Mechanisms of intergenerational transmission of polycystic ovary syndrome

Abstract

Developmental origins of adult disease (DoHAD) refers to critical gestational ages during human fetal development and beyond when the endocrine metabolic status of the mother can permanently program the physiology and/or morphology of the fetus, modifying its susceptibility to disease after birth. The aim of this review is to address how DoHAD plays an important role in the phenotypic expression of polycystic ovary syndrome (PCOS), the most common endocrinopathy of women characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. Clinical studies of PCOS women are integrated with findings from relevant animal models to show how intergenerational transmission of these central components of PCOS are programmed through an altered maternal endocrine–metabolic environment that adversely affects the female fetus and long-term offspring health. Prenatal testosterone treatment in monkeys and sheep have been particularly crucial in our understanding of developmental programming of PCOS because organ system differentiation in these species, as in humans, occurs during fetal life. These animal models, along with altricial rodents, produce permanent PCOS-like phenotypes variably characterized by LH hypersecretion from reduced steroid-negative feedback, hyperandrogenism, ovulatory dysfunction, increased adiposity, impaired glucose-insulin homeostasis and other metabolic abnormalities. The review concludes that DoHAD underlies the phenotypic expression of PCOS through an altered maternal endocrine–metabolic environment that can induce epigenetic modifications of fetal genetic susceptibility to PCOS after birth. It calls for improved maternal endocrine–metabolic health of PCOS women to lower their risks of pregnancy-related complications and to potentially reduce intergenerational susceptibility to PCOS and its metabolic derangements in offspring.

Transgenerational Inheritance of Reproductive and Metabolic Phenotypes in PCOS Rats

“…In particular, polycystic ovaries can be inherited as an autosomal dominant trait, the transfer of reproductive effects across generations has been termed "intergenerational transfer" (32). It is believed that both genetic and early-life environmental factors in the uterus may contribute to the development of PCOS (33).…”

Role of Anti-Müllerian Hormone in the Pathogenesis of Polycystic Ovary Syndrome

“…Following this discovery, numerous studies confirmed in various animal models that high testosterone levels during gestation could lead to the appearance of a PCOS phenotype in the offspring (mouse, ewe and non-human primate models) [for review see (57,65)]. In women with PCOS, the hypothesis of androgen-related prenatal programming is supported by a whole series of studies [see (17) for review], but the origin of this gestational hyperandrogenism remains unknown so far.…”

“…Besides the primary autocrine role of AMH in the deregulation of GCs of PCO, the recent discovery of the AMH receptor in a significant subset of GnRH neurons suggests possible extragonadal effects of AMH on the hypothalamic-pituitary-gonadal axis ( 16 ) that might be exacerbated in PCOS. Finally, recent data suggest that AMH could be involved in the epigenetic re-programming that is now believed to be the main mechanism leading to PCOS at puberty and adulthood ( 17 ). The goal of this review is also to discuss this exciting issue.…”

Fundamental Concepts and Novel Aspects of Polycystic Ovarian Syndrome: Expert Consensus Resolutions

“…Indeed, specific PCOS-susceptibility loci may explain family predisposition and the variable clinical presentation of PCOS, including neuroendocrine, reproductive, and metabolic abnormalities ( 70 ). On the other hand, maternal–fetal interactions account for early signs of hyperandrogenism in offspring of PCOS carriers, resulting not only from heritability, but also from the intrauterine androgen excess of maternal and/or fetal origin, with the contribution of a dysfunctional placenta ( 71 ). Overexposure to androgens in utero influences the activity of multiple pathways regulating gonadotropin-releasing hormone (GnRH) pulsatility, follicular development, ovarian steroidogenesis, and insulin–glucose homeostasis ( 72 ).…”