Is it low testosterone or something else?

Men with inadequate testosterone and clinical symptoms of deficiency may have hypogonadism. Here are the signs that should prompt lab study.

The diagnosis of hypogonadism demands both symptoms of testosterone deficiency and decreased blood testosterone levels.

Low testosterone is traditionally associated with diminished libido, fatigue, changes in body composition, impaired cognition, depressed/irritable mood and reduced bone mineral density (BMD). More recent findings suggest that testosterone deficiency may be associated with cardiovascular (CV) risk factors such as obesity, metabolic syndrome, and insulin resistance.

Evidence also is emerging on the role of testosterone in erectile physiology, particularly as it relates to the hormone's role in the vascular processes involved in erection. Because testosterone has effects throughout the body, suspicion of hypogonadism necessitates a wide-ranging patient evaluation (Figure 1).

There are several guidelines and other sources that have identified the signs and symptoms of androgen deficiency, and the list is being expanded through ongoing research.

Aging and hypogonadism The prevalence of hypogonadism increases with advancing age. Indeed, the question of hypogonadism arises much more frequently in older than in younger men. Furthermore, there are definite similarities between changes that men notice as they age and symptoms associated with young hypogonadal men.

Manifestations common to both groups include decreases in libido, erectile capacity, sexual body hair and beard growth, energy, work capacity, and cognitive function. Objective signs seen in young hypogonadal and aging men include reduced muscle mass and strength, reduced BMD, and increased abdominal obesity (Figure 2). These may be accompanied by hot flushes.

Compared with younger men, symptoms in older men develop slowly and progressively; they also tend to be variable and nonspecific. Because of these differences in the progression of symptoms, manifestations in aging men only suggest the possibility of hypogonadism. Documenting a low serum testosterone level becomes crucial to diagnosis. The case presented on page 85 illustrates the interplay of symptoms and testosterone levels in making a diagnosis.

Androgens and the CV system Prevalence of both male hypogonadism and CV disease increases with age. The link between testosterone and the vascular system is a logical one because vascular walls contain androgen receptors as well as estrogen receptors. Recent studies suggest that elements of CV disease might signal the presence of hypogonadism.

Given this evidence, clinicians should consider the diagnosis of hypogonadism in men with CV risk factors. Question these men about the presence of symptoms associated with hypogonadism (Table 1) and assess whether they display any signs of the condition. If this evaluation points to possible hypogonadism, then measure serum testosterone.

CV risk factors associated with hypogonadism include dyslipidemias, insulin resistance, metabolic syndrome, and elevated levels of prothrombotic elements, such as fibrinogen and plasminogen activator inhibitor type 1.

Large systematic reviews underscore the inverse relationship between androgen levels and CV risk. Issues remain controversial, but the weight of evidence is shifting to the view that androgens are necessary for CV health. Additionally, a growing body of knowledge suggests that testosterone replacement need not be restricted because of concerns about CV side effects. The exception is possible fluid retention in older men with congestive heart failure.

Androgens, lipids, and atherosclerosis Hypogonadism has been associated with low levels of HDL and elevated levels of total cholesterol, triglycerides, and LDL. Two studies have demonstrated a link between endogenous androgens and atherosclerosis. Higher testosterone was independently linked to lower relative risk (RR) of atherosclerosis in the Rotterdam study (RR = 0.4 for total testosterone levels in the highest tertile; RR = 0.2 for free testosterone [fT] levels in the highest tertile). Subjects were men and women older than 55 years (N = 1,000).

Conversely, low testosterone levels (defined as <282 ng/dL, or <9.8 nmol/L) plus clinical symptoms of hypogonadism have correlated with increased carotid atherosclerosis (measured by intima-medial thickness).

Testosterone replacement yields the most positive effects on lipid levels when men are truly hypogonadal (defined as testosterone <288 ng/dL, or <10 nmol/L). These findings are in contrast to earlier research that did not show a strong link between testosterone and lipid levels; early studies did not always use this strict definition of hypogonadism.

