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J Am Coll Cardiol, 2003; 41:413-419, doi:10.1016/S0735-1097(02)02763-8
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY: ATHEROSCLEROSIS

Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study

C. Noel Bairey Merz, MD, FACC*,*, B. Delia Johnson, PhD{dagger}, Barry L. Sharaf, MD, FACC{ddagger}, Vera Bittner, MD, FACC§, Sarah L. Berga, MD||, Glenn D. Braunstein, MD*, T. Keta Hodgson, RN*, Karen A. Matthews, PhD{dagger}, Carl J. Pepine, MD, FACC, Steven E. Reis, MD, FACC#, Nathaniel Reichek, MD, FACC**, William J. Rogers, MD, FACC§, Gerald M. Pohost, MD, FACC§, Sheryl F. Kelsey, PhD{dagger}, George Sopko, MD{dagger}{dagger} WISE Study Group

* Division of Cardiology, Department of Medicine, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
{dagger} Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
{ddagger} Division of Cardiology, Rhode Island Hospital, Providence, Rhode Island, USA
§ Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
|| Division of Reproductive Endocrinology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Division of Cardiology, Department of Medicine, University of Florida, Gainesville, Florida, USA
# Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
** Division of Cardiology, Department of Medicine, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania, USA
{dagger}{dagger} National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA

Manuscript received April 25, 2002; revised manuscript received September 23, 2002, accepted October 10, 2002.

* Reprint requests and correspondence: Dr. C. Noel Bairey Merz, c/o WISE Coordinating Center, University of Pittsburgh, 127 Parran Hall, Graduate School of Public Health, 130 DeSoto Street, Pittsburgh, Pennsylvania 15261, USA.
merz{at}cshs.org


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We sought to evaluate hypoestrogenemia of hypothalamic origin and its association with angiographic coronary artery disease (CAD) in premenopausal women.

BACKGROUND: Coronary artery disease in premenopausal women appears to have a particularly poor prognosis. Primate animal data suggest that premenopausal CAD is strongly determined by psychosocial stress-induced central disruption of ovulatory cycling and resulting hypoestrogenemia.

METHODS: We assessed reproductive hormone blood levels and angiographic CAD using core laboratories in 95 premenopausal women with coronary risk factors who were enrolled in the National Heart, Lung, and Blood Institute–sponsored Women’s Ischemia Syndrome Evaluation and were undergoing coronary angiography for evaluation for suspected ischemia.

RESULTS: Premenopausal women with angiographic CAD (n = 13) had significantly lower estradiol, bioavailable estradiol, and follicle-stimulating hormone (FSH) (all p < 0.05) than women without angiographic CAD (n = 82), even after controlling for age. Hypoestrogenemia of hypothalamic origin, defined as estradiol <184 pmol/l (50 pg/ml), FSH <10 IU/l, and luteinizing hormone <10 IU/l, was significantly more prevalent among the women with CAD than those without CAD (9/13 [69%] vs. 24/82 [29%], respectively, p = 0.01). Hypoestrogenemia of hypothalamic origin was the most powerful predictor of angiographic CAD in a multivariate model (odds ratio [OR] 7.4 [confidence interval (CI) 1.7 to 33.3], p = 0.008). Anxiolytic/sedative/hypnotic and antidepressant medication use were independent predictors of hypoestrogenemia of hypothalamic origin in a multivariate model (OR 4.6 [CI 1.3 to 15.7], p = 0.02, OR 0.10 [CI 0.01 to 0.92], p = 0.04, respectively).

CONCLUSIONS: Among premenopausal women undergoing coronary angiography for suspected myocardial ischemia, disruption of ovulatory cycling characterized by hypoestrogenemia of hypothalamic origin appears to be associated with angiographic CAD.

