Androgen Receptor Gene CAG Repeat Polymorphism Regulates the Metabolic Effects of Testosterone Replacement Therapy in Male Postsurgical Hypogonadotropic Hypogonadism

Giacomo Tirabassi,Giovanni Corona,Nicola Delli Muti,Mario Maggi,Giancarlo Balercia

doi:10.1155/2013/816740

Abstract

Aim. To evaluate the independent role of androgen receptor (AR) gene CAG repeat polymorphism on metabolic effects of testosterone replacement therapy (TRT) in male postsurgical hypogonadotropic hypogonadism, a condition frequently associated with hypopituitarism and in which the TRT-related metabolic effects are combined with those deriving from concomitant administration of metabolically active pituitary-function replacement therapies. Methods. 15 men affected by postsurgical hypogonadotropic hypogonadism were evaluated before and after TRT. Cardiovascular risk factors (CVRFs), pituitary-dependent hormones, and AR gene CAG repeat polymorphism were considered. Results. Testosterone, insulin-like growth factor 1 (IGF-1), and estradiol were the only hormones, which varied significantly between the two phases. All CVRFs significantly improved after TRT. The number of CAG triplets was positively and significantly correlated with all the variations (Δ-) of CVRFs (except for a significant negative correlation with Δ-high-density lipoprotein); the opposite occurred between the latter and Δ-testosterone. No correlation between Δ-IGF-1 or estradiol and Δ-CVRFs was found. At multiple linear regression, after correction for Δ-testosterone, nearly all the associations between the number of CAG triplets and Δ-CVRFs were confirmed. Conclusions. In male postsurgical hypogonadotropic hypogonadism, shorter AR gene CAG tract length seems to yield greater metabolic improvement after TRT, independently of the effects of concomitant pituitary-function replacement therapies.

Highlights

The androgen receptor (AR) gene is located on X chromosome at q11-q12 and is composed of eight exons [1]
Multiple linear regression analysis was carried out including as dependent variables the Δ-Cardiovascular risk factors (CVRFs) and as covariates both the number of CAG triplets and Δ-testosterone
After adjusting for Δ-testosterone, CAG repeat length was still positively and significantly associated with Δ-weight, Δ-glycemia, ΔHbA1c, Δ-triglycerides, Δ-homeostasis model assessment of insulin resistance (HOMA-IR), Δ-SBP, Δ-diastolic blood pressure (DBP), and negatively with Δ-high-density lipoprotein (HDL) cholesterol (Table 4); positive and almost significant (P = 0.05) association was evident with Δ-Low density lipoprotein (LDL) cholesterol (Table 4)

Summary

Introduction

The androgen receptor (AR) gene is located on X chromosome at q11-q12 and is composed of eight exons [1]. Exon 1 of the AR gene contains a polymorphic sequence of CAG repeat, which varies in number from 10 to 35 [2] and which encodes polyglutamine stretches of AR transactivation domain [3]. Other studies have shown that shorter CAG repeats are associated with prostate cancer [5], benign prostatic hypertrophy [6], prostate increase during androgen treatment [7], improved seminal parameters [8, 9], and improved mineral bone density [10]. Great uncertainty exists in the literature regarding the association between AR gene CAG repeat polymorphism and metabolic profile. While some authors found a connection of the low number of CAG repeats with low high-density lipoprotein (HDL) cholesterol levels [8, 11]

Methods

Results

Discussion

Conclusion