Relative Androgen Excess and Increased Cardiovascular Risk after Menopause: A Hypothesized Relation

Yongmei Liu1, Jingzhong Ding1, Trudy L. Bush1,{dagger}, J. Craig Longenecker1,3, F. Javier Nieto1, Sherita Hill Golden4 and Moyses Szklo1

1 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
2 Department of Epidemiology and Preventive Medicine, School of Medicine, University of Maryland, Baltimore, MD.
3 Department of Internal Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD.
4 Division of Endocrinology, School of Medicine, Johns Hopkins University, Baltimore, MD.
{dagger} Deceased.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 CHANGES IN HORMONE PROFILE
 CARDIOVASCULAR DISEASE RISK AND...
 SUMMARY
 REFERENCES
 
Many studies have investigated the role of estrogen during menopause; however, less attention has been paid to the role of androgen. Given the possible opposite effects of estrogen and androgen on cardiovascular disease risk, it is suggested that relative androgen excess may better predict the increased risk of cardiovascular disease in women over the age of 50 years than estrogen levels alone. Three phases of hormonal milieu changes are hypothesized as a better way to identify the hormone-cardiovascular disease risk association. A first phase, prepause, occurs before estrogen levels decline (approximately 2 years before menopause). A second phase, interpause, occurs from the end of prepause until approximately age 55. A third phase, postpause, occurs after interpause. The duration of the interpause phase, characterized by relative androgen excess, may be an independent risk factor of cardiovascular disease. This hypothesis could provide a basis for further clinical and epidemiologic research, and it could have important implications for establishing the initiation and duration of estrogen replacement therapy use as a means to prevent cardiovascular disease.

androgens; cardiovascular diseases; estradiol; estrogen replacement therapy; estrogens; menopause; testosterone


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 CHANGES IN HORMONE PROFILE
 CARDIOVASCULAR DISEASE RISK AND...
 SUMMARY
 REFERENCES
 
More light has been shed on the role of estrogens than on that of androgens during a woman's later life. To consider the important roles that both estrogens and androgens may play, we hypothesize a three-phase course, rather than the traditional dichotomization, to characterize the menopause-related changes in hormonal profile. We have termed these three phases: prepause, which occurs before estrogen levels start to decline approximately 2 years before menopause; interpause, which occurs from the end of prepause until approximately the age of 55 years; and postpause, which follows interpause. We postulate that interpause is characterized by relative androgen excess. Given the possibly opposite effects of estrogens and androgens on cardiovascular disease risk (1Go), it is proposed that relative androgen excess may better predict the increased risk of cardiovascular disease in women around menopause than estrogen levels alone.

This hypothesis may partially explain the observed increased risk of cardiovascular disease related to menopause, and it may illuminate some issues related to the use of hormone replacement therapy as a way to prevent cardiovascular disease. The discussion of the effects of interpause on noncardiovascular disease conditions (such as osteoporosis), although important, is beyond the scope of this commentary, which will focus exclusively on cardiovascular disease.


    CHANGES IN HORMONE PROFILE
 TOP
 ABSTRACT
 INTRODUCTION
 CHANGES IN HORMONE PROFILE
 CARDIOVASCULAR DISEASE RISK AND...
 SUMMARY
 REFERENCES
 
Hormonal profile during prepause
During prepause (before estrogen levels begin to decline), estradiol, the most biologically active estrogen, is produced primarily by the ovaries. The mean level of estradiol fluctuates between 5 and 35 ng/dl (2Go). Testosterone, the most potent androgen, is produced by the peripheral conversion of androstenedione and dehydroepiandrosterone (50 percent), the adrenal glands (25 percent), and ovaries (25 percent) (3Go). Testosterone circulates at mean levels of approximately 35 ng/dl and increases by approximately 20 percent at midcycle (4Go, 5Go). Zumoff et al. (6Go, 7Go) reported a gradual decline in androgens in premenopausal women, with testosterone levels in their forties being half of those in their twenties.

Hormonal changes during interpause
In the menopausal transition period, which starts 2 or 3 years before the last menstrual period, although hormone levels are markedly variable, rapid decreases of serum levels of estradiol and estrone have been reported in many studies (8GoGo–10Go). A 60 percent decline in estradiol levels until menopause has been observed in some prospective studies (11Go). Conversely, several studies (9Go, 10Go) have not shown a significant decline in the concentration of androgens during the transition period.

