HORMONES AND HEART DISEASE

In my cardiology practice, I have observed the same patterns of diseaseincidence as my colleagues: prior to menopause, females have a much lowerincidence of coronary heart disease than males. We may infer that femalesex hormones convey a protective effect against cardiovascular disease.This inference is confirmed by large studies such as the Nurses' HealthStudy1, designed to follow women with no known coronary diseaseprospectively. 48, 470 postmenopausal nurses were enrolled in this study. The risk for significant coronary artery disease was found to be twice as great in those women who did not take hormone replacement therapy.

I will discuss the effects of estrogen and progestins on three aspects of cardiovascular physiology. The effect most recognized as beneficial is the effect on blood lipids - primarily cholesterol and its components. Elevated levels of LDL-cholesterol (low density lipoprotein cholesterol) lead to incorporation of cholesterol into the endothelium (internal lining) of the blood vessels, which begins an atherosclerotic plaque. HDL-cholesterol (high density lipoprotein cholesterol) has an opposite efcThe effects of estrogen on blood clotting are more controversial. A study published more than twenty years ago, the Coronary Drug Project2, evaluated the effects of five different drug regimens which were considered to have beneficial effects on cholesterol levels. Two of those drug regimens involved estrogen, and the study showed an increased tendency to thromboembolic (blood clotting) disorders. I will discuss the reasons this study should not be extrapolated to today's treament of male to female transsexuals. Some effects of estrogen may even promote thrombolysis (dissolving of blood clots).

Of course, most published data on the effects of female sex hormones on the cardiovascular system have been from studies performed on genetic females, rather than male to female transsexuals. One could question whether these studies are applicable to the transsexual population. Evidence suggests that they are, certainly in respect to vasoreactivity, and probably in respect to cholesterol.

Lipids (Cholesterol, Triglycerides)

The PEPI (Postmenopausal Estrogen/Progestin Intervention) Trial3 comprised three treatment arms: estrogen alone; estrogen with medroxyprogesterone acetate (Provera); and estrogen with micronized progesterone. The LDL cholesterol was lowered in all treatment groups. The HDL cholesterol was higher in all groups, but the highest levels were obtained in women taking estrogen alone or with micronized progesterone.

Numerous other studies have confirmed the PEPI findings. In the August 28, 1997, New England Journal of Medicine, a study compared estrogen and progesterone with simvastatin, a standard drug treatment to lower cholesterol. It was found that estrogen increased HDL cholesterol comparably to simvastatin, and reduced both LDL-cholesterol and Lp(a), another lipoprotein which increases cardiac risk.4

When we consider the unquestionable benefits of lowering LDL-cholesterol, proven in many large scale trials, it becomes clear that estrogen therapy may play a beneficial role in preventing the cardiovascular complications of hypercholesterolemia.

Most studies indicate that estrogen increases plasma triglyceride levels. The significance of an elevated triglyceride in the absence of an elevated cholesterol is probably minimal, and the addition of progesterone seems to prevent much of the increase.

Thromboembolic Disorders

It has been thought that the risk of venous thrombosis and/or pulmonary embolism is increased in persons taking estrogen. In 1975 the Coronary Drug Project2 evaluated five drug regimens reported to lower cholesterol. These drugs included conjugated estrogens in 2.5 mg and 5 mg dosages, as well as thyroxine, niacin, and clofibrate. The estrogen components of the study were terminated early because of increased incidence of thromboembolism and nonfatal myocardial infarction. It should be noted that the TThe incidence of thrombotic complications is significantly increased in women taking the higher doses of estrogen found in oral contraceptives, especially if they also smoke cigarettes. This is a good reason to counsel transsexual patients against taking excessive doses of estrogen. Lower doses are much less dangerous.

In low doses, estrogen inhibits platelet aggregation and reduces PAI-1, plasminogen activator inhibitor.6 This promotes thrombolysis and helps to dissolve smaller intravascular thrombi.

Certain persons may have an increased risk for spontaneous thromboembolic disorders. The Leiden Factor V mutation occurs in 2 per cent of the population and increases risk of thrombosis 30 fold in women on oral contraceptives. These may be the persons who experience complications on low dose estrogen. Other abnormalities predisposing to blood clotting include deficiencies of Protein C or Protein S.

