The effectiveness and safety of mht depending on the type, route of administration of estrogens, and the type of progestogen. Analysis of data from clinical trials and international recommendations
Keywords:menopausal hormone therapy, menopause, transdermal estrogens, micronized progesterone, thromboembolism, stroke, breast cancer, sexual function
The hormone therapy remains the most effective method for treating of the vasomotor symptoms and genitourinary syndrome in menopause. The evidence available to date suggests that for women younger than 60 and with a postmenopause no more than 10 years without contraindications, the benefits of administering systemic hormone therapy for the treatment of vasomotor symptoms, sleep disorders and prevention of bone loss exceed possible risks. In addition, the data about statistically significant reduction in all-cause mortality in women who initiate hormone therapy before the age of 60 and/or 10 years after the onset of menopause have been obtained.
Menopausal hormone therapy (MHT) includes a wide range of hormonal drugs and administration routes that potentially have different risks and benefits, and therefore the term “class effect” is misleading and inappropriate. The risks of menopausal hormone therapy vary depending on the composition, dose and route of administration of hormones, as well as the timing of the onset and duration of use of both estrogens and progesterone. The use of transdermal estrogens in combination with progesterone seems safer for venous thromboembolism, especially in high-risk women. The use of transdermal estrogen drugs in comparison with oral estrogens is associated with a lesser likelihood of developing thrombotic risk, and possibly the risk of developing stroke and coronary heart disease. If progesterone is needed, micronized progesterone is a safer alternative.
MHT requires a periodic reassessment of the benefits and risks for deciding whether to continue or stop using it. The use of postmenopausal hormone therapy in women with menopausal disorders should be based on an assessment of all risk factors for cardiovascular disease, age and time from the onset of menopause. The duration of therapy should be motivated by the indications, and the decision should be taken in conjunction with the doctor.
The North American Menopause Society. “The 2017 hormone therapy position statement of The North American Menopause Society.” Menopause 24.7 (2017).
Baber, R.J., et al. “IMS Recommendations on women’s midlife health and menopause hormone therapy.” Climacteric 19 (2016): 109–50.
Rossouw, J.E., Anderson, G.L., Prentice, R.L., et al. “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.” JAMA 288 (2002): 321–33.
Cobin, R.H., Goodman, N.F. “American Association of Clinical Endocrinologists and American College of Endocrinology position statement on menopause – 2017 update.” Endocrine Practice 7 Vol. 23 (2017): 869–80.
Canonico, M., Fournier, A., Carcaillon, L., et al. “Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism results from the E3N cohort study.” Arterioscler Thromb Vasc Biol 30.2 (2010): 340–5.
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 107.1 (2008): 103–11.
Rossouw, J.E., Prentice, R.L., Manson, J.E., et al. “Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.” JAMA 297 (2007): 1465–77.
Manson, J.E., Aragaki, A.K., Rossouw, J.E., et al. “Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women’s Health Initiative randomized trials.” JAMA 318.10 (2017): 927–38. DOI: 10.1001/jama.2017.11217
Boardman, H.M., Hartley, L., Eisinga, A., et al. “Hormone therapy for preventing cardiovascular disease in post-menopausal women.” Cochrane Database Sys Rev 3 (2015): CD00229.
National Institutes of Health. “National Institutes of Health state-of-the-science conference statement: management of menopause-related symptoms.” Ann Intern Med 142 (2005): 1003–13.
Stanczyk, F.Z., Hapgood, J.P., Winer, S., et al. “Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.” Endocr Rev 34 (2013): 171–208.
Courtin, A., Communal, L., Vilasco, M., et al. “Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells.” Breast Cancer Res Treat 131 (2012): 49–63.
Lambrinoudaki, I. “Progestogens in postmenopausal hormone therapy and the risk of breast cancer.” Maturitas 77 (2014): 311–7.
Sood, R., Faubion, S.S., Kuhle, C.L., et al. “Prescribing menopausal hormone therapy: an evidence-based approach.” Int J Women’s Health 6 (2014): 47–57.
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 107 (2008): 103–11.
