EDITORIAL

Another Reason For Women to Avoid Estrogen?

CINDY L. GRINES, M.D., DEREK C. WHITE, B.S.,

and THEODORE SCHREIBER, M.D.

From the Detroit Medical Center Cardiovascular Institute, Detroit, Michigan

(J Interven Cardiol 2014;27:444–445)

The risks and benefits of hormone replacementtherapy (HRT) in postmenopausal women are stillcontroversial. According to early observational data,estrogen replacement was thought to be cardioprotec-tive. However data from several prospective, random-ized studies did not confirm this protective effect, infact some studies found an increase in cardiovascularevents including myocardial infarction, stroke as wellas venous thromboembolism.1–4 Unfortunately, thesestudies allowed enrollment of older patients (mean age63 years) several years after menopause; a scenariowhich is not clinically relevant since women takeestrogen in the early perimenopausal period to reducehot flashes.A subsequent analysis suggested that “younger”

postmenopausal women did not have increasedcardiovascular risk from HRT.5 Moreover, additionalstudies have shown that transdermal forms of estrogendid not seem to be associated with an increasein clotting potential. Based on these data, manygynecologists continue to prescribe HRT, however, atlower doses, shorter duration and more transdermaladministration.The potential cardiovascular benefits of estrogen

may include improvement in lipid profiles, enhancedendothelial function and insulin sensitivity. However,HRT also has detrimental effects including a pro-thrombotic effect and an increase in inflammatorymarkers. Therefore, despite the above findings of noharm for primary prevention in “younger” premeno-

pausal women, HRT is not recommended in patientswith established cardiovascular disease.Although there is controversy about HRT, based

on epidemiology studies, one may assume thatendogenous estrogen is beneficial. It appears thatpremenopausal women do have cardioprotection fromendogenous estrogen released from the ovaries.However, in postmenopausal women, endogenousestrogen typically arises from adipose tissue6 and isnot associated with a lower incidence of cardiovasculardisease7 with one study showing an increased risk.8

In addition, large studies have found that youngwomen (compared to young men) have very high riskof mortality after MI.9,10 Of course young women withAMI have many comorbidities, tend to present laterwith atypical symptoms of MI, and receive lessaggressive treatment; but even after risk‐adjustment,mortality in young women remained higher.10 Whetherthis is due to differences in collateral flow, baselinelower cardiac output making the female patientintolerant of myocardial infarction, or differencesin mechanism of MI (plaque erosion, spontaneousdissection or takotsubo stress cardiomyopathy) isunknown.In this current issue of the Journal of Interventional

Cardiology, Dong and colleagues suggest that endoge-nous estrogen may have a detrimental effect on no‐reflow after primary PCI for STEMI.11 They enrolled100 postmenopausal womenwhowere not taking HRT,and found that in patients who had no‐reflow (definedas myocardial blush grade<2), there were significantlyhigher levels of endogenous estrone, estradiol and sexhormone binding globulin. In a multivariate analysis,endogenous hormones were independently predictive

Address for reprints: Cindy L. Grines, M.D., 311 Mack Ave,Detroit, MI 48201. Fax: (313) 745 9021; e‐mail: Cgrines@dmc.org

© 2014, Wiley Periodicals, Inc.DOI: 10.1111/joic.12152

444 Journal of Interventional Cardiology Vol. 27, No. 5, 2014

of no‐reflow. Interestingly, the entire cohort of 100women were relatively young (age 63), diabetics(>40%) with late reperfusion (>5 hours), and lesionswere long (approximately 30mm) with high thrombusburden. Although we do not have a male comparatorarm, these women and lesions appear to be higher risk,and may not be representative of women reported inother STEMI clinical trials.Moreover, one does not know how many women

were peri‐menopausal versus late menopause. Whereasestrone is primarily generated by adipose tissue, theestradiol may be generated from adipose or fromresidual ovarian function. This may be of importancesince spontaneous coronary dissection (and perhapsother unusual mechanisms of MI), may occur duringtimes of widely fluctuation estrogen levels.12,13

