Prevalence of hypogonadism

In the Baltimore Longitudinal Study on Ageing, it was found that 19% of men over 60 years had low testosterone. The Hypogonadism in Males (HIM) study estimated the overall prevalence of hypogonadism at approximately 39% in men aged 45 years or older (18). It has been estimated that only 535% of hypogonadal males actually receive treatment for their condition (19,20).

Measuring testosterone levels in populations, while useful, is different from measuring hypogonadal symptoms. A subject can have low testosterone levels, but can also have no clinically significant symptomatology. Likewise, measurement of symptoms alone is not reliable, as hypogonadal symptoms are non-specific. The Massachusetts Male Ageing Study (MMAS) measured a combination of testosterone levels and hypogonadal symptoms and found between 6% and 12% of men had symptomatic androgen deficiency (21). An interesting observation from the MMAS was that half of the men found to have symptomatic androgen deficiency at one stage were found to be eugonadal when retested at a later stage (22). This is probably because there is subject-to-subject variation in testosterone secretion and in the testosterone threshold where symptoms become manifest. As discussed below, a measurement of low testosterone in a patient should be reconfirmed at a later stage before considering treatment.

Older men are more likely to have low testosterone levels: in the HIM study, for example, the prevalence of low testosterone in the 4554 age group was 34%, whereas it was 50% in men over 85 years (18). Likewise, in the Baltimore study the percentage of men with low testosterone increased from 12% in men in their 50s, to 49% in men over 80 years of age (23).

There appears to be no consistent evidence that the prevalence of hypogonadism differs between racial and ethnic groups (2426).

Higher rates of hypogonadism than those in the general population are associated with various common diseases or conditions. The HIM study calculated odds ratios for some common conditions (). It is not yet understood whether the low testosterone levels are a consequence of the disease, are connected with the diseases aetiology, or are one of the causes of the disease. Further studies are needed to determine if treating the associated hypogonadism is likely to improve the patients disease symptoms.

Odds ratios for hypogonadism for various comorbidities from the HIM Study (18)

Vascular tissue (including endothelium and vascular smooth muscle cells) contains androgen receptors, so it is to be expected that testosterone (or its metabolite, oestrogen) is likely to affect the cardiovascular system. In fact, the increased risk of cardiovascular disease in males compared with females has been taken to imply a role for testosterone (or oestrogen) in the disease. Human observational studies, however, have shown no associations between high testosterone levels and coronary artery disease, and testosterone has been shown to dilate the coronary arteries both in vitro and in vivo. Some studies have shown that testosterone can be considered to have a positive effect on reducing the risk factors for cardiovascular disease; for example, inverse relationships have been shown between testosterone levels and body mass index (BMI), waist circumference, waist-hip ratio, serum leptin, low-density lipoprotein (LDL) cholesterol, triglyceride and fibrinogen levels. Low testosterone is associated with dyslipidemia, hypertension, obesity and diabetes, all of which increase the risk of cardiovascular disease and are features of the metabolic syndrome (27,28).

A negative view of testosterones impact on cardiovascular disease comes from the observation that high-density lipoprotein (HDL) cholesterol levels decrease in patients on oral testosterone therapy, or when taken in supraphysiological doses by athletes (29,30). However, when given as a transdermal gel to hypogonadal men, there is either no significant change or only minor changes in HDL levels (28,31,32). Whatever the subtleties of the effects of testosterone on lipids, recent data have demonstrated that low testosterone concentrations are associated with an increased incidence of cardiovascular events, and an increase in acute myocardial infarction and stroke.

The relationship between testosterone and HDL is confounded by the fact that both HDL and testosterone are inversely related to BMI. In fact, epidemiological analyses have found that HDL levels are positively linked to testosterone levels in middle-aged men. Data from the MMAS have demonstrated that there is a strong, positive relationship between HDL and testosterone in men with cardiovascular disease (low total or free testosterone correlates with low HDL cholesterol) (31).

Recent work in the Rancho Bernardo, California population has shown that men with serum total testosterone levels in the lowest quartile (< 241 ng/dl) were associated with a higher risk (38%) of cardiovascular mortality, compared with those who have higher total testosterone levels, independent of age, obesity and lifestyle choices (33). In fact, those with low testosterone were 40% more likely to die (all-cause mortality) than those with higher levels. This is in contrast to what was found in the MMAS study where total testosterone levels were unrelated to all-cause mortality (34,35).

A meta analysis, published in 2007, of randomised trials that assessed the effect of exogenous testosterone on cardiovascular events, however, concluded that the inference that testosterone use in men is not associated with important cardiovascular effects was only weakly supported. Large randomised trials using men with and without cardiovascular disease and with cardiovascular end-points are needed to better assess the consequences of testosterone treatment on cardiovascular risk (36).

A recent study (2009) from Italy demonstrates that testosterone treatment in elderly patients with chronic heart failure improves insulin sensitivity and various cardiorespiratory and muscular outcomes (37).

