Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions

Abstract

The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. Human fetuses are at risk of abnormal programming via exposure to endocrine disrupting chemicals, inadvertent use of contraceptive pills during pregnancy, as well as from excess exposure to steroids due to disease states. Animal models provide an unparalleled resource to understand the developmental origin of diseases. In female sheep, prenatal exposure to testosterone excess results in an array of adult reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone, luteinizing hormone excess, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure. Prenatal testosterone treatment also leads to fetal growth retardation, insulin resistance, and hypertension. Mounting evidence suggests that developmental exposure to an improper steroidal/metabolic environment may mediate the programming of adult disorders in prenatal testosterone-treated females, and these defects are maintained or amplified by the postnatal sex steroid and metabolic milieu. This review addresses the steroidal and metabolic contributions to the development and maintenance of the PCOS phenotype in the prenatal testosterone-treated sheep model, including the effects of prenatal and postnatal treatment with an androgen antagonist or insulin sensitizer as potential strategies to prevent/ameliorate these dysfunctions. Insights obtained from these intervention strategies on the mechanisms underlying these defects are likely to have translational relevance to human PCOS.

Effect of maternal PCOS and PCOS-like phenotype on the offspring's health

“…Particularly in female sheep, prenatal exposure to testosterone results in an array of adult reproductive disorders that include disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) hypersecretion, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure (Padmanabhan and Veiga-Lopez, 2013b). Additionally, prenatal testosterone treatment leads to fetal growth retardation, insulin resistance, and hypertension in the female sheep (Padmanabhan et al, 2006, Cardoso et al, 2015). The adult phenotype of many of these animal models meets the established guidelines for diagnosis of PCOS and therefore can aid in understanding early developmental events associated with this syndrome.…”

Translational Insight Into Polycystic Ovary Syndrome (PCOS) From Female Monkeys with PCOS-like Traits

“…Each, however, accounts for only a small percentage of the estimated 70% heritability of PCOS, implying a considerable epigenetic contribution to the phenotypic expression of PCOS [9, 10]. The most comprehensive epigenetic phenotypes that mimic PCOS arise from animal models that employ experimentally-induced fetal testosterone(T) excess to permanently induce (‘program’) PCOS-like reproductive and metabolic traits in female rodents [11–13], sheep [14, 15] and nonhuman primates(NHPs) [16, 17]. The absence of a naturally occurring PCOS animal model, however, has hindered progress towards understanding pathogenic mechanisms that may bestow both genetic and epigenetic contributions to the etiology of PCOS.…”

An updated view of hypothalamic–vascular–pituitary unit function and plasticity

“…For example, polycystic ovarian syndrome (PCOS), the most common anovulatory cause of infertility 71 affecting >100 million women worldwide, is associated with a dysregulation of the normal pattern of LH secretion 72 . Whether the origin of this multi-factorial disorder is at the level of the hypothalamic-pituitary axis is unknown 73 , but PCOS is characterized by increases in GnRH pulse frequency and sensitivity of the pituitary gland to the neurohormone 74,75 . Consequently, potential interventions that modify the dynamics of GnRH output, its transport to the ME or its 79 .…”