriminate secondary, hypogonadotropic hypogonadism from PADAM. First, if repeated serum TT levels are below <337 ng/dl in an elderly man, a GnRH stimulation test should be conducted. A peak LH following GnRH stimulation of >15 mU/l precludes costly imaging studies to rule out secondary (hypogonadotropic) hypogonadism. On the other hand, elderly men who have TT levels below <337 ng/dl in the presence of a blunted LH response to GnRH (<15 IU/l) should undergo MRI to rule out pituitary disease.[28] The most recent WHO guidelines recommend a confirmatory TT if a morning level is below the lower limit of ‘the accepted normal values’ as well as assessment of LH, FSH, and prolactin.[30]
Compared with men having PADAM, those with secondary hypogonadism were significantly younger (52.5 vs 62.3 years; P<0.05) and had significantly lower levels of basal TT (167 vs 271 ng/dl), as well as significantly lower levels of basal LH and FSH and LH and FSH responses to GnRH administration.[28]
Finally, there is ongoing debate as to which androgenic fraction is the most reliable indicator of hypogonadism. Approximately 50-70% of circulating T is bound tightly to SHBG and is hence physiologically inactive. A further 20-30% is bound loosely to albumin and 1-3% circulates free in the serum. Only these latter two fractions are available to tissues and are thus termed BT. Free testosterone can be calculated[35,36] or measured by equilibrium dialysis. One measure of FT is the free androgen index (FAI=TT/SHBG ? 100).[37] Bioavailable T is measured using an ammonium sulphate precipitation method and may also be computed.
According to the most recent WHO guidelines,[30] TT assays may not indicate true androgenic status, particularly in elderly men. The WHO guidelines state that BT and cFT are the most reliable and accessible assays to establish male hypogonadism. Because, for example, serum TT may be normal in patients with primary testicular disorders (eg, Klinefelter syndrome) or increased SHBG, obtaining FT or BT may also be useful.[32] However, the validity and accessibility of a number of diagnostic tests (eg, equilibrium dialysis) and other, dynamic assessments are matters of ongoing debate.
A recent cross-sectional study of a cohort of 1072 men undergoing elective coronary angiography demonstrated that measures of TT were superior to computed FT or BT in the determination of hypogonadism. When TT levels were borderline, in the range of 216-346 ng/dl, estimates of FT proved superior to TT alone.[38]
Conclusion
Owing to demographic trends toward greater longevity, as well as increasing prevalences of obesity, metabolic syndrome, and DM, clinicians in western industrialized societies may be confronted with a burgeoning hypogonadism case burden in upcoming years. These trends merit enhanced vigilance for the problem in daily practice
Int J Impot Res. 2006;18(2):115-120. ?2006 Nature Publishing Group
Male Hypogonadism. Part II: Etiology, Pathophysiology, and Diagnosis
Posted 05/09/2006
A. Seftel
Abstract and Etiology
Abstract
Male hypogonadism has a multifactorial etiology that includes genetic conditions, anatomic abnormalities, infection, tumor, and injury. Defects in the hypothalamic-pituitary-gonadal axis may also result from type II diabetes mellitus and treatment with a range of medications. Circulating testosterone levels have been associated with sexual function, cognitive function, and body composition. Apart from reduced levels of testosterone, clinical hallmarks of hypogonadism include absence or regression of secondary sex characteristics, reduced fertility (oligospermia, azoospermia), anemia, muscle wasting, reduced bone mass (and bone mineral density), and/or abdominal adiposity. Some patients, particularly those with partial androgen deficiency of the aging male, also experience sexual dysfunction, reduced sense of vitality, depressed mood, increased irritability, difficulty concentrating, and/or hot flushes in certain cases of acute onset. As many patients with male hypogonadism?like patients with erectile dysfunction?do not seek medical attention, it is important for clinicians to be acquainted with the signs and symptoms of hypogonadism, and to conduct appropriate laboratory testing and other assessments to determine the causes and inform the treatment of this condition.