Santen, R.J. “Risk of breast cancer with progestins: critical assessment of current data.” Steroids 68 (2003): 953–64.
Mohammed, H., Russell, I.A., Stark, R., et al. “Progesterone receptor modulates ERα action in breast cancer.” Nature 523 (2015): 313–7.
Hellgren, M., Conard, J., Norris, L., Kluft, C. “Cardiovascular risk markers during treatment with estradiol and trimegestone or dydrogesterone.” Maturitas 62 (2009): 287–93.
Prior, J.C., Elliott, T.G., Norman, E., et al. “Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women.” PLoS One 9 (2014): e84698.
Asi, N., Mohammed, K., Haydour, Q., et al. “Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis.” Systematic Reviews 5 (2016): 121.
Espie, M., Daures, J.-P., Chevallier, T., et al. “Breast cancer incidence and hormone replacement therapy: results from the MISSION study, prospective phase.” Gynecol Endocrinol 23 (2007): 391–7.
Cordina-Duverger, E., Truong, T., Anger, A., et al. “Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France.” PLoS One 8 (2013): e78016.
Sitruk-Ware, R. “The levonorgestrel intrauterine system for use in peri- and postmenopausal women.” Contraception 75 (2007): 155–60.
Chlebowski, R.T., Hendrix, S.L., Langer, R.D., et al., Investigators WHI. “Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial.” Jama 289 (2003): 3243–53.
Anderson, G.L., Chlebowski, R.T., Aragaki, A.K., et al. “Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial.” Lancet Oncol 13 (2012): 476–86.
Lyytinen, H., Dyba, T., Ylikorkala, O., Pukkala, E. “A case-control study on hormone therapy as a risk factor for breast cancer in Finland.” Maturitas Conference Publication: 8th European Congress on Menopause, EMAS London United Kingdom (2009).
Lyytinen, H., Dyba, T., Pukkala, E., Ylikorkala, O. “Do the dose or route of administration of norethisterone acetate as a part of hormone therapy play a role in risk of breast cancer: National-wide case-control study from Finland.” Int J Cancer 127.1 (2010): 185–9.
Lyytinen, H., Pukkala, E., Ylikorkala, O. “Breast cancer risk in postmenopausal women using estradiolprogestogen therapy.” Obstet Gynecol 113.1 (2009): 65–73.
Løkkegaard, T., Nielsen, L.H., Keiding, N. “Risk of stroke with various types of menopausal hormone therapies. A National Cohort Study.” Stroke 48.8 (2017): 2266–9. DOI: 10.1161/strokeaha.117.017132
Marjoribanks, J., Farquhar, C., Roberts, H., Lethaby, A. “Long term hormone therapy for perimenopausal and postmenopausal women.” Cochrane Database Syst Rev 7 (2012): CD004143.
DOI: 10.1002/14651858. CD004143.pub4
Benkhadra, K., Mohammed, K., Al Nofal, A., et al. “Menopausal hormone therapy and mortality: a systematic review and meta-analysis.” J Clin Endocrinol Metab 100 (2015): 4021–8.
Clarke, S.C., Kelleher, J., Lloyd-Jones, H., et al. “A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT atherosclerosis study.” BJOG 109 (2002): 1056–62.
Mohammed, K., Abu Dabrh, A.M., Benkhadra, K., et al. “Oral vs transdermal estrogen therapy and vascular events: a systematic review and meta-analysis.” J Clin Endocrinol Metab 100 (2015): 4012–20. DOI: 10.1210/jc.2015–2237
Mikkola, T.S., Tuomikoski, P., Lyytinen, H., et al. “Vaginal estradiol use and the risk for cardiovascular mortality.” Hum Reprod 31 (2016): 804–9. DOI: 10.1093/humrep/dew014
Renoux, C., Dell’aniello, S., Garbe, E., Suissa, S. “Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study.” BMJ 340 (2010): 2519.
Nastri, C.O., Lara, L.A., Ferriani, R.A., et al. “Hormone therapy for sexual function in perimenopausal and postmenopausal women.” Cochrane Database Syst Rev 6 (2013): CD009672.