Abbreviations and Acronyms
  ATP
  adenosine triphosphate
  CAD
  coronary artery disease
  CRH
  corticotrophin-releasing hormone
  FSH
  follicle stimulating hormone
  LH
  luteinizing hormone
  NHLBI
  National Heart, Lung, and Blood Institute
  WISE
  Women’s Ischemia Syndrome Evaluation

It has only recently been realized that the higher gender-specific coronary mortality observed in women (1–3) is due to increased death rates among relatively young women. Specifically, Vaccarino et al. (4) demonstrated that among women under 50 years of age, the hospital mortality rate for myocardial infarction was more than twice that for age-matched men (6.1% vs. 2.9%, p < 0.001 for interaction between age and gender). Little is known regarding relatively young, premenopausal women and coronary artery disease (CAD) pathophysiology and management. Because much CAD prevalence is attributable to older, postmenopausal women (5,6), recent interest has focused on increased rates of coronary angiography in older women (7) as well as hormone replacement therapy in postmenopausal women (8–10). Evaluation of CAD in premenopausal women has been overlooked, despite its being the leading killer of women in this age group, outpacing even breast cancer (4).

Previous work in primates has suggested that premenopausal atherosclerosis is related to stress-induced central disruption of ovulatory cycling and resulting hypoestrogenemia. Specifically, atherosclerosis is enhanced in young female cynomolgus monkeys subjected to psychosocial stress and subordinate social status that result in hypoestrogenemia of hypothalamic origin (11–13). Accordingly, we tested the hypothesis that hypoestrogenemia of hypothalamic origin is associated with CAD in young women in the Women’s Ischemia Syndrome Evaluation (WISE).


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
The WISE study is a National Heart, Lung, and Blood Institute (NHLBI)–sponsored four-center investigation designed to improve diagnostic testing and advance new hypotheses relative to the pathophysiology of ischemic heart disease in women. Women undergoing clinically ordered coronary angiography for suspected ischemia, but without unstable myocardial ischemia, were recruited into WISE. Subjects underwent a physical examination that included heart rate, blood pressure, height, weight, body mass index, and waist-hip ratio determination; demographics; medical history; and quantitative coronary angiography. Coronary risk factors were defined according to the National Cholesterol Education Program, Adult Panel III (14). The complete design and methodology of the WISE study are described elsewhere (15).

Premenopausal status and menstrual phase status determination.   Premenopausal status and menstrual phase (follicular, luteal, menstrual, anovulatory) were determined using a previously published reproductive status algorithm developed for the WISE (15). Premenopausal status was defined as no current use of hormone or oral contraceptive therapy, age <55 years, follicle-stimulating hormone (FSH) <15 IU/l and luteinizing hormone (LH) > FSH, and no history of bilateral oophorectomy. Current menstrual cycling was not considered a determinative variable in the algorithm, because 13/95 (14%) of the premenopausal women had a prior hysterectomy and because we hypothesized that women with the full syndrome of hypoestrogenemia of hypothalamic origin would have functional hypothalamic amenorrhea. Perimenopausal women, defined as FSH 15–30 IU/l and FSH > LH, were not included in the premenopausal group. All determinations were blind to the coronary angiography.

Environmental stress, psychological, and social status assessment
Chronic (preceding five years) environmental stress was sampled by a single question at study entry using a five-point scale questionnaire previously demonstrated to be predictive of future adverse cardiac events in patients with CAD (16). A score of ≥4 indicates chronically elevated environmental stress. Additional psychological assessments evaluated in the current report included typical depression (17) and trait anxiety (18). A score of ≥16 on the Beck Depression scale was considered to be depressive symptoms, and a score ≥19 on the Spielberger trait anxiety scale was considered to be anxious. Current use of psychotropic medication was considered evidence of more chronic psychological distress. Socioeconomic status assessment included marital/partner status, years of education, and job situation.