Etiology
Hypogonadism is characterized by low serum testosterone (T) levels (<300 ng/dl) together with ≥1 clinical symptom or sign. Symptoms of postpubertal hypogonadism include[1-3] (1) sexual dysfunction, such as reduced libido, erectile dysfunction (ED), diminished penile sensation, difficulty attaining orgasm, as well as reduced ejaculate with orgasm; (2) reduced energy, vitality, or stamina; (3) depressed mood or diminished sense of well-being; (4) increased irritability; (5) difficulty concentrating and other cognitive problems; and/or (6) hot flushes in some cases of acute onset.
Signs of hypogonadism include (1) anemia; (2) muscle wasting (sarcopenia); (3) reduced bone mass or bone mineral density (BMD); (4) absence or regression of secondary sex characteristics; (5) abdominal adiposity (i.e. ‘pot belly’ obesity); and/or (6) oligospermia or azoospermia.
A number of hypothalamic-pituitary-gonadal (HPG) axis defects may induce hypogonadism ( Table 1 ).[2,4] The term primary (hypergonadotropic) hypogonadism refers to testicular disorders and is characterized by low serum T despite high levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Causes of primary hypogonadism include (1) genetic conditions (e.g. Klinefelter syndrome, gonadal dysgenesis); (2) anatomic defects; (3) infection; (4) tumor; (5) injury; (6) iatrogenic causes (surgery or certain medications); and/or (7) alcohol abuse.[3]
The term secondary (hypogonadotropic) hypogonadism denotes deficient release of gonadotropin-releasing hormone (GnRH) and is characterized by low-normal or low levels of FSH, LH, and T. Causes or manifestations of secondary hypogonadism include (1) hyperprolactinemia (often secondary to pituitary adenoma); (2) GnRH deficiency with anosmia (Kallmann syndrome); (3) hypothalamic lesions or disorders; and (4) pituitary lesions or disorders. The term normogonadotropic hypogonadism denotes symptoms or signs of hypogonadism together with low serum T and normal LH levels.
Conditions that may be associated with hypogonadism include type II diabetes mellitus (DM); cancer; acquired immune deficiency syndrome; cirrhosis of the liver; renal failure; hyperthyroidism or hypothyroidism; Cushing syndrome; protein-calorie malnutrition (and anorexia nervosa); morbid obesity; hemochromatosis or sickle-cell anemia; paraplegia and myotonia dystrophica; as well as certain psychiatric disorders, including depressive disorders.[5] In addition, several agents are associated with low circulating testosterone[3] ( Table 2 ).
Table 1. Differential Diagnosis of Male Hypogonadism
Primary (hypergonadotropic) hypogonadism
Testicular disorders (primary gonadal failure)
Undescended testes
Acquired bilateral torsion of testes
Orchitis (e.g. mumps orchitis)/cryptorchidism
Vanishing-testes syndrome (congenital anorchism or prepubertal functional castrate)
Seminiferous tubule dysgenesis (Klinefelter syndrome)
Pure gonadal dysgenesis (46XX and 46XY)
Sweyer syndrome (phenotypic female with gonads and genitalia identical to gonadal dysgenesis)
Noonan (Boonevie-Ullrich) syndrome
Hemochromatosis
Impaired Leydig cell activity
Inborn errors of testosterone biosynthesis
Leydig cell hypoplasia
Testicular unresponsiveness (LH receptor failure?)
