Can estrogen reduce CT heart scan scores?

A new analysis from the Women’s Health Initiative study has provided
persuasive evidence that estrogens help control CT heart scan scores.

How does that fit into rational heart disease prevention and the Track Your Plaque program?

Over the last decade, two large studies examined the use of estrogen in women: the Women’s Health Initiative (WHI) and the Heart and Estrogen/Progestin Replacement Study (HERS). Both studies suggested that there was no overall reduction in heart attack risk (Anderson GL et al 2004;Hulley S et al 1998). As a result, many millions of American women tossed their hormone preparations into the trash.

In HERS, 2763 postmenopausal women with coronary disease (history of heart attack, coronary angioplasty, bypass surgery, or 50% or more blockage of a coronary artery) were given 0.625 mg per day of “conjugated equine estrogens” (Premarin®) and 2.5 of medoxyprogesterone acetate (Provera®) or placebo. There was no reduction in heart attack or other major heart events. In fact, there was a small trend towards increased heart attacks during the first year of treatment, an effect that dissipated between years 3–5 of participation.

In WHI, 10,739 postmenopausal women (a significantly larger study than HERS) between the ages of 50–79 years, all of whom had previously undergone hysterectomy, received 0.625 mg per day of equine (horse) estrogens or placebo. During nearly 7 years of follow-up, there was no reduction in heart attack and modest increased risk for stroke. Interestingly, the subgroup of participants between the age of 50–59 showed 37% less likelihood of heart attack.

The WHI investigators wished to explore the discrepant outcomes among different age groups. Thus, they launched the Women’s Health Initiative–Coronary Artery Calcium Study (WHI–CACS) by enrolling 1064 women who had been participants in the main WHI study. All underwent CT heart scanning. All of these women were in the 50–50 year old age group (average age 55 years) at time of enrollment; they received, on average, 7.4 years of estrogens.

The surprising results: a striking relationship of estrogen and coronary calcium scores. Women who used estrogen had 42% less calcium than women not taking estrogens. Mean score for women taking estrogen: 83; mean score for those on placebo: 123. Women who most reliably used estrogens had 61% less calcium. The likelihood of a high heart scan score that exceeded 300 was up to 61% less in women taking estrogen.

Dr. Davis comments:

Though the study design was imperfect, the trends observed were so dramatic that they demand our attention.

The pitfall of this study—heart scans were performed after and not before the start of estrogen replacement—do, unfortunately, diminish the confidence of the results. Ideally, such a study would involve obtaining CT heart scans on all participants at the start and then again after receiving the period of treatment, estrogen or placebo.

Of course, the WHI-CACS design was followed out of necessity because of the unexpected finding that, in the original WHI study, only women in the 50–59 year old age group appeared to enjoy reduction in heart attack risk with estrogen supplementation.

Nonetheless, these more recent data, along with other suggestive studies, suggest that estrogen replacement may indeed have an important contribution to make to reduce both heart attack risk and impact on heart scan scores.

An editorial that accompanied the WHI-CACS report by Drs. Michael Mendelsohn and Richard Karas, both from Tufts-New England Medical Center, Boston, remarked that “the results of the WHI-CACS study . . . should prove somewhat reassuring to women who have recently undergone menopause and are considering hormone-replacement therapy for relief of symptoms. In retrospect, failure of hormone-replacement therapy to reduce the incidence of CHD [coronary heart disease] events in the WHI trial is not surprising: the results were driven mainly by effects in older women . . . Unfortunately, the initial WHI results were unfairly generalized, creating widespread concern that hormone-replacement therapy is neutral or even harmful, with respect to cardiovascular disease, in all women, including younger women considering hormone-replacement therapy for the relief of menopausal symptoms.”

Why doesn’t estrogen replacement benefit women in older age groups? This question was not answered by this study. However, a number of explanations are possible. Perhaps older women have more advanced, complex plaque more prone to “rupture”. Because estrogen has a modest blood clot-promoting effect, the coronary plaque reducing effect of estrogens may be counterbalanced by the blood clot increasing effect.

Some other issues are concerning:

• Both HERS and WHI used “conjugated equine estrogens,” a euphemism for estrogens from female horses. Horse estrogens bear only a vague resemblance to human estrogens. Why horse? Is it superior? No, but horse estrogens are more easily patent protectable, thus profits can be protected. Humans estrogens (estradiol, estriol, and estrone) are readily available—but they’re inexpensive and not patent protectable. (The Women’s International Pharmacy in Madison, Wisconsin, for instance, mixes perfect duplicates of human estrogens to your doctor’s specifications and costs less than $20 per month.) No such studies on a large scale (and thereby very costly) have been conducted using human estrogen preparations. Maybe it’s better (in fact, I bet that it is) but there’s simply not enough clinical data.
• HERS used horse estrogen and progestins. Progestins, like horse estrogens, are synthetic versions that do not fully resemble human progesterone. Thus, the possible negative effects may also be due to the fact that the preparation was non-human. Like estrogens, there are insufficient data in humans using human progesterone.

It also bothers me that most of the investigators for both studies were rather heavily supported by Wyeth money. It couldn’t have tainted the investigators entirely, since the original conclusions panned horse estrogens. Nonetheless, it should always makes us a bit leery when the investigators also receive other financial support from the companies or hold substantial stock ownership.

As an interesting aside, Wyeth Pharmaceuticals is also the company that has petitioned the FDA to ban the distribution of “bio-identical” hormones like estrogen, progesterone, and testosterone by compounding pharmacies, even if prescribed by a physician. I wonder if they’ve got something up their sleeve.

Despite all my misgivings, I believe that it is of value for women to:

1) Consider hormonal supplementation for coronary artery disease prevention, especially in the 5th decade.

2) Talk to their gynecologists about the possibility of being assessed for their hormonal status—estrogens, progesterone, DHEA, testosterone—as the peri-menopausal years get under way, which usually begins around age 40. By this I mean an individualized program tailored to your body type and levels, not the “one size fits all” approach (necessarily) taken in these studies.

3) Ask specifically for “bio-identical” hormones. Seek another opinion if your physician refuses to discuss it and reflexively insists on Premarin®, Provera®, or some other non-human or synthetic preparation. (Would your husband accept pig or alligator testosterone? Then you shouldn’t accept non-human preparations either just to enrich a drug manufacturer.)

Despite the shortcomings of these Wyeth-supported trials, the WHI-CACS trial does add to our insights into the various methods to control coronary plaque. The evidence increasingly points to the possible benefits of estrogen replacement, particularly in the 50–59 year old age group.

References:

Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated equine estogens in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701–1712.

Grady D, Herrington D, Bittner V et al. cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II). JAMA 2002:288:49–57.

Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605–613.

Copyright 2007, Track Your Plaque.