PCOS-like phenotype in rats after intrauterine EV exposure: puberty and adulthood

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting female fertility. It has been hypothesized that PCOS has its origins during intrauterine life, where prenatal exposure to endocrine-disrupting environments during critical developmental windows induces developmental disruptions, leading to long-term reproductive dysfunction. While prenatal androgen exposure is a well-established factor, the role of estrogenic imbalance remains critical, yet less analyzed. Estradiol valerate (EV) is widely used to induce PCOS-like phenotypes; however, its potential role in disrupting early development and altering postnatal reproductive function remains unknown. This study evaluated whether prenatal exposure to EV results in PCOS-like reproductive alterations that manifest at puberty or adulthood in rats. For this purpose, gravid rats were subcutaneously injected with EV or sesame oil (Vh) on gestational day 18. Offspring were euthanized at puberty or adult stage, in estrus. Compared with the Vh group, EV-exposed offspring exhibited early-onset reproductive disruptions during puberty, including precocious vaginal opening, estrous acyclicity, low testosterone levels, and a decreased ovulatory response accompanied by precyst formation. In adult life, these alterations had progressed into a PCOS-like phenotype, characterized by body weight gain, increased testosterone levels, acyclicity, anovulation, and the presence of follicular cysts. These findings indicate that prenatal exposure to EV is sufficient to induce a progressive reproductive phenotype that resembles PCOS in adulthood.