Reproductive hormone and lipoprotein core laboratories
Reproductive hormone assays (estradiol, bioavailable estradiol, estrone, progesterone, FSH, LH) were performed at the WISE reproductive hormone core laboratory from stored serum samples by an experienced technician (19). Validated steroid and protein assay methods were used, samples were assayed in batches of 100, and each determination was measured in duplicate. Methodology was maintained for the duration of the study. Previous work from this laboratory has demonstrated within- and between-assay coefficients of variation, respectively, of 15% and 16% for estrone, 8% and 12% for estradiol, and 3.7% and 4.2% for bioavailable estradiol (20). For the purpose of these analyses, "hypothalamic hypoestrogenemia" was defined as blood estradiol level <184 pmol/l (50 pg/ml), FSH level <10 IU/l, and LH level <10 IU/l. This definition was prospectively derived from examination of hypothalamic hypoestrogenemia primate animal (12,13) and human data (21).

Lipoprotein determinations were performed at a lipid core laboratory enrolled in the Centers for Disease Control and Prevention lipid standardization program previously used in multiple NHLBI-sponsored lipid-lowering intervention trials using the Friedewald formula, as previously published (22). The coefficients of variation for total cholesterol, high-density lipoprotein cholesterol, and hypoestrogenemia were 1.80%, 1.23%, and 3.93%, respectively.

Measurement of coronary angiography
An experienced core laboratory assessed coronary angiography. Measurements included quantitative assessment of the presence, severity, and complexity of epicardial coronary artery stenosis, using previously published methods, and a coronary severity score (23). For these analyses, angiographic CAD was defined as ≥70% luminal diameter stenosis in at least one epicardial coronary artery. Analyses using an alternative definition for CAD of ≥50% luminal diameter stenosis in at least one epicardial coronary artery provided similar results and are not presented.

Statistical analysis
Comparisons between women with and without angiographic CAD were performed by the Wilcoxon rank-sum test for continuous measures and by the Fisher exact test for discrete measures. Spearman correlations were performed between reproductive hormone levels and the coronary severity score. A p value of ≤0.05 was considered statistically significant. Stepwise logistic regression analysis was used to model angiographic CAD as a function of hypoestrogenemia of hypothalamic origin and other coronary risk factors, and to model hypoestrogenemia of hypothalamic origin as a function of psychosocial and other factors. Summary statistics for the regression models included the c-statistic (a measure of association of predicted probabilities and observed prevalence of a binary outcome) and R2 (rescaled for use in logistic regression). All analyses were performed using the SAS 6.12 software.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Among the 855 WISE participants with complete demographic, reproductive status, and coronary angiographic data, 95 (11%) were premenopausal, denied use of hormone therapy or oral contraceptives, and had no prior diagnosis of CAD (Table 1). Notably, despite a high prevalence of coronary risk factors, only a minority (14%) of these premenopausal women had angiographic CAD.


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  		Table 1 Premenopausal WISE Women Demographic and Coronary Risk Factor Variables

 
Coronary risk factor assessment among the women with (n = 13) and without (n = 82) angiographic CAD (Table 1) demonstrated a higher prevalence of diabetes mellitus (p = 0.02) and a higher waist-hip ratio (p = 0.01) in the CAD group. The global adenosine triphosphate (ATP) III coronary event risk calculation (13) was significantly higher in the CAD group (p = 0.05). Assessment of chronic comorbid conditions was similar between the groups, although aspirin use was higher (p = 0.004) and there was a trend toward greater corticosteroid drug use among the women with CAD (p = 0.09) (Table 1).

There were no group differences in historical reproductive variables, and current menstrual cycle phase was similarly distributed between the two groups (Table 2). Notably, among the 33 women with hypoestrogenemia of hypothalamic origin, 20 (61%) were categorized as anovulatory during the current cycle. There were no differences between the women with and without CAD with regard to reported environmental stress, depression, anxiety, psychotropic medication use, anorexia/bulimia, weight cycling, or socioeconomic status, indicated by marital status, education, and job situation/category (data not shown).


