Demographic, physical and lifestyle factors associated with androgen status: the Florey Adelaide Male Ageing Study (FAMAS)

Atlantis, Evan; Martin, Sean; Haren, Matthew T.; O’Loughlin, Peter; Taylor, Anne; Anand‐Ivell, Ravinder; Ivell, Richard; Wittert, Gary

doi:10.1111/j.1365-2265.2008.03463.x

Cited by 44 publications

(41 citation statements)

References 62 publications

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“…Despite these important physiological roles and the identification of INSL3 as a unique marker of Leydig cells, very little is known about the molecular mechanisms that regulate Insl3 expression in these cells. INSL3 is constitutively expressed in Leydig cells and, unlike testicular steroids, it is regulated independently of the hypothalamo-pituitary-gonadal axis (Anand-Ivell et al 2006, Atlantis et al 2009, Ivell & Anand-Ivell 2009). This absence of direct hormonal regulation was also reported in studies of the rat and mice Insl3 gene promoter (Zimmermann et al 1998, Koskimies et al 2002.…”

Section: Discussionmentioning

confidence: 99%

The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

Mendoza-Villarroel¹,

Di-Luoffo²,

Camiré³

et al. 2014

Journal of Molecular Endocrinology

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Insulin-like 3 (INSL3), a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults. Despite its importance, little is known about the molecular mechanisms controlling INSL3 expression. Reduced Insl3 mRNA levels were reported in the testis of mice deficient for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), an orphan nuclear receptor known to play critical roles in cell differentiation and lineage determination in several tissues. Although COUP-TFII-deficient mice had Leydig cell dysfunction and impaired fertility, it remained unknown whether Insl3 expression was directly regulated by COUP-TFII. In this study, we observed a significant decrease in Insl3 mRNA levels in MA-10 Leydig cells depleted of COUP-TFII. Furthermore, a K1087 bp mouse Insl3 promoter was activated fourfold by COUP-TFII in MA-10 Leydig cells. Using 5 0 progressive deletions, the COUP-TFII-responsive element was located between K186 and K79 bp, a region containing previously uncharacterised direct repeat 0-like (DR0-like) and DR3 elements. The recruitment and direct binding of COUP-TFII to the DR0-like element were confirmed by chromatin immunoprecipitation and DNA precipitation assay respectively. Mutation of the DR0-like element, which prevented COUP-TFII binding, significantly decreased COUP-TFII-mediated activation of the K1087 bp Insl3 reporter in CV-1 fibroblast cells but not in MA-10 Leydig cells. Finally, we found that COUP-TFII cooperates with the nuclear receptor steroidogenic factor 1 (SF1) to further enhance Insl3 promoter activity. Our results identify Insl3 as a target for COUP-TFII in Leydig cells and revealed that COUP-TFII acts through protein-protein interactions with other DNA-bound transcription factors, including SF1, to activate Insl3 transcription in these cells.

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Section: Discussionmentioning

confidence: 99%

The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

Mendoza-Villarroel¹,

Di-Luoffo²,

Camiré³

et al. 2014

Journal of Molecular Endocrinology

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“…This in part because there is a complex relationship between metabolic disorders and circulating androgens in men (Atlantis et al 2009, Mah & Wittert 2010, Araujo & Wittert 2011, Grossmann 2011, both of which may affect prostate biology in different ways. Moreover, the role of androgen deprivation therapy (ADT) for PCa continues to evolve, with both efficacy and side effects of this treatment coming into sharper focus.…”