Androgen-resistant states and enzyme defects
Testicular feminization (absence of androgen receptors)
Incomplete androgen insensitivity (Reiffenstein syndrome)
5-Reductase deficiency
External testicular insults
Trauma
Radiation treatment
Chemotherapy
Autoimmune syndromes (e.g. anti-Leydig cell antibody-associated disorders)
Sertoli-cell only syndrome
Secondary (hypogonadotropic) hypogonadism
GnRH deficiency
Hypothalamic lesions
Tumors
Encephalitis
Granuloma
Abscess
Craniopharyngioma
Isolated GnRH deficiency
Idiopathic (Kallmann syndrome or fertile-eunuch syndrome)
Prader-Willi syndrome
Lawrence-Moon-Bardet-Biedl syndrome
Alstr?m syndrome
Fertile-eunuch syndrome
Familial cerebellar syndrome
Hyperprolactinemia
Prolactinoma
Certain drugs
Hemochromatosis
Neurosarcoid
Myotonic dystrophy
Pituitary disorders (gonadotrophin deficiency)
Isolated LH deficiency
Pasqualini syndrome
Eunuchoidism
Absent secondary sexual characteristics
Oligospermia
Tumors
Pituitary infarction, apoplexy
Empty sella syndrome
Hemochromatosis
Cranial trauma with or without pituitary-stalk transection
Irradiation
Hypophysitis
FSH=follicle-stimulating hormone; GnRH=gonadotropin-releasing hormone; LH, luteinizing hormone.
Sources: AACE guidelines[2] and Rehman et al.[4]
Table 2. Agents That May Cause low Circulating Testosterone
Cytotoxic agents
Spironolactone
Corticosteroids, ketoconazole, aminoglutethimide, ethanol
Decrease Leydig-cell testosterone production
Anticonvulsants, hepatic microsomal liver enzyme inducers
Augment testosterone metabolism
Gonadotropin-releasing hormone agonists, estrogens, anabolic steroids, psychotropic medications, post-transplant immunosuppressants, corticosteroids, ethanol
Reduce gonadotropin secretion
Adapted with permission from Hameed et al.[3]
Pathophysiology
Effects of Testosterone on Sexual Function
It has been suggested that normal or low-normal T levels are necessary to maintain normal sexual function, whereas increases in fat-free and lean-tissue mass rise in a dose-dependent manner over the normal range of circulating T.[6,7]
In a recent study of androgen-deficient patients undergoing subdermal T implantation (T pellets), Handelsman’s group determined thresholds for T and free T (FT) below which symptoms of androgen deficiency returned as T levels declined.[8] Reduced libido and lack of motivation and/or energy recurred when T reached approximately 280 ng/dl in patients with secondary (hypogonadotropic) hypogonadism and 337 ng/dl in patients with primary (hypergonadotropic) hypogonadism.
Testosterone appears to play a role in maintaining sexual function, especially libido, although androgen deficiency per se is infrequently the sole cause of ED in hypogonadal males, particularly elderly men.[9] Preclinical evidence suggests that T promotes erectile responses via both the central and peripheral nervous systems.[10-12] For instance, T modulates α-adrenergic (antierectile) sensitivity of cavernosal smooth muscle.[13]
Preclinical work in DM-prone rats also suggests that decreases in penile nitric oxide synthase (NOS) expression or activity associated with low serum androgens contribute to the pathophysiology of diabetic ED.[14] Other investigations have suggested that androgen deprivation blunts erectile responses via structural changes in the corpora that culminate in decreased blood storage (i.e. veno-occlusive dysfunction) without influencing NOS activity.[15]
In man, it is believed that androgens mediate nocturnal penile tumescence, whereas erectile responses to visual stimuli are androgen independent.[9,16] It has also been suggested that the influence of T on erectile function may be mediated partly via effects on genital sensitivity and that the T metabolite 5α-dihydrotestosterone may also play a role in maintaining erections.[17,18]
T levels in the corpora cavernosa and peripheral blood during transitions from penile flaccidity to tumescence and rigidity, and then detumescence were compared in healthy subjects and ED patients.[19] In healthy volunteers, T levels increased significantly in corporal blood during the transition from flaccidity (2.9 ng/ml) to tumescence (4.3 ng/ml; P<0.001) and rigidity (4.4 ng/ml), followed by a return to 3.5 ng/ml during detumescence. In ED patients, the rise in cavernous T was of lower magnitude: from 2.6 to 3.0 ng/ml during tumescence (P < 0.05). Similar patterns were observed with respect to T concentrations in peripheral blood.
