Merlin G Butler1, Ann M Manzardo. 1. Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 4015, Kansas City, KS, 66160, USA, mbutler4@kumc.edu.
Abstract
PURPOSE: Total body mass impacts reproductive health and infertility which has increased in the United States with rising rates of obesity. Overlapping genetic and environmental factors contribute to obesity and infertility including the androgen receptor (AR), a steroid hormone-activated transcription factor that is key in regulating androgen activity and sensitivity to sex hormones, weight and body composition in both males and females. The AR gene which is X-linked contains a polymorphic CAG trinucleotide repeat which varies in length and inversely correlated with gene expression. METHODS: We examined the AR gene CAG repeat length and measures of weight and body mass index (BMI) in 27 non-syndromic obese and 33 lean controls and for the first time compared with 28 individuals with Prader-Willi syndrome (PWS), a rare obesity-related genetic disorder with natural sex hormone deficits to examine the effects of AR gene CAG repeat length on androgen-mediated response and obesity-related factors relevant to human infertility and reproduction. RESULTS: Mean CAG repeat length in base pairs (278 ± 7.9) did not significantly differ by subject group (F = 2.6, p = 0.08) but was strongly positively correlated with height standard deviation (SD) among males (r = 0.31, p < 0.05), mainly lean and obese, but not PWS (r = 0.02, p = 0.94). A negative correlation was observed for weight SD among females (r = -0.29, p < 0.04) when grouped together. CONCLUSIONS: The results were consistent with an androgen-mediated effect on height and weight negligible in PWS and supporting the role of sex hormones and AR gene interaction in obesity and infertility, both cardinal features of PWS. CAG repeat length of the AR gene is a marker for increased androgen sensitivity with shorter lengths predicting smaller stature in non-PWS adult males possibly due to accelerating fusion of bone growth plates and reducing the growth phase. Increased androgen effects from shorter CAG repeat lengths in non-PWS females could impact pregnancy-related weight gain and pregnancy outcomes.
PURPOSE: Total body mass impacts reproductive health and infertility which has increased in the United States with rising rates of obesity. Overlapping genetic and environmental factors contribute to obesity and infertility including the androgen receptor (AR), a steroid hormone-activated transcription factor that is key in regulating androgen activity and sensitivity to sex hormones, weight and body composition in both males and females. The AR gene which is X-linked contains a polymorphic CAG trinucleotide repeat which varies in length and inversely correlated with gene expression. METHODS: We examined the AR gene CAG repeat length and measures of weight and body mass index (BMI) in 27 non-syndromic obese and 33 lean controls and for the first time compared with 28 individuals with Prader-Willi syndrome (PWS), a rare obesity-related genetic disorder with natural sex hormone deficits to examine the effects of AR gene CAG repeat length on androgen-mediated response and obesity-related factors relevant to humaninfertility and reproduction. RESULTS: Mean CAG repeat length in base pairs (278 ± 7.9) did not significantly differ by subject group (F = 2.6, p = 0.08) but was strongly positively correlated with height standard deviation (SD) among males (r = 0.31, p < 0.05), mainly lean and obese, but not PWS (r = 0.02, p = 0.94). A negative correlation was observed for weight SD among females (r = -0.29, p < 0.04) when grouped together. CONCLUSIONS: The results were consistent with an androgen-mediated effect on height and weight negligible in PWS and supporting the role of sex hormones and AR gene interaction in obesity and infertility, both cardinal features of PWS. CAG repeat length of the AR gene is a marker for increased androgen sensitivity with shorter lengths predicting smaller stature in non-PWS adult males possibly due to accelerating fusion of bone growth plates and reducing the growth phase. Increased androgen effects from shorter CAG repeat lengths in non-PWS females could impact pregnancy-related weight gain and pregnancy outcomes.
Authors: Merlin G Butler; Mariana F Theodoro; Douglas C Bittel; Paul J Kuipers; Daniel J Driscoll; Zohreh Talebizadeh Journal: Am J Med Genet A Date: 2007-03-01 Impact factor: 2.802
Authors: Cynthia L Ogden; Margaret D Carroll; Lester R Curtin; Margaret A McDowell; Carolyn J Tabak; Katherine M Flegal Journal: JAMA Date: 2006-04-05 Impact factor: 56.272
Authors: Paul G Voorhoeve; Willem van Mechelen; André G Uitterlinden; Henriette A Delemarre-van de Waal; Steven W J Lamberts Journal: Clin Endocrinol (Oxf) Date: 2011-06 Impact factor: 3.478