Similar to this current report, prior studies haveshown that high thrombus burden, low initial flow,larger baseline infarct size, low ejection fraction,anterior MI, prior MI, C‐reactive protein, elevatedblood counts, high SYNTAX score, and delay inreperfusion were predictive of no‐reflow after primaryPCI.14–16 The potential mechanism of no‐reflow ismultifactorial, and may include platelet and leukocyteplugging, distal embolization, myocardial edema, and/or reperfusion injury. The current study confirms thesefindings, but also suggests that among postmenopausalwomen, estrogen levels are predictive. Although thisstudy is limited by a very small sample size, one mayspeculate that the prothrombotic and proinflammatoryeffects of estrogen could be playing a role. Whetherfluctuating or abnormal hormone levels create unusualmechanisms of MI or increase the risk of no‐reflowand death in women with infarction, needs furtherinvestigation.

References

1. Gabriel SR, Carmona L, Roque M, et al. Hormone replacementtherapy for preventing cardiovascular disease in post‐menopaus-al women. Cochrane Database Syst Rev 2005; CD002229.

2. Rossouw JE, AndersonGL, Prentice RL, et al. Risks and benefitsof estrogen plus progestin in healthy postmenopausal women:Principal results from the Women’s Health Initiative randomizedcontrolled trial. JAMA 2002;288:321.

3. Anderson GL, Limacher M, Assaf AR, et al. Effects ofconjugated equine estrogen in postmenopausal women withhysterectomy: The Women’s Health Initiative randomizedcontrolled trial. JAMA 2004;291:1701.

4. Prentice RL, Langer RD, StefanickML, et al. Combined analysisof Women’s Health Initiative observational and clinical trial dataon postmenopausal hormone treatment and cardiovasculardisease. Am J Epidemiol 2006;163:589.

5. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausalhormone therapy and risk of cardiovascular disease by age andyears since menopause. JAMA 2007;2997:1465.

6. Freeman W, Sammel D, Lin Garcia R, et al. Obesity andreproductive hormone levels in the transition to menopause.Menopause 2010;17:718–726.

7. Chen Y, Zeleniuch‐Jacquotte A, Arslan AA, et al. Endogenoushormones and coronary heart disease in postmenopausal women.Atherosclerosis 2011;216:414–419.

8. Scarabin‐Carre v, CanonicoM, Brailly‐Tabard S, et al. High levelof plasma estradiol as a new predictor of ischemic arterial diseasein older postmenopausal women: The three city cohort study.J Am Heart Assoc 2012;1:3001388.

9. VaccarinoV, Parsons L, EveryNR, et al. Sex‐based differences inearly mortality after myocardial infarction. National Registry ofMyocardial Infarction 2 participants. N Engl J Med 1999;341:217–225.

10. Zhang Z, Fang J, Gillespie C, et al. Age‐specific genderdifferences in in‐hospital mortality by type of acute myocardialinfarction. Am J Cardiol 2012;109:1097–1103.

11. Dong M, Mu N, Ren F, et al. Prospective study of effects ofendogenous estrogens on myocardial no‐reflow risk in postmen-opausal women with acute myocardial infarction. J IntervCardiol 2014. doi: 10.1111/joic.12137. [Epub ahead of print].

12. Brenner R, Weilenmann D, Maeder M, et al. Clinical character-istics, sex hormones, and long‐term follow‐up in swisspostmenopausal women presenting with Takotsubo cardiomy-opathy. Clin Cardiol 2012;6:340–347.

13. Tweet MS, Hayes SN, Pitta SR, et al. Clinical features,management and prognosis of spontaneous coronary arterydissection. Circulation 2012;126:579–588.

14. Niccoli G, Burzotta F, Galiuto L, Crea F.Myocardial no‐reflow inhumans. J Am Coll Cardiol 2009;54:281–292.

15. Ndrepepa G, Tiroch K, Keta D, et al. Predictive factors andimpact of no reflow after primary percutaneous coronaryintervention in patients with acute myocardial infarction. CircInterv 2010;3:27–33.

16. Romano M, Buffoli F, Tomasi L, et al. The no‐reflowphenomenon in acute myocardial infarction after primaryangioplasty: Incidence, predictive factors and long termoutcome. J Cardiovasc Med 2008;9:59–63.

Vol. 27, No. 5, 2014 Journal of Interventional Cardiology 445

EDITORIAL