Type 2 diabetes (T2D) is an increasingly common condition in female individuals of reproductive age,^1,2 which has resulted in increased use of antidiabetic medication (ADM) during pregnancy.^3,4 In the general nonpregnant population, metformin is often the first-line pharmacological treatment for T2D, and insulin or other second-line noninsulin ADMs, including sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, can be switched to or added to maintain glycemic control if needed.⁵ Notably, the use of second-line noninsulin ADM has increased in the last decade.^6,7

Background: Maternal polycystic ovary syndrome (PCOS) has been proposed as a model for investigating the role of prenatal androgen exposure in the development of neuropsychiatric disorders. However, women with PCOS are at higher risk of developing psychiatric conditions and previous studies are likely confounded by genetic influences.Methods: A Swedish nationwide register-based cohort study was conducted to disentangle the influence of prenatal androgen exposure from familial confounding in the association between maternal PCOS and offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD). PCOS-exposed offspring (n = 21 280) were compared with unrelated PCOS-unexposed offspring (n = 200 816) and PCOS-unexposed cousins (n = 17 295). Associations were estimated with stratified Cox regression models.Results: PCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring. Associations were stronger in girls for ADHD and ASD but not TD/CTD [ADHD: adjusted hazard ratio (aHR) = 1.61 (95% confidence interval (CI) 1.31–1.99), ASD: aHR = 2.02 (95% CI 1.45–2.82)] than boys [ADHD: aHR = 1.37 (95% CI 1.19–1.57), ASD: aHR = 1.46 (95% CI 1.21–1.76)]. For ADHD and ASD, aHRs for girls were stronger when compared with PCOS-unexposed cousins, but slightly attenuated for boys.Conclusions: Estimates were similar when accounting for familial confounding (i.e. genetics and environmental factors shared by cousins) and stronger in girls for ADHD and ASD, potentially indicating a differential influence of prenatal androgen exposure v. genetic factors. These results strengthen evidence for a potential causal influence of prenatal androgen exposure on the development of male-predominant neuropsychiatric disorders in female offspring of women with PCOS.

If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F₀) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F₁) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F₃) in the androgenized lineage. In contrast, following the male germline, F₃ male offspring (mF₃) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F₃ females in the androgenized lineage and eight genes in the obese lineage. In mF₃ male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F₁ and F₂ offspring in the female germline did not develop anxiety-like behavior, while the F₂ male offspring (mF₂) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.