A 5 alpha-reductase (SRD5A2) polymorphism is associated with serum testosterone and sex hormone-binding globulin in men, while aromatase (CYP19A1) polymorphisms are associated with oestradiol and luteinizing hormone reciprocally

Bu B. Yeap, Matthew W. Knuiman, David J. Handelsman, Ken K. Y. Ho, Jennie Hui, Mark L. Divitini, Gillian M. Arscot, Brendan McQuillan, Joseph Hung, John P. Beilby

Research output: Contribution to journalArticle

Abstract

Context Pituitary luteinizing hormone (LH) stimulates testicular production of testosterone (T) which is metabolized to dihydrotestosterone (DHT) by 5 alpha-reductase and to oestradiol (E2) by aromatase. How the activity of population variants in these enzymes impacts on gonadal function is unclear. We examined whether polymorphisms in 5 alpha-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations. Design Cross-sectional analysis of 1865 community-dwelling men aged 50.4 +/- 16.8 years. Measurements Early morning sera assayed for T, DHT and E2 (mass spectrometry), and SHBG and LH (immunoassay). Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR. Regression models were adjusted for age and cardiometabolic risk factors. Results SRD5A2 polymorphism rs9282858 GA vs. GG was associated with higher serum T (+1.5 nmol/L, P <0.001) and higher SHBG (+3.3 nmol/L, P = 0.001). CYP19A1 polymorphisms were associated with higher serum E2 and lower LH in reciprocal fashion, from which the two-copy haplotype rs10046 = T/rs2899470 = G/rs11575899 = I/rs700518 = G/rs17703883 = T was associated with higher E2 (63.4 vs. 56.5 pmol/L, P = 0.001) and lower LH (3.9 vs. 4.5 IU/L, P = 0.001) compared to null copies. Conversely, rs10046 = C/rs2899470 = T/rs11575899 = D/rs700518 = A/rs17703883 = C was associated with lower E2 (51.8 vs. 62.0 pmol/L, P = 0.001) and higher LH (5.7 vs. 3.9 IU/L, P <0.001). These haplotypes were associated primarily with differences in E2 in men Conclusions A 5 alpha-reductase polymorphism predicts circulating T and SHBG, while aromatase polymorphisms predict E2 and LH in reciprocal fashion. Age and aromatase polymorphisms interact to affect E2 and LH. How these functional polymorphisms impact on male reproductive and general health outcomes requires further study.

Original languageEnglish
Pages (from-to)301-311
Number of pages11
JournalClinical Endocrinology
Volume90
Issue number2
DOIs
Publication statusPublished - Feb 2019

Cite this

@article{c32f5362a946413eabc4ec5c8a2517fd,
title = "A 5 alpha-reductase (SRD5A2) polymorphism is associated with serum testosterone and sex hormone-binding globulin in men, while aromatase (CYP19A1) polymorphisms are associated with oestradiol and luteinizing hormone reciprocally",
abstract = "Context Pituitary luteinizing hormone (LH) stimulates testicular production of testosterone (T) which is metabolized to dihydrotestosterone (DHT) by 5 alpha-reductase and to oestradiol (E2) by aromatase. How the activity of population variants in these enzymes impacts on gonadal function is unclear. We examined whether polymorphisms in 5 alpha-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations. Design Cross-sectional analysis of 1865 community-dwelling men aged 50.4 +/- 16.8 years. Measurements Early morning sera assayed for T, DHT and E2 (mass spectrometry), and SHBG and LH (immunoassay). Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR. Regression models were adjusted for age and cardiometabolic risk factors. Results SRD5A2 polymorphism rs9282858 GA vs. GG was associated with higher serum T (+1.5 nmol/L, P <0.001) and higher SHBG (+3.3 nmol/L, P = 0.001). CYP19A1 polymorphisms were associated with higher serum E2 and lower LH in reciprocal fashion, from which the two-copy haplotype rs10046 = T/rs2899470 = G/rs11575899 = I/rs700518 = G/rs17703883 = T was associated with higher E2 (63.4 vs. 56.5 pmol/L, P = 0.001) and lower LH (3.9 vs. 4.5 IU/L, P = 0.001) compared to null copies. Conversely, rs10046 = C/rs2899470 = T/rs11575899 = D/rs700518 = A/rs17703883 = C was associated with lower E2 (51.8 vs. 62.0 pmol/L, P = 0.001) and higher LH (5.7 vs. 3.9 IU/L, P <0.001). These haplotypes were associated primarily with differences in E2 in men Conclusions A 5 alpha-reductase polymorphism predicts circulating T and SHBG, while aromatase polymorphisms predict E2 and LH in reciprocal fashion. Age and aromatase polymorphisms interact to affect E2 and LH. How these functional polymorphisms impact on male reproductive and general health outcomes requires further study.",
keywords = "5 alpha-reductase, aromatase, dihydrotestosterone, luteinizing hormone, oestradiol, sex hormone-binding globulin, testosterone, GENOME-WIDE ASSOCIATION, GONADOTROPIN-SECRETION, ANDROGEN CONCENTRATIONS, GENETIC-VARIATIONS, STEROID CONTROL, ESTROGEN-LEVELS, DIHYDROTESTOSTERONE, AROMATIZATION, PHENOTYPE, VARIANTS",
author = "Yeap, {Bu B.} and Knuiman, {Matthew W.} and Handelsman, {David J.} and Ho, {Ken K. Y.} and Jennie Hui and Divitini, {Mark L.} and Arscot, {Gillian M.} and Brendan McQuillan and Joseph Hung and Beilby, {John P.}",
year = "2019",
month = "2",
doi = "10.1111/cen.13885",
language = "English",
volume = "90",
pages = "301--311",
journal = "Clinical Endocrinology",
issn = "0300-0664",
publisher = "John Wiley & Sons",
number = "2",

}

TY - JOUR

T1 - A 5 alpha-reductase (SRD5A2) polymorphism is associated with serum testosterone and sex hormone-binding globulin in men, while aromatase (CYP19A1) polymorphisms are associated with oestradiol and luteinizing hormone reciprocally

AU - Yeap, Bu B.

