Heart Disease and Hormone Replacement Therapy (HRT)

The ongoing mixed messages regarding the cardiovascular safety of hormone replacement therapy (HRT) in the treatment of menopause are despairing for both patients and doctors alike. It is important to think about the relationship between women’s hormones, heart disease, and menopause in broad principles–otherwise, we’d be a candle in the wind to the next press release or statistic.

Previously I have expressed why, I believe, menopausal women considering bioidentical HRT (BHRT) don’t need to worry as much about breast cancer. Now, I’d like to focus on whether or not BHRT is indicated in the prevention of heart disease.

Every year over 400,000 women die of cardiovascular heart disease (as compared to about 40,000 women who die annually of breast cancer) making it the leading cause of death in women. So, the impact of bioidentical HRT on heart disease, one way or the other, is of utmost importance. Notice, I write “BHRT” and not just “HRT.” This is an important difference.

Now, without knowing any statistics, what do we know about women and their hormone cycles, menopause, and risk of heart disease?

1. Premenopausal, reproductive, women produce varying daily amounts of estradiol and progesterone which result in a menstrual period approximately every 28 days, unless they are pregnant or breast-feeding. The term “hormonal,” although unfortunately many times used in a derogatory way, is a good way to remember that reproductive women have different hormone levels at different times of the month. (Click here and press “play all” to interactively see how these hormone levels change over a normal menstrual cycle.)
2. Women in menopause or postmenopause do not produce ANY significant amounts of estradiol or progesterone anymore, and therefore have an estrogen and progesterone deficiency. (Click here to view hormone levels before, during, and after menopause.)
3. Heart disease is rare in premenopausal women, more common in prematurely menopausal, much more common in postmenopausal women, and very common in men.

From the above basic observations, scientists hypothesized that estrogen was the reason why women in general, and especially women before menopause, are protected from heart disease in comparison to men. Estrogen was thought so much to be protective against heart disease, particularly due to its positive effects on cholesterol, that in 1963 the oral unopposed estrogen Premarin (which is not bioidentical) was actually tested in men with heart disease. This counterintuitive use of estrogen (a primarily female hormone) on these men was attempted because men with a history of heart disease have the highest risk of recurrent cardiac events and so were therefore thought ideal candidates for a secondary prevention study of estrogen which could quickly discern its positive or negative outcomes. In 1966, however, a randomized trial using Premarin in men with heart disease was stopped early due an increased risk of blood clots and heart attacks. This negative result halted clinical trials on estrogens and cardiovascular disease for the next 20 years or so, although women still used Premarin for menopausal symptoms and classic animal experiments since the 1950’s continued to demonstrate that estrogens prevent hardening of the arteries (atherosclerosis) and significantly improve cholesterol.

In 1987, a pivotal follow-up report of the Lipids Research Clinics Program, which observed about 2200 postmenopausal women over 8.5 years, showed that estrogen (primarily Premarin) significantly reduced cardiac events in women. In 1991, a UCSD review of 24 observational studies showed around a 50% reduced risk of cardiac events in postmenopausal women ingesting Premarin. In 1992, a landmark UCSF meta-analysis of 32 observational studies showed that postmenopausal women taking Premarin (3 studies included a cyclic progestin) had about a 35% reduced risk of fatal heart disease. In 1998, at a time when Premarin was the most commonly prescribed drug in the US, a UCSD meta-analysis of 25 observational studies showed an estimated 30% reduced risk of heart disease in women using Premarin and a 34% reduced risk in 7 observational studies which used Premarin and cyclic progestin or cyclic progesterone. In 2001, the Nurses’ Health Study, which followed over 70,000 healthy postmenopausal women between 1976 and 1996, reported that nurses taking Premarin showed an approximately 40% reduced risk of cardiovascular disease.

So why the change of heart? With all of these observational studies showing a positive cardiovascular effect, why is there so much ongoing controversy about whether or not HRT is beneficial for heart disease? Well, observational studies are limited in that they may be biased by confounding factors, so the necessary randomized trials were initiated. The most famous of these randomized trials, the Women’s Health Initiative (WHI), was stopped prematurely and claimed in 2002 that HRT increases the risk of heart disease in healthy postmenopausal women. This was the biggest blow HRT has received in our lifetime and many women and physicians are still living in fear of its press releases.

Now, when new information contradicts more than 30 years of observational knowledge and basic science and animal experiments, it’s a good time to think twice and start asking questions before jumping to any conclusions.

(Note: While answering these questions is outside the scope of this article, some clues to this paradox are: unopposed estrogen (estrogen administered without a progestin or progesterone) was found to increase the risk of uterine cancer; the type of hormones used in the Women’s Health Initiative matters; the method of hormone administration used in the WHI matters, and the difference between bioidentical hormone replacement therapy (BHRT) and conventional HRT matters.)