The rise in cavernous T levels from flaccidity to tumescence was also somewhat more marked in patients with psychogenic rather than organic ED.[19] The investigators suggested that the difference between peripheral and cavernous T concentrations during the flaccid phase might serve as a useful marker of bioavailable T (BT) and T receptor density in corporal smooth muscle.[19]
Effects of Testosterone on Cognitive Function and Affect
Cognitive performance, including mental-rotation tasks, is related to androgen levels across the normal range in healthy volunteers.[20,21] In addition, certain studies have shown that androgen replacement enhances cognitive and language functions (but not memory).[22-24]
In vivo studies have also suggested that endogenous androgens confer potentially beneficial neuroprotective effects within the hippocampus and limit accumulation of β-amyloid protein?a central pathophysiologic defect in Alzheimer’s disease.[25,26] In addition, a study of nondemented patients with Parkinson’s disease demonstrated that the degrees of patient- and informant-reported apathy were inversely related to FT levels.[27]
On the other hand, Kenny and co-workers recently determined that intramuscular T (i.m. T) injections did not significantly affect a wide range of cognitive indices in elderly hypogonadal men with early cognitive impairment and BT<128 ng/dl.[28] I.m. T also did not affect activities of daily living or depression ratings.
In the Rancho Bernardo Study, depression rating scales were inversely related to BT levels (P=0.0007) irrespective of age, physical activity, or alterations in body weight.[29] Although certain elderly dysthymic men and patients with treatment-refractory depression have low T levels, there is no strong evidence that reduced T levels play a pivotal pathophysiologic role in major depression.
At the time of writing, there is insufficient evidence to recommend testosterone replacement therapy (TRT) as first-line therapy for major depressive disorder in men with hypogonadism, although adjunctive T treatment may enhance clinical outcomes in patients with treatment-refractory depression.[30-33] Moreover, certain elderly men report an enhanced sense of well-being on TRT,[34,35] although this may be an indirect effect of other physiologic changes.
Effects of Testosterone on Body Composition
Androgens may promote bone formation. In two recent studies of young healthy men, serum sex hormone binding globulin (SHBG) emerged as an independent positive predictor of bone turnover or BMD.[36,37] The decrease in bone mass with advancing age may be associated with declining insulin-like growth factor (IGF-1) levels as well as T concentrations.[38]
Partly by facilitating commitment of pluripotent mesenchymal cells, androgens may also foster skeletal-muscle hypertrophy and hence promote lean body mass.[39] Exogenous T increases satellite-cell populations within muscles, with attendant rises in numbers of myoblasts and large-myofiber myonuclei, as well as formation of larger motoneurons. On the other hand, data suggesting that reduced muscle strength in elderly men relates to reversible declines in androgen levels are conflicting.[38,40-42]
Androgens also attenuate adipogenesis in man. The effects of TRT on adipogenesis may differ in different anatomic regions. In a recent study of men randomized to a GnRH agonist together with i.m. testosterone enanthate (TE) injections at five doses over the range of 25-600 mg weekly,[7] lowering T levels was associated with increases in adipose-tissue stores, with particularly marked rises in subcutaneous depots. However, increasing T levels above baseline via i.m. T injections preferentially mobilized smaller, deeper i.m. adipose-tissue deposits. Overall fat mass was inversely correlated with TE doses across all sites.[7]
Diagnosis
In addition to recognizing presenting symptoms, conducting appropriate laboratory testing is central to diagnosing male hypogonadism.[3] According to the Second International Consultation on Erectile Dysfunction of the World Health Organization (WHO),[43] a blood sample for serum T determination should be obtained between 0800 and 1100 hours, when T levels typically peak in healthy young men. This circadian rhythmicity may be abolished or blunted in men with advancing age[44] or during certain forms of TRT.
