The Role of Obesity and Type 2 Diabetes Mellitus in the Development of Male Obesity-associated Secondary Hypogonadism

S. A. Saboor Aftab; S. Kumar; T. M. Barber

Disclosures

Clin Endocrinol. 2013;78(3):330-337. 

In This Article

Male SH in T2DM

Prevalence

Since the first description of the high prevalence of SH in men with T2DM, the importance of this association has increasingly been recognized.[9] On the basis of current literature, specific assays and currently recommended reference ranges for testosterone, the prevalence of male SH in T2DM was estimated to be 29% (range 25–40%), with a higher prevalence of 50% if obesity and T2DM occur concurrently.[9,22,46] The prevalence of SH in young men (aged 18–35 years) with T2DM has been shown to be as high as 33%.[47]

Pathogenesis

There are a number of possible mechanisms whereby male SH is associated with T2DM, and it is likely that complex mechanisms pertain.[1,5] Given the strong coexistence of male SH, obesity and T2DM outlined in the previous section, it is possible that much of the association between SH and T2DM is mediated via obesity-related factors such as enhanced aromatase activity. However, it is clear that the concurrence of obesity with T2DM appears to be a greater risk factor for SH than the presence of either of these entities alone.[9,22,46] This implies that other factors relating to T2DM per se (i.e. independent of obesity) may be involved. The existing literature suggests that plasma testosterone levels in men with T2DM correlate with insulin resistance, BMI, elevated inflammatory markers such as CRP and not per se with the duration and degree of hyperglycaemia. Consistent with this observation is the fact that male SH is rare in type 1 diabetes mellitus.[2,8–10] Despite these observations, however, further investigation is required to elucidate a possible direct role of hyperglycaemia in the development of male SH.

The obesity-related pathogenic mechanisms that may play a role in the development of male SH in T2DM include the effects of insulin resistance at various levels, including effects on lipases.[1,48] The presence of low testosterone levels in men is known to lead to a reduction in muscle mass and an increase in visceral fat mass, insulin resistance and enhanced activity of lipoprotein lipase (LPL), the main enzymatic regulator of triglyceride uptake into the fat cell (preferentially visceral fat).[1,48] Hypogonadism induces LPL at the adipose tissue level, thereby promoting the storage of triglycerides. Hypogonadism also inhibits hormone-sensitive lipase, which limits β oxidation that ultimately increases fat mass.[49] This in turn results in an increase in oestradiol formation through enhanced adipose tissue aromatase activity as described in the previous section.[2] Other effects of insulin resistance and compensatory hyperinsulinaemia (features of T2DM) include suppression of hepatic SHBG synthesis, and suppression of the hypothalamic–pituitary unit through effects of inflammatory mediators that are known to be increased in insulin-resistant states.[2,50] Impaired insulin signalling within hypothalamic neurones in insulin-resistant states may also play a role in the development of SH. This hypothesis is based on data from neuron-specific insulin receptor knock-out male mice, in which a 60–90% decrease in serum LH concentration was observed, and a normal or supernormal LH release in response to GnRH stimulation was demonstrated.[51] These results imply that insulin acts on hypothalamic neurons to facilitate GnRH release and thus promote gonadotrophin secretion.[51] Regarding the role of oestradiol in male SH associated with T2DM, a recent study in 240 T2DM men with and without SH, found that free oestradiol concentrations were directly related to free testosterone concentrations, irrespective of age or surprisingly BMI. The diminished availability of testosterone as a substrate for aromatization in the adipose tissue may therefore be a major determinant of oestradiol levels. Thus, as the testosterone level falls, oestradiol levels may start coming down due to lack of substrate for the aromatase enzyme. This hypothesis has been supported by the European Male Ageing Study.[52] The pathogenic mechanisms implicated in the development of MOSH in T2DM have been outlined in Fig. 1.

A further mechanism that may mediate a link between male T2DM and SH is the role of inflammatory mediators such as tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), which have been shown to suppress hypothalamic GnRH and LH secretion in vitro.[17,53] Molecules such as C-reactive protein (CRP) have been demonstrated to exhibit markedly increased concentrations in hypogonadal men with T2DM compared with men who have T2DM and normal testosterone levels.[54] This important observation is consistent with the hypothesis that inflammatory mediators such as CRP may contribute to the suppression of the gonadal axis and the development of male SH in T2DM, and the presence of inflammatory mediators may also worsen insulin resistance through interference with insulin signal transduction.[17,18,53] Levels of these inflammatory mediators are also known to be increased in obesity, thereby providing a possible link between obesity, T2DM and SH in men.[18,19,55]

The role of SHBG in the pathogenesis of male SH in T2DM is unclear, although lower SHBG concentrations are strongly predictive of the development of T2DM, and higher SHBG concentrations appear to be protective.[56] SHBG, produced by the liver, binds testosterone with high affinity and is an important regulator of androgen homeostasis in its role as a modulator of androgen delivery to the peripheral tissues.[8] SHBG concentrations are inversely correlated with BMI and degree of insulin resistance.[22,57] The link between obesity and SHBG may be mediated via the effects of obesity-induced insulin resistance, resulting in higher insulin levels (compensatory hyperinsulinaemia) that subsequently suppress hepatic production of SHBG. A drop in SHBG would thus result in reduced delivery of testosterone to the peripheral tissues, and this may represent one mechanism whereby hypogonadism develops. A drop in SHBG may also result in increased availability of free testosterone as a substrate for aromatase to convert to oestradiol.

There is substantial evidence that male hypogonadism results in the development of adverse metabolic features, including insulin resistance and T2DM.[58,59] In a study on 702 middle-aged men without diabetes or metabolic syndrome (MetS) at baseline followed for 11 years, the men with lower baseline levels of testosterone had a several-fold higher risk of developing MetS and dysglycaemia following adjustment for age.[58]

Ethnic or geographical variations in the manifestation of MOSH are unclear and it is likely that several factors play a role. In a recent study on Japanese men, an inverse association was demonstrated between free testosterone levels and MetS (independent of age, BMI and waist circumference). Serum LH and FSH levels were similar between those men with low and normal free testosterone levels, indicating SH.[59] Another study on an Indian Asian population found no correlation of hypogonadism with components of the metabolic syndrome.[41]

In addition to central hypothalamo–pituitary mechanisms, peripheral mechanisms both at the level of the liver (reduced SHBG production) and testes (reduced testosterone production) may also play important roles in the development of SH in men with T2DM. In addition to SHBG, a further peripheral mediator of the development of male SH in the presence of T2DM is reduced (human chorionic gonadotrophin-induced testosterone secretion) within the testicular Leydig cells. Such secretory activity has been demonstrated to be inversely related to the level of insulin resistance in men with abnormal glucose tolerance.[60]

To summarize this section, the development of male SH in T2DM is likely to implicate pathogenic mechanisms, some distinct and some similar to obesity-induced SH, that highlight the close epidemiological and mutually pathogenetic links between obesity, SH and T2DM.

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