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  		Table 2 Premenopausal WISE Women Historical Reproductive Variables

 
Comparison of reproductive hormone levels by angiographic CAD status is shown in Figure 1. The women with angiographic CAD had significantly lower estradiol, bioavailable estradiol, estrone, and FSH levels than the women without angiographic CAD. Correlation analyses demonstrated moderate correlations between the coronary severity score and estradiol (r = –0.18, p = 0.08) and bioavailable estradiol (r = –0.19, p = 0.06). Overall, 33/95 (35%) of the women had hypoestrogenemia of hypothalamic origin, and women with angiographic coronary disease had a significantly higher prevalence of this than women without CAD (9/13 [69%] vs. 24/82 [29%], p = 0.01) (Table 2). Women with hypothalamic hypoestrogenemia also had a higher mean coronary artery severity score (13.8 ± 14.6 vs. 7.9 + 10.0, p = 0.005, respectively) than women without hypothalamic hypoestrogenemia.



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  		Figure 1 Reproductive hormone levels stratified by angiographic coronary artery disease (CAD) (≥70% luminal diameter stenosis in at least one epicardial coronary artery) (n = 95 women) (to convert bioavailable estradiol, estradiol, and estrone from picograms per milliliter to picomoles per liter, divide picomoles per liter by 3.671). The bottom and top of the boxes represent the 25th and 75th percentiles, respectively. The center horizontal line gives the sample median. The central vertical lines (the whiskers) range from the box to the 1.5 interquartile ranges from each side of the box (where an interquartile range is the distance between the 25th and the 75th percentile).

 
We next evaluated whether hypoestrogenemia of hypothalamic origin, and hypoestrogenemia alone (estradiol <184 pmol/l [50 pg/ml]), independently contributed to the presence of angiographic CAD. Correlations and partial correlations among estradiol, LH, and FSH demonstrated that they were highly related (r values above 0.5, p values <0.001). In a multivariate model, we initially evaluated demographics, risk factors, blood lipoprotein levels, psychologic scores, and medication usage (Table 3). The presence of hypothalamic hypoestrogenemia, aspirin use, and ATP-III 10-year risk >3% were the only remaining significant predictors after reducing the model through stepwise logistic regression. In a separate model, hypoestrogenemia alone was also a significant independent predictor. Although the specificity of prediction with hypoestrogenemia alone was lower than that with hypoestrogenemia of hypothalamic origin (67% vs. 71%, respectively), this difference was not significant. In separate models without the hypoestrogenemia variable, aspirin use and the ATP III global coronary risk score were the only remaining significant predictors, with diabetes entering as a potentially significant variable (p = 0.07).


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  		Table 3 Significant Predictors of Coronary Artery Disease*

 
We evaluated whether higher rates of recent illness or hospitalization leading to the index coronary angiography in women in our study with CAD could have a potential confounding effect of acutely lowering blood reproductive hormone levels (24). We assessed recent acute illness, defined as unstable angina in the past six weeks, renal dysfunction, asthma, or current antibiotic use, by angiographic CAD status and found no group differences in any of the medical comorbidity variables.

Finally, we explored potential biobehavioral associations between the psychosocial variables and hypoestrogenemia of hypothalamic origin as a possible mechanistic link to CAD. Angiographic CAD was significantly more prevalent in the women with than those without hypoestrogenemia of hypothalamic origin (9/33 [27%] vs. 4/62 [6%], p = 0.01). Coronary risk factors, ATP III coronary risk, historical reproductive variables, and psychological and social variables did not differ between women with and without hypoestrogenemia of hypothalamic origin (data not shown), although there was a trend toward more diabetes mellitus among the women with hypoestrogenemia of hypothalamic origin (10/33 [30%] vs. 9/61 [15%], p = 0.07, respectively). Notably, women with hypoestrogenemia of hypothalamic origin took less antidepressant medication (1/33 [3%] vs. 11/62 [18%], p = 0.05) but had a trend toward taking more antianxiety/sedative/hypnotic medication (9/33 [27%] vs. 9/62 [14%], p = 0.13) than the other group. In regression models with and without CAD as a predictor of hypoestrogenemia of hypothalamic origin, anxiolytic/sedative/hypnotic medication use, absence of antidepressant use, and diabetes mellitus were significant independent predictors (Table 4).


