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Ovarian dysfunction and the premenopausal origins of coronary heart disease

Kaplan, Jay R. PhD1; Manuck, Stephen B. PhD2

doi: 10.1097/gme.0b013e31815eb18e
Personal Perspective

Objective: The menopausal loss of cyclic ovarian function is believed to contribute to coronary heart disease (CHD). However, ovarian function varies substantially throughout the premenopausal years, with disruptions in hormonal activity ranging from mild to profound. Here we propose our "precocious acceleration" hypothesis, which holds that to the extent cyclic ovarian function affords protection against CHD, even mild ovulatory abnormalities in young women will accelerate development of this disease.

Design: Data relating to the expression and incidence of premenopausal ovarian dysfunction in women and its relationship to CHD are reviewed. Also reviewed are the results from experiments conducted with socially housed cynomolgus monkeys (Macaca fascicularis), focused on the causes, occurrence, and pathobiological sequelae of premenopausal ovarian dysfunction. The implications of the foregoing material for understanding the health of peri- and postmenopausal women are then considered.

Results: Epidemiological and clinical studies indicate that common premenopausal reproductive abnormalities (manifested along a continuum from mild subclinical alterations to complete suppression) are associated with increased risk of CHD. This increased risk is probably mediated by different pathways, depending on whether the reproductive deficits relate to hypoestrogenemia (functional hypothalamic anovulatory syndrome) or hyperandrogenemia (polycystic ovary syndrome). Furthermore, although clinically obvious expressions of these syndromes affect perhaps 10% of premenopausal women, evidence suggests that a much larger number may experience subclinical dysfunction capable of increasing CHD risk.

Conclusions: Epidemiological data and systematic studies in nonhuman primates provide initial support for the precocious acceleration hypothesis, suggesting that efforts to protect the health of postmenopausal women would best begin during the premenopausal years.

Epidemiological data and systematic studies in nonhuman primates suggest that subclinical as well as clinically identified premenopausal ovarian dysfunction, regardless of cause, may predispose women to the precocious development of coronary artery atherosclerosis. These observations suggest that efforts to prevent coronary heart disease in postmenopausal women should begin during the premenopausal years.

From the 1Wake Forest University Primate Center, Winston-Salem, NC; and 2Behavioral Physiology Laboratory, Department of Psychology, Clinical Psychology Center, University of Pittsburgh, Pittsburgh, PA.

Received September 28, 2007; revised and accepted October 17, 2007.

Funding/support: This work was supported by a grant from the National Institutes of Health (HL079421) This article was written with the support of NIH grants HL45666, HL079421, and HL40962.

Financial disclosure: None reported.

Address correspondence to: Jay R. Kaplan, PhD, Wake Forest University School of Medicine, Medical Center Blvd., Winston Salem, NC 27157. E-mail:

©2008The North American Menopause Society