Correspondence
Hormone Replacement and Cardiovascular Risk Factors
N Engl J Med 1993; 329:1041-1043September 30, 1993
- Article
To the Editor:
Nabulsi et al. (April 15 issue)1 present convincing data that postmenopausal hormone-replacement therapy, whether with estrogen alone or with estrogen and progestin, greatly decreases the risk of cardiovascular disease. In their editorial, Martin and Freeman reiterate what has become almost conventional wisdom -- namely, that replacement therapy with progestins “attenuates [the] beneficial effects of estrogen on lipid levels” and therefore, presumably, may weaken the protective effect of estrogen-replacement therapy against cardiovascular disease2. I should like to cite a number of studies that offer reassurance that progestins probably do not have such a deleterious effect. Two recent studies, one of oral synthetic progestins3 and one of transdermal synthetic progestins,4 found no lowering of serum high-density lipoprotein (HDL) levels, in contrast to three frequently cited papers of a decade or so ago5-7 (two from the same laboratory) that did report such an effect. Another recent study8 reported that oral micronized progesterone does not lower HDL levels. Spagnoli et al.9 showed that synthetic progestogens inhibit atherogenesis in rabbits fed cholesterol (Martin and Freeman also cite this study), and Haarbo et al.10 reported that synthetic progestogens do not inhibit the antiatherogenic effect of estrogen replacement in cholesterol-fed rabbits after ovariectomy.
10 ReferencesBarnett Zumoff, M.D.
Beth Israel Medical Center, New York, NY 100031
Nabulsi AA ,Folsom AR ,White A , et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993;328:1069-1075
Full Text | Web of Science | Medline2
Martin KA ,Freeman MW . Postmenopausal hormone-replacement therapy. N Engl J Med 1993;328:1115-1117
Full Text | Web of Science | Medline3
Haarbo J ,Hassager C ,Jensen SB ,Riis BJ ,Christiansen C . Serum lipids, lipoproteins, and apolipoproteins during postmenopausal estrogen replacement therapy combined with either 19-nortestosterone derivatives or 17-hydroxyprogesterone derivatives. Am J Med 1991;90:584-589
Web of Science | Medline4
Whitehead MI ,Fraser D ,Schenkel L ,Crook D ,Stevenson JC . Transdermal administration of oestrogen/progestagen hormone replacement therapy. Lancet 1990;335:310-312
CrossRef | Web of Science | Medline5
Hirvonen E ,Malkonen M ,Manninen V . Effects of different progestogens or lipoproteins during postmenopausal replacement therapy. N Engl J Med 1981;304:560-563
Full Text | Web of Science | Medline6
Malkonen M ,Manninen V ,Hirvonen E . Effect of danazol and lynestrenol on serum lipoproteins in endometriosis. Clin Pharmacol Ther 1980;28:602-604
CrossRef | Web of Science | Medline7
Jensen J ,Nilas L ,Christiansen C . Cyclic changes in serum cholesterol and lipoproteins following different doses of combined postmenopausal hormone replacement therapy. Br J Obstet Gynaecol 1986;93:613-618
CrossRef | Medline8
Ottosson UB ,Johansson BG ,von Schoultz B . Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gynecol 1985;151:746-750
Web of Science | Medline9
Spagnoli LG ,Palmieri G ,Mauriello A ,Orlandi A ,Bancheri C ,Pasetto N . High-dose synthetic progestogens inhibit foam and smooth muscle cell proliferation and atherosclerotic plaque formation in aortas of rabbits fed a hypercholesterolemic diet. Atherosclerosis 1990;82:27-36
CrossRef | Web of Science | Medline10
Haarbo J ,Leth-Espensen P ,Stender S ,Christiansen C . Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits. J Clin Invest 1991;87:1274-1279
CrossRef | Web of Science | Medline
To the Editor:
Nabulsi et al. conclude that adding progestin to postmenopausal estrogen therapy does not adversely affect risk factors for cardiovascular disease. We have also proposed that progestins should not necessarily be considered metabolically adverse1. However, their finding that HDL levels were similarly high in users of estrogen alone and of estrogen with progestin is at odds with the majority of reports. These show that progestins attenuate at least to some degree the increased levels of HDLs induced by estrogen. This discrepancy can be explained partly by the authors' inability to standardize the timing of blood sampling during the pill-taking cycle. Since the metabolic effects of progestins are most prominent at the end of the progestin phase of therapy,1 somewhat lower levels of HDLs might have been evident if all the estrogen-progestin users had been studied at that time.
Medroxyprogesterone acetate and other C-21 progestins have an obvious advantage over C-19 progestins, such as levonorgestrel, because they allow some of the estrogen-induced increase in HDLs to persist. On the other hand, medroxyprogesterone acetate only weakly opposes the increase in triglycerides seen in users of conjugated equine estrogens, whereas combined therapies involving C-19 progestins can reduce triglyceride levels2. Increased levels of triglycerides, particularly low-density lipoprotein triglycerides, may increase the susceptibility of low-density lipoproteins to lipid peroxidation, a potentially important cause of cardiovascular disease3. Clearly, the best combination of postmenopausal estrogen and progestin has yet to be established.
