Free Standard AU & NZ Shipping For All Book Orders Over $80!
Register      Login
Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
Shopping Cart: ( empty )
You are here: Home > Journals > RD > RD04092
RESEARCH ARTICLE
Contents Vol 17(3)

Early origins of polycystic ovary syndrome

Daniel A. Dumesic* A C D , R. Dee Schramm* A and David H. Abbott* A B
+ Author Affiliations
- Author Affiliations

A Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA.

B Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53715, USA.

C Departments of Obstetrics and Gynecology and Internal Medicine, The Mayo Clinic, Rochester, MN 55905, USA.

D Corresponding author. Email: danieldumesic@aol.com

Reproduction, Fertility and Development 17(3) 349-360 https://doi.org/10.1071/RD04092
Submitted: 26 April 2004  Accepted: 29 November 2004   Published: 14 February 2005

Abstract

The prenatally androgenised female rhesus monkey has become a model for polycystic ovary syndrome (PCOS) in women, with early prenatal androgenisation entraining a permanent PCOS-like phenotype characterised by luteinising hormone (LH) hypersecretion due to reduced hypothalamic sensitivity to steroid negative feedback and relative insulin excess associated with increased abdominal adiposity. These combined reproductive and metabolic abnormalities occur in combination with ovarian hyperandrogenism and follicular arrest in adulthood, and with premature follicle differentiation and impaired embryo development during gonadotrophin therapy for in vitro fertilization (IVF). The ability of prenatal androgen excess in fetal rhesus monkeys to entrain multiple organ systems in utero provides evidence that the hormonal environment of intrauterine life programmes target tissue differentiation, raising the possibility that hyperandrogenism in human fetal development promotes PCOS in adulthood. This hypothesis developed in prenatally androgenised female rhesus monkeys, however, also must include data from clinical studies of PCOS to clarify the homology between human and non-human primates in intrafollicular steroidogenesis and its impact on oocyte developmental competency. By doing so, future studies promise to develop new clinical strategies that will lead to improved pregnancy outcome and reduced pregnancy loss in women with disorders of insulin action, including PCOS, obesity and diabetes mellitus.

Extra keywords: adiposity, hyperandrogenism, hyperinsulinaemia, insulin receptor, luteinising hormone, prenatal androgenisation.


Acknowledgments

The authors wish to thank Rebekah R. Herrmann for preparation of the manuscript and Bob Becker for his contribution towards preparation of the figures. All human studies were approved by the Mayo Institutional Review Board. Non-human primates at the WPRC were maintained in accordance with the recommendations of the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and experimental protocols were reviewed and approved by the Graduate School Animal Care and Use Committee of the University of Wisconsin–Madison. The WPRC is accredited by AAALAC as part of the UW-Madison Graduate School. This work was supported by the National Institutes of Health Grants U01 HD044650–01 and R01 RR 13635, Mayo Clinical Research Grant 2123–01, Mayo Grant M01-RR-00585, Grant P51 RR 000167 to the National Primate Research Center, University of Wisconsin, Madison and Serono Pharmaceuticals.


References

Abbott, D. H. , Dumesic, D. A. , Eisner, J. R. , Colman, R. J. , and Kemnitz, J. W. (1998). Insights into the development of PCOS from studies of prenatally androgenized female rhesus monkeys. Trends Endocrinol. Metab. 9, 62–67.
| Crossref | GoogleScholarGoogle Scholar | Abbott D. H., Eisner J. R., Colman R. J., Kemnitz J. W., and Dumesic D. A. (2002c). Prenatal androgen excess programs for PCOS in female rhesus monkeys. In ‘Polycystic Ovary Syndrome’. (Eds R. J. Chang, A. Dunaif and J. Hiendel.) pp. 119–133. (Marcel Dekker, Inc: New York, NY, USA.)

Adams, J. , Polson, D. W. , and Franks, S. (1986). Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. BMJ 293, 355–359.
| PubMed | Dewailly D., Cortet-Rudelli C., and Deroubaix-Allard D. (1997). Definition, clinical manifestations, and prevalence of PCOS. In ‘Androgen Excess Disorders in Women’. (Eds R. Azziz, J. E. Nestler and D. Dewailly.) pp. 259–268. (Lippincott-Raven Publishers: Philadelphia, PA, USA.)

Diamanti-Kandarakis, E. , Mitrakou, A. , Hennes, M. M. I. , Platanissiotis, D. , Kaklas, N. , Spina, J. , Georgiadou, E. , Hoffmann, R. G. , Kissebah, A. H. , and Raptis, S. (1995). Insulin sensitivity and antiandrogen therapy in women with polycystic ovary syndrome. Metabolism 44, 525–531.
| Crossref | GoogleScholarGoogle Scholar | PubMed | Goy R. W., and Kemnitz J. W. (1983). Early, persistent and delayed effects of virilizing substances delivered transplacentally to female rhesus monkeys. In ‘Applications of Behavioral Pharmacology in Toxicology’. (Eds G. Zbinden, V. Cuomo, G. Racagni and B. Weiss.) pp. 303–314. (Raven Press: New York, NY, USA.)

