Oral, but not transdermal, estrogen increases CRP

Susan Jeffrey

April 15, 2003

Tue, 15 Apr 2003 21:00:00

Bethesda, MD - In a head-to-head crossover comparison, oral estrogen therapy (ET) was associated with a sustained increase in the inflammatory marker C-reactive protein (CRP) among postmenopausal women while estrogen delivered via a transdermal patch was not. The rise in CRP was accompanied by a decrease in insulinlike growth factor (IGF-1), an anti-inflammatory growth factor.

The new report appears in the April 16, 2003 issue of the Journal of the American College of Cardiology.

"Because CRP is a powerful predictor of an adverse prognosis in otherwise healthy postmenopausal women, the route of administration may be an important consideration in minimizing the adverse effects of ET on cardiovascular outcomes," the researchers, with first author Dr Wangpen Vongpatanasin (University of Texas Southwestern Medical Center, Dallas), conclude.

Those adverse effects were shown most definitively in the Women's Health Initiative (WHI) reported last year, a randomized trial using oral estrogen plus progestin. "One could postulate that we might not have the same result if this study were repeated using a transdermal form of estrogen," Vongpatanasin told heartwire in an interview. "We don't know that for sure, but I think it's an intriguing hypothesis."

Avoiding the liver

Recent randomized trials such as WHI and a variety of other randomized clinical and angiographic trials have failed to confirm the cardiovascular benefit from hormone replacement therapy that was first observed in epidemiological studies. Investigation in the meantime has shown that estrogen causes sustained increases in CRP, which in turnas was shown recently by researchers using the Women's Health Study datais the "strongest independent predictor of myocardial infarction and cardiovascular mortality in apparently healthy women," Vongpatanasin et al write.

Because CRP is produced mainly in the liver, they hypothesized that oral estrogen may raise CRP when the liver is exposed to high concentrations of estrogen after gastrointestinal absorption. Transdermal estrogen is absorbed directly into the bloodstream, bypassing the liver, thereby possibly avoiding the increase in CRP seen with oral estrogens.

To test this hypothesis, Vongpatanasin and colleagues, some at the University of California, Davis, used a randomized, crossover, placebo-controlled design to investigate the differential effects of transdermal and oral estrogen on CRP and other inflammatory cytokines in 21 postmenopausal women.

Each woman underwent eight weeks of treatment with each of three combinations of oral estrogen therapy (0.625 mg/day conjugated equine estrogen [CEE]), transdermal estradiol (100 g/day) and placebo in random order; that is, placebo patch and oral estrogen, oral placebo and transdermal estrogen, and both an oral placebo and placebo patch.

Measures of CRP, interleukin (IL)-1-, IL-6, and tumor necrosis factor- were taken before and after each eight-week treatment period. They also measured IGF-1, an anabolic peptide also produced in the liver, which has been shown to have an anti-inflammatory property.

They found that CRP was significantly increased compared with baseline only with oral estrogen therapy. Similarly, IGF-1 was significantly reduced with estrogen therapy, although none of the other cytokines measured showed any significant change. The transdermal preparation had no significant effect on any of the parameters measured.

Effect of eight weeks of oral vs transdermal estrogen vs placebo on inflammatory cytokines



Oral CEE


Transdermal estradiol


1.50 (0.80-4.50)
3.70 (1.55-6.20)
1.15 (0.73-3.70)
1.40 (0.7-4.00)
*For comparison between baseline and three treatment groups. Changes with oral CEE were significant at p<0.01 compared with baseline, placebo, and transdermal estradiol.Findings expressed as median value (interquartile range) for hs-CRP, mean value +SEM for IGF-1.To download table as a slide, click on slide logo below

Vongpatanasin pointed out that their study is small and still has used only surrogate, not clinical, end points to measure the effects of estrogen on risk. What can be said, though, is that the action of estrogen is "far more complex than we thought and suggests that the effects of one preparation probably cannot be extrapolated to others, particularly in terms of route of estrogen replacement," she said.

The National Institutes of Health are considering repeating previous trials on a smaller scale using other doses and routes of administration, she added. Their group also hopes to do further work in this area, looking at other intermediate effects of different modes of administrationother than those on CRPincluding effects on hypertension and on harder clinical end points (death, MI, etc).

The work is still important, she says, because many women feel they cannot stop taking hormone replacement therapy in the face of debilitating menopausal symptoms. "A large percentage of women are still going to require hormones, and rather than simply say, 'Tough it out, just stop it,' why don't we try to understand what went wrong, and what are the bad mediators in terms of side effects?" she said. "If we can figure that out, perhaps we can find a way to give some sort of estrogen replacement that does not have these effects."

Related links

1. [Heartwire > News; Mar 17, 2003]

2. [Heartwire > News; Mar 6, 2003]

3. [Heartwire > News; Jan 16, 2003]

4. [Heartwire > News; Oct 29, 2002]


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