The editorial accompanying the article draws attention to the low plasma Lp(a) levels in estrogen users (unadjusted mean [±SD], 99 ±105 μg per milliliter, as compared with 118 ±120 μg per milliliter in nonusers). Most studies of Lp(a) and cardiovascular risk suggest a noncontinuous relation, with a threshold of 200 or 300 μg per milliliter. Since the distribution of Lp(a) in the Atherosclerosis Risk in Communities study is so severely skewed, the presentation of simple means and standard deviations does not allow the reader to assess how many women in each group were at risk because of their abnormal Lp(a) levels. Unless a lower prevalence of abnormal Lp(a) values can be demonstrated in estrogen users, it is questionable whether this intriguing effect of estrogen can be considered beneficial.
3 ReferencesDavid Crook, Ph.D.
John C. Stevenson, F.R.C.P.
Wynn Institute for Metabolic Research, London NW8 9SQ, United Kingdom1
Crook D ,Stevenson JC . Progestogens, lipid metabolism and hormone replacement therapy. Br J Obstet Gynaecol 1991;98:749-750
CrossRef | Medline2
Crook D ,Cust MP ,Gangar KF , et al. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on serum lipids and lipoproteins. Am J Obstet Gynecol 1992;166:950-955
Web of Science | Medline3
Regnstrom J ,Nilsson J ,Tornvall P ,Landou C ,Hamsten A . Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man. Lancet 1992;339:1183-1186
CrossRef | Web of Science | Medline
To the Editor:
Characteristics described in Table 2 of the report by Nabulsi et al. indicate that current users and nonusers of hormone-replacement therapy may differ according to body-mass index (the weight in kilograms divided by the square of the height in meters). Excess body weight was present in 23 percent of estrogen-progestin users and in 51 percent of nonusers. More important, abdominal obesity (high waist-to-hip ratio) was more prevalent in nonusers. Adjustments were made for age and body-mass index, but the authors did not indicate whether a correction had been made for the waist-to-hip ratio. This might be an important bias, since abdominal obesity has been associated with hypertriglyceridemia, low HDL cholesterol levels,1-3 and glucose intolerance4.
4 ReferencesJ.-C. Daubresse, M.D.
Hopital Civil, B-6000 Charleroi, Belgium1
Foster CJ ,Weinsier RL ,Birch R , et al. Obesity and serum lipids: an evaluation of the relative contribution of body fat and fat distribution to lipid levels. Int J Obes 1987;11:151-161
Web of Science | Medline2
Lapidus L ,Bengtsson C ,Larsson B ,Pennert K ,Rybo E ,Sjostrom L . Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. BMJ 1984;289:1257-1261
CrossRef | Web of Science | Medline3
Seidell JC ,Cigolini M ,Charzewska J , et al. Indicators of fat distribution, serum lipids, and blood pressure in European women born in 1948 -- the European Fat Distribution Study. Am J Epidemiol 1989;130:53-65
Web of Science | Medline4
Kissebah AH ,Vydelingum N ,Murray R , et al. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 1982;54:254-260
CrossRef | Web of Science | Medline
To the Editor:
Martin and Freeman concluded that all postmenopausal women should be considered candidates for hormone-replacement therapy. Hormone-replacement therapy is already being administered to some women with a history of breast cancer, but only when they demand it, usually as treatment for menopausal symptoms rather than as prophylaxis against heart disease or osteoporosis. Such patients are rarely studied or followed systematically. Their incidence of recurrent breast cancer, osteoporosis, heart disease, and associated mortality is neither documented nor reported. Thus, the potential risks and benefits of hormone-replacement therapy in this population have been neither confirmed nor disproved. An unequivocal conclusion about the risk of hormone-replacement therapy in regard to recurrent breast cancer is simply not possible at this time. There is no direct evidence that estrogens administered to women with a history of breast cancer are harmful1,2. There are suggestions of a potential benefit in regard to both the incidence of recurrence3 and death from breast cancer4. The Food and Drug Administration recently approved in concept the study of this question. This is quite important, since approximately 100,000 survivors are added every year to the ranks of the women who have been treated for breast cancer.
4 ReferencesAvrum Z. Bluming, M.D.
University of Southern California, Los Angeles, CA 900331
Henderson IC . Risk factors for breast cancer development. Cancer 1993;71:Suppl:2127-2140
CrossRef | Web of Science | Medline2
Wile AG ,Opfell RW ,Margileth DA . Hormone replacement therapy in previously treated breast cancer patients. Am J Surg 1993;165:372-375
CrossRef | Web of Science | Medline3
Palshof T ,Mouridsen HT ,Daehnfeldt JL . Adjuvant endocrine therapy of primary operable breast cancer: report of the Copenhagen breast cancer trials. Eur J Cancer 1980;1:183-187
Medline4
Henderson BE ,Paganini-Hill A ,Ross RK . Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991;151:75-78
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Our report indicated that both combination hormone-replacement therapy (primarily conjugated equine estrogen plus medroxyprogesterone acetate) and estrogen alone are associated with reduced cardiovascular risk factors in postmenopausal women. Dr. Zumoff cites additional studies confirming that low-dose synthetic progestins do not reverse the beneficial effects of estrogen-replacement therapy on serum lipid levels.