Additionally, initial studies of androgens and lipids used injections of long-acting, high-dose testosterone esters, which produced transient supraphysiologic androgen levels. Such high levels adversely affect lipid profiles, which may promote atherogenesis. Newer forms of testosterone replacement (e.g., patches, gels, and buccal pellets) provide more physiologic testosterone replacement within the normal range.

Metabolic syndrome

There is a relationship between testosterone levels and elements of the metabolic syndrome. Recent evidence suggests a correlation between increasing insulin resistance, an important component of the metabolic syndrome, and decreasing testosterone secretion; conversely, increasing insulin sensitivity has been associated with increasing testosterone levels.

Muller and colleagues also have shown that higher levels of testosterone are associated with greater insulin sensitivity and reduced risk of the metabolic syndrome. In this study, the number of metabolic syndrome components present correlated inversely with total testosterone levels (P <.001 for trend). Tong demonstrated that frequency of the metabolic syndrome increased with declining tertiles of total testosterone in Chinese men.

Supporting this line of evidence is the finding that men receiving androgen-deprivation therapy for prostate cancer demonstrate increasing amounts of insulin resistance, independent of age and BMI. The relationship between testosterone and insulin sensitivity has extended to fT and bioavailable testosterone. Some have speculated that the link is mediated through body fat.

Obesity

There is an inverse correlation between testosterone levels and BMI, waist circumference, visceral fat, and serum insulin levels. Basaria and colleagues have shown that men with prostate cancer receiving androgen-deprivation therapy had statistically higher BMI and higher fat mass. These findings suggest that increased weight is a potential marker for hypogonadism.

Sexual function

Testosterone is an integral part of male sexual function, not only for libido but also for erectile physiology. Up to 36% of men with ED also have low testosterone levels.

Androgens are necessary for the erectile response; they are responsible for both endothelium-dependent and endothelium-independent activity leading to smooth muscle relaxation in the corpora cavernosa. High adrenergic tone in the penile vessels causes vasoconstriction and maintains a state of flaccidity when men are not engaging in sexual activity.

Blood flow in the corpora cavernosa is increased by fT as well. Testosterone replacement restored erectile function in androgen-deficient men who ceased to respond to sildenafil (Viagra) when their testosterone levels fell. A number of studies have shown that replacing testosterone in hypogonadal men restores multiple aspects of sexual functioning.

Androgen deficiency is rarely the sole cause of ED in hypo-gonadal males, however. ED is predominantly a vascular disease. Like other vascular diseases, ED is a manifestation of endothelial dysfunction. Risk for CV disease and ED overlapped by >90% in one study. This was reinforced in the same population by finding a much greater incidence of insulin resistance and metabolic syndrome than had been previously shown in studies of the general population. The case summarized on page 85 illustrates this as well.

Testosterone affects libido, but the level of testosterone needed to maintain libido is at the low end of the normal male range. Nevertheless, diminished libido was the second-most reported symptom that led hypogonadal men to schedule replacement of subdermal testosterone implants.

Body composition

Sarcopenia—defined as age-related loss of muscle mass, strength, and function—raises risk of falls, fractures, and disability. Decreased apparent fT concentration has been associated with increased risk of falls (as reported by subjects) and impairment of static and dynamic balance in older men.

It has been shown that low testosterone (i.e., either apparent fT concentration or fT index >2 SD lower than the mean values for young men) is associated with sarcopenia but that total testosterone is not a significant determinant of appendicular skeletal muscle mass index. This confirms other findings that fT and bioavailable testosterone are better markers of androgenic status in elderly men than is total testosterone.

Conversely, ascending doses of exogenous testosterone have led to increased fat-free body mass and muscle strength. These changes were similar for older (N = 60, aged 60-75) and younger (N = 61, aged 19 to 35) eugonadal men who received doses of testosterone enanthate (25-600 mg weekly for 20 weeks) after suppression of endogenous testosterone production using a gonadotropin-releasing hormone agonist.