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  		Table 4 Significant Predictors of Hypoestrogenemia of Hypothalamic Origin

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Our findings demonstrate, for the first time, that hypoestrogenemia of hypothalamic origin is associated with CAD in premenopausal women undergoing coronary angiography for suspected myocardial ischemia. These results support the concept that female protection is lost when ovarian function is disrupted. Notably, traditional coronary risk factors, with the exception of diabetes, were similarly prevalent in women with and without CAD, suggesting that hypothalamic hypoestrogenemia may be a particularly potent risk factor for premenopausal women. These results are consistent with previous primate work demonstrating that atherosclerosis is significantly accelerated in monkeys with hypoestrogenemia secondary to disrupted ovarian function of hypothalamic origin induced by stress due to social subordination (11–13), as well as with work in humans demonstrating elevated CAD risk associated with premature menopause in women (25–27).

The current study results also provide a potential mechanism to explain the greater CAD mortality experienced in relatively younger women when compared with age-matched men with CAD (10). In this study, neither CAD severity nor medical treatment regimens could account for the increased mortality observed in these younger women, suggesting the possibility of inherent gender-specific pathophysiologic differences. Previous animal (28) and human work (4,29) has demonstrated that hypoestrogenemia in females is accompanied by coronary artery dysfunction, characterized by a diminution of normal vasodilation and even vasoconstriction in response to a stressor. Our current results document that premenopausal women with CAD may have hypoestrogenemia and, therefore, may have more adverse coronary arterial dysfunction. Although we are unable to link these results with mortality in this relatively small sample size, they suggest that premenopausal women with CAD could be at higher mortality risk stemming from hypoestrogenemia-related adverse physiologic effects.

Previous animal (11–13) and human investigation (21,30,31) document an association between environmental psychologic stress and functional hypothalamic amenorrhea, which was present in our study in 61% of the women with hypoestrogenemia of hypothalamic origin and probably represents the full syndrome of centrally mediated disruption of ovarian function. Additional factors identified for functional hypothalamic amenorrhea in humans include intense physical exercise (32), anorexia/bulimia (33), and weight loss (34). Biologic mechanisms linking these various forms of stress, both physical and psychologic, with functional hypothalamic amenorrhea may include corticotrophin-releasing hormone (CRH) suppression of gonadotropin-releasing hormone-producing neurons in the central nervous system (35), resulting in impaired folliculogenesis in the ovary (36), although recent work by two of the authors of the present study (S.L.B., K.A.M.) suggests that CRH may not be the stimulus (36). The subgroup size of 20 women (21%) with functional hypothalamic amenorrhea in our study unfortunately was too small to assess associations with this entity alone, but using the larger subsample of 35% women with hypoestrogenemia of hypothalamic origin, we found no associations with body mass index, reported levels of physical activity, weight cycling, anorexia/bulimia, or recent acute illness. This lack of association may be due to inadequate statistical power or may suggest that these factors were not an operative cause of the hypoestrogenemia of hypothalamic origin in the women in our study. Notably, the mean age of women in our study (43 years) is older than that in previous studies of functional hypothalamic amenorrhea (32–34), and we had very low prevalences of intense exercise, low body weight, and anorexia/bulimia, suggesting that the triggers of centrally disrupted ovarian function may differ by age in women.

