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

J Am Coll Cardiol. 2003 Feb 5;41(3):413-9. doi: 10.1016/s0735-1097(02)02763-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age Factors
  • Coronary Angiography
  • Coronary Artery Disease / blood*
  • Coronary Artery Disease / diagnostic imaging
  • Coronary Artery Disease / etiology*
  • Estrogens / blood*
  • Female
  • Humans
  • Hypothalamic Diseases / blood*
  • Hypothalamic Diseases / complications*
  • Hypothalamic Diseases / diagnostic imaging
  • Middle Aged
  • Myocardial Ischemia / blood*
  • Myocardial Ischemia / diagnostic imaging
  • Myocardial Ischemia / etiology*
  • National Institutes of Health (U.S.)*
  • Predictive Value of Tests
  • Premenopause / blood*
  • Risk Factors
  • Sex Factors
  • United States


  • Estrogens