AU - Knuiman, Matthew W.

AU - Handelsman, David J.

AU - Ho, Ken K. Y.

AU - Hui, Jennie

AU - Divitini, Mark L.

AU - Arscot, Gillian M.

AU - McQuillan, Brendan

AU - Hung, Joseph

AU - Beilby, John P.

PY - 2019/2

Y1 - 2019/2

N2 - Context Pituitary luteinizing hormone (LH) stimulates testicular production of testosterone (T) which is metabolized to dihydrotestosterone (DHT) by 5 alpha-reductase and to oestradiol (E2) by aromatase. How the activity of population variants in these enzymes impacts on gonadal function is unclear. We examined whether polymorphisms in 5 alpha-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations. Design Cross-sectional analysis of 1865 community-dwelling men aged 50.4 +/- 16.8 years. Measurements Early morning sera assayed for T, DHT and E2 (mass spectrometry), and SHBG and LH (immunoassay). Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR. Regression models were adjusted for age and cardiometabolic risk factors. Results SRD5A2 polymorphism rs9282858 GA vs. GG was associated with higher serum T (+1.5 nmol/L, P <0.001) and higher SHBG (+3.3 nmol/L, P = 0.001). CYP19A1 polymorphisms were associated with higher serum E2 and lower LH in reciprocal fashion, from which the two-copy haplotype rs10046 = T/rs2899470 = G/rs11575899 = I/rs700518 = G/rs17703883 = T was associated with higher E2 (63.4 vs. 56.5 pmol/L, P = 0.001) and lower LH (3.9 vs. 4.5 IU/L, P = 0.001) compared to null copies. Conversely, rs10046 = C/rs2899470 = T/rs11575899 = D/rs700518 = A/rs17703883 = C was associated with lower E2 (51.8 vs. 62.0 pmol/L, P = 0.001) and higher LH (5.7 vs. 3.9 IU/L, P <0.001). These haplotypes were associated primarily with differences in E2 in men Conclusions A 5 alpha-reductase polymorphism predicts circulating T and SHBG, while aromatase polymorphisms predict E2 and LH in reciprocal fashion. Age and aromatase polymorphisms interact to affect E2 and LH. How these functional polymorphisms impact on male reproductive and general health outcomes requires further study.

AB - Context Pituitary luteinizing hormone (LH) stimulates testicular production of testosterone (T) which is metabolized to dihydrotestosterone (DHT) by 5 alpha-reductase and to oestradiol (E2) by aromatase. How the activity of population variants in these enzymes impacts on gonadal function is unclear. We examined whether polymorphisms in 5 alpha-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations. Design Cross-sectional analysis of 1865 community-dwelling men aged 50.4 +/- 16.8 years. Measurements Early morning sera assayed for T, DHT and E2 (mass spectrometry), and SHBG and LH (immunoassay). Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR. Regression models were adjusted for age and cardiometabolic risk factors. Results SRD5A2 polymorphism rs9282858 GA vs. GG was associated with higher serum T (+1.5 nmol/L, P <0.001) and higher SHBG (+3.3 nmol/L, P = 0.001). CYP19A1 polymorphisms were associated with higher serum E2 and lower LH in reciprocal fashion, from which the two-copy haplotype rs10046 = T/rs2899470 = G/rs11575899 = I/rs700518 = G/rs17703883 = T was associated with higher E2 (63.4 vs. 56.5 pmol/L, P = 0.001) and lower LH (3.9 vs. 4.5 IU/L, P = 0.001) compared to null copies. Conversely, rs10046 = C/rs2899470 = T/rs11575899 = D/rs700518 = A/rs17703883 = C was associated with lower E2 (51.8 vs. 62.0 pmol/L, P = 0.001) and higher LH (5.7 vs. 3.9 IU/L, P <0.001). These haplotypes were associated primarily with differences in E2 in men Conclusions A 5 alpha-reductase polymorphism predicts circulating T and SHBG, while aromatase polymorphisms predict E2 and LH in reciprocal fashion. Age and aromatase polymorphisms interact to affect E2 and LH. How these functional polymorphisms impact on male reproductive and general health outcomes requires further study.

KW - 5 alpha-reductase

KW - aromatase

KW - dihydrotestosterone

KW - luteinizing hormone

KW - oestradiol

KW - sex hormone-binding globulin

KW - testosterone

KW - GENOME-WIDE ASSOCIATION

KW - GONADOTROPIN-SECRETION

KW - ANDROGEN CONCENTRATIONS

KW - GENETIC-VARIATIONS

KW - STEROID CONTROL

KW - ESTROGEN-LEVELS

KW - DIHYDROTESTOSTERONE

KW - AROMATIZATION

KW - PHENOTYPE

KW - VARIANTS

U2 - 10.1111/cen.13885

DO - 10.1111/cen.13885

M3 - Article

VL - 90

SP - 301

EP - 311

JO - Clinical Endocrinology

JF - Clinical Endocrinology

SN - 0300-0664

IS - 2

ER -