Association of CYP17, CYP19, CYP1B1 , and COMT Polymorphisms with Serum and Urinary Sex Hormone Concentrations in Postmenopausal Women

Abstract

Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5-untranslated region T3 C), CYP19 [intron 4 (TTTA) n ‫؍‬ 7-13 and a 3-bp deletion (؊3)], CYP1B1 (Val 432 Leu), and COMT (Val 108/158 Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2-and 16␣-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(؊3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P ‫؍‬ 0.01), 23% lower free estradiol (P ‫؍‬ 0.01), and 22% higher sex hormone-binding globulin concentrations (P ‫؍‬ 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P ‫؍‬ 0.003), 18% higher estradiol (P ‫؍‬ 0.02), and 21% higher free estradiol concentrations (P ‫؍‬ 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P ‫؍‬ 0.08) and 31% higher 16␣-hydroxyestrone concentrations (P ‫؍‬ 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.

Associations between the CYP17, CYPIB1, COMT and SHBG polymorphisms and serum sex hormones in post-menopausal breast cancer survivors

“…Our results for CYP17 add to the growing number of studies reporting little or no association for genetic control by this particular SNP and hormone levels [18,19,[30][31][32][33][34][35][36]. Similarly, there is little evidence that circulating hormone levels vary substantially by the CYP1B1 or COMT genotypes [18,19,35,36]; however, the relationship with urinary metabolites of estrogen has been more consistent with higher concentrations observed for the variant genotypes [19,37].…”

“…Similarly, there is little evidence that circulating hormone levels vary substantially by the CYP1B1 or COMT genotypes [18,19,35,36]; however, the relationship with urinary metabolites of estrogen has been more consistent with higher concentrations observed for the variant genotypes [19,37]. One reason for the lack of an observed effect may be due to the limited ability of most previous studies to look at polymorphisms for several genes or SNPs jointly.…”

“…Although several studies have explored the relationship between these polymorphisms and sex hormone levels in healthy women [18,19], little is known about these associations in breast cancer patients. Therefore, this study examined the associations between genetic polymorphisms in the CYP17, COMT, CYP1B1, and SHBG genes with serum levels of total estrone, total estradiol, free estradiol, and estrogen precursor hormones in a cohort of postmenopausal breast cancer patients enrolled in the Health, Eating, Activity and Lifestyle (HEAL) study.…”

Aromatase (CYP19) gene variants influence ovarian response to standard gonadotrophin stimulation

“…On the other hand, PCOS women homozygous for short alleles had higher testosterone/ estradiol ratios, higher testosterone levels and higher LH/FSH ratios compared to women homozygous for long alleles [17], probably due to their reduced aromatase activity. Regarding CYP19(TTTA) 7 allele, significant associations with lower estrone, estrone sulphate and estradiol concentrations have been reported [24,25]. This allele has been also associated with lower sperm concentration and motility in normozoospermic and oligospermic men, due to potential impairment of the aromatase activity [21].…”

Genetic polymorphisms, hormone levels, and hot flashes in midlife women

“…While no studies have directly tested this association, a few studies have shown that polymorphisms in certain genes that encode estrogen synthesis and metabolizing enzymes are associated with altered hormone levels [9][10][11][12][13][14][15]. Specifically, a polymorphism in CYPc17α has been associated with higher estradiol and progesterone levels [9], higher estradiol only in women of low body mass index (BMI) [15], higher estrone levels [14], and higher SHBG levels [13]. A polymorphism in CYP19 (aromatase) has been associated with lower estradiol [10,11] and estrone levels [10].…”