Those questions are still largely unanswered, but a very interesting trial published recently aimed to reopen the question of the true effects of HRT on cardiovascular outcomes in postmenopausal women. The findings of the Kronos Early Estrogen Prevention Study (KEEPS) came out recently.1 The lead author and lead investigator Dr. S. Mitchell Harman is a close friend of mine who served recently as my Chief of Endocrinology at the Phoenix VA and then became my interim successor as Chief of Medicine when I moved to the Greater Los Angeles VAMC because of my wife’s Sjogren’s-driven need for a more humid climate.
The KEEPS trial was a 4-year, randomized, double-blind, placebo-controlled trial in 727 women aged 45 to 54 years who were all newly menopausal, so that the effects of HRT could be assessed right after the onset of menopause. The KEEPS investigators hoped to demonstrate a favorable effect on cardiovascular outcomes with the administration of HRT so early on, but the trial was unfortunately too small to come up with those results. However, the trial went for its full planned duration, because there were absolutely no harmful effects seen with either oral conjugated estrogen therapy or with transdermal estrogen therapy, each of which was given together with oral progesterone.
There was a trend toward a slower increase in coronary artery calcium (CAC) scores in the minority of women who had elevated scores to begin with. But overall there was no difference in the rate of progression of either CAC scores or of carotid
intima-media thickness as measured by ultrasound; the latter is a standard research measure used to detect subtle differences in the rate of progression of cardiovascular disease. A pessimist would observe quite correctly that estrogens did not show a protective effect on cardiovascular outcomes, apart from the hint of a slower rate of progression of CAC scores in those with elevated levels at the onset. But an optimist would say that these results demonstrate the cardiovascular safety of early postmenopausal HRT, since there was no signal at all of a harmful effect.
So where does this leave us now? Unfortunately, we are completely bereft of definitive answers, and we are unlikely to get meaningful new data anytime soon, as there is currently zero enthusiasm at the NIH for devoting scarce resources to a re-examination of these same issues.
The bottom line is that we can agree that cardiovascular worries need to be put into proper perspective and that they have been overblown, at least in the lay press. I further believe that younger postmenopausal women who have solid indications for such therapy, be they hot flushes or advanced osteoporosis, should not be denied the benefits of HRT because of cardiovascular concerns.
I would be willing to consider long-term open-ended therapy in at least some of these patients. And let’s also not forget that estrogens clearly reduce the incidence of colon cancer and may well reduce the prevalence of the much-dreaded Alzheimer disease that awaits many older women.
I’ll be the first to acknowledge that this editorial is ending with not a bang, but a whimper. But that’s about the best I can come up with given the extremely severe limitations of the data available to us. I’ll consider this editorial a success if it encourages you to at least keep an open mind on the issue of the cardiovascular effects of estrogens and to accept my premise that we still lack so much of the data we truly need to reach definitive conclusions.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
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