The Authors' Reply: Oestradiol concentrations are not elevated in obesity-associated hypogonadotrophic hypogonadismWe would like to thank Dhindsa and colleagues for their interest and comments on our recent review article published in Clinical Endocrinology entitled 'The Role of Obesity and Type 2 Diabetes Mellitus in the development of Male Obesity-associated Secondary Hypogonadism'. We would also like to thank the Editor for the opportunity to respond. We would like to confirm that we agree with the useful comments raised and provide further comment below.In our published review, we commented that the mechanisms implicated in the pathogenesis of secondary hypogonadism in men and its association with obesity and type 2 diabetes mellitus are multiple, complex and incompletely understood. We also stated that one of the pathogenic mechanisms implicated in the development of male obesity-associated secondary hypogonadism is increased aromatase activity within adipocytes. This results in increased peripheral conversion of testosterone into oestradiol and subsequent negative feedback on secretion of luteinizing hormone secretion from the pituitary. The suppressive effect of such a mechanism on the male hypothalamo-pituitary-gonadal axis results in a reduction in plasma testosterone levels and secondary hypogonadism. Consistent with this hypothesis, it has been reported in the literature that obese men show increased levels of oestrogens and decreased levels of bioavailable androgens within the serum. 1 It has also been noted that use of aromatase inhibitors in men with obesity-related hypogonadism may normalize serum testosterone, again consistent with an important pathogenic role for aromatization in this condition. 2 However, we acknowledge that there is controversy in the literature regarding the role of aromatization in the pathogenesis of male obesity-associated secondary hypogonadism. There is some inconsistency in the literature regarding relationships between serum levels of testosterone and oestradiol and the severity of obesity in this condition. We acknowledge that in some studies on obese men, serum levels of free oestradiol directly correlate with free testosterone. 3,4 One explanation for this direct correlation is that with increasing obesity in men, as serum levels of testosterone fall (following suppression of the male gonadal axis), serum oestradiol levels would also be expected to fall eventually due to lack of substrate (testosterone) for the aromatase enzyme. This hypothesis has been supported by the European Male Ageing Study. 3,4 We feel that it is important to emphasize that there are many potential mechanisms that underlie the complex pathogenesis of male obesity-associated secondary hypogonadism other than enhanced aromatase activity, as outlined in our published review article. These include the increasingly important roles of leptin, inflammatory mediators (TNF-a, IL-1b, CRP), the role of sleep disruption and the serotoninergic system and endogenous kisspeptin. We also outline the effects o...
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