Section: Introductionmentioning

confidence: 99%

Androgens, diabetes and prostate cancer

Grossmann¹,

Wittert²

2012

Endocrine-Related Cancer

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Metabolic disorders such as diabetes, obesity and the metabolic syndrome have been shown to modulate prostate cancer (PCa) risk and aggressiveness in population-based and experimental studies. While associations between these conditions are modest and complex, two consistent findings have emerged. First, there is observational evidence that obesity and associated insulin excess are linked to increased PCa aggressiveness and worse outcomes. Secondly and somewhat paradoxically, long-standing diabetes may be protective against PCa development. This apparent paradox may be due to the fact that long-standing diabetes is associated with insulin depletion and decreased IGF1 signalling. Men with obesity or diabetes have moderate reductions in their androgen levels. The interconnectedness of metabolic and androgen status complicates the dissection of the individual roles of these factors in PCa development and progression. Metabolic factors and androgens may promote prostate carcinogenesis via multiple mechanisms including inflammation, adipokine action, fatty acid metabolism and IGF signalling. Moreover, androgen deprivation, given to men with PCa, has adverse metabolic consequences that need to be taken into account when estimating the risk benefit ratio of this therapy. In this review, we will discuss the current epidemiological and mechanistic evidence regarding the interactions between metabolic conditions, sex steroids and PCa risk and management.

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“…55 However, and possibly most important, it remains unclear whether age is actually an independent predictor of a lower TT, as after adjusting for comorbidities no relationship of age with TT was found in either the European Male Ageing Study 13 or the Florey Adelaide Male Ageing Study. 33 Including SHBG in the multivariate analysis of TT provided additional insight into the relationship of age with TT as age became a significant predictor of a lower TT after adjusting for SHBG and also remained significant with the inclusion of either BMI, WC or WHt ratio with SHBG in the model. This suggests that the lack of relationship of TT with age on univariate analysis is in part due to the confounding effect of the positive relationship of age with SHBG.…”

Section: Discussionmentioning

confidence: 99%

“…32 We also excluded men who were current smokers as this is associated with increases in TT, SHBG and LH, [11][12][13]29,33,34 as well as being associated with lower whole body and abdominal percentage fat mass. 35 Furthermore, by excluding men with severe obesity, which can result in hypogonadotropic hypogonadism, [16][17][18] we were able to reduce the chance that suppression of LH was also contributing to a reduction in testosterone levels in men with increased adiposity.…”

Section: Discussionmentioning

confidence: 99%

Waist-to-height ratio as a predictor of serum testosterone in ageing men with symptoms of androgen deficiency

Allan¹,

Peverill²,

Strauss³

et al. 2011

Asian J Androl

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The decline in serum testosterone in ageing men may be mediated in part by obesity; however, it is uncertain which measure of adiposity is most closely associated with testosterone levels. We have examined the relationships of age, adiposity and testosterone levels in ageing men with symptoms consistent with hypoandrogenism but who were otherwise in good health. We conducted a cross-sectional study of non-smoking men aged o54 years recruited from the community and who were free of cancer or serious medical illness. Height (Ht), weight and waist circumference (WC) were measured, and body mass index (BMI) and waist-to-height (WHt) ratio were calculated. Two morning blood samples were collected for measurement of total testosterone (TT), sex hormone binding globulin (SHBG) and luteinizing hormone (LH). Free testosterone (cFT) was calculated. Multivariate linear regression analysis was performed to assess their relationship with measures of adiposity. Two hundred and seven men aged 54-86 years were studied. On univariate analysis WHt ratio was more strongly correlated with TT and cFT than either WC or BMI. Furthermore, in models of TT and cFT, the addition of Ht to WC resulted in an increase in the magnitude of the regression coefficients for both WC (inverse correlate) and Ht (positive correlate), with the contributions of both WC and Ht both being significant (P,0.05 for all). In conclusion, WHt ratio is the best anthropometric predictor of both TT and cFT in this group of healthy but symptomatic ageing men.

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Demographic, physical and lifestyle factors associated with androgen status: the Florey Adelaide Male Ageing Study (FAMAS)

Cited by 44 publications

References 62 publications

The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells

Androgens, diabetes and prostate cancer

Waist-to-height ratio as a predictor of serum testosterone in ageing men with symptoms of androgen deficiency

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