Hormone Replacement Therapy and Heart Disease

In recent years I have seen men have their testosterone levels checked more often than their cholesterol profile. What’s more interesting is the amount pharmaceuticals have invested to create testosterone supplements for men with “low T”: there are gels and rubs and various other products. But what about women? The last anyone talked about our hormonal needs was in 2002 when the HERS (Heart and Estrogen/Progestin Replacement Study) and WHI (Women’s Health Initiative) trials put a kibosh on the use of hormone replacement therapy (HRT) for the prevention and possibly treatment of cardiovascular disease (CVD).

But is it really that simple? What about women who are suffering from peri-menopausal symptoms like hot flashes or insomnia for years? Or the ones who must have their ovaries remove and are immediately put into ‘surgical menopause’? What about the long-term risk of osteoporosis? And what about some of us who are physically menopausal but mentally aren’t there yet? Is it vain to say, “I’m not ready for the sagging skin or those crow’s feet?”

I did my cardiology training after the HERS and WHI studies were released about HRT. Therefore, I was taught an absolute: HRT, i.e. estrogen, is bad for women after menopause. Period. It does nothing good for the heart and therefore it should not be used. That’s easy enough. The young residents and fellows wouldn’t dare challenge a gray haired man who would be grading them. That’s OK in an academic setting, but in practice it can be a challenging decision. I have had to convince my well-read, “google-researching” female patients why, in general, I think it is not good for them or why, in their particular situation, I think they could be on HRT if they so chose. I could comb through the evidence with them but what’s worth more is explaining the physiology and maybe that will help guide therapy.

Estrogen is an interesting hormone, as it takes on different roles in different environments: it does good things in good environments and does bad things to bad environments. Take a clean, smooth artery and expose it to estrogen and it stays that way. Having more estrogen is the main reason why most women don’t develop heart disease until 10 years later than men do. Take an artery with plaque on it and expose it to estrogen and that’s bad news. This is why estrogen should not be used for secondary prevention of CVD, i.e. when women have known heart disease and are trying to avoid more.

The benefits of estrogen depend on many different factors, including: 1) the route of administration – pill or patch; 2) the dose; 3) when it is started in relation to menopause; 4) the simultaneous use of other medications – statins for cholesterol, in particular; and of course, 5) one’s genetic makeup.

Let’s start with the route of administration. When oral estrogen is absorbed through the gut, it passes through the liver where it can influence the production of cholesterol (specifically good cholesterol), and that of coagulation factors. Estrogen is responsible for the higher levels of good cholesterol in women than men before menopause; coagulation factors increase the risk of forming blood clots where they don’t belong. With estrogen patches, however, the hormone is absorbed directly into the blood instead of passing through the liver. This may explain why there has been a lower incidence of developing clots and other complications in women who use the patch. A 2012 KEEPS Trial (Kronos Early Estrogen Prevention Study) showed that transdermal administration of estrogen had a neutral effect on lipid profile and a positive effect on insulin resistance, which influences the development of diabetes. Another study called the ESTHER Trial (published in 2007) followed by a meta-analysis in 2008 showed that estrogen patches were not associated with an increased risk of blood clots. Thus, transdermal routes have shown lower rates of adverse effects than oral estrogen.

The WHI study was essentially a game changer for women and heart disease. Prior to it, estrogen was believed to decrease the rate of heart disease, while after it, it was thought to increase it. Critics of the study, however, worry that it involved higher doses of estrogen than necessary. More recent data suggests that lower doses of estrogen may provide benefits without exposing women to the harmful effects. Doses of conjugated equine estrogens
The timing of estrogen replacement has been a much-debated topic. The older studies, including WHI and HERS, included women who were on average 10 years into menopause. By that time, there is usually significant plaque formation in the once smooth arteries. The recent KEEPS study found that exposing women to estrogen within 36 months of menopause did not cause an increase in such plaque formation, as the estrogen was predominantly working on healthy arteries, only recently deprived of the body’s natural estrogen.

The HERS trial showed that the increased cardiovascular risks of being on HRT was not seen in the subset of women on statins. Common statins include Lipitor, Zocor, and Crestor and their generics atorvastatin, simvastatin, and rosuvastatin. This may be a consideration when evaluating a patient who would like to start HRT. In these patients, taking statins may confer some protection from developing CVD. And lastly, a woman’s genetic makeup may actually determine whether she may benefit or be harmed from HRT. This factor will likely take years to be incorporated into clinical practice.

I hope that this article has simplified and summarized the current thinking about women, HRT, and heart disease. What’s important to know is that estrogen replacement should not be used to prevent development of heart disease or slow down its progression. What is equally important to understand is that it’s not a “one size fits all” approach. Clinical trials are necessary to help clarify which women will benefit the most from HRT. If a woman chooses to be on HRT to control her peri-menopausal symptoms, whatever they may be, there are options when the therapy is tailored to the individual.