In 2007, it was estimated that 23.6 million people, or 7.8% of the US population, had diabetes (38). Projections based on data from the National Health and Nutrition Examination Surveys (NHANES) show that by 2021 there are anticipated to be approximately 33 million people with diabetes in the United States, representing 13.5% of the population (39).

Low testosterone concentrations are known to occur in association with type 2 diabetes. However, clinicians have often not related low testosterone concentrations to clinical hypogonadism. The first attempt to measure free testosterone and to establish hypogonadism as a feature of male type 2 diabetes was made by Dhindsa et al. in 2004 (40). This has been confirmed in several other studies including the HIM study (41). In the HIM study, a diabetic man was approximately twice as likely to be hypogonadal compared with a non-diabetic man (18). Prevalence in diabetic men has been estimated at 3350% (18,40,42). With such a high prevalence, hypogonadism is a candidate for the most common complication of male type 2 diabetes. Analysis of gonadotropin levels demonstrates that the hypogonadism in type 2 diabetes is mostly hypogonadotropic (secondary) hypogonadism (40). There is no relation between the degree of hyperglycaemia and testosterone concentration (40,43).

C-reactive protein, a marker for systemic inflammation, has been found to be markedly elevated in patients with secondary hypogonadism and type 2 diabetes. The concentrations of C-reactive protein in these patients are twice as high as those in eugonadal type 2 diabetics, whose C-reactive protein levels are already elevated compared with non-diabetics. Such patients have also been shown to have mild anaemia, low bone mineral density (BMD) in the arms and ribs, and increased adiposity when compared with eugonadal type 2 diabetics (44,45). These features are similar to those of hypogonadal patients without diabetes. Another intriguing observation is that prostate-specific antigen (PSA), a marker for prostate cancer, is significantly lower in type 2 diabetics and this is related to their lower plasma testosterone concentrations (46). The clinical significance of this remains to be elucidated.

Interestingly, low testosterone concentrations predict the development of type 2 diabetes. Utilising data from the NHANES III survey, it was found that men in the lowest free testosterone tertile were four times as likely to have diabetes as those in the highest free testosterone tertile (47).

Type 1 diabetes does not seem to be associated with hypogonadism, suggesting that hypogonadism is specific to type 2 diabetes and not related specifically to hyperglycaemia (43).

Obesity amongst adult men had a prevalence of 33.3% in 20052006 according to the most recent NHANES review (48). An adult who has a BMI between 25 and 29.9 kg/m2 is considered overweight, whereas an adult who has a BMI of 30 kg/m2 or higher is considered obese. This is not a rigid rule as BMI does not directly measure body fat, so athletes, for example, may have high BMIs even though they are not overweight (49).

The health risks associated with obesity are well known, increasing the risk for type 2 diabetes, hypertension, atherosclerotic diseases and coronary heart disease. Obesity is strongly associated with type 2 diabetes: approximately 83% of diabetic patients are overweight or obese (50). Obesity is also associated with low total testosterone and reduced SHBG levels. There is an inverse linear relationship between total testosterone and BMI, and free testosterone concentrations also decrease with increasing BMI. There is an inverse relationship between serum total and free testosterone levels and visceral fat mass. Thus, the degree of hypogonadism is positively correlated to the degree of obesity in obese men (51,52).

A person with metabolic syndrome is defined as having central obesity in addition to any two of these four factors: hypertension ( 130/85 mm Hg), reduced HDL (< 40 mg/dl in males), raised triglycerides ( 150 mg/dl) or raised fasting plasma glucose ( 100 mg/dl)(53). It is considered a high risk for coronary heart disease (19,54). As the constituent elements of metabolic syndrome are themselves correlated with testosterone concentrations, it is perhaps not surprising that hypogonadism is also associated with the metabolic syndrome, as has been shown in a number of epidemiological studies (55,56).

Low testosterone levels are correlated with insulin resistance in both epidemiological and interventional studies, and this may be attributable to the effect of testosterone on adiposity. Low testosterone levels increase fat mass and decrease lean muscle, resulting in increased adipose tissue (52).

Adipose tissue affects testosterone levels by increasing the aromatisation of testosterone to estradiol, because the aromatase enzyme is concentrated in adipocytes. This reduces serum and tissue testosterone levels. The estradiol produced by aromatisation also provides negative feedback on the HPG axis, further reducing testosterone. Thus, adiposity potentially leads to hypogonadism, which itself promotes further adiposity. illustrates the main hypogonadal-obesity-insulin resistance connections and also includes other factors such as TNF- (an adipokine), which is elevated in obese males (42,51,57,58).

