Steroidogenic vs. metabolic programming of reproductive neuroendocrine, ovarian, and metabolic dysfunctions — ASN Events
  1. Schedule
  2. Invited Speaker Abstract
  3. Symposium 4: Developmental programming of the reproductive axis
  4. Steroidogenic vs. metabolic programming of reproductive neuroendocrine, ovarian, and metabolic dysfunctions

Steroidogenic vs. metabolic programming of reproductive neuroendocrine, ovarian, and metabolic dysfunctions (#100)

Vasantha Padmanabhan 1
  1. Professor, Department of Pediatrics, Obstetrics and Gynecology, Molecular and Integrative Physiology, and Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA

Exposure of developing fetus / offspring to abnormal endocrine environment contributes to the development of adult pathologies. Our studies with sheep have found that exposure to excess testosterone during fetal life, in addition to advancing neuroendocrine puberty, results in a polycystic ovary syndrome (PCOS) phenotype characterized by progressive loss of cyclicity, functional hyperandrogenism, polycystic ovarian morphology, LH excess, neuroendocrine feedback defects, enhanced pituitary sensitivity to GnRH, insulin resistance, and hypertension. Importantly, postnatal overfeeding amplified the severity of the reproductive phenotype with majority of the females becoming anovulatory. Comparative studies of prenatal testosterone (aromatizable androgen), prenatal dihydrotestosterone (non-aromatizable androgen), and prenatal testosterone plus flutamide (an androgen antagonist) treated females on reproductive and metabolic outcomes found that at the neuroendocrine level reduced sensitivity to estradiol negative feedback, luteinizing hormone excess, increased pituitary sensitivity to gonadotropin-releasing hormone, and insulin resistance are organized by androgenic programming. In contrast, disruption in estradiol positive feedback appears to be organized by both androgenic and estrogenic pathways former contributing to amplitude and generation of LH surges and the latter timing of the surge.  At the ovarian level increased estradiol release, mulitfollicular ovarian phenotype, and enhanced follicular persistence appear to be programmed via estrogenic actions of prenatal testosterone.  Prenatal intervention with androgen antagonist prevented pubertal advancement and ablation of LH surges although timing and amplitude defects remained the same. In contrast, prenatal intervention with insulin sensitizer prevented development of insulin resistance without preventing reproductive defects. Once PCOS phenotype was established, postnatal intervention with insulin sensitizer improved insulin sensitivity and prevented further deterioration of reproductive axis. These findings are of translational relevance and likely to help target appropriate interventions aimed towards prevention and amelioration of fertility and metabolic dysfunctions.  Supported by NIH P01 HD44232.