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.

Fig. 1

Schematic of neuroendocrine feedback systems involved in the control of GnRH/LH secretion that are reprogrammed by prenatal T excess. Upper panel: Pattern of secretion of GnRH/LH in control female sheep; lower panel: Pattern of secretion of GnRH/LH in prenatal T-treated female sheep. (1) E₂ negative feedback: GnRH/LH release is under the control of negative feedback action of E₂, which is predominant during the prepubertal and anestrus period. Prenatal T-treatment decreases the sensitivity of the neuroendocrine axis to E₂, resulting in increased LH pulse frequency. (2) E₂ positive feedback: Positive feedback actions of E₂ responsible for generation of the preovulatory GnRH/LH surge and onset of cyclicity. Prenatal T-treated females present delayed and dampened LH surge. (3) P₄ negative feedback: After puberty (right panels), elevated concentrations of P₄ reduce secretion of GnRH/LH pulses preventing ovulation to occur during the luteal phase. Prenatal T-treatment decreases the sensitivity of the neuroendocrine axis to P₄, leading to increased LH pulsatile release. Panels illustrating the hormonal profile in control females have been modified from [46].

Fig. 2

Impact of prenatal exposure to T excess on the reproductive neuroendocrine axis in female sheep. Prenatal T-excess (middle panel) results in impaired steroid feedback mechanisms and increased pituitary responsiveness to GnRH, leading to increased frequency and amplitude of LH pulses (LH hypersecretion). Prenatal intervention with androgen antagonist (left panel) prevents the organizational alterations programmed by T excess during fetal life. Postnatal interventions with androgen antagonist and insulin sensitizer agents (right panel) improve neuroendocrine functions and prevent further deterioration of the reproductive system. These interventions are believed to revert/ameliorate (red X) organizational modifications programmed prenatally by T excess.

Fig. 3

Schematic showing the impact of prenatal T-treatment on the ovary. Prenatal T-treatment causes multifollicular ovarian phenotype by increasing primordial follicular activation/recruitment (A) and follicular arrest/persistence (B). Increased follicular activation may result from increased phosphorylation of FOXO transcription factors, decrease in inhibitory AMH levels, or follicular atresia. Follicular arrest may stem from reduced gonadotropin sensitivity through increased follistatin and AMH, reduced insulin sensitivity due to decreased adiponectin, or lack of follicular atresia. Green lines indicate activation, red lines indicate inhibition, and the thickness of the lines represents the intensity of activation or inhibition. The factors in blue blocks have not been investigated in prenatal T-treated sheep but have been reported in other models of T treatment.

Fig. 4

Self-perpetuating vicious cycle involving the three systems (neuroendocrine, ovarian, and metabolic) and main alterations observed in females exposed to prenatal T excess.