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

Abstract and Introduction

Abstract

Obesity, secondary (hypogonadotrophic) hypogonadism (SH), sleep disorders [such as obstructive sleep apnoea (OSA)] and type 2 diabetes mellitus (T2DM) in men have complex interlinks both with respect to mutual aetiopathogenesis as well as therapeutics. Correction of the attendant hypogonadism in obese men may serve to break this link and have beneficial effects beyond restoration of normal sexual function. Male obesity-associated secondary hypogonadism (MOSH) should be regarded as a distinct clinical entity and subtype of SH. A high index of suspicion for the presence of MOSH must be maintained by clinicians when assessing obese men. The pathogenesis of MOSH remains incompletely understood. Furthermore, the optimal management of MOSH and its associated sequelae will require long-term prospective studies that in turn will inform the development of future clinical guidelines for this important and prevalent condition.

Introduction

It has been widely recognized that complex interlinks exist between body composition, androgen levels, obesity, secondary (hypogonadotrophic) hypogonadism (SH), vascular disease, sleep disorders [such as obstructive sleep apnoea (OSA)] and type 2 diabetes mellitus (T2DM) in men.[1–5] This is with respect to mutual aetiopathogenesis as well as treatment. It is also well recognized that male SH is associated with cardiovascular (CV) and cerebrovascular diseases like coronary artery disease and ischaemic stroke, presumably through its association with cardio-metabolic risk factors.[1–8] The prevalence of SH in obese men has been noted in several studies.[2,5,6]

Several diseases may produce secondary hypogonadism in obese men. However, even in the absence of organic disease of the hypothalamo–pituitary unit, obesity itself is a known cause of male SH.[1,5,7] This particular subtype of SH occurring in obese men, where obesity-related mechanisms play the central role in the development of the SH, is discussed as a distinct clinical entity in this review. The diagnosis of this male obesity-associated SH (henceforth abbreviated as MOSH) should be preceded by the exclusion of other hypothalamo–pituitary lesions and primary hypogonadism. The pathogenesis, clinico-pathological correlates and optimal management of MOSH are incompletely understood on the basis of the current literature. Owing to demographic trends towards greater longevity and an increasing prevalence of T2DM and obesity, it is likely that this distinct variety of SH in obese men will become even more prevalent within our population in the future. However, MOSH is a health concern that is often underdiagnosed and under-recognized. Clinical features, as those of SH due to other causes, include sexual dysfunction (erectile dysfunction and poor libido), osteopenia and osteoporosis, reduced feelings of well-being, fatigue, impaired mood and concentration, sarcopaenia, increased fat mass and dyslipidaemia.[1] Keeping the above in mind, MOSH may be clinically defined as obesity-induced symptomatic secondary hypogonadism in men, in whom other causes of hypogonadism have been excluded. This is notwithstanding the fact that several obese men may not present with the typical symptoms and signs related to hypogonadism, especially in the initial stages.

Of particular interest are the pathogenetic and therapeutic links between male SH, obesity and obesity-related conditions such as T2DM and the metabolic syndrome.[2] The mechanisms implicated in the association of male SH with obesity, T2DM and cardio-metabolic features are complex.[5] Although the pathogenesis of MOSH and its optimal management with testosterone replacement therapy (TRT) remain incompletely understood, the current literature has provided some important insights outlined below:

  • Male obesity per se is associated with lower plasma testosterone levels.[6] There is also an independent association between plasma testosterone concentration and insulin sensitivity in men.[7,8] Obese men with T2DM appear to be at particularly high risk of developing SH.[9,10]

  • The effects of TRT on the CV system and long-term CV morbidity and outcomes are unclear.[11–13] This is notwithstanding the fact that TRT has been shown to have beneficial effects on glycaemic control, markers of metabolic syndrome and inflammation, total and LDL-cholesterol, lipoprotein a (Lpa) and sexual health in hypogonadal men with T2DM and/or metabolic syndrome.[14,15] In nondiabetic men, there is an inverse relationship between testosterone levels and HbA1C.[16] The value of TRT in obese men without any of the other components of metabolic syndrome needs more investigation.

  • Inflammation is an important link between obesity and T2DM. Although low levels of plasma testosterone in men are associated with a proinflammatory profile, the causality of this association and the effect of short-term TRT is not clear.[17–19]

Thus, there are several implications for the study of MOSH. If MOSH remains clinically unrecognized, this can subsequently lead to significant morbidity including osteopenia, metabolic problems, CV events and sleep problems.[2,20,21] Therefore, it is important that MOSH is identified early through effective screening programmes, and that MOSH is managed appropriately with TRT and weight reduction. In the current literature, there are no reported studies comparing TRT vs weight reduction in patients with MOSH. Weight reduction in patients with MOSH is recommended, as is the case in the management of obese patients generally. However, encouragement of weight reduction alone (without TRT) cannot be endorsed and recommended as an effective treatment for MOSH and its associated sequelae unless clear evidence is produced to demonstrate this. There is clearly a real need for increased awareness of MOSH amongst healthcare professionals.[6,9,22,23]

An up-to-date literature search was conducted by extensive review of different randomized controlled trials, reviews and multicentre studies on MOSH using keywords like Obesity, Male Secondary Hypogonadism, Diabetes, Sleep etc. Search engines, websites and databases such as Pubmed, Google, Cochrane database and The University of Warwick Libraries were used for the literature search. Although a comprehensive overview of male SH is beyond the scope of this article, this review will focus on MOSH as a clinically distinct subtype of male SH. Following a brief outline of the physiology of the male gonadal axis and pathogenesis of male SH, we discuss the prevalence of MOSH and the complex inter-relationships between MOSH, obesity and obesity-related conditions such as T2DM and sleep disorders.

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