Correspondence
Postmenopausal Hormone-Replacement Therapy
N Engl J Med 2002; 346:63-65January 3, 2002
- Article
To the Editor:
In the July 5 issue of the Journal, Manson and Martin review the clinical controversies surrounding hormone-replacement therapy.1 The findings of the Heart and Estrogen/Progestin Replacement Study (HERS) suggest reasons to be cautious about the use of hormone-replacement therapy in women who are 65 years of age or older. Of 2763 women (mean age, 67 years) with established coronary heart disease, women who were randomly assigned to receive hormone-replacement therapy had an excess risk of one additional blood clot per 64 women and of one additional gallbladder operation per 69 women during a four-year period.2,3 Hormone-replacement therapy was significantly associated with worsening urinary incontinence.4 Side effects of hormone-replacement therapy included breast tenderness and uterine bleeding, and only 70 percent of the women remained adherent to therapy by the end of year 3.2
Manson and Martin did not include stroke in their evaluation of benefits and risks. Among 652 women (mean age, 71 years) who had had a transient ischemic attack or nondisabling stroke, women who were randomly assigned to receive oral estradiol did not have lower rates of death or stroke.5 The risk of fatal stroke was significantly increased (relative risk, 3.86; 95 percent confidence interval, 1.09 to 13.63) with the use of estrogen therapy.5
Before older women begin receiving hormone-replacement therapy, clinicians should inform them of the increased risk of blood clots, gallbladder disease, urinary incontinence, and fatal stroke. Clinicians should correct the misperception that hormone-replacement therapy is cardioprotective, since both the Women's Health Initiative6 and HERS reported an increased risk of cardiovascular events in the first one to two years of use. Clinicians should alert women that, in 1999, the Food and Drug Administration removed the treatment of osteoporosis as an indication for estrogen therapy because of the lack of evidence from randomized trials of the effect of estrogen on the risk of fracture.
6 ReferencesSally E. McNagny, M.D., M.P.H.
77 Suffolk Rd., Wellesley, MA 02481
mcnagny@aol.com Nanette K. Wenger, M.D.
Emory University School of Medicine, Atlanta, GA 303031
Manson JE ,Martin KA . Postmenopausal hormone-replacement therapy. N Engl J Med 2001;345:34-40
Full Text | Web of Science | Medline2
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
CrossRef | Web of Science | Medline3
Grady D ,Wenger NK ,Herrington D , et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. Ann Intern Med 2000;132:689-696
Web of Science | Medline4
Grady D ,Brown JS ,Vittinghoff E ,Applegate W ,Varner E ,Snyder T . Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001;97:116-120
CrossRef | Web of Science | Medline5
Viscoli CM ,Brass LM ,Kernan WN ,Sarrel PM ,Horwitz RI . Estrogen after ischemic stroke: effect of estrogen replacement on risk of recurrent stroke and death in the Women's Estrogen for Stroke Trial (WEST). Stroke 2001;32:329-329 abstract.
Web of Science6
HRT update. Bethesda, Md.: Women's Health Initiative, June 2001. (Accessed December 12, 2001, at http://www.nhlbi.nih.gov/whi/hrt.htm.)
To the Editor:
As a primary care physician, I have a concern regarding the statement by Manson and Martin that “the addition of a sufficient dose of a progestin . . . eliminates” the risk of the development of endometrial cancer. Population-based studies have provided limited and conflicting data regarding the risk of endometrial cancer associated with the use of hormone-replacement therapy.1 There is evidence that this risk is dependent on the dose and the duration of progestin therapy, as well as the duration of hormone-replacement therapy as a whole.2 There are numerous hormone-replacement preparations available that contain variable doses of estrogens and different types and doses of progestins. It should not be assumed these are all safe for the endometrium.
In 1996, I reported to the Committee on Safety of Medicines in the United Kingdom a case of endometrial carcinoma in an otherwise healthy woman who had received a combination of 2 mg of estradiol and 75 μg of levonorgestrel (Nuvelle) for 51 months. Although such a case may reflect preexisting disease, Manson and Martin should have cautioned primary care physicians to investigate any episode of unexpected vaginal bleeding in a patient who is receiving hormone-replacement therapy even if it is a formulation that combines estrogen and progestin.
2 ReferencesNaguib Hilmy, M.B., B.Ch.
Whaddon House Surgery, Bletchley MK3 7EA, United Kingdom
naguib.hilmy@miltonkeynes-pct. nhs. uk 1
Grady D ,Gebretsadik T ,Kerlikowske K ,Ernster V ,Petitti D . Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304-313
CrossRef | Web of Science | Medline2
Beresford SA ,Weiss NS ,Voigt LF ,McKnight B . Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997;349:458-461
CrossRef | Web of Science | Medline
To the Editor:
Manson and Martin use a patient who has osteopenia and a single first-degree relative with a history of breast cancer as an example of someone who is a poor candidate for hormone-replacement therapy. Although it is well accepted that women with a family history of breast cancer have an increased risk of breast cancer, it has been difficult to prove that the risk of breast cancer is increased after hormone-replacement therapy in women with such a family history, as compared with those without a family history.1,2 A large, prospective cohort study that included 275,000 patient-years of follow-up and more than 1000 postmenopausal cases of breast cancer,3 which was designed specifically to answer this question, was unable to demonstrate a statistically significant increase in the risk of breast cancer in this subgroup of patients, as compared with those who had no family history of breast cancer. An approach involving the exclusion of a large percentage of would-be users from the potential benefits of hormone-replacement therapy solely on the basis of the presence of a family history of breast cancer is not based on the evidence.
