Estrogen-Metabolizing Gene Polymorphisms, But Not Estrogen Receptor-α Gene Polymorphisms, Are Associated with the Onset of Menarche in Healthy Postmenopausal Japanese Women

Abstract

Both onset and cessation of menstruation have strong genetic inclination. We aimed to identify genetic factors influencing the onset of menarche and natural menopause in a Japanese population by investigating the polymorphisms of estrogen receptor-alpha and estrogen-metabolizing enzyme genes. Three hundred seventeen postmenopausal Japanese women, aged 46 yr and over, were enrolled in this study under informed consent. Genomic DNA was extracted from peripheral leukocytes, and PCR-based restriction fragment length polymorphism assays were used to determine estrogen receptor-alpha: PvuII, XbaI, and estrogen-metabolizing enzymes; CYP17, estrogen biosynthesis (high activity, A2/A2, CYP1A1), hydroxylation (high inducibility, vt/vt, and COMT), inactivation (low activity, L/L) genotypes. There were no significant differences in ages at menarche and natural menopause or years of menstruation among each PvuII or XbaI genotype and seven combinations of PvuII and XbaI genotypes. We found that ages at menarche in women with A1/A2 (higher activity of CYP17; 13.6 +/- 1.2 yr) were significantly earlier than in those with A1/A1 (lower activity of CYP17; 14.1 +/- 1.3 yr). There were no significant differences in age at natural menopause and years of menstruation among each CYP17, CYP1A1, or COMT genotype. The small sample size of each combination of estrogen-metabolizing genotypes made it impractical to evaluate the effects of the interdependency of each genotype, including extreme genotype categories such as A2/A2L/Lvt/vt vs. A1/A1H/Hwt/wt genotypes, on ages at menarche and/or natural menopause. The results suggest that the estrogen-metabolizing CYP17 genotype influences age at menarche in healthy postmenopausal Japanese women.

Estrogen‐metabolizing gene polymorphisms in the assessment of breast carcinoma risk and fibroadenoma risk in Caucasian women

“…Individual variability in estradiol metabolism genes (with some dependence on ethnic background) has been characterized as a significant contributor to 3,11,12,20 Furthermore, SNPs of these genes have been evaluated in patients with a variety of conditions, such as early menarche and late menopause, 21 increased mammographic breast density, 22 and elevated plasma estrogen levels, 23 that are associated with an increased breast carcinoma risk.…”

Análise dos genes CYP1A1,CYP1B1 e CYP17 em meninas com puberdade precoce central

“…Para alguns investigadores, o estradiol talvez não fosse consequência do início do processo de puberdade, mas poderia ser também um fator contribuinte no amadurecimento do eixo HHO (Gorai et al, 2003;Moenter et al, 2003;Ronnekleiv et al, 2012 (Ronnekleiv et al, 2010).…”

“…A maioria dos estudos que avalia a influência dos fatores genéticos no determinismo da puberdade precoce correlacionam fatores centrais, relacionados aos neurotransmissores (Ottem et al, 2002;Dungan et al, 2006;Navarro et al, 2007;Freitas et al, 2006). Poucos estudos avaliaram o componente periférico como desencadeante da puberdade precoce Gorai et al, 2003). Portanto, nosso estudo pretendeu aumentar o conhecimento sobre este componente.…”

“…Acredita-se que neste último processo, o estradiol talvez não fosse apenas consequência, mas possivelmente um fator contribuinte no amadurecimento precoce do eixo hipotalâmico-hipofisário-ovariano (Gorai et al, 2003;Moenter et al, 2003;Ronnekleiv et al, 2012). Por esta razão, escolhemos os polimorfismos que poderiam alterar a esteroidogênese e, consequentemente, as concentrações séricas de estrogênio e/ou aumento de metabólitos com maior ação sobre o receptor esteroídico.…”

“…Entretanto, alguns investigadores já avaliaram estes genes em relação à idade da menarca (Gorai et al, 2003;Haiman et al,1999;Mitchell et al, 2008).…”