A long-term study of testosterone-gel therapy in hypogonadal men (N = 163; follow-up 42 months) led to significantly increased lean body mass and decreased fat mass. Muscle strength did not rise significantly, however.

A review of androgen therapy in older men determined that standard-dose testosterone therapy consistently leads to modestly increased muscle mass (1.5-2.5 kg) and reduced fat mass (1-2 kg). These effects plateau with continuing therapy. The authors characterized changes in muscle strength as questionable and too small to be of significance in frail older men.

Bone density

Bone contains both androgen and estrogen receptors. Testosterone replacement in androgen-deficient men delivers to the bone both testosterone and estrogen, as testosterone is aromatized to an estrogenic form. Evidence suggests that testosterone aromatizability (i.e., conversion to estrogen) is crucial for effects on bone.

Low testosterone (apparent fT concentration) has been linked to low BMD in an observational cohort of older men (50-85 years old). Total testosterone and fT index concentrations were not associated with BMD, highlighting the importance of proper testosterone measurement.

Depression

Depression can decrease libido. More evidence suggests, however, that the reverse is true — the incidence of depressive illness is increased in men with hypogonadism. A historical cohort study evaluating medical records revealed that hypogonadal men were at significantly higher risk of being diagnosed with depressive illness compared with eugonadal men (21.5% vs. 7.1%; P = .01). Hypogonadism was significantly associated with depression in this study.

This association is especially true for older men. One study found that median total testosterone levels were lower in men older than 60 years old with dysthymic disorder compared with men without depressive symptoms and to those with major depressive disorder. A majority of men with dysthymic disorder had testosterone levels in the hypogonadal range (i.e., ≤300 ng/dL); median total testosterone was 295 ng/dL. Testosterone replacement reverses at least some of these effects.

One study examined hypogonadal men who scheduled replacement of subdermal testosterone implants based on symptom recurrence. More than half (56%) of subjects reported loss of motivation, while 48% listed cantankerous mood as among the symptoms prompting their return for testosterone implants.

Fatigue

Lack of energy was the most commonly reported recurring symptom of androgen deficiency in hypogonadal men (88%) scheduling replacement of subdermal testosterone implants. Most characterized severity of this problem as moderate or very problematic (78%). Nearly half (44%) reported somnolence after lunch.

Cognition

Data suggest an association between cognitive function and endogenous androgen levels. High testosterone levels predicted better performance on several tests of cognitive function in a population-based cohort of older men. Higher bioavailable testosterone was associated with superior performance on assessments of verbal memory and mental control. This link, though relatively weak, was independent of age, education, BMI, alcohol use, cigarette smoking, and depression.

Another report showed that about 42% of hypogonadal men who returned for replacement of subdermal testosterone implants based on symptom recurrence reported inability to concentrate as a recurring symptom.

Findings regarding whether testosterone supplementation improves cognition are mixed. Spatial memory, spatial ability, and verbal memory significantly improved compared with baseline and placebo in men 50-80 years given weekly IM injections of 100 mg testosterone enanthate for six weeks. In another report, transdermal testosterone given for one year to men older than 65 years with low bioavailable testosterone significantly improved some, but not all, measures of cognitive function compared with placebo. Scores on one cognitive test for placebo and testosterone subjects were significantly correlated with 12-month testosterone levels (P = .016).

Immune function

A review summarizing the link between sex steroids and immune function found that androgens increase activity of T-suppressor cells (i.e., CD4-/CD8+ cells). Patients with Klinefelter's syndrome, a male hypogonadal state, have an increased incidence of the autoimmune disease systemic lupus erythematosus. Abnormal cytokine levels have been reported in untreated Klinefelter's syndrome patients with no autoimmune disorders; androgen replacement significantly reversed these findings.

References

For a list of references used in this article, please contact the editor via e-mail (editor@clinicaladvisor.com) or telephone (646.638.6077).

André T. Guay, MD, is director of the Center for Sexual Function at the Lahey Clinic Northshore in Peabody, Mass.
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