After menopause, estradiol levels continue to decline initially but then level off after 1–3 years, resulting in approximately 3 ng/dl, corresponding to a 7–10-fold decline as compared with premenopausal levels (2Go, 12Go). Most studies of the effect of menopause on androgen levels have shown a slow decline in testosterone levels after the last menstrual period. For example, a prospective study reported 16 percent and 18 percent decreases of testosterone and androstenedione, respectively, within 6 months after the last menstrual period, and these decreases continued to about 30 percent after 3 years (13Go). Two other longitudinal studies (10Go, 11Go) observed a 15 percent decline in testosterone concentrations up to 3 years after menopause.

Whereas the dramatic fall of estrogen levels after menopause results from the depletion of ovarian function, the moderate decline in the circulating testosterone after menopause is poorly understood. Up to 4 years after menopause, the ovaries secrete only small amounts of estrogens (3Go), but secretion of testosterone remains at the same levels, or may even increase, perhaps as a result of stimulation by increased luteinizing hormone levels (14Go, 15Go). However, the sources of postmenopausal circulating testosterone are redistributed as follows: 40 percent from peripheral conversion of androstenedione and dehydroepiandrosterone, 10 percent from the adrenal glands, and 50 percent from ovaries (3Go). The lower proportion derived from adrenal glands after menopause implies that direct testosterone secretion from the adrenal glands declines. In addition, the decline in androstenedione levels may lead to the decline of its main metabolite, testosterone (13Go). Crilly et al. (16Go) termed the significant decline in androgens around the ages of 51–55 years as adrenopause, which may result from reduced adrenal secretion of androgens. However, no prospective studies have clearly defined the temporal course and nature of adrenopause.

Hormonal profile in postpause
About 4 years after menopause, estradiol and estrone stabilize at low levels (2Go, 17Go). With depleted secretion of estrogens from the ovaries, the peripheral aromatization of androgens may become the only source of estrogens (3Go). Some androgens, dehydroepiandrosterone and dehydroepiandrosterone sulfate, in particular, are known to decline gradually with age in postmenopausal women (18GoGo–20Go). However, most studies did not find a substantial change in testosterone and androstenedione concentrations with age (19GoGoGoGo–23Go). Prospective studies with long periods of follow-up are lacking.

In summary, during interpause, estrogen levels decline rapidly around menopause, while simultaneously there is a more gradual decline of androgen levels up to about age 55. In contrast to estrogens, the decline of androgens is not precipitous during interpause, so that the decline of circulating androgen levels does not parallel that of estrogens. This may create a period of relative androgen excess, compared with what occurs in prepause (figure 1). However, the aromatization of androgens to estrogens increases with age (24Go), and androgens may be the only source of estradiol in postpause (3Go). Thus, it is not surprising that variations in androgen levels appear to parallel variations in estrogen levels. Therefore, a new balance between estrogens and androgens may be established in postpause.



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FIGURE 1. A schematic presentation of the changes in plasma estradiol and testosterone levels during prepause, interpause, and postpause. The decline of estradiol is well established. The decline of testosterone is less well described, especially in the postpausal period. LMP, last menstrual period.

 

    CARDIOVASCULAR DISEASE RISK AND THE HYPOTHESIS OF AN ANDROGENIC HORMONAL MILIEU
 TOP
 ABSTRACT
 INTRODUCTION
 CHANGES IN HORMONE PROFILE
 CARDIOVASCULAR DISEASE RISK AND...
 SUMMARY
 REFERENCES
 
Opposite effects of estrogens and androgens on cardiovascular disease risk factors
Exogenous estrogen induces vasodilation (25Go, 26Go), decreases plasma fibrinogen (26Go), and improves insulin sensitivity in in vitro and in vivo studies (27Go). It also decreases total cholesterol, low density lipoprotein cholesterol, lipoprotein(a), and apolipoprotein B and increases high density lipoprotein cholesterol (27Go, 28Go). On the other hand, unfavorable effects of excess androgen on the arterial wall and on the lipid profile, such as decreased high density lipoprotein and increased triglycerides, low density lipoprotein, and total cholesterol, have been reported (29GoGoGoGoGoGoGo–36Go). A population-based longitudinal study (37Go) showed that dehydroepiandrosterone and dehydroepiandrosterone sulfate were positively related to diastolic and systolic blood pressure. The free androgen index (testosterone/sex hormone-binding globulin ratio) was found to be positively associated with low density lipoprotein in Australian-born women aged 45–56 years (38Go).