Goy, R. W. , and Robinson, J. A. (1982). Prenatal exposure of rhesus monkeys to patent androgens: morphological, behavioral, and physiological consequences. Banbury Report 11, 355–378.
Goy R. W., Uno H., and Sholl S. A. (1988). Psychological and anatomical consequences of prenatal exposure to androgens in female rhesus. In ‘Toxicity of Hormones in Perinatal Life’. (Eds T. Mori and H. Nagasawa.) pp. 127–142. (CRC Press: Boca Raton, FL, USA.)

Hamilton-Fairley, D. , Kiddy, D. , Watson, H. , Paterson, C. , and Franks, S. (1992). Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin. Br. J. Obstet. Gynaecol. 99, 128–131.
| PubMed | Kemnitz J. W., Holston K. A., and Colman R. J. (1998). Nutrition, aging and reproduction in rhesus monkeys. In ‘Nutrition and Reproduction’. (Eds W. Hansel, G. A. Bray and D. H. Ryan.) pp. 180–195. (Louisiana State University Press: Baton Rouge, LA, USA.)

Kiddy, D. S. , Hamilton-Fairley, D. , Bush, A. , Short, F. , Anyaoku, V. , Reed, M. J. , and Franks, S. (1992). Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 36, 105–111.
| PubMed | Mishell D. R.Jr, Davajan V., and Lobo R. A. (1991). ‘Infertility, Contraception and Reproductive Endocrinology.’ 3rd edn. (Blackwell Scientific Publications: Cambridge, UK.)

Moghetti, P. , Castello, R. , Negri, C. , Tosi, F. , Perrone, F. , Caputo, M. , Zanolin, E. , and Muggeo, M. (2000). Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J. Clin. Endocrinol. Metab. 85, 139–146.
| Crossref | GoogleScholarGoogle Scholar | PubMed | Resko J. A., and Ellinwood W. E. (1984). Sexual differentiation of the brain of primates. In ‘Sexual Differentiation: Basic and Clinical Aspects’. (Eds M. Serio, M. Motta, M. Zanisi and L. Martini.) pp. 169–181. (Raven Press: New York, NY, USA.)

Resko, J. A. , Buhl, A. E. , and Phoenix, C. H. (1987). Treatment of pregnant rhesus macaques with testosterone propionate: observations on its fate in the fetus. Biol. Reprod. 37, 1185–1191.
| PubMed | Wild R. A. (1996). Hyperandrogenism: Implications for cardiovascular, endometrial, and breast disease. In ‘Reproductive Endocrinology, Surgery, and Technology’. (Eds E. Y. Adashi, J. A. Rock and Z. Rosenwaks.) pp. 1617–1634. (Lippincott-Raven Publishers: Philadelphia, PA, USA.)

Willis, D. , and Franks, S. (1995). Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-1 insulin-like growth factor receptor. J. Clin. Endocrinol. Metab. 80, 3788–3790.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

Willis, D. , Mason, H. , Gilling-Smith, C. , and Franks, S. (1996). Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J. Clin. Endocrinol. Metab. 81, 302–309.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

Willis, D. , Watson, H. , Mason, H. , Galea, R. , Brincat, M. , and Franks, S. (1998). Premature response to LH of granulosa cells from anovulatory women with polycystic ovaries: relevance to mechanism of anovulation. J. Clin. Endocrinol. Metab. 83, 3984–3991.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

Wu, X. K. , Zhou, S. Y. , Liu, J. X. , Pollanen, P. , Sallinen, K. , Makinen, M. , and Erkkola, R. (2003). Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome. Fertil. Steril. 80, 954–965.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

Yang, X. , Hsu-Hage, B. , Zhang, H. , Zhang, C. , and Zhang, Y. (2002). Women with impaired glucose tolerance during pregnancy have significantly poor pregnancy outcomes. Diabetes Care 25, 1619–1624.
| PubMed |

Yding Andersen, C. (1993). Characteristics of human follicular fluid associated with successful conception after in vitro fertilization. J. Clin. Endocrinol. Metab. 77, 1227–1234.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

Zelinski-Wooten, M. B. , Hess, D. L. , Baughman, W. L. , Molskness, T. A. , Wolf, D. P. , and Stouffer, R. L. (1993). Administration of an aromatase inhibitor during the late follicular phase of gonadotropin-treated cycles in rhesus monkeys: effects on follicle development, oocyte maturation, and subsequent luteal function. J. Clin. Endocrinol. Metab. 76, 988–995.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

Zheng, P. , Wei, S. , Bavister, B. D. , Yang, J. , Ding, C. , and Ji, W. (2003). 17β-estradiol and progesterone improve in vitro cytoplasmic maturation of oocytes from unstimulated prepubertal and adult rhesus monkeys. Hum. Reprod. 18, 2137–2144.
| Crossref | GoogleScholarGoogle Scholar | PubMed |

Zumoff, B. , Freeman, R. , Coupey, S. , Sanger, P. , Markowitz, M. , and Kream, J. (1983). A chronobiologic abnormality in luteinizing hormone secretion in teenage girls with polycystic-ovary syndrome. N. Engl. J. Med. 309, 1206–1209.
| PubMed |




* Drs Dumesic, Schramm and Abbott contributed equally to this manuscript.