Alcohol, nicotine and cannabis each reshape PCOS biology in distinct ways, review finds

Polycystic ovary syndrome affects roughly one in ten women of reproductive age, and a new review argues that what those women smoke, drink or consume may meaningfully alter the course of the disorder. The paper, published in Discover Endocrinology and Metabolism, draws on 87 peer-reviewed studies to map how alcohol, nicotine and cannabis intersect with the hormonal machinery of PCOS. Rather than treating substance use as a single risk factor, the authors describe substance-specific pathways that they argue compound the syndrome's core biology of hyperandrogenemia, insulin resistance and disrupted ovulation.

At the same time, the authors cite animal models in which ethanol metabolites increase CYP17A1 enzyme activity in ovarian theca cells, augmenting androgen production independently of gonadotropin stimulation. The review acknowledges that the human and animal data do not align perfectly, and suggests that both hepatic and ovarian mechanisms likely contribute to alcohol-induced androgen excess in PCOS, though their relative importance may depend on drinking patterns and genetic susceptibility.

The review frames this as an argument against the simple binary of drinker versus non-drinker, urging clinicians to quantify consumption patterns instead.

Nicotine tells a different story, one that depends heavily on body phenotype. In lean patients, the authors report, this pathway remains quiescent, apparently because baseline expression of the adrenal CYP17A1 gene is lower.

The nicotine picture is not entirely consistent, however. The review notes that three independent longitudinal studies linked smoking with 2.3-fold increased odds of insulin resistance, yet the multicenter PCOSACT trial found no significant difference in HOMA-IR values between smokers and non-smokers. The authors suggest body composition may modulate nicotine’s metabolic impact, a possibility they say underscores the need for stratified analyses in future work. Smoking-induced oxidative stress, they add, appears to preferentially damage granulosa cells in insulin-resistant phenotypes, where glutathione peroxidase activity is already compromised.

Rodent studies provide complementary mechanistic insights: THC alters the firing frequency of hypothalamic GnRH neurons through cannabinoid receptor type 1 (CB1)-mediated suppression of potassium channels.

Beyond the classical endocrine axes, the authors point to emerging findings: metabolomic analyses associate substance use with altered gut microbiota composition in PCOS patients, and neuroimaging reveals that chronic nicotine and alcohol use alter functional connectivity between the hypothalamus and ovarian autonomic nerve networks in PCOS.

The evidence base carries substantial caveats, and the review is unusually explicit about them. Approximately 85 percent of clinical studies rely on self-reported substance use, and preclinical models frequently employ doses exceeding typical human exposure by five- to tenfold. Temporal ambiguity plagues 89 percent of published studies, which rely on cross-sectional designs, so whether substance use precedes PCOS onset or merely exacerbates existing pathology remains unresolved. Dose-response thresholds for nicotine’s metabolic effects and cannabis’s ovulatory impacts lack consensus. Demographic bias compounds the problem: 78 percent of randomized controlled trials recruited predominantly obese, Western populations, leaving lean women and non-European ethnicities underrepresented. Most animal models, the authors note, fail to recapitulate the heterogeneous PCOS phenotype, focusing narrowly on androgen-exposed rodents whose findings may not translate to human pathophysiology.

What the field most needs, they conclude, are longitudinal designs and controlled interventions that can establish temporal relationships, pin down dose-response thresholds and test the mechanisms the review has mapped. Until then, the substance-PCOS connection remains a set of well-documented associations with plausible biology, rather than proven causal pathways.

Subject of Research: How alcohol, nicotine and cannabis use interact with the hormonal and metabolic biology of polycystic ovary syndrome

Article Title: Impact of substance abuse on polycystic ovarian syndrome

Article References: Ajayi, L. O., Onaolapo, M. C., Akanbi, G. B., Ayodele, A. H., Alabi, M. O., Gbenga, G. O., Akano, O. P., & Ajayi, A. F. (2025). Impact of substance abuse on polycystic ovarian syndrome. Discover Endocrinology and Metabolism, 1(1), Article 10. https://doi.org/10.1007/s44417-025-00004-1

Image Credits: AI Generated

DOI: 10.1007/s44417-025-00004-1

Keywords: polycystic ovary syndrome, PCOS, substance abuse, alcohol, nicotine, cannabis, hyperandrogenism, SHBG, testosterone, insulin resistance, ovulation, systematic review