Androgens alone appear to promote atherosclerosis, but estrogens seem to counteract its harmful effect. A clinical trial of 25 postmenopausal women with non-insulin-dependent diabetes mellitus and low sex hormone-binding globulin (a marker for hyperandrogenicity) further confirmed that estrogen therapy significantly increases sex hormone-binding globulin and high density lipoprotein cholesterol and decreases free testosterone, glycosylated hemoglobin, total cholesterol, and low density lipoprotein cholesterol (39Go). This study suggests that the detrimental effects of hyperandrogenicity on cardiovascular disease risk factors may be reversed by estrogen replacement therapy.

Opposite effects of estrogens and androgens on cardiovascular disease risk
The association between endogenous estrogen levels and cardiovascular disease risk has not yet been clearly established (1Go, 40Go, 41Go). However, numerous cohort studies of exogenous estrogen have suggested a potential benefit of estrogen replacement therapy on cardiovascular disease incidence in postmenopausal women (27Go). On the other hand, the recently reported Heart and Estrogen/progestin Replacement Study, a randomized clinical trial in women over the age of 55 years, found that estrogen plus progestin in postmenopausal women did not prevent recurrent myocardial infarction (42Go). It should be noted that no clinical trials of women younger than age 55 have been reported. Most studies of endogenous estrogen levels and cardiovascular disease risk have been limited by small sample size and possibly by analysis of the period after menopause as a single entity. Further studies of estrogens and cardiovascular disease risk that treat interpause and postpause as separate phases may be needed, if the proposed hypothesis that those hormonal milieus in the two stages are different from each other is true.

Adverse effects of androgens on cardiovascular disease risk have also been suggested (43GoGoGo–46Go). Hyperandro-genicity with a pattern of obesity (43Go, 47Go, 48Go), hirsutism (48Go), or polycystic ovary syndrome (49Go) has been found to be associated with an increased risk of coronary heart disease. More recently, endogenous free testosterone levels in postmenopausal women have been found to be significantly associated with the degree of coronary artery disease (measured by angiography) independently of body mass index and other risk factors, such as diabetes, hypertension, smoking, and hypercholesterolemia (1Go). These studies support the possibility of a causal relation between testosterone and the risk of cardiovascular disease. Although a recent cross-sectional study in pre- and postmenopausal women (50Go) found that women in the highest tertiles of androgen levels had significantly lower carotid intimal-medial thickness, some population-based cohort studies (37Go, 51Go) suggested that higher levels of dehydroepiandrosterone sulfate in middle-aged women may indicate increased cardiovascular disease risk. More prospective studies are needed to examine the relation between the physiologic level of circulating androgens and cardiovascular disease risk. The possible effects of estrogens and androgens on cardiovascular disease risk factors and risk are illustrated in figure 2.



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FIGURE 2. The interrelations between estradiol and testosterone on cardiovascular disease risk in postmenopausal women. +, an increase in risk or level; -, a decrease in risk or level. CVD, cardiovascular disease; HDL, high density lipoprotein; LDL, low density lipoprotein.

 
Interpause and cardiovascular disease risk
Given the possible atherosclerotic effect of androgens and given that levels of estrogens and androgens are at their maximum divergence during interpause, one might expect hormone-related cardiovascular disease risk to be higher in this phase than in either pre- or postpause.

