Part of the Interindividual Variation in Serum Testosterone Levels in Healthy Men Reflects Differences in Androgen Sensitivity and Feedback Set Point: Contribution of the Androgen Receptor Polyglutamine Tract Polymorphism

ObjectiveThe human androgen receptor (AR) contains a polyglutamine and a polyglycine stretch which are highly polymorphic and are coded respectively by a CAG and GGN repeat in exon 1 of the AR gene. Although the in vitro studies indicated a possible effect of the GGN repeat polymorphism on the AR gene transcription and clinical observations suggest that it might modulate the androgen action, its functional significance remains unclear. We wanted to assess whether the GGN repeat affects the serum testosterone levels in healthy men, which is the expected outcome through feedback regulation if it influences androgen action as has been shown to be the case for the CAG repeat.Design and patientsA population based cross-sectional cohort study including 1476 healthy young, middle-aged, and elderly men.MeasurementTestosterone and LH levels were determined by immunoassay; free testosterone (FT) levels were calculated. Genotyping of the GGN repeat was performed using the sequencing technique.ResultsThe GGN repeat number was significantly associated with circulating testosterone and FT levels (P=0.017 and P=0.013 respectively). However, taking into account that age, body mass index, and CAG are already in the regression model, the GGN repeat could explain only a small part of the variation of both testosterone and FT.ConclusionTo our knowledge, this study is the first to demonstrate a significant positive association between the GGN repeat and androgen levels in a large cohort of healthy men. Although the present study thus adds credence to the view that the polyglycine tract in the AR can modulate AR action, this effect appears to be only small so that its clinical relevance remains questionable.

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Mice lacking β-carotene-15,15’-dioxygenase exhibit reduced serum testosterone, prostatic androgen receptor signaling, and prostatic cellular proliferation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00261.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. R1135-R1148 ◽

Cited By ~ 2

Author(s):

Joshua W. Smith ◽

Nikki A. Ford ◽

Jennifer M. Thomas-Ahner ◽

Nancy E. Moran ◽

Eric C. Bolton ◽

...

Keyword(s):

Androgen Receptor ◽

Cellular Proliferation ◽

Serum Testosterone ◽

Cell Number ◽

Immunofluorescent Staining ◽

Receptor Signaling ◽

Ki 67 ◽

Androgen Receptor Signaling ◽

Testosterone Levels ◽

Β Carotene

β-Carotene-15,15’-dioxygenase (BCO1) cleaves dietary carotenoids at the central 15,15’ double bond, most notably acting on β-carotene to yield retinal. However, Bco1 disruption also impacts diverse physiological end points independent of dietary carotenoid feeding, including expression of genes controlling androgen metabolism. Using the Bco1−/− mouse model, we sought to probe the effects of Bco1 disruption on testicular steroidogenesis, prostatic androgen signaling, and prostatic proliferation. Male wild-type (WT) and Bco1−/− mice were raised on carotenoid-free AIN-93G diets before euthanasia between 10 and 14 wk of age. Weights of the prostate and seminal vesicles were significantly lower in Bco1−/− than in WT mice (−18% and −29%, respectively). Serum testosterone levels in Bco1−/− mice were significantly reduced by 73%. Bco1 disruption significantly reduced Leydig cell number and decreased testicular mRNA expression of Hsd17b3, suggesting inhibition of testicular testosterone synthesis. Immunofluorescent staining of the androgen receptor (AR) in the dorsolateral prostate lobes of Bco1−/− mice revealed a decrease in AR nuclear localization. Analysis of prostatic morphology suggested decreases in gland size and secretion. These findings were supported by reduced expression of the proliferation marker Ki-67 in Bco1−/− prostates. Expression analysis of 200 prostate cancer- and androgen-related genes suggested that Bco1 loss significantly disrupted prostatic androgen receptor signaling, cell cycle progression, and proliferation. This is the first demonstration that Bco1 disruption lowers murine circulating testosterone levels and thereby reduces prostatic androgen receptor signaling and prostatic cellular proliferation, further supporting the role of this protein in processes more diverse than carotenoid cleavage.

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