Abstract
Objective:Onset and symptoms of menopause, and response to hormone therapy (HT) show large interindividual variability. SULT1A1 encodes for a highly expressed enzyme that metabolizes estrogens. We evaluated the relationship between genetic variation in SULT1A1, menopause age, symptoms, and response to HT.Methods:Women enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic were randomized to 48 months of treatment with oral conjugated equine estrogen (n = 34), transdermal 17β-estradiol (E2) (n = 33), or placebo (n = 35). Linear regression models and ANOVA were used to test for association of SULT1A1 copy number, rs3760091, rs750155, and rs9282861 (SULT1A1∗2), with age at menopause and symptoms, levels of estrogens (estrone [E1], estrone sulfate [E1S], E2, and estradiol sulfate [E2S]), before and after HT.Results:SULT1A1 gene copy number affected the minor allele frequency for each single nucleotide polymorphisms tested. Before administration of exogenous hormones, increasing number of G alleles at rs9282861 was associated with earlier age at menopause (P = 0.014), lower frequency of night sweats (P = 0.009), and less severe insomnia (P = 0.046). After 48 months of treatment, SULT1A1 genotype was not associated with the presence of menopausal symptoms. In women randomized to oral conjugated equine estrogen, increasing number of the A allele at rs750155 was associated with lower E1S and E2S (P = 0.004 and 0.017), whereas increasing number of the C allele at rs3760091 was associated with lower E2S/E2 (P = 0.044).Conclusions:Interindividual variability in onset of menopause and symptoms before initiation of HT is explained in part by genetic variation in SULT1A1 and may represent a step toward individualizing HT treatment decisions.
Highlights
Interindividual variability in onset of menopause and symptoms before initiation of hormone therapy (HT) is explained in part by genetic variation in SULT1A1 and may represent a step toward individualizing HT treatment decisions
The onset of menopause, symptom severity, and the response to menopausal hormone therapy (HT) vary among women. This variation is thought to be multifactorial involving gene-environment interactions, with the heritability estimates of age at menopause ranging from 31% to 78%
As estrogen production by the ovaries decreases, circulating estrogen levels drop by approximately 90% and the conversion of androgens to estrogens by aromatase in the adipose tissue and skin becomes the predominant source of endogenous estrogens
Summary
Women enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic were randomized to 48 months of treatment with oral conjugated equine estrogen (n 1⁄4 34), transdermal 17b-estradiol (E2) (n 1⁄4 33), or placebo (n 1⁄4 35). The participants were randomized to 48 months on one of three treatments: oral conjugated equine estrogen (oCEE; 0.425 mg/d), transdermal 17b-estradiol (tE2; 50 mg/d), both with micronized progesterone (200 mg/d for the first 12 d of the month) or placebo pills and patch.[13] Menopausal symptoms, including night sweats, hot flashes, insomnia, and palpitations, were scored at baseline before administration of exogenous hormones and at the end of the 48-month treatment period and recorded on a scale of 0 to 5 (with 0 being no symptom and 5 being severe).
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