Coelingh Bennink, H.J. “Are all estrogens the same?” Maturitas 47.4 (2004): 269–75.
Shifren, J.L., Desindes, S., McIlwain, M., et al. “A randomized, open-label, crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women.” Menopause 14.6 (2007): 985–94.
Hodis, H.N., Mack, W.J., Azen, S.P., et al. “Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research Group. Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women.” N Engl J Med 349.6 (2003): 535–45.
Rosen, R., Brown, C., Heiman, J., et al. “The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function.” J Sex Marital Ther 26.2 (2000): 191–208.
Meston, C.M. “Validation of the Female Sexual Function Index (FSFI) in women with female orgasmic disorder and in women with hypoactive sexual desire disorder.” J Sex Marital Ther 29.1 (2003): 39–46.
Wiegel, M., Meston, C., Rosen, R. “The female sexual function index (FSFI): cross-validation and development of clinical cutoff scores.” J Sex Marital Ther 31.1 (2005): 1–20.
Nappi, R.E., Cucinella, L. “Advances in pharmacotherapy for treating female sexual dysfunction.” Expert Opin Pharmacother 16.6 (2015): 875–87.
Al-Azzawi, F., Bitzer, J., Brandenburg, U., et al. “Therapeutic options for postmenopausal female sexual dysfunction.” Climacteric 13.2 (2010): 103–20.
Taylor, H.S., Manson, J.E. “Update in hormone therapy use in menopause.” J Clin Endocrinol Metab 96.2 (2011): 255–64.
Harman, S.M., Black, D.M., Naftolin, F., et al. “Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial.” Ann Intern Med 161.4 (2014): 249–60.
Maclennan, A.H., Broadbent, J.L., Lester, S., Moore, V. “Oral oestrogen and combined oestrogen/ progestogen therapy versus placebo for hot flushes.” Cochrane Database Syst Rev 4 (2004): CD002978.
Suckling, J., Lethaby, A., Kennedy, R. “Local oestrogen for vaginal atrophy in postmenopausal women.” Cochrane Database Syst Rev 4 (2006): CD001500.
Politano, C.A., Valadares, A.L., Pinto-Neto, A., Costa-Paiva, L. “The metabolic syndrome and sexual function in climacteric women: a cross-sectional study.” J Sex Med 12.2 (2015): 455–62.
Merghati-Khoei, E., Sheikhan, F., Shamsalizadeh, N., et al. “Menopause negatively impacts sexual lives of middle-aged Iranian women: a cross-sectional study.” J Sex Marital Ther 40.6 (2014): 552–60.
Valadares, A.L., Pinto-Neto, A.M., de Souza, M.H., et al. “The prevalence of the components of low sexual function and associated factors in middle-aged women.” J Sex Med 8.10 (2011): 2851–8.
Valadares, A.L., Pinto-Neto, A.M., Osis, M.J., et al. “Prevalence of sexual dysfunction and its associated factors in women aged 40–65 years with 11 years or more of formal education: a population-based household survey.” Clinics (Sao Paulo) 63.6 (2008): 775–82.
Burger, H.G., Dudley, E.C., Cui, J., et al. “A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition.” J Clin Endocrinol Metab 85.8 (2000): 2832–8.
Ambler, D.R., Bieber, E.J., Diamond, M.P. “Sexual function in elderly women: a review of current literature.” Rev Obstet Gynecol 5.1 (2012): 16–27.
Davison, S.L., Bell, R., Donath, S., et al. “Androgen levels in adult females: changes with age, menopause, and oophorectomy.” J Clin Endocrinol Metab 90.7 (2005): 3847–53.
Nappi, R.E. “To be or not to be in sexual desire: the androgen dilemma.” Climacteric 18.5 (2015): 672–4.
Cobin, R.H., Goodman, N.F. “American association of clinical endocrinologists and American college of endocrinology position statement on menopause – 2017 update.” Endocrine practice 7.23 (2017): 869–80.
Copyright (c) 2017 С. О. Шурпяк
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.