Sheep models of polycystic ovary syndrome phenotype

Abstract

Polycystic ovary syndrome (PCOS) is a fertility disorder affecting 5-7% of reproductive-aged women. Women with PCOS manifest both reproductive and metabolic defects. Several animal models have evolved, which implicate excess steroid exposure during fetal life in the development of the PCOS phenotype. This review addresses the fetal and adult reproductive and metabolic consequences of prenatal steroid excess in sheep and the translational relevance of these findings to PCOS. By comparing findings in various breeds of sheep, the review targets the role of genetic susceptibility to fetal insults. Disruptions induced by prenatal testosterone excess are evident at both the reproductive and metabolic level with each influencing the other thus creating a self-perpetuating vicious cycle. The review highlights the need for identifying a common mediator of the dysfunctions at the reproductive and metabolic levels and developing prevention and treatment interventions targeting all sites of disruption in unison for achieving optimal success.

Figure 1

Developmental ontogeny of the GnRH neural circuitry (top panel), ovary (middle panel), and pancreas (bottom panel) in sheep and humans. The schema is developed based on information from following publications: 1) human hypothalamus (Kaplan, 1976; Seminara et al., 1998; Schwanzel-Fukuda, 1999), 2) ovine hypothalamus (Polkowska et al., 1987; Matwijiw et al., 1989; Brooks and McNeilly, 1992; Caldani et al. 1995), 3) human ovary (Francavilla et al., 1990; Bukovsky et al., 2005; Makabe et al., 2006), 4) ovine ovary (McNatty et al. 2000; Rhind et al., 2001; Sawyer et al. 2002), 5) human pancreas (Fowden, 1985; Bouwens et al., 1997; Fowden and Hill, 2001), and 6) ovine pancreas (Reddy et al., 1988; Fowden and Hill, 2001). Abbreviations used: Hypothalamus: GnRH neurons: appearance of first GnRH immunoreactive neurons, Olf. GnRH: GnRH neurons visible in olfactory bulb, and Hyp. GnRH: appearance of GnRH neurons in the hypothalamus. Ovary: Im: implantation.

Figure 2

Self-perpetuating vicious cycle involving the three systems (neuroendocrine, ovarian, and metabolic) impacted by prenatal T excess. Abbreviations: E₂: oestradiol, LH: luteinizing hormone, P₄: progesterone.