Lamy, Olivier

Papadakis, Georgios E.

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L E T T E R T O T H E E D I T O R - R E S P O N S EResponsetoLetter to theEditor:“MenopausalHormoneTherapy Is Associated With Reduced and Total VisceralAdiposity: The OsteoLaus Cohort”Georgios E. Papadakis1 and Olivier Lamy2,31Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, CH-1011 Lausanne,Switzerland; 2Center of Bone Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne UniversityHospital, CH-1011 Lausanne, Switzerland; and 3Service of Internal Medicine, Centre HospitalierUniversitaire Vaudois, Lausanne University Hospital, CH-1011 Lausanne, SwitzerlandORCiD numbers: 0000-0002-0099-6755 (G. E. Papadakis).W e thank Dr. Turner and Professor Kerber for theirinterest in our article on the association betweenmenopausal hormone therapy (MHT) and reduced androidand visceral adiposity (1). Their letter brings additionalinsight to the results of our study, providing important datafrom animal studies that corroborate our findings andsuggest underlying pathophysiological mechanisms.In our article,we considered thebenefits ofMHT toderivefrom the direct effect of estrogen on adipose tissue, given theabsence of significant differences between groups regardingpotential intermediary factors such as caloric intake andphysical activity. Nevertheless, as acknowledged in the ar-ticle’s Discussion, the assessment of confounding factors wasonly partial, thus preventing us from drawing definitiveconclusions. In their letter, Turner et al. highlight an elegantstudy in ovariectomized rodents that revealed that 17b-estradiol supplementation restored normal lipolytic function,in contrast to physical exercise alone (2). These data implythat MHT in our study may have reduced android fat andvisceral adipose tissue via alteration of basic lipolytic rate.The authors attribute the absence of residual effect inpast users to the eventual downregulation of estrogenreceptor and subsequent loss of function of importantestrogen-associated metabolic pathways. Although thisspeculation remains plausible, we would like to stressthat the response of the target organs after MHT with-drawal seems to be tissue-specific, given our previousfindings of a less pronounced rebound effect on bonedensity and microarchitecture (3).Based on several animal studies, Turner et al. (4) supportthe theory of “eu-estrogenemia,” arguing in favor of thecritical window hypothesis to explain that the estrogen re-ceptor has distinct responses according to the timing of es-trogen administration. Extrapolating these data to humans,we would expect that early MHT use would have morefavorable outcomes, as suggested by subgroup analysis of theWomen’s Health Initiative (5). More recently, the mostconvincing clinical data in favor of this hypothesis come fromthe ELITE randomized clinical trial, which showed reducedcarotid artery intima-media thickness after 6months ofMHTselectively in early (,6 years) comparedwith late (.10 years)postmenopausal women (6). In OsteoLaus, however, wewere able to detect a benefit for bodymass index, android fat,andvisceral adipose tissue despite abroader age of the studiedpopulation (50 to 80 years). A possible explanation is thatMHT duration was long (12.26 8.8 years), for a mean ageof 62.66 6.7 years in current users. It is likely thatMHTwasstarted early after menopause in the majority of the partic-ipants, who thus fulfilled the criteria of eu-estrogenemia.In the light of the aforementioned evidence, we agreewith Turner et al. that the findings of our observationalstudy should encourage further research to explore theoptimal use of MHT.AcknowledgmentsFinancial Support: The detailed sources of funding of theOsteoLaus study are listed in the article “Menopausal HormoneISSN Print 0021-972X ISSN Online 1945-7197Printed in USACopyright © 2018 Endocrine SocietyReceived 6 August 2018. Accepted 15 August 2018.First Published Online 20 August 2018Abbreviation: MHT, menopausal hormone therapy.doi: 10.1210/jc.2018-01681 J Clin Endocrinol Metab, November 2018, 103(11):4035–4036 https://academic.oup.com/jcem 4035Therapy Is Associated With Reduced and Total Visceral Adi-posity: The OsteoLaus Cohort” (1).Correspondence and Reprint Requests: Georgios E.Papadakis, MD, Service of Endocrinology, Diabetes andMetabolism, Centre Hospitalier Universitaire Vaudois, LausanneUniversity Hospital, Avenue de la Sallaz 8-10, CH-1011 Lausanne,Switzerland. E-mail: georgios.papadakis@chuv.ch.Disclosure Summary: The authors have nothing todisclose.References1. Papadakis GE, Hans D, Rodriguez EG, Vollenweider P, Waeber G,Marques-Vidal P, Lamy O. Menopausal hormone therapy is asso-ciated with reduced total and visceral adiposity: the OsteoLauscohort. J Clin Endocrinol Metab. 2018;103(5):1948–1957.2. Spangenburg EE, Wohlers LM, Valencia AP. Metabolic dysfunctionunder reduced estrogen levels: looking to exercise for prevention.Exerc Sport Sci Rev. 2012;40(4):195–203.3. Papadakis G, Hans D, Gonzalez-Rodriguez E, Vollenweider P,Waeber G, Marques-Vidal PM, Lamy O. The benefit of menopausalhormone therapy on bone density and microarchitecture persistsafter its withdrawal. J Clin Endocrinol Metab. 2016;101(12):5004–5011.4. Turner RJ, Kerber IJ. A theory of eu-estrogenemia: a unifyingconcept. Menopause. 2017;24(9):1086–1097.5. Roehm E. A reappraisal of Women’s Health Initiative Estrogen-Alone Trial: long-term outcomes in women 50–59 years of age.Obstet Gynecol Int. 2015;2015:713295.6. Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ,Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ,Selzer RH, Azen SP; ELITE Research Group. Vascular effectsof early versus late postmenopausal treatment with estradiol.N Engl J Med. 2016;374(13):1221–1231.4036 Letter to the Editor - Response J Clin Endocrinol Metab, November 2018, 103(11):4035–4036

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