Daily progestin is not physiologic. When it first became evident that unopposed estrogen causes endometrial cancer in women with a uterus, progestins were administered for 7, 10, or 12 days each month, usually in the form of medroxyprogesterone acetate (MPA), mimicking the cyclic production of progesterone by the premenopausal ovary. Although this regimen was effective in protecting against endometrial cancer, the cyclic administration of EPT induced undesirable uterine bleeding, which caused many women to stop the therapy. To avoid cyclic bleeding and improve compliance, continuous combined EPT preparations were introduced, which involved daily exposure to progestin—a level that is clearly not physiologic.
Because it appears from the WHI study that progestins may be mostly responsible for the increased risks of cardiovascular disease, stroke, and breast cancer—since the estrogen-alone arm of the trial continues—it may be prudent to minimize the duration of progestin treatment in postmenopausal women. Several studies have demonstrated that the cyclic administration of progestin for 2 weeks every 2 to 3 months may be as protective against endometrial cancer as monthly administration.4-6 Moreover, if they receive the lowest effective dose of daily estrogen (as outlined) and bi- or tri-monthly cyclic progesterone, most women will experience little or no bleeding.
Has estrogen changed? Why the Women’s Health Initiative confounded expectations
Prior to the Women’s Health Initiative (WHI), estrogen therapy (ET) and estrogen-progestin therapy (EPT) were widely assumed to protect against cardiovascular disease. This assumption had been substantiated by epidemiologic studies, as well as experimental and clinical trials, which consistently reported that ET/EPT had beneficial effects on the lipid profile. Also noted were direct effects on vessel walls, evident in decreasing arteriosclerosis and increased vasodilatation.1 Were all these studies erroneous? Or is there an explanation for both pre- and post-WHI findings?
Observational studies are somewhat notorious for selection and compliance biases. Women who take hormones generally are healthier, better educated, and wealthier than nonusers; they also have fewer coronary risk factors. Thus, the favorable outcomes observed with ET and EPT may have simply reflected these women’s greater health at baseline. But I don’t think so.
Although these confounding factors may have exaggerated the benefits of ET/EPT, it is unlikely that they masked the increased risk observed with the WHI and other recently published prospective, randomized studies, such as the Heart and Estrogen/progestin Replacement Study (HERS)2 and the Women’s Estrogen for Stroke Trial (WEST).3 Moreover, the other benefits (osteoporosis and colon cancer protection) and risks (thromboembolic events and breast cancer) previously reported in observational studies have been appropriately confirmed by prospective, randomized studies. Only the cardiovascular benefits have not. Instead, they have been completely negated. Why?
There is no clear answer, but 1 explanation may be that the significant improvement in cardiovascular health care for women over the past 2 decades has obscured the cardiovascular benefits of EPT manifested 15 years ago in epidemiologic studies.
Indeed, 20 and 30 years ago, cardiovascular disease was considered a disease of men; very few women were evaluated or treated for hypertension or hyperlipidemia, 2 major cardiovascular disease risk factors. In women, ET/EPT may have been therapeutic, either indirectly by improving the lipid profile or directly by decreasing plaque formation and inducing vasodilatation through regulation of nitric oxide, prostaglandin synthetase, and membrane ionic permeability.1
During the past 15 years, women’s health care has changed greatly. Women who have hypertension or hyperlipidemia—especially those who participate in clinical trials2-4—are commonly treated with potent lipid-lowering agents and antihypertensive medications. These agents’ protective effects against cardiovascular disease would obscure any potential vascular benefits of ET/EPT. Consequently, only the adverse vascular effects of ET/EPT would be noted, since its potential benefits would have been usurped by the stronger cardiotropic statins and antihypertensive drugs.
Consider this corollary: Had the WHI patients at risk for fracture been treated with bisphosphonates, I doubt very much that the protective effects of ET/EPT on bone would have been noted. This hypothesis is supported by the recent Estrogen in the Prevention of Atherosclerosis Trial.5 In this prospective study, 222 post-menopausal women with low-density lipoprotein cholesterol levels in excess of 130 mg/dL were randomized to receive either 17-ß estradiol or placebo and were angiographically monitored for progression of coronary atherosclerosis.
The results revealed that the women randomized to 17-ß estradiol experienced significantly less progression of atherosclerosis than the placebo group. However, in those study patients who were also taking lipid-lowering therapy (statins), 17-ß estradiol did not confer additional benefits on coronary atherosclerosis.
It appears, then, that ET/EPT served its purpose for cardiovascular protection when there was a need for it—prior to the widespread use of cardioprotective agents. Now, with vastly improved women’s health care, ET/EPT for cardiovascular protection is neither needed nor safe.
Role of progestin. The fact that the estrogenonly arm of the WHI has not been interrupted supports the hypothesis that the progestin in the EPT preparation is mostly responsible for the increased risk of breast cancer and atherosclerosis, including coronary heart disease and stroke.
Moreover, medroxyprogesterone acetate (MPA)—the progestin used in the WHI—may be key to the cardiovascular risks6 observed in the trial. A different progestin, such as micronized progesterone or norethindrone acetate, may not confer similar risks.7 Indeed, the Postmenopausal Estrogen/Progestin Interventions study found that the addition of MPA to conjugated equine estrogen in postmenopausal women negated some of the beneficial effects of conjugated equine estrogen on the lipid profile, whereas the addition of micronized progesterone did not.8
Moreover, animal studies have found that MPA6—but not norethindrone acetate9 or micronized progesterone—negates the beneficial effects of estrogen on coronary plaque formation. Thus, it appears that different progestins have variable effects on atherosclerosis and that, among the various clinically available progestins, MPA may be particularly deleterious to cardiovascular health. Unfortunately, the results of these animal studies may not apply to humans. Still, they should serve as hypotheses for future prospective, randomized clinical trials.
Whether the WHI findings can be generalized to other hormone preparations is unclear. At present, the burden of proof for greater safety and efficacy lies with the sponsors of the other products.
REFERENCES
1. Farhat MY, Lavigne MC, Ramwell PW. The vascular protective effects of estrogen. FASEB J. 1996;10:615-624.
2. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in menopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605-613.
3. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen replacement therapy after ischemic stroke. N Engl J Med. 2001;345:1243-1249.
4. Writing group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized control trial. JAMA. 2002;288:321-323.
5. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis. Ann Intern Med. 2001;135:939-953.
6. Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Artherioscler Thromb Vasc Biol. 1997;17:217-221.
7. Riis BJ, Lehmann HJ, Christiansen C. Norethisterone acetate in combination with estrogen: effects on the skeleton and other organs. Am J Obstet Gynecol. 2002;187:1101-1116.
8. Alexanderson P, Haarbo J, Sandholdt I, Shalmi M, Lawaetz H, Christiansen C. Norethindrone acetate enhances the antiatherogenic effect of 17-beta-estradiol: a secondary prevention study of aortic atherosclerosis in ovariectomized cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol. 1998;18:902-907.
9. The Writing group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA. 1995;273:199-208.