Insights into the Development of Polycystic Ovary Syndrome (PCOS) from Studies of Prenatally Androgenized Female Rhesus Monkeys

https://doi.org/10.1016/S1043-2760(98)00019-8Get rights and content

Abstract

The developmental pathophysiology of polycystic ovary syndrome (PCOS) is unknown. However, prenatally androgenized female rhesus monkeys exhibit ovarian and endocrinological features that mimic those found in women with PCOS. Thus, prenatal androgen excess may provide an etiology for hyperandrogenism and anovulation in adulthood.

Section snippets

PCOS: a syndrome without a resolved etiology

PCOS represents a combination of anovulation, hyperandrogenism, hyperinsulinemia and dyslipidemia usually accompanied by LH hypersecretion and polycystic-appearing ovaries (Ehrmann et al. 1995Franks 1995). PCOS is a complex, multifactoral syndrome with a multitude of heterogeneous clinical presentations. The complexity of PCOS pathophysiology is of such magnitude that its etiology remains unknown, its treatment is unresolved and, until recently, its definition remained unclear (Zawadzki and

Prenatal androgen excess: a key event in the etiology of PCOS?

Our interest in the developmental origins of PCOS began when women with classical 21-hydroxylase deficiency, the most prevalent form of congenital adrenal hyperplasia (CAH), demonstrated features that closely mimicked those found in PCOS (Hague et al. 1990Barnes et al. 1994). Despite normalization of adrenal androgen excess after birth, the women with CAH exhibited anovulation, ovarian hyperandrogenism, LH hypersecretion, polycystic-appearing ovaries and insulin resistance in adulthood.

Risk of anovulation is increased with a combination of prenatal androgen excess and adiposity in female rhesus monkeys

Our research has involved discrete experimental induction of pre- and postnatal androgen excess in female nonhuman primates to ascertain the effect of hormonally induced differentiation on socio-sexual behavior, reproductive endocrinology, fertility and growth [rhesus monkeys, Macaca mulatta (Goy and Resko 1972); marmoset monkeys, Callithrix jacchus (Abbott 1984)]. The comprehensive treatment and study of prenatal androgenization in female rhesus monkeys (Goy et al. 1988) provides a

Prenatal androgen excess alters the relationship between adiposity and glucose–insulin homeodynamics in female rhesus monkeys

In addition to its impact on the reproductive endocrine axis, prenatal androgenization of female rhesus monkeys may permanently alter the relationship between adiposity and glucose–insulin homeodynamics. BMI correlates positively with fasting serum insulin levels, but only in prenatally androgenized females (Abbott et al. 1997). Preliminary results also indicate that elevated adiposity in prenatally androgenized females is associated with reduced dynamic insulin responsiveness, impaired glucose

Synopsis and conclusions

The striking similarities between adult female rhesus monkeys, androgenized prenatally, and women with PCOS are outlined in Table 1. There are three key components that appear to be of fundamental importance in both groups. First, LH hypersecretion is a defining pathophysiology indicative of hypothalamic dysfunction in both groups [PCOS (Arroyo et al. 1997Taylor et al. 1997); monkeys (Dumesic et al. 1997)]. Second, hyperinsulinemia appears to play a pivotal role in the mechanism of anovulation

Avenues for future investigation

Our findings have demonstrated an association between hyperinsulinemia and the mechanism of hyperandrogenic anovulation in female monkeys that experienced androgen excess during fetal life. We now need to test the implications of these findings and to determine whether: (1) chronic elevation of circulating insulin levels induces anovulation in otherwise regularly ovulating, normo-insulinemic, prenatally androgenized females but not in controls; and (2) improvement of insulin sensitivity in

Acknowledgements

This work was supported, in part, by NIH grants RR00167 and AG11913, and research awards from the University of Wisconsin-Madison Medical and Graduate School Research Committees. The authors thank S.G. Eisele (Reproduction Research Services) and the Animal Care Staff of WRPRC for reproductive management and maintenance of the animals. Preparation of this manuscript was facilitated by R.A. Becker and the staff and resources of the Wisconsin Regional Primate Research Center (WRPRC) Library. The

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