An increase in cardiovascular disease risk after menopause is seen in many (22Go, 52GoGoGoGo–56Go), but not all (57Go, 58Go), studies. The Nurses' Health Study (58Go) reported an increase in coronary heart disease risk in bilaterally oophorectomized women who did not use estrogen replacement therapy after their surgical menopause. However, an increased risk was not found among naturally postmenopausal women not using estrogen replacement therapy, a finding that could be explained by the fact that this study dichotomized risk groups according to the last menstrual period. Rather than the date of the last menstrual period itself, a better cutoff point to observe a change in cardiovascular disease risk might be 2–3 years before the last menstrual period, as the latter would better discern the period when estrogens start to decline without a parallel decline in androgens, which is consistent with the fact that the lipoprotein profile begins to change in an unfavorable direction about 2 years before the last menstrual period (59Go). Furthermore, the possibility that a menopause-related increase in cardiovascular disease risk may attenuate after about age 55 may also explain why, in the Nurses' Health study, no increase in risk was seen after natural menopause (58Go).

According to the suggested hypothesis, the longer a woman's exposure to the predominantly androgenic hormonal milieu in the interpausal period, the higher her cardiovascular disease risk would be. Early menopause has been found to be associated with increased cardiovascular disease risk (27Go, 60Go). In a recent cohort study (61Go), it was found that, although estrogen replacement therapy was associated with a lower risk of acute myocardial infarction among women whose menopause occurred before age 55, this benefit was not seen in those whose menopause occurred after age 55. This finding indicates that estrogen replacement therapy may be less beneficial on cardiovascular disease risk among women who have a shorter interpausal period with its attending dominant androgenic hormonal milieu.

Other prospective studies have also indicated the possibility of increased cardiovascular disease risk in the interpausal period. The Nurses' Health Study (62Go) found cardiovascular benefit in estrogen replacement therapy; however, this benefit was less apparent in older women, especially those in their seventh decade. In addition, natural history studies have found that the likelihood of lipid abnormalities is highest in the first decade after menopause and attenuates after age 60 (63Go). These results support the proposed hypothesis, in contradistinction with a simpler hypothesis that considers decreased estrogens alone as the explanatory factor. Furthermore, we believe that this hypothesis is not inconsistent with that of the Heart and Estrogen/progestin Replacement Study previously mentioned (42Go), which included only women above age 55.


    SUMMARY
 TOP
 ABSTRACT
 INTRODUCTION
 CHANGES IN HORMONE PROFILE
 CARDIOVASCULAR DISEASE RISK AND...
 SUMMARY
 REFERENCES
 
The notion that low estrogen levels contribute to an increased cardiovascular disease risk in postmenopausal women should also consider the role of the balance between estrogens and androgens before, around, and after menopause. The interpausal period is proposed as a special phase, during which the hormonal milieu is relatively more androgenic than that in either pre- or postpause. We hypothesize that this relative androgen excess is a key factor explaining the increased risk of cardiovascular disease in interpausal women. The duration of exposure to relative androgen excess is proposed as a possible independent risk factor of cardiovascular disease.

Over 40 million women in the United States are aged 50 years or older (64Go) and thus face increased risks of coronary heart disease, cancer, and osteoporosis (27Go). A recent editorial (65Go) has encouraged investigation of the potential risks and benefits of estrogen replacement therapy and specification of the timing and duration of its use. If the proposed hypothesis is true, estrogen replacement therapy may be particularly beneficial for women in the interpausal period. Ascertainment of the onset of the interpausal period may use the irregularity of the menstrual cycle during the transitional period of menopause,

Most epidemiologic studies of the roles of estrogens and androgens in a woman's later life have used a cross-sectional design and are thus subject to many types of bias, particularly prevalence-incidence bias. In addition, no prospective studies spanning the three hypothesized phases and obtaining serial hormone measurements have been performed. Long-term prospective studies that begin before estrogen levels decline and that monitor both estrogen and androgen levels over time are needed to test this proposed hypothesis.


    ACKNOWLEDGMENTS
 
The authors thank Dr. Belinda Chen, Jacqueline B. Hetmanski, Kristin Dolte, and Elizabeth Harro for their assistance and comments in preparing the manuscript and Dr. Ralf Berman who encouraged us to publish this hypothesis.


    NOTES
 
Reprint requests to Dr. Yongmei Liu, 2024 E. Monument Street, Suite 2500, Baltimore, MD 21205 (e-mail: yongmeiliu{at}hotmail.com).


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 CHANGES IN HORMONE PROFILE
 CARDIOVASCULAR DISEASE RISK AND...
 SUMMARY
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Received for publication June 29, 2000. Accepted for publication February 14, 2001.