The interrelationship between hypogonadism and insulin resistance (after (42,51)). LH, luteinizing hormone. Low testosterone stimulates an increase in adiposity. Adipose tissue contains high concentrations of aromatase, which reduces testosterone concentrations by converting it to estradiol. The estradiol negatively feeds back on the HPG system, reducing testosterone production in the Leydig cells. Increasing adipose tissue increases insulin resistance, which negatively impacts the Leydig cells as well as inhibiting the release of luteinizing hormone (LH) via the release of adipokines (inflammatory cytokines) such as TNF-. Leptin, released in response to increased adiposity, also inhibits the release of LH via its effect on the release of gonadotropin-releasing hormone

However, it seems likely that testosterone may suppress insulin resistance independently of its effects on adiposity. The withdrawal of testosterone therapy in hypogonadal patients that had been stabilised on this therapy leads to an increase in insulin resistance within 2 weeks and prior to significant weight gain (59). A recent study showed that supervised diet and exercise increased testosterone levels in hypogonadal men with metabolic syndrome and newly diagnosed type 2 diabetes. In addition, a small dose (50 mg/day) of testosterone gel improved both glycemic control and insulin sensitivity over and above the improvements because of diet and exercise (60). The mechanism underlying the insulin sensitising effects of testosterone needs to be elucidated.

An important proviso to this discussion is that further research into the role of hypogonadism in obesity, metabolic syndrome and diabetes is required to gain a better understanding of the pathogenic mechanisms involved and that, at present, it is not known whether hypogonadism is the cause or the consequence of these conditions.

Osteoporosis is an under-recognised problem in men. Ten to twenty per cent of individuals with osteoporosis over 50 years old in the United States are men (25). Up to 13 million men are at increased risk because of low BMD and up to 2 million of these have osteoporosis (61,62). Men have almost 30% of all hip fractures and men are twice as likely to die in hospital than women after a hip fracture. Hip fracture incidence is low until after 75 years, when the risk increases exponentially. Vertebral fractures are also common, although they are only about half as common in men compared with women (63).

There are many suspected causes of osteoporosis, and the most frequent are corticosteroid use, Cushings syndrome, hypogonadism and excessive alcohol consumption. In a study of elderly men in a nursing home who have experienced hip fractures, 66% were hypogonadal (64).

Other common secondary causes are smoking, low calcium intake and vitamin D deficiency or insufficiency (61).

Various epidemiological studies in men have examined associations between testosterone and estradiol levels and BMD. Estradiol levels in men have been consistently and positively associated with BMD. Testosterone is also positively associated with BMD, but the relationship is weaker than that of estradiol (65,66).

Interventional studies have shown that testosterone replacement therapy in hypogonadal males increased spine BMD and trabecular connectivity (61,67). However, studies of testosterone therapy in men with osteoporosis are limited and none have used fractures as an end-point; so although there is significant evidence of an association between hypogonadism and osteoporosis, there is no established causal link between the two.

Testosterone levels are lower in men being treated with corticosteroids. Systemic glucocorticoids can reduce testosterone biosynthesis in the testis; in addition, glucocorticoids impact the HPG axis by inhibiting the release of LH (17,68). As a result, patients being treated with glucocorticoids for such chronic conditions as rheumatoid and osteoarthritic inflammation, skin inflammations, asthma, chronic obstructive pulmonary disease (COPD) and inflammatory bowel disease are at an increased risk of hypogonadism.

There have been some studies that suggest that COPD patients have a higher incidence of hypogonadism than the general population and that glucocorticoid treatment is only part of the reason. The pathophysiology of this remains unclear, but suggestions have been made that it might be connected with chronic hypoxia, and a systemic inflammatory response (68). A number of studies have shown that testosterone therapy can improve lean body mass and BMD and strength in hypogonadal men with COPD (17).

Long-acting opioids such as methadone, morphine sulphate, fentanyl and oxycodone for the treatment of chronic pain often result in opioid-induced androgen deficiency (OPIAD). In a casecontrol study of 40 cancer survivors it was found that 90% of those on opioid treatment were hypogonadal compared with only 40% of the control group (69). The mechanism for OPIAD is thought to involve suppression of GnRH release by the hypothalamus, thereby inducing secondary hypogonadism (17,70).

Apart from the effects of testicular cancers, which may have a direct impact on testosterone secretion, the prolonged radiation treatment, chemotherapy using antimitotic drugs or corticosteroids or pain treatment medications characteristic of cancer treatment are likely to induce hypogonadism (17). These drugs may induce Leydig cell dysfunction or germinal epithelial failure (71). The HPG axis may also be affected by androgen-, or ectopic adrenocorticotropin hormone-producing tumours, leading to secondary hypogonadism (17).

Androgen deficiency is strongly associated with AIDS wasting syndrome, and testosterone therapy in HIV-positive hypogonadal men increases lean body and muscle mass and perceived well-being, and decreases depression (7274). Approximately 2050% of HIV-infected men receiving highly active antiretroviral therapy are hypogonadal. While these prevalence levels may superficially appear similar to the background figures in the population, most studies are based on middle-aged populations. HIV patients with AIDS are younger and therefore, comparisons have to be carried out with appropriately age-matched controls.

The cause of this hypogonadism is probably as a result of a number of factors, including lipodystrophy induced by highly active retroviral medications; testicular atrophy caused by opportunistic infection; disruption of the HPG axis resulting from malnutrition; and the results of medications such as the antimycotic ketoconazole, which inhibits steroid biosynthesis (17).

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