Opinion

VIEWPOINT

Frederick William Danby, MD, FRCPC Department of Surgery (Dermatology), Geisel School of Medicine at Dartmouth, Manchester, New Hampshire.

Menopausal Hormone Replacement Therapy in Dermatology Dermatologists provide care for perimenopausal and menopausal women with hormone-related complaints: hair loss, acne climacterica, acne rosacea, acne inversa (hidradenitis suppurativa), dry skin, wrinkling, hirsutism, pruritus vulvae, and other vulvar dermatoses. The question, “Should I take hormone replacement therapy (HRT)?” is usually unspoken. The answer was complicated in 2002 by the estrogen-progestin arm of the Women’s Health Initiative (WHI) study with the reported increased risk of invasive breast cancer.1 In the WHI study,1 the estrogen-only arm studied use of estrogens from pregnant mares’ urine (Premarin). Natural ovarian estradiol-17β (E2) was not used as a control. Premarin’s several estrogens were conjugated with sulfate as conjugated equine estrogens (CEE). The major component, estrone sulfate, converts to estradiol following oral administration. The estrogen-progestin trial used CEE plus a synthetic progestin, medroxyprogesterone acetate (MPA) (Provera). Medroxyprogesterone acetate is approximately 200 times more powerful than natural progesterone, is androgenic, and is a mimic of 5α-dihydrotestosterone (DHT). There was no natural progesterone control. The increased incidence of breast cancers occurred in the 5.6-year CEE-MPA (Prempro) trial. Invasive breast cancers developed in 206 of 8506 women in the treated group and in 155 of 8102 women receiving placebo. The hazard ratio (HR) was 1.24, statistically significant on primary analyses.2 On the final analyses, this effect was apparent only in those patients exposed to HRT before the trial. During the 7.2 years of the Premarin-alone trial, there were 168 breast cancers (104 invasive) in 5310 women. The placebo group developed 216 breast cancers (135 invasive) in 5429 women. All participants had undergone hysterectomy, so no progestin therapy was required. The HR was 0.79 for the estrogen-only group. With longer follow-up, estrogen alone use by postmenopausal women statistically significantly decreased the risk of breast cancer.3

tures per year among US women aged 65 to 69 years. “Estrogen has been demonstrated to actually reduce calcified plaque burden in the coronary arteries. Even statins have not been demonstrated to be this effective in women.”5(p322)

Timing and Delivery Alternative regimens demonstrate 5 advantages over those used in the WHI study, including starting menopausal HRT early, using estradiol-17β as the estrogen, avoiding use of MPA as the progestin, and using the transdermal route in a standardized format. When started almost immediately after menopause, HRT using estradiol-17β and norethisterone (norethindrone) acetate showed “a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.”6 Transdermal estradiol-17β and oral micronized progesterone (E2/P) showed beneficial effects on markers of breast epithelial proliferation whereas CEE-MPA “significantly increased proliferation at both the cell level and at the mRNA level, and significantly enhanced mammographic breast density, an important risk factor for breast cancer.”7(p12) Furthermore, “CEE/MPA affected around 2,500 genes compared with just 600 affected by E2/P.”7(p12) Use of oral but not transdermal estrogens was associated with a higher risk of recurrent venous thromboembolic event (VTE) among 1023 consecutive postmenopausal women aged 45 to 70 years with a confirmed first VTE.8 The US Food and Drug Administration (FDA) is concerned about claims for safety, effectiveness, and superiority of compounded “bio-identical” creams and gels, stating that claims like these “mislead women and health care professionals, giving them a false sense of assurance about using potentially dangerous hormone products.”9

The Pendulum Swings Risks of Receiving vs Not Receiving Estrogen Corresponding Author: Frederick William Danby, MD, FRCPC, Adjunct Assistant Professor of Surgery (Dermatology), Department of Surgery (Dermatology), Geisel School of Medicine at Dartmouth, 721 Chestnut St, Manchester, NH 03104-3002 ([email protected]). jamadermatology.com

Use of CEE-MPA was associated with an increased incidence of invasive breast cancers. Was the cancer caused by CEE or by MPA? Was the Premarin alone protective against the development of breast cancer? The statistics do not support either suggestion. The most that one might state is that CEE does not seem to present a risk for the development of breast cancer in women who have undergone hysterectomy but that MPA (Provera) may be a risk if used for periods longer than 5.7 years. Gambacciani et al4 estimated that discontinuation of HRT may result in more than 43 000 excess bone frac-

In 2012, an international consensus panel was convened and supported by the American Society for Reproductive Medicine, the Asia Pacific Menopause Federation, the Endocrine Society, the European Menopause and Andropause Society, the International Menopause Society, the International Osteoporosis Foundation, and the North American Menopause Society. The following core recommendations10(pp203-204) for menopausal HRT were issued to provide guidance regarding the appropriate use of menopausal HRT for selected conditions: • MHT is the most effective treatment for vasomotor symptoms associated with menopause at any age, but JAMA Dermatology December 2014 Volume 150, Number 12

