Difficult conversations: Management of estradiol deficiency

“Impact of hormone therapy on the bone density of women with premature ovarian insufficiency: A systematic review” by Costa et al. [ [1] Costa G.P.O. Ferreira-Filho E.S. Simoes R.D.S. Soares-Junior J.M. Baracat E.C. Maciel G.A.R. Impact of hormone therapy on the bone density of women with premature ovarian insufficiency: a systematic review. Maturitas. 2023; 167: 105-112https://doi.org/10.1016/j.maturitas.2022.09.011 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar ] is a call for action, i.e., education and advocacy. What is the first-line hormone therapy for primary ovarian insufficiency (POI) supported by the best evidence? Women with POI have low bone mineral density. Inadequate therapy fails to remedy this. A recent report in the New York Times, “Women have been misled about menopause,” [ [2] Dominus S. Women Have Been Misled About Menopause. The New York Times, 2023https://www.nytimes.com/2023/02/01/magazine/menopause-hot-flashes-hormone-therapy.htmlDate accessed: February 12, 2023 Google Scholar ] demonstrates that shared decision making remains a difficult conversation [ [3] Prober C.G. Grousbeck H.I. Meehan W.F. Managing difficult conversations: an essential communication skill for all professionals and leaders. Acad. Med. J. Assoc. Am. Med. Coll. 2022; 97: 973-976https://doi.org/10.1097/ACM.0000000000004692 Crossref Scopus (4) Google Scholar ]. Women younger than 45 with estradiol deficiency have a metabolic derangement associated with increased morbidity and mortality [ [4] Asllanaj E. Bano A. Glisic M. et al. Age at natural menopause and life expectancy with and without type 2 diabetes. Menopause N Y N. 2019; 26: 387-394https://doi.org/10.1097/GME.0000000000001246 Crossref PubMed Scopus (15) Google Scholar ]. Generally, prospective, double-blind, controlled trials are considered the highest level of evidence for therapeutic studies [ [5] Oxford Centre for Evidence-Based Medicinen.d. Levels of Evidence (March 2009) — Centre for Evidence-Based Medicine (CEBM), University of Oxford. Accessed February 12, 2023. https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009. Google Scholar ]. The authors found only one such study in their review of 335 reports. The only double-blind, controlled trial, conducted by the US National Institutes of Health (NIH) [ [6] Popat V.B. Calis K.A. Kalantaridou S.N. et al. Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement. J. Clin. Endocrinol. Metab. 2014; 99: 3418-3426https://doi.org/10.1210/jc.2013-4145 Crossref PubMed Scopus (91) Google Scholar ], provided the average daily production rate of estradiol (100 micrograms per day) by transdermal patch and monthly, cyclic, oral progestogen. The NIH hormone regimen restored bone mineral density to normal over three years and was well tolerated. There is evidence that oral estrogen treatment has a higher risk of thromboembolism than transdermal estradiol replacement, yet this more physiologic approach is underutilized in clinical practice [ [7] Vinogradova Y. Coupland C. Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019; 364k4810https://doi.org/10.1136/bmj.k4810 Crossref PubMed Scopus (217) Google Scholar ]. Currently the best evidence supports the NIH regimen of replacement estradiol in young women using the 100 microgram dose delivered by the transdermal route. Future research should build on this hard evidence rather than from a standpoint of equipoise.