THINKING OF HISTORY NAMS Chicago, Illinois OUT OF THE BOX - PDF document

THINKING OF HISTORY NAMS Chicago, Illinois OUT OF THE BOX September 26, 2019 The History of Hormones – RATHER THAN A CHRONOLOGICAL REHASH OF HISTORY, THIS WILL Have we delivered what we promised? BE A REVIEW OF THE HISTORY OF MENOPAUSAL HORMONE Wulf H. Utian THERAPIES FROM A PERSONAL MB.BCh, PhD, DSc(Med), FRCOG, FACOG, FICS CONSULTANT IN WOMEN’S HEALTH PERSPECTIVE TO CONSIDER HOW Professor Emeritus, Case Western Reserve University Consultant, The Cleveland Clinic WE GOT TO WHERE WE ARE Scientific Director, Rapid Medical Research, Cleveland, OH Executive Director Emeritus and Founding President, NAMS Co-Founder and Honorary Past President, International Menopause Society DOCUMENTED PROMISES Menopause Milestones Anti-aging silver bullets ____________________   Cessation of aging and longer lives  No more osteoporotic fractures Recognition of Association with 1929 estrogen 1975 cancer WHI disease identified scare Study reproductive failure  Over 50% less CHD and heart attacks 2002 EPT 1978 Termination IMS 2004 E-only Launched  No more hot flashes and night sweats Termination 1989 1950’s 2007 Combined NAMS data analysis  No skin wrinkles Started Beginning of 2009 E+P follow-up aggressive  Complete bladder control 2011 E-only HRT follow-up Progestin ↓ ↓  No depression and better memory and mood 1700 1800 1900 2019  No increase in cancer risk Negative WHI 2013 Reanalysis connotations Adapted from Utian, 1980 1

Groote Schuur Hospital, University of Cape Town, 1967 SERENDIPITY – JOURNAL CLUB World’s first Menopause Research Clinic September 1964 “The fate of the non-treated postmenopausal woman. A plea for the maintenance of adequate estrogen from the puberty to the grave.” Wilson RA and Wilson TA. Journal of the American Geriatric Society 1963;11:347 This was my personal black swan ! The purpose of the 1968 review was listed as: I can best summarize the background to my future  “1. To analyze the current thoughts regarding the studies by quoting from my first published analysis menopause. of the narrative and non-scientific literature that existed in 1968.  2. To draw attention to the paucity of authoritative research and published data. The critical review opened with the observation  3. To serve as an indication for the urgent need for that “ most of what is published is based on research, particularly into the nature of the menopause and emotional and philosophical premises; the ‘change the methods for the relief of menopausal symptoms and of life’ is an emotional subject not only to women, disorders; the process of ‘ageing’ and, in particular, the but to men and doctors.” occurrence of osteoporosis and atherosclerosis in postmenopausal women; and the metabolic and vascular Utian WH. Feminine forever? Current concepts on the menopause. A changes following acute hormone withdrawal, e.g. after critical review. S Afr J Obstet Gynecol 6:7-10, 1968. bilateral oophorectomy in the pre- and postmenopausal female. ” 2

My Assessment of the State of the Art 1968 MY CONCLUSION - 1968 QUOTE : “ Several questions urgently require answers: “ Ideally these potent hormones should not  Is the climacteric a normal physiologic stage in the life of the human female, or is it a be administered by medical practitioners in simple result of ovarian failure and oestrogen deficiency? the absence of definite climacteric  Are the manifestations of ageing directly related to diminution of circulating sex hormones? symptoms until there is a clear evidence of  Can the administration of exogenous oestrogen or other sex hormones prevent the the relationship between the development of manifestations of ageing? carcinoma and the administration of  Are the oestrogens at present available for administration equivalent in effect to circulating endogenous oestrogens? oestrogens. ”  Does long-term oestrogen administration result in an increased incidence of breast or uterine carcinoma? Wulf H. Utian, S Afr J Gynec Obstet , 6:7-10, 1968  Do oestrogens have a direct effect on the psychological state and sense of well being in the postmenopausal patient? UNQUOTE Utian WH. Feminine forever? Current concepts on the menopause. A critical review. S Afr J Obstet Gynecol 6:7-10, 1968. Geneva van Keep and Utian May 1973 An all-day pub crawl leads to: Perhaps the most pivotal day  A menopause club – to become the in the history of International Menopause Society - the first formal platform for scientific discussion menopause-related medicine  A newsletter – to become Maturitas  Meetings in exotic places – to become the International Menopause Congresses 3

