Venus and the Heart: Endocrine Influences on Cardiovascular Health in Women

 

 Buy Article Permissions and Reprints

The influence of gonadal steroids on the heart and vascular system represents the crossroads of reproductive science and cardiology. This field has received considerable attention as the genesis of the observed difference in cardiovascular risk born by men and women. The unexpected initial results of the Women's Health Initiative (WHI) study rocked the field when estrogens did not appear to provide the beneficial effects on heart disease anticipated by prior epidemiologic studies. The results of this study, their interpretation, and extrapolation to other groups of women have likewise received ample attention during the years subsequent to the first WHI publication. Nevertheless, the WHI provided a wake-up call to investigators in the field to recognize the complexity of the physiologic connections between gonadal steroids and cardiovascular health.

Although estrogens have for a long time drawn the most attention in the debates surrounding the influence of gonadal steroids on the heart, androgens have more recently staged a comeback, and with good reason. First of all, circulating concentrations of estradiol are generally only two- to fourfold higher in women than in men, except during ovulation and pregnancy. In contrast, androgens are an order of magnitude higher in men than in women, and free testosterone can be 50 times higher. Second, androgen excess states have been associated with increased cardiovascular risk, with polycystic ovary syndrome (PCOS) being the best example. Strangely, androgen deficiency (rather than excess) in men has also been associated with increased cardiovascular risk. Consequently, the response of the cardiovascular system in men and women to androgens and estrogens appears to be fundamentally different and imprinted long before adulthood.

In this issue of Seminars in Reproductive Medicine, entitled “Venus and the Heart: Endocrine Influences on Cardiovascular Health in Women,“ we explore this complex relationship between the endocrine system and heart disease in women and in particular those areas in need of future investigation. No issue on the influence of hormones on the heart would be complete without consideration of PCOS, but we wanted to provide a broader and fresh perspective on cardiovascular disease and PCOS beyond the insulin resistance, which is the topic of many other articles. In the first article of this issue, entitled “Characterizing Cardiovascular Risk in Women with Polycystic Ovary Syndrome: More than the Sum of Its Parts?” and written by Drs. Chang and Wild, the authors critically evaluate the evidence that adverse cardiovascular risk profile associated with PCOS translates into increased events (acute coronary syndrome and sudden death). They review the pitfalls in existing studies and the difficulties in documenting cardiovascular disease attributable to PCOS and androgen excess itself. In the second article, entitled “Androgens in Polycystic Ovary Syndrome: The Role of Exercise and Diet,” Dr. Giallauria and colleagues initially discuss the abundant evidence linking PCOS with adverse cardiovascular risk factors and the possible links between insulin resistance and hyperandrogenism. They end by reviewing their work and other studies demonstrating the benefits of diet and exercise for not only the insulin resistance but also the hyperandrogenism of PCOS. Their work has profound public health implications, due to the prevalence of PCOS and the abundant evidence that children at risk for PCOS can be ascertained prior to puberty.

A more extreme form of androgen excess in women is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). If androgens truly are a risk factor for cardiovascular disease, then adult women with 21OHD should bear the greatest burden of this risk. Despite the prevalence of 21OHD, which occurs in 1 of 14,000 live births worldwide, adults with 21OHD have received surprisingly little study in this regard. Dr. Merke and her colleagues at the National Institutes of Health are conducting a natural history study to ascertain, among other issues, how cardiovascular function and disease in 21OHD evolves over time. In their review, entitled “Cardiovascular Disease Risk in Adult Women with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency,” Drs. Kim and Merke review how glucocorticoid treatment and the abnormalities in the hypothalamic-pituitary-adrenal axis intersect to influence various cardiovascular risk factors.

Another phase of reproductive life characterized by androgen (and estrogen) excess is pregnancy. Today we are beginning to recognize that pregnancy is a major metabolic and cardiovascular stress test and perhaps a physiologic imperative necessitating the rich diversity of hormonal influences on cardiovascular system. Understanding the hormonal influences on the normal adaptations to the stress of pregnancy will augment not only our knowledge concerning the pathophysiology of disease states such as preeclampsia, gestational hypertension, and gestational diabetes but might also lead to potential treatments of these disorders and to strategies designed to prevent the development of increased cardiovascular risk for these women long after parturition. In the next contribution, “Late Cardiovascular Consequences of Gestational Diabetes Mellitus,” Dr. Bentley-Lewis explores how a common metabolic derangement observed during the stress of pregnancy translates into cardiovascular risk later in life. The lessons learned from these studies might have broader implications to hormonal influence on the cardiovascular system for both men and women.

Medical and reproductive endocrinologists alike generally neglect the autonomic nervous system, but this paracrine/neuroendocrine system exerts profound influence on cardiovascular function. Indeed, many aspects of the sympathetic nervous system differ between men and women, and hormonal influences change after menopause. We are fortunate to have two contributions on this topic from leading investigators in the field. Pregnancy is one such example of how the autonomic nervous system participates in the regulation of the cardiovascular system in response to hormonal changes. In the penultimate paper in this issue, Drs. Fu and Levine discuss these unique changes in neuroendocrine regulation in an article entitled “Autonomic Circulatory Control during Pregnancy in Humans.” Finally, Dr. Vongpatanasin delivers a perspective on the differences between the regulation in the autonomic nervous system observed in men and women and how this influence changes in estrogen deficiency. This contribution, entitled “Autonomic Regulation of Blood Pressure in Menopause,” reviews the literature in animals and humans that tries to dissect the major consequences of estrogen deficiency on the autonomic nervous system and the effects of estrogen replacement on the autonomic nervous system. Surprisingly, even the route of estrogen administration appears to be a significant variable in this equation.

We hope that you enjoy this issue, which has a distinctly different flavor than is typical for a journal devoted to reproductive endocrinology. We also hope that these contributions help you to appreciate the complex relationships between reproductive hormones and cardiovascular function, as well as the broad implications of reproductive physiology on human health.