We disagree with Drs. Crook and Stevenson that the timing of blood drawing may account for our findings. The random timing of blood sampling that we employed reflects the average level of risk factors in users of combination hormone-replacement therapy. This is more relevant than a possible metabolic alteration for a few days per month. Although we only presented mean Lp(a) levels, Rose and Day1 have shown that differences in means usually reflect differences in high levels as well. In fact, the percentage of women with Lp(a) levels ≥ 200 μg per milliliter was lowest among the users of estrogen plus progestin (11 percent), as compared with users of estrogen alone (15 percent), former users of hormone-replacement therapy (20 percent), and those who had never used hormone-replacement therapy (20 percent).
As Dr. Daubresse points out, the mean waist-to-hip ratio differed between the current users and the nonusers. After body-mass index was accounted for, adjustment for the waist-to-hip ratio did not affect the results.
1 ReferencesAzmi A. Nabulsi, M.B., B.Ch.
Burroughs Wellcome Co., Research Triangle Park, NC 27708Aaron R. Folsom, M.D.
University of Minnesota, Minneapolis, MN 55454Alice White, Ph.D.
Burroughs Wellcome Co., Research Triangle Park, NC 277081
Rose G ,Day S . The population mean predicts the number of deviant individuals. BMJ 1990;301:1031-1034
CrossRef | Web of Science | Medline
Author/Editor Response
We agree with Drs. Crook and Stevenson that the epidemiologic data concerning Lp(a) suggest that there is a threshold level below which the risk does not seem to correlate with the measured value. Thus, the finding of Nabulsi et al. that the mean Lp(a) level fell during hormone-replacement therapy may not have important health implications, if the decline did not reflect the Lp(a) levels of patients who crossed this threshold. An assessment of the number of women in each treatment group with abnormally high Lp(a) levels would be valuable. As we mentioned in our editorial, however, there is no information from clinical trials to date demonstrating that pharmacologic reductions in Lp(a), regardless of initial levels, confer a health benefit.
Dr. Zumoff refers to several clinical studies to support the notion that progestins do not antagonize the beneficial effects of estrogen. The study by Haarbo et al. of oral synthetic progestins1 actually demonstrated an increase in HDL levels when estrogen was used alone, but no such increase when progestins were added. Therefore, the conclusion from this study is that progestins negate the increase in HDL levels seen with estrogen alone. With regard to transdermal estrogens and progestins, a number of studies suggest that their effect on lipid profiles is attenuated, as compared with that of oral preparations, presumably because of the relatively low dose of medication reaching the liver. If transdermal progestins are eventually shown to prevent estrogen-induced endometrial hyperplasia and cancer, the lack of effect on lipids would represent a potential therapeutic benefit. Finally, although the study by Ottosson et al.2 demonstrated that micronized progesterone does not decrease HDL, it included perhaps the most compelling evidence to date that both C-19 and C-21 progestins antagonize the beneficial effect of estrogen on HDL.
In our editorial, we cited a primate study demonstrating a lack of effect of natural progesterone on atherosclerosis3. We agree that the rabbit studies mentioned by Dr. Zumoff are also encouraging. Although there are recent studies, including that of Nabulsi et al., suggesting that progestins may not have the negative effect that was initially feared, the risk of ischemic heart disease with combined hormone use remains unclear.
Dr. Bluming correctly points out that the effect of hormone-replacement therapy on the risk of breast cancer is controversial. The study by Wile et al.4 demonstrates no obvious adverse effect of estrogen on the recurrence of breast cancer, but is limited by the small number of patients studied. We agree that the issue of hormone replacement for women with a history of breast cancer deserves further study.
4 ReferencesKathryn A. Martin, M.D.
Mason W. Freeman, M.D.
Massachusetts General Hospital, Boston, MA 021141
Haarbo J ,Hassager C ,Jensen SB ,Riis BJ ,Christiansen C . Serum lipids, lipoproteins, and apolipoproteins during postmenopausal estrogen replacement therapy combined with either 19-nortestosterone derivatives or 17-hydroxyprogesterone derivatives. Am J Med 1991;90:584-589
Web of Science | Medline2
Ottosson UB ,Johansson BG ,von Schoultz B . Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gynecol 1985;151:746-750
Web of Science | Medline3
Adams MR ,Kaplan JR ,Manuck SB , et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys: lack of an effect of added progesterone. Arteriosclerosis 1990;10:1051-1057
CrossRef | Medline4
Wile AG ,Opfell RW ,Margileth DA . Hormone replacement therapy in previously treated breast cancer patients. Am J Surg 1993;165:372-375
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
D.P McDonnell. (1999) The Molecular Pharmacology of SERMs. Trends in Endocrinology & Metabolism 10:8, 301-311
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