Abstract and Introduction
Abstract
Objective: The aim of this study was to determine if premenopausal ovarian reserve is associated with susceptibility for atherosclerosis.
Methods: Female cynomolgus macaques (n = 66, women’s equivalent age = 45 y) consumed an atherogenic diet for ~5 months before the measurement of a marker of ovarian reserve (antimüllerian hormone [AMH]), plasma lipids, follicular phase estradiol, and body weight (BW). Monkeys were then ovariectomized (OVX; n = 17), remained premenopausal (n = 20), or were induced to have reduced ovarian reserve (ROR, n = 29). After 26 additional months consuming the diet, atherosclerosis measurements and risk variables were reassessed.
Results: No differences in baseline AMH, plasma lipids, BW, and estradiol or postdiet lipids and BW were observed among the groups subsequently assigned to the OVX, premenopausal control, or reduced ovarian reserve conditions. Postdiet measurements of atherosclerosis extent did not differ among the groups. However, analysis of plaque size by tertile of baseline AMH revealed that plaques were largest in monkeys that began the experiment with the lowest baseline AMH, followed by those in the middle and high tertiles (plaque extent: low AMH, 0.76 ± 0.12 mm2; mid AMH, 0.46 ± 0.1 mm2; high AMH, 0.34 ± 0.08 mm2; P = 0.02). Baseline AMH and plaque size were also correlated negatively (r = -0.31, P = 0.01). Plasma lipids were also correlated significantly with plaque extent (all P < 0.01) but not with AMH.
Conclusions: We report for the first time an inverse relationship between a marker of ovarian reserve (AMH) and subsequent atherosclerosis risk.
Introduction
Cardiovascular disease remains the leading cause of mortality in postmenopausal women.[1] Coronary heart disease (CHD) due to atherosclerosis accounts for most of those deaths, with more than 50% of women experiencing sudden cardiac death. Furthermore, many of these women succumb without previously reported symptoms.[2] Because the underlying atherosclerosis probably develops over a period of decades, these data emphasize the need for improved methods of assessment that would allow earlier identification of women at risk for CHD. However, gaps in knowledge still exist regarding the initiation and progression of atherosclerosis in this population. For example, the Framingham Risk Score has been reported to underestimate risk in perimenopausal and early postmenopausal women. Hence, data from a group of young (~55 y), nondiabetic, postmenopausal women revealed detectable coronary artery calcium, indicative of subclinical atherosclerosis, despite having a low Framingham risk score.[3]
Although evidence is accumulating in support of an interventional “window of opportunity” for estrogen treatment in the reduction of CHD in early postmenopausal women,[4] the nature of the association between CHD risk and loss of ovarian function (menopause) is still controversial. For example, in a meta-analysis of 18 studies, no relationship between postmenopause status and cardiovascular disease was found, and only a modest effect of early menopause (surgical > natural) was observed.[5] Conflicting data on this subject may be due, in part, to the inability to account for the variability in type of “menopause” being investigated, including natural versus surgical (hysterectomy with or without oophorectomy) and early (premature ovarian failure) versus later menopause. Furthermore, it has not been possible in most studies to account for variations in the length of the menopausal transition (2-10 years) or to account for women who may have experienced reproductive dysfunction prior to the menopausal transition. Data from women and nonhuman primates suggest that premenopausal ovarian function may affect risk for chronic disease postmenopausally.[6,7] More precise estimations of ovarian reserve using antimüllerian hormone (AMH), along with application of improved clinical staging of reproductive aging using criteria such as those from Stages of Reproductive Aging Workshop criteria[8] for the classification of women in the menopausal transition, may increase understanding of the aforementioned relationships.
AMH is a protein hormone in the transforming growth factor-[beta] family and is produced by the granulosa cells of small growing (preantral and small antral) follicles in the ovary of rodents and nonhuman and human primates. AMH is positively correlated with primordial follicle numbers (ovarian reserve) in both women[9,10] and Old World nonhuman primates[11] (r > 0.7 for both). Decreases in AMH parallel follicle loss as women approach menopause,[12] and AMH has been reported to fall to very low levels as early as 5 years before the final menstrual period.[13] Although AMH’s main role is believed to be the regulation of primordial follicle recruitment,[14,15,16,17] recent reports in mice indicate that AMH may have neuroprotective effects in the brain.[18] It is not known currently whether AMH has direct effects on other nonovarian tissues.
The purpose of the study presented here was to determine retrospectively whether premenopausal ovarian reserve, as indicated by plasma AMH concentration, is associated with subsequent atherosclerosis progression. The data thus represent an opportunistic observation from a larger study designed to determine the effect of ovarian reserve on risk for chronic disease.[19]
Menopause. 2012;19(12):1353-1359. © 2012 The North American Menopause Society
