Was the main negative estradiol study in men wrong?

[Nelson Vergel]

Was increased mortality due to high CRP or high estradiol?


The study (abstract below) is one of the most cited when mentioning the negative effect of estradiol in men's mortality due to cardiovascular disease. It was a review of men with previous heart disease history. It used the immunoassay estradiol blood test which was later found to overestimate estradiol due to interference from C-Reactive Protein (CRP), an inflammatory protein linked with increased cardiovascular risk and inflammation.


This study found that estradiol levels of < 21.80 pg/ml and > 30.11 pg/ml (measured by the immunoassay test) resulted in greater mortality in men. No CRP measurements were reported in these men with history of chronic heart failure.


In the another study, immunoassay E2 but not the more accurate liquid chromatography/mass spectrometry (LC/MS) E2 levels were associated inversely with ankle-brachial index (ABI), a quick, noninvasive way to check the risk of peripheral artery disease . Importantly, this association was lost after adjustment for serum CRP, suggesting interference with the E2 immunoassay, possibly by CRP or a CRP-associated factor. This implies that the observed inverse relation between serum immunoassay E2 levels and heart disease risks in the previously mentioned study may be misleading. Also, previous findings of associations between high serum E2 levels and inflammation-related phenotypes such as atherosclerotic coronary vascular disease- CVD (7, 8, 10) may have been the result of interference with the immunoassay-based E2 levels. Indeed, similar to the lack of association between MS-based E2 levels and ABI in the present study, we found no association between MS-based E2 levels and cardiovascular events in the Swedish MrOS study (11). Therefore, it seems appropriate to suggest a reevaluation of previous association studies between immunoassay-based E2 levels and CVD phenotypes or other inflammation-related end points in studies with MS E2 levels available. In this respect, a recent study by Yeap et al (18) reported a lack of association of low E2 levels measured by liquid chromatography tandem MS and CVD, diabetes, and frailty. - See more at: http://press.endocrine.org/doi/full/10.1210/jc.2012-3861#sthash.e066HOpS.dpuf





Reference:

Circulating estradiol and mortality in men with systolic chronic heart failure.
JAMA 2009 May 13;301(18):1892-901.
Circulating estradiol and mortality in men with systolic chronic heart failure.


Abstract

CONTEXT:

Androgen deficiency is common in men with chronic heart failure (HF) and is associated with increased morbidity and mortality. Estrogens are formed by the aromatization of androgens; therefore, abnormal estrogen metabolism would be anticipated in HF.


OBJECTIVE:

To examine the relationship between serum concentration of estradiol and mortality in men with chronic HF and reduced left ventricular ejection fraction (LVEF).


DESIGN, SETTING, AND PARTICIPANTS:

A prospective observational study at 2 tertiary cardiology centers (Wroclaw and Zabrze, Poland) of 501 men (mean [SD] age, 58 [12] years) with chronic HF, LVEF of 28% (SD, 8%), and New York Heart Association [NYHA] classes 1, 2, 3, and 4 of 52, 231, 181, and 37, respectively, who were recruited between January 1, 2002, and May 31, 2006. Cohort was divided into quintiles of serum estradiol

quintile 1, < 12.90 pg/mL;
quintile 2, 12.90-21.79 pg/mL;
quintile 3, 21.80-30.11 pg/mL;
quintile 4, 30.12-37.39 pg/mL;
and quintile 5, > or = 37.40 pg/mL.

Quintile 3 was considered prospectively as the reference group.


MAIN OUTCOME MEASURES:

Serum concentrations of estradiol and androgens (total testosterone and dehydroepiandrosterone sulfate [DHEA-S]) were measured using immunoassays.


RESULTS:

Among 501 men with chronic HF, 171 deaths (34%) occurred during the 3-year follow-up. Compared with quintile 3, men in the lowest and highest estradiol quintiles had increased mortality (adjusted hazard ratio

---

, 4.17; 95% confidence interval [CI], 2.33-7.45 and HR, 2.33; 95% CI, 1.30-4.18; respectively; P < .001). These 2 quintiles had different clinical characteristics (quintile 1: increased serum total testosterone, decreased serum DHEA-S, advanced NYHA class, impaired renal function, and decreased total fat tissue mass; and quintile 5: increased serum bilirubin and liver enzymes, and decreased serum sodium; all P < .05 vs quintile 3). For increasing estradiol quintiles, 3-year survival rates adjusted for clinical variables and androgens were

quintile 1, < 12.90 pg/mL; 3 Year Survival Rate: 44.6%
quintile 2, 12.90-21.79 pg/mL; 3 Year Survival Rate: 65.8 %
quintile 3, 21.80-30.11 pg/mL; 3 Year Survival Rate: 82. 4%
quintile 4, 30.12-37.39 pg/mL; 3 Year Survival Rate: 79.0 %
and quintile 5, > or = 37.40 pg/mL. 3 Year Survival Rate: 63.6 %

All respectively significantly different than control group (quintile 3) (P < .001).

 

[MikeXL]

I think that it is very hard to compare the two studies. They were designed with different end points in mind

 

[Nelson Vergel]

I am not comparing them. All I am saying that old studies that used the old immunoassay estradiol test should not be used to draw conclusions about cardiovascular mortality since that test actually may be measuring estradiol + CRP. CRP is a known variable in inflammation and cardiovascular disease.

 

[johndoesmith]

Nelson that is an interesting question you have.

One thing I will say, is that mortality seems to increase more with LOW estradiol, and CRP being elevated would not explain that. I think this study shows that low E2 is much much more of a health concern than high E2 is.

For the "high" E2 groups, it certainly seems possible that CRP is playing a role, or rather that whatever condition is causing elevated CRP is playing a role.

 

[mike7]

Great info, very thought provoking, thanks for posting it.