Menopause Live (31 May, 2010) from IMS

Shifren and Schiff have recently published a comprehensive CME review on the role of hormone therapy (HT) in the management of menopause [1]. The article addresses the following issues: vasomotor symptoms, urogenital atrophy, incontinence, osteoporosis, cardiovascular disease, cancer (breast, endometrial, ovarian, colorectal), depression and mood. Each section discusses treatment options including alternative non-hormonal medications and complementary, non-pharmacological therapies. Safety issues and health concerns that are related to HT comprise another main theme of the manuscript. Although the beneficial effects of HT in the early menopause overweigh potential, minimal risks in a healthy population, the age factor and duration of therapy may change this equation. The combination of prescribing the lowest effective dose of HT and using it for the shortest duration, and the prerequisite requirement that the patient will always be well-informed on all issues pertinent to menopause and therapy are the key recommendations of the authors.

Comment
This complete overview of the management of menopause recommends using HT in the lowest effective dose for the shortest duration, with an annual re-assessment of the need for continuation of therapy. This is in accordance with recommendations issued recently by national and international menopause societies [2–4]. 

Although various options for HT are discussed by the authors, including cyclic or continuous combinations of estrogen plus progestin, several important considerations which are relevant for the safety of therapy seem to be missing. 

As far as breast cancer risk is concerned, the authors put forward the perception that there is an increased risk after 5 years of use. However, they do not mention two recent studies showing no increase in risk with the use of micronized progesterone or dydrogesterone. The E3N cohort study [5], involving almost 100,000 women with 8.1 years of follow-up, showed a relative risk (RR) of 1 (95% confidence interval (CI) 0.83–1.22) for estrogen plus micronized progesterone, and a RR of 1.16 (95% CI 0.94–1.43) for estrogen plus dydrogesterone vs. a RR of 1.69 (95% CI 1.5–1.91) with other progestogens. The UK-based General Practice Research Database provided a nested case-control analysis based on 1482 incident cancer cases and 8892 matched control women [6]. The odds ratio (OR) of developing breast cancer for the estrogen–dydrogesterone combination (E/D) was 0.74 (95% CI 0.54–1.01). A direct comparison of the breast cancer risk for E/D users compared to users of other hormone therapies yielded an OR of 0.76 (95% CI 0.56–1.05).

As far as venous thromboembolism risk is concerned, the ESTHER study [7], a case–control study comparing 271 cases and 610 controls, showed no significant association of venous thromboembolism risk with either micronized progesterone or a pregnane derivative plus transdermal estrogens: the ORs were 0.7 (95% CI 0.3–1.9) and 0.9 (95% CI 0.4–2.3), respectively vs. an OR of 3.9 (95% CI 1.5–10) with norpregnane derivatives. The same study [8] showed no increase in risk of venous thromboembolism in women at risk using transdermal estrogens.

Although there is no published randomized trial confirming the results of these observational studies, it seems preferable to use transdermal estrogens and progesterone or dydrogesterone, at least in women at risk of breast cancer or venous thromboembolism.

Henri Rozenbaum
Former President of the European Menopause Society and the French Menopause Society (AFEM)

References
1. Shifren JL, Schiff I. Role of hormone therapy in the management of menopause. Obstet Gynecol 2010;115:839-55. Published April.
http://www.ncbi.nlm.nih.gov/pubmed/20308847
2. Les Recommandations de L’AFEM. Prise en charge de la femme ménopausée: place du traitement hormonal. Reprod Hum Horm 2007;20:384-91.
http://www.menopauseafem.com/medical/endirect2.php3?id=704
3. Pines A, Sturdee DW, Birkhäuser MH, Schneider HPG, Gambacciani M, Panay N, on behalf of the Board of the International Menopause Society. IMS updated recommendations on postmenopausal hormone therapy. Climacteric 2007;10:181-94.
http://www.ncbi.nlm.nih.gov/pubmed/17487645
4. Estrogen and progestogen use in postmenopausal women: 2010 position statement of the North American Menopause Society. Menopause 2010;17:242-55
http://www.ncbi.nlm.nih.gov/pubmed/20154637
5. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103-11
http://www.ncbi.nlm.nih.gov/pubmed/17333341
6. Schneider C, Jick SS, Meier CR. Risk of gynecological cancers in users of estradiol/dydrogesterone or other HRT preparations. Climacteric 2009;12:514-24
http://www.ncbi.nlm.nih.gov/pubmed/19905903
7. Canonico M, Oger E, Plu-Bureau G, et al., for the Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER Study. Circulation 2007;115:840-5
http://www.ncbi.nlm.nih.gov/pubmed/17309934
8. Canonico M, Oger E, Conard J, et al. Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. J Thromb Haemost 2006;4:1259-65
http://www.ncbi.nlm.nih.gov/pubmed/16706969