When Lowest Dose for Shortest Amount of Time Does Not Apply

Menopause for most women occurs between the ages of 46 and 55 years, but about 5% of women experience menopause early, between the ages of 40 and 45 years. Approximately 1% of women experience menopause prematurely, before the age of 40 years. BSO is the most common reason for premature or early menopause.1 Multiple adverse long-term health outcomes are associated with premature or early menopause, including coronary heart disease, dementia, parkinsonism, glaucoma, osteoporosis, mood disorders, sexual dysfunction, and early death. Although replacing estrogen reduces some of these risks, it may not completely eliminate the increased risk of parkinsonism, glaucoma, mood disorders, and sexual dysfunction.2 Reproduction is not the only function of the ovaries. The ovaries are also an endocrine organ with important functions mediated by receptors for ovarian hormones found in most tissues and organs. Premenopausally, the ovaries secrete primarily estrogen, progesterone, and testosterone, whereas postmenopausally, they secrete primarily testosterone, androstenedione, and dehydroepiandrosterone.3 Surgical removal of the ovaries before the natural age of menopause or primary ovarian insufficiency (POI) results in loss of estrogen, progesterone, and testosterone. Irrespective of the cause, women experiencing premature or early menopause are exposed to abnormal hormonal deprivation. The Women's Health Initiative (WHI) trials were not designed to study premature or early menopause (the youngest age of women was 50 years), and the results do not directly apply to these women. Although current clinical practice guidelines suggest the use of the lowest dose of hormone therapy for the shortest time needed to achieve treatment of symptoms in postmenopausal women, this recommendation does not apply to women experiencing premature or early menopause. In women with POI or BSO before the natural age of menopause, the goal of hormone therapy is not simply to manage symptoms, but also to replace the lost endocrine function of the premenopausal ovaries. The old term “estrogen replacement therapy” is a better term for this important medical practice.4 The confusion between “estrogen replacement therapy” and “estrogen therapy” (ET) is dangerous, and has caused mistreatment in many women after the publication of the WHI trial results. Although data are available regarding the range of estrogen doses and estradiol levels needed to preserve and maintain bone health,5–7 similar data are not available regarding estradiol levels (serum or tissue) needed to preserve cardiovascular or brain health. Higher doses of estradiol may be needed to approximate premenopausal levels; however, more precise data are lacking. Estrogen-containing contraceptives (which contain much higher doses of estrogen than postmenopausal hormone therapy) are commonly used in women with POI to provide hormone replacement and contraception. For women with early BSO, higher doses of postmenopausal ET (at least the equivalent of 100 mcg of transdermal estradiol) may be needed to provide an estrogen milieu that is physiological for premenopausal menstruating women. A progestogen is needed in addition to ET to protect the endometrium, if the uterus remains intact. However, most women who undergo BSO also undergo hysterectomy (concurrently or preceding). Unless a strong contraindication exists (such as a hormone-dependent cancer), women with BSO or POI before the age of 45 years will benefit from ET. Several medical societies recommend that hormone therapy be initiated in women with premature or early menopause and continued at least until the natural age of menopause.2 Longer duration therapy can be considered if symptoms dictate.8 Women with early BSO not only lose estrogen and progesterone but also lose about 50% of their androgen production.9 Early BSO is associated with sexual dysfunction,10 and testosterone has been associated with improved sexual function in women with oophorectomy.11,12 The Endocrine Society endorses treatment of postmenopausal women with properly diagnosed hypoactive sexual desire disorder; however, it does not routinely recommend the use of testosterone after BSO or in women with POI.13 Questions regarding safety and efficacy of testosterone therapy in women remain, and no Food and Drug Administration (FDA)-approved testosterone preparations for women are currently available in the United States. Answer: The Correct Answer is E Answer A is incorrect because the lack of severe vasomotor symptoms is not a reason to avoid treatment with systemic estrogen in this age range. The results of the WHI trials do not apply to women who experience estrogen deprivation at or before age 45 years. ET (or better “estrogen replacement therapy”) is needed to protect against the multiple adverse long-term health consequences of early estrogen deprivation. Answer B is incorrect. Although local vaginal ET may be needed in addition to systemic ET (if systemic ET is not sufficient to treat vaginal symptoms), it does not provide the systemic ET needed to protect the bone, the brain, and the cardiovascular system. Answer C is incorrect for the same reasons. ET may help alleviate mood symptoms associated with menopause in some women; however, a combination of hormone therapy and an antidepressant may be needed if symptoms are severe.14 Answer D is incorrect because none of the answers include the prescription of systemic ET, which is the first-line therapy.

- 1.Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR, Rocca WA. Premature or early menopause: Long-term health consequences. Maturitas 2010;65:161–166 [DOI] [PMC free article] [PubMed] [Google Scholar] - 2.Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 2015;18:483–491 [DOI] [PMC free article] [PubMed] [Google Scholar] - 3.Rocca WA, Ulrich LG. Oophorectomy for whom and at what age? Primum non nocere. Maturitas 2012;71:1–2 [DOI] [PubMed] [Google Scholar] - 4.Gatta LA, Jiang X, Schnatz P. Hormone therapy in women with primary ovarian insufficiency or early menopause. Menopause 2015;22:923–925 [DOI] [PubMed] [Google Scholar] - 5.Rogers A, Saleh G, Hannon RA, Greenfield D, Eastell R. Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women. J Clin Endocrinol Metab 2002;87:4470–4475 [DOI] [PubMed] [Google Scholar] - 6.Ettinger B, Pressman A, Sklarin P, Bauer DC, Cauley JA, Cummings SR. Associations between low levels of serum estradiol, bone density, and fractures among elderly women: The study of osteoporotic fractures. J Clin Endocrinol Metab 1998;83:2239–2243 [DOI] [PubMed] [Google Scholar] - 7.Benetti-Pinto CL, Ferreira VB, Yela DA. Long-term follow up of bone density in women with primary ovarian insufficiency. Menopause 2015;22:946–949 [DOI] [PubMed] [Google Scholar] - 8.North American Menopause Society. The 2012 hormone therapy position statement of The North American Menopause Society. Menopause 2012;19:257–271 [DOI] [PMC free article] [PubMed] [Google Scholar] - 9.Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: Changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005;90:3847–3853 [DOI] [PubMed] [Google Scholar] - 10.Madalinska JB, van Beurden M, Bleiker EM, et al. The impact of hormone replacement therapy on menopausal symptoms in younger high-risk women after prophylactic salpingo-oophorectomy. J Clin Oncol 2006;24:3576–3582 [DOI] [PubMed] [Google Scholar] - 11.Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: A randomized trial. Obstet Gynecol 2005;105:944–952 [DOI] [PubMed] [Google Scholar] - 12.Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682–688 [DOI] [PubMed] [Google Scholar] - 13.Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: A reappraisal: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2014;99:3489–3510 [DOI] [PubMed] [Google Scholar] - 14.Toffol E, Heikinheimo O, Partonen T. Hormone therapy and mood in perimenopausal and postmenopausal women: A narrative review. Menopause 2014;22:1–15 [DOI] [PubMed] [Google Scholar]