Cigarettes, genetic background, and menopausal timing: the presence of single nucleotide polymorphisms in cytochrome P450 genes is associated with increased risk of natural menopause in European-American smokers.

Natural menopause is a sentinel event in the female life course that marks the cessation of reproductive functioning and impacts the risks of several serious conditions in maturing women. The onset of menopause is considered a marker of overall aging and health that is associated with risks of coronary artery disease, osteoporosis, and all-cause mortality.1–3 The reported typical menopause age of approximately 51 years has been highly reproduced in series across time, both domestically and globally.4–7 Those entering menopause earlier than the age of 45 years experience higher-than-average menopause-related disease risks and mortality.8–10 More than 20 million women in the United States currently smoke—a figure that represents nearly 18% of the adult female population.11 Globally, it is estimated that more than 200 million women are smokers.12 Smoking has repeatedly been identified as a risk factor for earlier time to menopause (TTM), hastening its onset by approximately 1 to 2 years.4–7,13–18 Of the more than 4,000 chemicals found in tobacco smoke, a subset contributes to the development of hypoestrogenism through mechanisms that include oxidative metabolism of estrogens and inhibition of aromatase.19–21 In addition, polyaromatic hydrocarbons (PAHs) are a powerful class of carcinogens in cigarettes that are cytotoxic to both murine and human oocytes in vitro.14,22–26 Many PAHs are protoxins that require bioactivation by enzymes in the cytochrome P450 (CYP) superfamily to exert their toxic effects.27,28 A prevailing theory of reproductive senescence is that women are born with a complete complement of oocytes, which can never be replenished,29 and that chemicals in tobacco that hasten the natural trajectory of oocyte atresia increase the risk of menopause entry and hasten TTM. Factors that enhance the toxicity of these chemicals could increase the risk of menopause further. A comprehensive assessment of potential modifiers of the risk of smoking in relation to menopause timing is currently lacking in the literature. Of great importance is that smoking and menopause have overlapping negative health consequences that could worsen health outcomes in aging women.30 We have recently described that the effects of smoking on the prevalence and severity of hot flashes vary according to the presence of specific single nucleotide polymorphisms (SNPs) in genes responsible for the metabolism of sex steroids and/or the bioactivation of PAHs.31 In the current investigation, we hypothesized that genetic variation in these pathways is associated with further acceleration of onset of menopause in smokers. To test this hypothesis, we examined the risk of menopause in smokers from a population-based cohort of reproductive-age women and evaluated whether the risk of menopause entry in smokers was modified by the presence of relevant gene variants. A candidate gene approach was used to select variants that (1) could potentiate the effects of tobacco-related ovotoxins such as PAHs through mechanisms such as increased bioactivation (CYP1B1 and CYP3A4) and/or (2) had a known association with menopause onset or menopausal symptoms (COMT, CYP1B1, and CYP3A4).32–34