To summarize, "The effects of estrogen on hemostasis and thrombosis are highly dose dependent... in general, the balance is shifted away from thrombosis with low dose estrogen, and towards thrombosis with high dose estrogen."7

Vasoreactivity

The layer of smooth muscle which surrounds the arteries constricts and relaxes in response to certain stimuli. The major stimulus is the biochemical pathway called the renin-angiotensin system. Angiotensin, an inactive precursor compound, is enzymatically converted to a strong vasoconstrictor called angiotensin II, which produces elevation of blood pressure and a tendency to endothelial dysfunction. Opposing this effect are the vasodilating compounds thromboxane, bradykinin, and nitric oxide, which staETwo studies in the June 1997 Journal of the American College of Cardiology reported on arterial reactivity in transsexual males taking estrogen8,9. They studied male to female transsexuals on long term estrogen, compared with matched male controls8,9 and female controls9. They found significantly enhanced vascular reactivity in the transsexual groups, comparable to genetic females. The significance of this is that vascular reactivity allows for arterial relaxation and prevents spasm.

Conclusion and Recommendations

In conclusion, a regimen of relatively low dose estrogen, with or without micronized progesterone, can be expected to confer long term reduced risk of cardiovascular disease in postmenopausal females and in male to female transsexuals.

General evaluation of cardiovascular risk factors should include a measurement of blood pressure and a lipid profile (total cholesterol, LDL- and HDL-cholesterol, triglycerides) before and after initiation of therapy. Persons who smoke cigarettes should be emphatically urged to stop smoking, and should be made aware of the consequences and greatly increased risk of cardiovascular disease if they continue to smoke.

The routine use of low dose (81 mg) aspirin in male to female transsexuals, especially over age 40, should be considered, for persons who have no bleeding disorders or contraindication to taking aspirin. This low dose may help to counteract any possible increased incidence of thrombotic events. Transdermal or injectable estrogen may have a reduced risk for thrombotic problems, since they are less likely than oral estrogen to stimulate the liver to produce proteins involved in the clotting process.

Certain persons may be at increased risk of cardiovascular disease, and should have special evaluation prior to the initiation of estrogen therapy. Persons with a history of hypertension should be followed closely and treated appropriately, preferably with medication which inhibits angiotensin-converting enzyme. Persons with a past history or family history of blood clotting disorders should have laboratory evaluation for conditions such as Factor V Leiden mutation.

Persons with a family history of cardiovascular disease should have more extensive screening, with electrocardiograms and probably treadmill exercise testing. The finding of coronary heart disease should be managed in the usual manner. Such persons should not be automatically rejected for estrogen therapy. If appropriate attention is given to reducing other risks, an informed decision may be made between patient and physician to proceed.

REFERENCES

1. Stampfer MJ et al., "Postmenopausal estrogen therapy and cardiovascular disease: Ten-year follow-up from the Nurses' Health Study", The New England Journal of Medicine, Vol. 325, 1991:756-62

2. The Coronary Drug Project, Journal of the American Medical Association, Vol. 231, 1975: 360-81

3. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women, Journal of the American Medical Association, Vol. 273(3), 1995:199-208

4. Darling GM et al., "Estrogen and Progestin Compared with Simvastatin for Hypercholesterolemia in Postmenopausal Women", The New England Journal of Medicine, Vol. 337, No. 9, August 28, 1997: 595-601

5. Daly E et al., "Risk of Venous Thromboembolism in Users of Hormone Replacement Therapy", The Lancet, Vol. 348, October 12, 1996: 977-80

6. Julian D, Wenger NK, Heart Disease In Women, Mosby 1997, p. 253

7. Ibid., p. 252

8. McCrohon JA et al., "Arterial Reactivity Is Enhanced in Genetic Males Taking High Dose Estrogens", Journal of the American College of Cardiology, Vol. 29, No. 7, June 1997:1432-6

9. New G et al., "Long-Term Estrogen Therapy Improves Vascular Function in Male to Female Transsexuals", Journal of the American College of Cardiology, Vol. 29, No. 7, June 1997:1437-44

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