3 ReferencesSalomon Banarer, M.D.
Washington University School of Medicine, St. Louis, MO 63110
sbanarer@im.wustl. edu 1
Collaborative Group on Hormonal Factors in Breast Cancer
CrossRef | Web of Science | Medline2
Shairer C ,Lubin J ,Troisi R ,Sturgeon S ,Brinton L ,Hoover R . Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-491[Erratum, JAMA 2000;284:2597.]
CrossRef | Web of Science3
Sellers TA ,Mink PJ ,Cerhan JR , et al. The role of hormone replacement therapy in the risk of breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 1997;127:973-980
Web of Science | Medline
To the Editor:
The majority of studies of the secondary prevention of cardiovascular disease, including HERS1 and the Estrogen Replacement and Atherosclerosis Trial,2 used conjugated equine estrogens alone or in combination with medroxyprogesterone acetate. In the first year of HERS, an increase in cardiovascular events and thromboembolic events was observed.1 Similar results have been reported by the Women's Estrogen for Stroke Trial.3 Moreover, in the Estrogen Replacement and Atherosclerosis Trial no benefit of hormone-replacement therapy with respect to the incidence of coronary luminal narrowing or death from cardiovascular causes was found in patients with atherosclerosis.2 On the basis of the results of these studies, Manson and Martin and the American Heart Association4 propose that women with cardiovascular disease are poor candidates for hormone-replacement therapy.
It is not known whether treatment with conjugated equine estrogens and medroxyprogesterone acetate can provide vascular protection comparable to that afforded by “natural” 17β-estradiol and progesterone.1 The mechanism by which conjugated equine estrogens affect vascular growth is distinct from that of 17β-estradiol. Moreover, human vascular cells metabolize 17β-estradiol, resulting in the formation of novel vasoprotective catechol estrogens.5 Finally, synthetic progestins such as medroxyprogesterone acetate may abrogate the beneficial effects of estrogens.6
Conjugated equine estrogens and medroxyprogesterone acetate do not replace natural estrogen and progesterone; they are given instead of these agents. Clinical trials of long-term treatment with 17β-estradiol and progesterone might help to answer questions regarding estrogen and cardiovascular protection.
6 ReferencesMatthias Barton, M.D.
Raghvendra K. Dubey, Ph.D.
University Hospital Zurich, CH-8091 Zurich, Switzerland
bartonm@swissonline.ch 1
Barton M . Postmenopausal oestrogen replacement therapy and atherosclerosis: can current compounds provide cardiovascular protection? Expert Opin Investig Drugs 2001;10:789-809
CrossRef | Web of Science | Medline2
Herrington DM ,Reboussin DM ,Brosnihan KB , et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522-529
Full Text | Web of Science | Medline3
Viscoli CM ,Brass LM ,Kernan WN ,Sarrel PM ,Horwitz RI . Estrogen after ischemic stroke: effect of estrogen replacement on risk of recurrent stroke and death in the Women's Estrogen for Stroke Trial (WEST). Stroke 2001;32:329-329 abstract.
Web of Science4
Mosca L ,Collins P ,Herrington DM , et al. Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104:499-503
CrossRef | Web of Science | Medline5
Dubey RK ,Jackson EK . Cardiovascular protective effects of 17β-estradiol metabolites. J Appl Physiol 2001;91:1868-1883
Web of Science | Medline6
Miyagawa K ,Rosch J ,Stanczyk F ,Hermsmeyer K . Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997;3:324-327
CrossRef | Web of Science | Medline
To the Editor:
Most randomized, placebo-controlled trials have shown no benefit of soy or phytoestrogens on vasomotor or other classic symptoms of menopause.1,2 In vitro and in vivo studies provide no evidence that such supplementation protects against breast cancer or is even safe.3,4 Concurrent use of high doses of phytoestrogen supplements and tamoxifen in women with breast cancer should be discouraged until further information is available, because of the potential for isoflavones to antagonize the desired antiestrogenic effects of tamoxifen.5