Although psychometric measures of environmental stress, anxiety, and depression did not appear to be associated with hypoestrogenemia of hypothalamic origin, this may have been due to the relatively high levels of psychologic stress in both groups of women in our study undergoing evaluation for suspected myocardial ischemia, compounded by the psychosocial assessment falling in close temporal proximity to the coronary angiography. Our findings that the use of anxiolytic/sedative/hypnotic medications and the absence of use of antidepressant medications were independent predictors of hypoestrogenemia of hypothalamic origin suggest biobehavioral links because these medications are prescribed by physicians and may therefore more accurately reflect ongoing clinical distress. The differing directions of associations between the two classes of medications (anxiolytic/sedative/hypnotics vs. antidepressants) with hypothalamic hypoestrogenemia might be interpreted as demonstrating the difference between medications that treat symptoms (anxiolytic/sedative/hypnotic) and those that beneficially alter central nervous system function (antidepressants). Alternatively, the negative association with antidepressant drug use could signify untreated depression in women in our study because there were no group differences in the self-reported depression scores. Further work validating these results and prospectively assessing social and psychologic links is needed.

Not surprisingly, we did find a significantly higher prevalence of diabetes mellitus among premenopausal women with CAD in our study, but notably our results also demonstrate a strong independent association between diabetes and hypoestrogenemia of hypothalamic origin. Indeed, these findings are consistent with previous epidemiologic data, which demonstrate that diabetic premenopausal women have more frequent menstrual irregularities (37), lower blood estrogen levels, and higher androgen levels than non-diabetic women (38), factors that probably contribute to the lower fertility rates observed in diabetic premenopausal women. Menstrual irregularity is also predictive of future diabetes (39) and may be a marker for polycystic ovary syndrome (40), although the low levels of LH observed in women in our study suggest that polycystic ovary disease was not a contributor in this population. Our finding of a diabetes-related estrogen deficiency, if validated in prospective study, may provide an explanation for the relatively greater coronary risk that diabetes conveys for women than men, which has been observed repeatedly in previous studies (41) and which remains unexplained.

Our multivariate analyses suggest that hypothalamic hypoestrogenemia is a significant predictor of CAD, consistent with a previous report demonstrating an inverse relationship between estrogen levels and coronary artery severity in premenopausal women (42) and with numerous animal studies implicating estrogen as a key player in atherosclerosis (43,44). Notably, Kaplan and co-workers have demonstrated that contraceptive hormone treatment inhibits the acceleration of atherosclerosis observed in subordinate, estrogen-deficient female monkeys (45). The use of hormone replacement therapy with conjugated equine estrogen-medroxyprogesterone acetate in older postmenopausal women remains of uncertain value (10). Simple replacement of estrogen may not fully address the underlying hormonal abnormalities that are associated with hypoestrogenemia of hypothalamic origin.

Limitations.   The current study results are limited by our small sample size that reduces the confidence of our findings. Specifically, calculations using a two-tailed alpha of 0.05 with 80% power indicate that group differences had to be at least 37% to be detectable in the present sample. Also, our cross-sectional design precludes inferring a causal relationship between hypothalamic hypoestrogenemia and angiographic CAD. Coronary artery disease may actually lead to hypoestrogenemia of hypothalamic origin through unknown pathophysiologic mechanisms, rather than resulting as a consequence, as we have hypothesized. Alternatively, a common explanatory mechanism, such as chronic stress, could have an etiologic role in both disorders. Our measure of environmental stress was a single question rather than a scale and is probably less reliable and valid.

Conclusions
Among premenopausal women with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia, hypoestrogenemia of hypothalamic origin is associated with angiographic CAD. Use of anxiolytic/sedative/hypnotic medication is an independent predictor of hypoestrogenemia of hypothalamic origin in a multivariate model, suggestive of a biobehavioral link. These findings suggest the possibility that estrogen deficiency due to central disruption of ovarian function may be a risk factor for CAD in premenopausal women.


   Footnotes
 
This work was supported by contracts from the National Heart, Lung, and Blood Institutes, nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, and N01-HV-68164; a GCRC grant, MO1-RR00425, from the National Center for Research Resources; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Denville, New Jersey, The Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, California, and The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania.


   References
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 Discussion
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