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archderm.jamanetwork.com/ by a Florida International University Medical Library User on 06/15/2015

1261

Opinion Viewpoint

benefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopause. • MHT is effective and appropriate for the prevention of osteoporosis-related fractures in at-risk women before age 60 years or within 10 years after menopause. • Randomized clinical trials and observational data as well as meta-analyses provide evidence that standard-dose estrogenalone MHT may decrease coronary heart disease and all-cause mortality in women younger than 60 years of age and within 10 years of menopause. Data on estrogen plus progestin MHT in this population show a similar trend for mortality, but in most randomized clinical trials no significant increase or decrease in coronary heart disease has been found. • Local low-dose estrogen therapy is preferred for women whose symptoms are limited to vaginal dryness or associated discomfort with intercourse. • Estrogen as a single systemic agent is appropriate in women after hysterectomy but additional progestogen is required in the presence of a uterus. • The option of MHT is an individual decision in terms of quality of life and health priorities as well as personal risk factors such as age, time since menopause and the risk of venous thromboembolism, stroke, ischemic heart disease and breast cancer. • The risk of venous thromboembolism and ischemic stroke increases with oral MHT but the absolute risk is rare below age 60 years. Observational studies point to a lower risk with transdermal therapy. • The risk of breast cancer in women over 50 years associated with MHT is a complex issue. The increased risk of breast cancer is primarily associated with the addition of a progestin to estrogen

Conclusions Millions of menopausal women experience gynecological and vasomotor symptoms and dermatological conditions that may respond to HRT. This consensus statement10 offers comprehensible guidance. Estradiol delivered by a transdermal patch of appropriate dose plus oral micronized progesterone if indicated by an intact uterus, initiated in the window of opportunity, will probably be effective and safe for most women. Dermatologists provide care for these women every day for acne, hair loss, dry skin, hirsutism, and vulvar dermatoses. It is time for dermatologists to perform the long-term randomized controlled studies examining the efficacy and potential harms of menopausal HRT for relief of dermatologic conditions. Menopausal HRT may ameliorate the dermatologic concerns, but the problems triggered by hormone deficiency are not solely cosmetic or symptomatic; they are systemic.

phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

ARTICLE INFORMATION Published Online: September 24, 2014. doi:10.1001/jamadermatol.2014.1225. Conflict of Interest Disclosures: None reported. Additional Contributions: Tobias J. DeVilliers, MD, President, International Menopause Society, provided invaluable assistance in clarifying the findings of the consensus conference and reviewing this work for accuracy. He was not compensated for his contribution. REFERENCES 1. 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 Controlled Trial. JAMA. 2002;288(3): 321-333. 2. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping

1262

therapy and related to the duration of use. The risk of breast cancer attributable to MHT is small and the risk decreases after treatment is stopped. • The dose and duration of MHT should be consistent with treatment goals and safety issues and should be individualized. • In women with premature ovarian insufficiency, systemic MHT is recommended at least until the average age of the natural menopause. • The use of custom-compounded bio-identical hormone therapy is not recommended. • Current safety data do not support the use of MHT in breast cancer survivors.

3. Chlebowski RT, Manson JE, Anderson GL, et al. Estrogen plus progestion and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. J Natl Cancer Inst. 2013;105(8):526-535. 4. Gambacciani M, Ciaponi M, Genazzani AR. The HRT misuse and osteoporosis epidemic: a possible future scenario. Climacteric. 2007;10(4):273-275. 5. Utian WH. A decade post WHI, menopausal hormone therapy comes full circle—need for independent commission. Climacteric. 2012;15(4): 320-325. 6. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012;345:e6409.

and different gene regulations than oral conjugated equine estrogens/medroxyprogesterone acetate in the breasts of healthy women in vivo. Gynecol Endocrinol. 2012;28(suppl 2):12-15. 8. Olié V, Plu-Bureau G, Conard J, Horellou MH, Canonico M, Scarabin PY. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women. Menopause. 2011;18(5): 488-493. 9. US Food and Drug Administration (FDA). Bio-identicals: sorting myths from facts. US FDA Protecting and Promoting Your Health website. Updated December 7, 2013. http://www.fda.gov /forconsumers/consumerupdates/ucm049311.htm. Accessed July 11, 2014. 10. de Villiers TJ, Gass ML, Haines CJ, et al. Global consensus statement on menopausal hormone therapy. Climacteric. 2013;16(2):203-204.

7. Murkes D, Lalitkumar PG, Leifland K, Lundström E, Söderqvist G. Percutaneous estradiol/oral micronized progesterone has less-adverse effects

JAMA Dermatology December 2014 Volume 150, Number 12

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archderm.jamanetwork.com/ by a Florida International University Medical Library User on 06/15/2015

jamadermatology.com

Menopausal hormone replacement therapy in dermatology.

Menopausal hormone replacement therapy in dermatology. - PDF Download Free
49KB Sizes 0 Downloads 6 Views