5 ReferencesSusan R. Davis, M.D., Ph.D.
Jean Hailes Foundation, Clayton, VIC 3121, Australia
suedavis@netlink.com. au 1
Dalais FS ,Rice GE ,Wahlqvist ML , et al. Effects of dietary phytoestrogens in postmenopausal women. Climacteric 1998;1:124-129
CrossRef | Medline2
Baber RJ ,Templeman C ,Morton T ,Kelly GE ,West L . Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric 1999;2:85-92
CrossRef | Medline3
Davis SR ,Dalais FS ,Simpson ER ,Murkies AL . Phytoestrogens in health and disease. Recent Prog Horm Res 1999;54:185-211
Web of Science | Medline4
Hargreaves DF ,Potten CS ,Harding C , et al. Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast. J Clin Endocrinol Metab 1999;84:4017-4024
CrossRef | Web of Science | Medline5
Schwartz JA ,Liu G ,Brooks SC . Genistein-mediated attenuation of tamoxifen-induced antagonism from estrogen receptor-regulated genes. Biochem Biophys Res Commun 1998;253:38-43
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: McNagny and Wenger reinforce many of the points we made in our article. Hormone-replacement therapy should not be prescribed for the express purpose of preventing cardiovascular disease, and clinical decision making should be based on the noncoronary benefits and risks of these hormones. Evidence of an early excess risk of cardiovascular events attributable to hormone-replacement therapy has been obtained from primary-prevention as well as secondary-prevention clinical trials. Moreover, the risk does not appear to be confined to older women. The results of the Women's Estrogen for Stroke Trial,1 which were published after the submission of our article, are consistent with findings from the randomized trials we reviewed, as well as with our observational analyses of hormone-replacement therapy and stroke in the Nurses' Health Study.2
Hilmy is correct in asserting that not all doses and formulations of progestin have been documented to protect the endometrium. However, the regimens we focused on in our review have been demonstrated to provide such protection.3
Banarer misunderstood our point about women with a first-degree relative with breast cancer. We did not suggest that hormone-replacement therapy disproportionately increases the risk of breast cancer in this subgroup. Our point was that women with such a family history have an increased base-line risk of breast cancer; a further 30 to 40 percent elevation in the risk with the use of long-term hormone-replacement therapy could lead to an unacceptably high absolute risk. Although we state that such women are appropriate candidates for the short-term use of hormone-replacement therapy (i.e., use for less than five years), which does not appreciably augment the risk of breast cancer, we believe that long-term therapy would have an unfavorable benefit-to-risk ratio in this subgroup of women. This is especially true in the absence of evidence of a cardioprotective effect of these hormones and in the light of the availability of other options for the prevention of osteoporotic fractures.
We agree with Barton and Dubey that long-term clinical trials of 17β-estradiol would be of interest. However, most of the evidence of a cardioprotective role of hormone-replacement therapy has been derived from observational studies of conjugated equine estrogens with or without medroxyprogesterone acetate. Moreover, although 17β-estradiol may have some theoretical advantages over conjugated equine estrogens and medroxyprogesterone acetate, its vascular benefits remain unproved. Both the Women's Estrogen for Stroke Trial1 and the Papworth Hormone-Replacement Therapy Atherosclerosis Study,4 which evaluated 17β-estradiol, have found no evidence of a cardiovascular benefit and have raised the possibility of harm — findings similar to those in the trials of conjugated equine estrogen and medroxyprogesterone acetate.
Davis is mistaken that evidence is lacking that soy reduces vasomotor symptoms. Although, as we stated, soy is not as effective as hormone-replacement therapy for this indication, several trials do report small-to-moderate benefits of this therapy in some women.5 Moreover, we did not assert that soy prevents breast cancer.
5 ReferencesJoAnn E. Manson, M.D., Dr.P.H.
Brigham and Women's Hospital, Boston, MA 02115
jmanson@rics.bwh. harvard. edu Kathryn A. Martin, M.D.
Massachusetts General Hospital, Boston, MA 021141
Viscoli CM ,Brass LM ,Kernan WK ,Sarrel PM ,Suissa S ,Horwitz RI . A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243-1249
Full Text | Web of Science | Medline2
Grodstein F ,Manson JE ,Colditz GA ,Willett WC ,Speizer FE ,Stampfer MJ . A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933-941
Web of Science | Medline3
Gibbons WE ,Thorneycroft IH . Protecting the endometrium: opposing the hyperplasia/malignancy potential of ERT. J Reprod Med 1999;44:Suppl:203-208
Web of Science | Medline4
Clarke S ,Kelleher J ,Lloyd-Jones H ,Sharples L ,Slack M ,Schofield PM . Transdermal hormone replacement therapy for secondary prevention of coronary artery disease in postmenopausal women. Eur Heart J 2000;21:Suppl:212-212 abstract.
Web of Science5
Vincent A ,Fitzpatrick LA . Soy isoflavones: are they useful in menopause? Mayo Clin Proc 2000;75:1174-1184
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Matthias Barton, Matthias R Meyer, Judy L Bolton, Eric R Prossnitz. (2010) Lung cancer and hormone replacement therapy. The Lancet 375:9709, 117-118
CrossRef2
Tomaz Kocjan, Gordana M Prelevic. (2003) Hormone replacement therapy update: who should we be prescribing this to now?. Current Opinion in Obstetrics and Gynecology 15:6, 459-464
CrossRef3
Matthias Barton, Renata Carmona, Jana Ortmann, José E. Krieger, Tobias Traupe. (2003) Obesity-associated activation of angiotensin and endothelin in the cardiovascular system. The International Journal of Biochemistry & Cell Biology 35:6, 826-837
CrossRef
