Abstract
The beneficial effects of metformin, especially its capacity to ameliorate insulin resistance (IR) in polycystic ovary syndrome (PCOS), explains why it is widely prescribed. However, its effect on the offspring of patients with PCOS remains uncertain. This study investigated the impact of metformin treatment on the first- and second-generation female offspring born to letrozole-induced PCOS-IR rats. Forty-five female Wistar rats were implanted with continuous-release letrozole pellets or placebo and treated with metformin or vehicle control. Rats exposed to letrozole showed PCOS-like reproductive, endocrine, and metabolic phenotypes in contrast to the controls. Metformin significantly decreased the risk of body weight gain and increased INSR expression in F1 female offspring in PCOS-IR rats, contributing to the improvement in obesity, hyperinsulinemia, and IR. Decreased FSHR expression and increased LHCGR expression were observed in F1 female rats of the PCOS-IR and PCOS-IR+Metformin groups, suggesting that FSHR and LHCGR dysfunction might promote the development of PCOS. Nevertheless, we found no significant differences in INSR, FSHR, and LHCGR expression or other PCOS phenotypes in F2 female offspring of PCOS-IR rats. These findings indicated widespread reproductive, endocrine, and metabolic changes in the PCOS-IR rat model, but the PCOS phenotypes could not be stably inherited by the next generations. Metformin might have contributed to the improvement in obesity, hyperinsulinemia, and IR in F1 female offspring. The results of this study could be used as a theoretical basis in support of using metformin in the treatment of PCOS-IR patients.
Highlights
Polycystic ovary syndrome (PCOS), a heterogenic disorder, affects 8–13% of reproductive-aged women; it is associated with reproductive and metabolic disorders, including hyperandrogenism, luteinizing hormone (LH) hypersecretion, infertility, polycystic ovaries, and insulin resistance (IR), with an increased risk of cardiovascular disease and type 2 diabetes [1]
This study aimed to investigate the impact of metformin on reproductive alterations and developmental, endocrine, and metabolic characteristics in the first- and second-generation female offspring born to letrozole-induced polycystic ovary syndrome (PCOS)-IR rats
We observed that pregnancy outcomes significantly improved after metformin treatment
Summary
Polycystic ovary syndrome (PCOS), a heterogenic disorder, affects 8–13% of reproductive-aged women; it is associated with reproductive and metabolic disorders, including hyperandrogenism, luteinizing hormone (LH) hypersecretion, infertility, polycystic ovaries, and insulin resistance (IR), with an increased risk of cardiovascular disease and type 2 diabetes [1]. Infertility has dominated clinical research involving PCOS patients, providing substantial evidence for an increased prevalence of pregnancy complications and less favorable pregnancy outcomes in women with PCOS, including preterm delivery, gestational diabetes, and hypertensive disorders [5, 6]. Metabolic dysfunction, comorbidity, and pregnancy complications of women with PCOS are likely to result in a suboptimal intrauterine environment that could have a detrimental impact on the health of infants and prepubertal children and contribute to an increased risk of developing PCOS in female offspring [9, 10]. The underlying pathophysiological mechanisms of pregnancy complications and their association with the offspring’s health remain unclear
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