Ovarian hyperandrogenism in adult female rhesus monkeys exposed to prenatal androgen excess

Eisner, Joel R.; Barnett, Melissa A.; Dumesic, Daniel A.; Abbott, David H.

doi:10.1016/s0015-0282(01)02947-8

Cited by 135 publications

(84 citation statements)

References 36 publications

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“…These animals, exposed to high concentrations of testosterone in utero, develop, as adults, many of the typical features of PCOS such as hypersecretion of LH, ovarian hyperandrogenism, anovulation in relation to increased body weight and insulin resistance. [16][17][18] This strongly suggests that the phenotype of PCOS represents the downstream effects of androgen excess and that these may arise by 'programming' of the hypothalamic-pituitary-ovarian axis by androgen in prenatal life. It is important to note that the Rhesus monkeys were given very large doses of androgen, high enough to exceed the normal barriers of high circulating concentrations of sex hormone-binding globulin (SHBG) and placental aromatase activity (which efficiently converts maternal androgen to oestrogens).…”

Section: Introductionmentioning

confidence: 99%

Polycystic ovary syndrome in adolescents

2008

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Background: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women and typically presents during adolescence. The clinical and biochemical presentation is heterogeneous, but elevated serum concentrations of androgens are the most consistent biochemical abnormality and may be considered to be the hallmark of the syndrome. Many women with PCOS also have insulin resistance and hyperinsulinaemia, which may contribute to the clinical and endocrine abnormalities. The aetiology of PCOS is not clear but studies in the Rhesus monkey suggest that exposure to excess androgen during intrauterine life results in many of the features of human PCOS, including ovarian dysfunction, abnormal LH secretion and insulin resistance. Objective: To review the studies from the literature, including those of the author, regarding aetiology, presentation and management of PCOS in adolescents. Results and conclusions: We have proposed that PCOS in adolescents arises as a result of a genetically determined disorder of ovarian function that results in hyper-secretion of androgens, possibly during fetal life and also during physiological activation of the hypothalamic-pituitary-ovarian in infancy and at the onset of puberty. There is plentiful evidence for a genetic basis for PCOS (it appears to be a complex endocrine disorder resulting from the effects of a several genes), but environmental factors, notably nutrition, influence the clinical and biochemical phenotype. Obesity unmasks or amplifies symptoms, endocrine and metabolic abnormalities. The increasing incidence of childhood obesity has resulted in an alarming Increase not only in distressing symptoms but also impaired glucose tolerance and even diabetes among adolescent girls with PCOS. The search for PCOS genes in this condition, that is not only heterogeneous but also presents only in women of reproductive age, is not straightforward and has produced few convincing candidates so far. In due course, however, identification of the major susceptibility loci is likely to provide key insight into the aetiology of the syndrome and improve diagnosis and management.

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Section: Introductionmentioning

confidence: 99%

Polycystic ovary syndrome in adolescents

2008

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“…In androgenized adult female monkeys, a high response to recombinant HCG in testosterone and 17alfa hydroxyprogesterone was also observed after 24 hours of stimulation. The exaggerated thecal cell steroid response to recombinant hCG in the prenatally androgenized female monkeys was attributed to a heightened 17a-hydroxylase activity of cytochrome P450c17a, a key enzyme in ovarian thecal cell steroid production (Eisner et al, 2002). Recent evidence has also shown that in addition to 17a-hydroxylase, increased T production in PCOS theca cells does not result from deregulation of "androgenic" 17aHSD activity or altered expression of AKRs that may express 17aHSD activity but rather the increased synthesis of T precursors is the primary factor driving enhanced T secretion in PCOS (Nelson et al, 2001).…”

Section: Resultsmentioning

confidence: 99%

Response to the gonadotropin releasing hormone agonist leuprolide in immature female sheep androgenized in utero

Recabarren¹,

Sir-Petermann

Lobos³

et al. 2005

Biol. Res.

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Similar to women with Polycystic Ovary Syndrome (PCOS), female sheep treated prenatally with testosterone (T-females) are hypergonadotropic, exhibit neuroendocrine defects, multifollicular ovarian morphology, hyperinsulinemia and cycle defects. Hypergonadotropism and multifollicular morphology may in part be due to developmentally regulated increase in pituitary responsiveness to GnRH and may culminate in increased ovarian estradiol production. In this study, we utilized a GnRH agonist, leuprolide, to determine the developmental impact of prenatal testosterone exposure on pituitary-gonadal function and to establish if prenatal exposure produces changes in the reproductive axis similar to those described for women with PCOS. Eight control and eight T-females were injected intravenously with 0.1 µg of leuprolide acetate per kilogram of body weight at 5, 10 and 20 weeks of age. Blood samples were collected by means of an indwelling jugular vein catheter at 0, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 hours after leuprolide. Area under the curve (AUC) of LH response to leuprolide increased progressively between the three ages studied (P<0.05). AUC of LH in Tfemales was higher than in control females of the same age at 5 and 10 weeks of age (P<0.05), but similar at 20 weeks of age. AUC of estradiol response was lower at 10 but higher at 20 weeks of age in T-females compared to controls of the same age (P<0.05). Our findings suggest that prenatal T treatment alters the pituitary and ovarian responsiveness in a manner comparable to that observed in women with PCOS.

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“…The post receptor insulin signaling pathway and/or defective insulin secretion may be associated with an intrinsic abnormality (Holte, Bergh et al 1995;Dunaif 1997). Probably, the metabolic abnormalities in PCOS begin very early in life, during the prenatal or prepubertal period, and an early exposure to androgens during growth may affect the body fat distribution and insulin action (Abbott, Dumesic et al 2002;Eisner, Barnett et al 2002). These observations have shown convincing proof that PCOS patients have insulin resistance and/or hyperinsulinemia, especially when they are anovulatory and obese with central fat distribution.…”

Section: Hyperinsulinemia and Insulin Resistancementioning

confidence: 98%