A morning T level ≤300 ng/dl should be confirmed and if there is a need to differentiate primary from secondary hypogonadism, levels of LH and FSH should be evaluated.[43] According to the guidelines of the American Association of Clinical Endocrinologists (AACE), exceedingly low T levels (≤150 ng/dl) warrant pituitary imaging even in the absence of other signs or symptoms.[2] Some authorities recommend sellar magnetic resonance imaging with thyroxine, cortisol, and prolactin assessments when secondary hypogonadism is considered likely.[45] According to Australian consensus guidelines:[46]
primary (hypergonadotropic) hypogonadism is indicated by serum T<231 ng/dl with LH>1.5 times the upper limit of normal (1.5 ? ULN);
secondary (hypogonadotropic) hypogonadism is indicated by T<231 ng/dl without LH elevations;
Leydig-cell failure is indicated by T=231-432 ng/dl with LH>1.5 ? ULN; and
androgen resistance is indicated by T>864 ng/dl with LH>1.5 ? ULN.
Total T assays may not indicate true androgenic status, particularly in elderly men. According to the most recent WHO guidelines,[43] BT (normal range=92-420 ng/dl) and FT (normal=5-21 ng/dl) are the most reliable assays to establish male hypogonadism. As serum T may be normal in patients with primary testicular disorders (e.g. Klinefelter syndrome) or increased SHBG, obtaining FT or BT may also be useful.[2] However, the validity and accessibility of a number of diagnostic tests (e.g. equilibrium dialysis) and other, dynamic assessments are matters of ongoing debate.
Recent data from the Massachusetts Male Ageing Study (MMAS) provide perspectives on normal androgen ranges.[47] In the MMAS, the threshold for abnormally low total T as established by the 2.5th percentile was 251 ng/dl for healthy men aged 40-49 years, 216 ng/dl for ages 50-59, 196 ng/dl for ages 60-69, and 156 ng/dl for ages 70-79. Corresponding 2.5th-percentile values for FT were 5.3, 4.2, 3.7, and 2.2 ng/dl, while corresponding values for BT were 99.7, 79.8, 69.7, and 41.8 ng/dl.
In the MMAS, the mean FT in men aged 40-49 years was 14.3 ng/dl, with a range of 3.7 ng/dl (mean-2 standard deviations (s.d.)), to 24.9 ng/dl (mean+2 s.d.). The mean FT in men aged 70-79 was 7.6 ng/dl (0.8-14.4 ng/dl). The mean BT in men aged 40-49 years was 270.9 ng/dl (69.2-469.7 ng/dl) and the mean BT in men aged 70-79 was 144.1 ng/dl (14.4-270.9 ng/dl).[47]
As with ED, signs and symptoms of hypogonadism often go unreported to physicians. Therefore, it is important to maintain a proactive dialogue with the patient about possible symptoms such as low libido, ED, impaired concentration, and fatigue to uncover hypogonadism. It is also often important to inquire about increased fatigue during TRT because this may be a manifestation of treatment-related sleep apnea.
Conclusions
In summary, male hypogonadism has a multifactorial etiology that includes congenital abnormalities, injury, infection, cancer, diabetes, treatment with certain medications, and alcohol abuse. In addition to obtaining androgen and other hormone levels, it is important to be familiar with the signs (e.g. anemia, oligospermia/azoospermia, muscle wasting) and symptoms (e.g. sexual dysfunction, mood disturbances, cognitive problems) because many patients do not report these manifestations. Assessment of presenting signs and symptoms, in concert with evaluations of the HPG axis, enables diagnosis of primary (hypergonadotropic) or secondary (hypogonadotropic) hypogonadism, which may prompt further work-ups and treatment.
Correspondence: Dr A Seftel, Department of Urology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-5046, USA. E-mail: adseftel@aol.com
Int J Impot Res. 2006;18(3):223-228. ?2006 Nature Publishing Group