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


Clin Endocrinol. 2013;78(3):330-337. 

In This Article

Male Obesity-associated Secondary Hypogonadism

Prevalence and Diagnosis

Obesity in men is believed to be one of the most frequent associates of subnormal free testosterone levels. Male obesity is frequently associated with testosterone levels within the hypogonadal range and a biochemical picture of SH. Furthermore, the prevalence of male SH increases linearly with BMI. Obesity is associated with low testosterone levels in diabetic men.[33] However, an inverse relationship between BMI and testosterone concentrations has been found in men regardless of diabetic status.[22,34] In one study on 160 obese men, the final analysis showed that more than 40% of those with a BMI ≥ 40 kg/m2 had a free testosterone level <225 pmol/l.[6] From a study on 1849 men done to define the prevalence of hypogonadism, subnormal free testosterone levels were demonstrated in 40% of obese (BMI ≥ 30 kg/m2) men with normal glucose tolerance, and in 50% of obese men with diabetes aged ≥45 years.[22]

In light of our current understanding of the pathophysiology of MOSH, a clinical diagnosis of MOSH could be made if all of the following defining features are present:

  • Male with BMI ≥ 30 kg/m2

  • The presence of any of the signs/symptoms that suggest hypogonadism such as impaired or worsening sexual/physical/mental performance, impaired sexual characteristics/breast pain/true gynaecomastia, sleep problems/dysglycaemia, flushing episodes/low bone mineral density, unexplained anaemia

  • (In the presence of normal SHBG) Morning total testosterone level below the lower limit for healthy young men in a reliable assay, confirmed twice. (In the presence of an abnormal SHBG level) Free/bioavailable testosterone level below the lower limit for healthy young men in a reliable assay

  • Low or inappropriately normal FSH, LH levels in the absence of another obvious cause of hypopituitarism

  • Other causes of hypogonadism have been systematically excluded

The presence of hypogonadism should be suspected in obese men with any of the suggestive clinical features outlined above. It would seem prudent to screen for the presence of MOSH in such patients who are at high risk for this condition. As data on the cost effectiveness of this approach are lacking currently, this should be a focus for future studies. Given that male hypogonadism per se is associated with important comorbidities (including adverse effects on bone health, sexual health, psychosocial functioning, body composition and metabolic health), and given the well-demonstrated efficacy of treatment of male hypogonadism,[14,15,30,32] it would seem reasonable to presume that similar improvements to health would also result from treatment with TRT in patients with MOSH, although clearly, further studies on the use of TRT in this condition are required to generate the evidence that is required, and on which to base future clinical guidelines for the appropriate and effective management of MOSH.


Male obesity is associated with increased aromatase activity within adipocytes resulting in peripheral conversion of testosterone into oestradiol and a subsequent rise in serum oestradiol levels.[2] Oestradiol in turn exerts a negative feedback effect on LH secretion from the pituitary, modulated by the presence of oestrogen receptors located in the hypothalamo–pituitary unit. Oestradiol therefore suppresses the HPT axis and leads to a reduction in plasma testosterone levels and SH.[35] Severe obesity in men is often associated with a combination of decreased serum levels of testosterone and elevated serum levels of oestradiol. Due to the suppressive effects of oestradiol on the HPT axis, decreased levels of testosterone occur without an appropriate compensatory increase in gonadotrophin secretion, with progressive development of SH.

Hypogonadism in men can itself worsen obesity and promote increased fat mass that in turn may worsen the hypogonadal state. Low testosterone levels leads to a reduction in muscle mass and an increase in the volume of visceral fat.[1,5] The observation that reduced endogenous androgen production promotes central adiposity in men may be explained on the basis of the differential effects of testosterone on fat turnover rates in subcutaneous and visceral adipose tissue. Furthermore, muscle tissue requires the presence of androgens for sustenance and prevention of excessive atrophy.[21] In male hypogonadism, there is a preferential deposition of adipose tissue within abdominal depots. With increasing adipose tissue mass (including that in abdominal depots), there is a further increase in aromatase activity that is associated with an even greater conversion of testosterone to oestradiol (often termed the 'testosterone-oestradiol shunt'). This further decreases testosterone levels that in turn further increases the preferential deposition of fat within abdominal depots: a 'hypogonadal-obesity cycle'.[7] Aromatase inhibitors interrupt this cycle through reducing serum oestradiol levels, thereby releasing the inhibitory effects of oestradiol on the HPT axis and restoring the depressed levels of LH, FSH and testosterone.[36] The increased levels of testosterone reverse the preferential abdominal fat deposition.

The relationship between levels of testosterone and oestradiol and obesity is complex as discussed below.[37–40] Oestradiol levels are increased in mild-to-moderate obesity, but do not show further rise in severely obese men. Free testosterone levels continue to decrease as the severity of obesity worsens, possibly because of androgen sequestration in adipose tissue. A further mechanism that mediates obesity-related effects on the male HPT axis is through leptin. Although normal physiological levels of leptin are required for proper reproductive function in both men and women, obesity is associated with increased levels of leptin.[37] Excessive serum levels of leptin in male obesity may in turn exert a direct negative action on LH/hCG-stimulated testicular androgen production and decrease Leydig cell responsiveness to gonadotrophin stimulation.[5,9,37,41] Increased levels of leptin may therefore play an important role in the pathogenesis of MOSH.

Inflammatory mediators associated with obesity may also contribute to the suppression of the HPT axis and the subsequent development of MOSH.[2] Inflammatory mediators may exert a direct inhibitory effect on the HPT axis, or may contribute to SH through indirect mechanisms such as worsening of insulin resistance at the level of the hypothalamo–pituitary unit, (insulin responsiveness in the brain being important for the maintenance of HPT axis functioning).[42] A further mechanism whereby obesity influences the development of MOSH is through effects on sleep quality. Obesity-associated OSA is known to disrupt the HPT axis, including interference with overnight LH secretion from the pituitary.[20,43]

The effects of the above-mentioned factors on the hypothalamo–pituitary unit may be mediated at least in part through further upstream pathways. The neuropeptide, kisspeptin is thought to be an essential gatekeeper in the control of reproduction.[44] Kisspeptins play a central role in the modulation of GnRH, gonadotrophins and testosterone secretion in men. Inactivating mutations of kisspeptin are associated with hypogonadotrophic hypogonadism. It has been hypothesized that kisspeptin may mediate the effects of obesity on the development of MOSH.[45] There are data that link kisspeptin expression with individual factors known to regulate GnRH secretion and which are also associated with male obesity, including hyperglycaemia, inflammation, leptin and oestrogen. The kisspeptin system may play an important role in integrating a range of metabolic inputs, and may thus be an important link between energy status and the HPT axis.[45] Reduced endogenous kisspeptin release could be a common central pathway mediating obesity-related metabolic factors and MOSH.[45]

Thus, the pathogenesis of MOSH involves complex inter-relationships between key modulators (oestradiol, adipokines and inflammatory mediators) and perhaps other, as yet unknown, mechanisms. It is important that a clearer understanding of MOSH pathogenesis is developed through focused research efforts in this field in the future. A summary of the major known pathogenic pathways based on our current understanding from the existing literature is shown in Fig. 1.

Figure 1.

A complex interplay of factors in the pathogenesis of MOSH.