Nonhuman primate models of polycystic ovary syndrome
Highlights
► Early-to-mid gestation testosterone excess recapitulates PCOS phenotypes in monkeys. ► Transient maternal and fetal hyperglycemia accompany testosterone exposure. ► Epigenetic changes in visceral fat implicate altered TGF-β signaling. ► T-exposed monkeys may provide a close, epigenetic molecular mimic of PCOS.
Introduction
Polycystic ovary syndrome (PCOS) afflicts 15% of women in their reproductive years (Fauser et al., 2012), increasing a woman’s lifetime risk of type 2 diabetes mellitus (type 2 DM) and cardiovascular disease (Wild et al., 2010). Progress towards prevention of PCOS, however, has been hindered by an incomplete knowledge of its pathogenesis. Polycystic ovary syndrome is characterized by at least two of the following criteria: hyperandrogenism, intermittent or absent menstrual cycles (often accompanied by luteinizing hormone (LH) excess), and increased numbers of small ovarian antral follicles (Fauser et al., 2012). While a hyperandrogenic polycystic ovary is central to PCOS pathophysiology (Gilling-Smith et al., 1997, Franks et al., 2008, Nelson et al., 1999), visceral obesity and insulin resistance are frequent co-morbidities (Ehrmann et al., 2006, Kiddy et al., 1990). Pre- or peri-pubertal metabolic dysfunction is one of the first phenotypic traits observed in adolescent girls likely to develop PCOS (Coviello et al., 2006, Marshall, 2006), an alarming finding since obesity now affects ∼15% of American children (Dietz, 1998, Hedley et al., 2004). Overweight or obese adolescent girls have higher circulating androgen levels than their lean counterparts (Ibanez et al., 2003, Chhabra et al., 2005, McCartney et al., 2006), with such hyperandrogenism predisposing adolescents to PCOS (Rosenfield, 2007, Zumoff et al., 1983, McCartney, 2010).
Twin (Vink et al., 2006) and genetic (Goodarzi, 2008, Urbanek et al., 2007, Ewens et al., 2010) studies demonstrate high heritability of PCOS, particularly hyperandrogenism (Legro et al., 1998). The most reliable PCOS gene candidate is a member of the TGF-ß superfamily encoding for the extra-cellular matrix protein, fibrillin 3 (Ewens et al., 2010). The allelic fibrillin variant, A8, is linked with PCOS and manifests a distinct metabolic phenotype, even in immediate male kin, which includes insulin resistance (Urbanek et al., 2007). Circulating levels of the TGF-ß superfamily peptide, anti-mullerian hormone (AMH), are derived from ovarian granulosa cells and are elevated in women and adolescents with PCOS (Pellatt et al., 2010, Siow et al., 2005, Hart et al., 2010), as well as in infant girls born to women with PCOS (Sir-Petermann et al., 2012, Crisosto et al., 2012). As daughters born to PCOS women are at increased risk for PCOS in adulthood (Vink et al., 2006), their contribution to evaluation of PCOS antecedents is relevant, particularly because reproductive and metabolic features of PCOS are established in these young girls before signs and symptoms fully manifest in adulthood (Rosenfield, 2007, Franks, 2002, Shayya and Chang, 2010, Roe and Dokras, 2011).
Consistent with an early onset of PCOS pathophysiology, aspects of PCOS-like phenotypes are reliably produced in females rhesus monkeys (Abbott et al., 2002, Abbott et al., 2005), sheep (Padmanabhan and Veiga-Lopez, 2011, this issue), and rats and mice (Walters et al., 2012; McNeilly, this issue) by in utero exposure to fetal male levels of testosterone (T), suggesting that the intrauterine environment may fundamentally affect the etiology of PCOS in such prenatal androgenized (PA) females (Abbott et al., 2008a, Abbott et al., 2008b). Furthermore, adult female macaques have been identified with naturally occurring PCOS-like traits in which high T levels may be heritable (Arifin et al., 2008; DH Abbott, unpublished results). Consequently, fetal T programming of PCOS-like reproductive traits has been formulated as the fetal origins of PCOS hypothesis (Abbott et al., 2002), but the underlying cellular and molecular mechanisms are still poorly understood.
This review will thus examine nonhuman primate contributions to animal models for PCOS, focusing on reproductive, endocrinological and metabolic phenotypes generated by T or other steroids throughout life and the insights regarding PCOS pathogenesis such experimental manipulations provide. As rhesus monkeys share ∼93% of their genome with humans (Gibbs et al., 2007), their human-like reproductive (Kaplan et al., 2010), metabolic (Zhang et al., 2011), developmental (Trounson and Grieshammer, 2012) and aging (Colman et al., 2009) traits provide readily translatable outcomes for human disease.
Section snippets
PCOS-like phenotypes
Adult female rhesus monkeys previously exposed to fetal male levels of T during early-to-mid gestation provide the most comprehensive epigenetic mimic of PCOS in women (Abbott et al., 2005, Abbott et al., 2009, Xu et al., 2011). Fetal male T levels are achieved in fetal female monkeys by means of daily subcutaneous (s.c.) injections of their dams with 10–15 mg testosterone propionate (TP) for 15–40 consecutive days between 40 and 80 days of gestation (early-to-mid gestation T exposure, E) or for
In utero exogenous T: fetal programming for PCOS-like metabolic dysfunction in female monkeys
EPA fetal monkeys develop many PCOS-like metabolic traits as adults (Abbott et al., 2005, Abbott et al., 2009, Dumesic et al., 2005, Zhou et al., 2007a), including increased visceral and total abdominal adiposity, hyperlipidemia, insulin resistance, impaired insulin secretion, hyperglycemia and type 2 DM. Emulating PCOS women, most EPA monkeys respond to six months of daily treatment with the thiazolidinedione insulin sensitizer, pioglitazone, by decreasing insulin resistance and fasted basal
Molecular epigenetic signature of fetal T exposure in female monkeys
Alteration of the epigenome is a mechanism whereby gestational T excess (Xu et al., 2011, Auger et al., 2011, Hogg et al., 2012), or its hyperglycemic consequences (Pirola et al., 2010, Pirola et al., 2011), reprogram gene expression in EPA monkeys enabling development of PCOS-like traits in adulthood. Differentially methylated genes identified in EPA infant (>100) and adult (>300) visceral fat are involved in the regulation of adipogenesis, intermediate metabolism and cell proliferation.
Clinical significance for PCOS of in utero T induction of PCOS-like phenotypes in monkeys
With the certainty of a PCOS-like phenotype in adulthood. EPA monkeys provide opportunities to determine fetal, infant and juvenile antecedents of PCOS that will enable early targeting of amelioration or prevention in humans. In addition, as TP injections given to pregnant monkey dams impair the dams’ abilities to regulate blood glucose, as in humans, subsequent maternal hyperglycemia results in increased fetal exposure to glucose and increased fetal and neonatal growth. Infant EPA female
Acknowledgements
The authors thank Amber K. Edwards at the Wisconsin National Primate Research Center (WNPRC) and Dr. Alice F. Tarantal at the California National Primate Research Center (CNPRC) for expert technical assistance. This work was supported by the National Institutes of Health R01-RR013635 to D.H.A., R01-DK079888 to M.O.G., U01-HD044650 to D.A.D., P50-HD044405 to Andrea Dunaif, T32-DK07786 to Michael J. MacDonald (Postdoctoral Fellows Training Award), P51-RR000167 to WNPRC, P51-RR000169 to CNPRC,
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