1 st International Congress on Menopause LaGrande Motte, France, 1976 The Food and Drug Administration believes that the new findings Climacteric symptoms and complaints result from : linking postmenopausal estrogen 1. Decreased ovarian activity with subsequent hormonal administration to endometrial deficiency causing early symptoms (hot flushes, perspiration, and cancer must be considered atrophic vaginitis) and late symptoms related to changes in various end organs. carefully by every physician who prescribes these drugs and every 2. Sociocultural factors determined by the woman ’ s environment. patient who takes them. 3. Psychological factors resulting from the individual woman ’ s character. FDA Statement, 1976 The variety of symptomatology results from interaction between these three components. Utian WH, Serr D. The climacteric syndrome. In: Consensus on Menopause Research. MTP Press, Lancaster, 1976, pp. 1-4. INFLUENTIAL MENOPAUSE AND THE TWO MOST NEFARIOUS HORMONE THERAPY STUDIES MISDIRECTIONS IN THE HISTORY OF STUDY FIRST PUBLICATIONS PRIMARY FOCUS WOMEN’S HEALTH Groote Schuur Hospital (UCT) Studies 1970 Menopause specific Rancho Bernado 1972 CHD Nurses Health Study 1976 Multiple 1960 Onwards – The Feminine Forever Gang Nachtigall NYU Study 1979 Menopause specific > Too many prescriptions for the wrong reasons Melbourne Women’s Healthy Aging 1990 Multiple/menopause Million Women Study 1996 Breast cancer PEPI 1997 CHD HERS 1998 CHD SWAN 2000 Multiple/menopause 2002 Onwards – The WHI false reporting Cache County 2002 Alzheimer's WHI 2002 CHD, BC, Osteo. > Too few prescriptions for the wrong reasons E3N EPIC 2005 CHD, VTE ESTHER 2007 HRT, VTE KEEPS 2009 CHD DOPS 2012 Osteoporosis ELITE 2016 CHD/vascular Utian 2019 Utian, 2019 4

Menopause Management Editorial, What Has Been Changing? July 2002  Knowledge about physio-pathology of  “ While the merits and demerits of the menopause data and the wisdom of the decision  The Health System to terminate this arm of the WHI study  Women ’ s attitudes and awareness will be debated for years, the manner  Decline in appeal of MHT in which the study was terminated  Alterations in MHT usage was poorly planned, abrupt and  Development of pharmaceutical alternates inhumane. Predictably, the media  Mega marketing of compounded drugs, herbs, “ food supplements ” etc. response was enormous, ranging  Menopause and public health policy from thoughtful to sensational. ” Utian WH: Managing Menopause After HERS II and WHI: Coping with the Aftermath. Menopause Management, July 2002,Vol. 11 – No. 4. ONE MORE LOOK AT THOSE DOCUMENTED PROMISES  Cessation of aging and longer lives DO YOU THINK THAT THESE  No more osteoporotic fractures PROMISES HAVE BEEN  Over 50% less CHD and heart attacks FULFILLED?  No more hot flashes and night sweats  No skin wrinkles  Complete bladder control  No depression and better memory  No increase in cancer risk 5

Finally, have my 1968 questions been answered? “ Most of the time QUOTE : “ Several questions urgently require answers: 1.Is the climacteric a normal physiologic stage in the life of the human in our world female, or is it a simple result of ovarian failure and oestrogen deficiency? 2.Are the manifestations of ageing directly related to diminution of circulating sex hormones? truth is just opinion. ” 3.Can the administration of exogenous oestrogen or other sex hormones prevent the manifestations of ageing? 4.Are the oestrogens at present available for administration equivalent in effect to circulating endogenous oestrogens? 5.Does long-term oestrogen administration result in an increased incidence of breast or uterine carcinoma? Michael Ondaatje, Anil ’ s Ghost. 6.Do oestrogens have a direct effect on the psychological state and sense of well being in the postmenopausal patient?.” UNQUOTE Utian WH. Feminine forever? Current concepts on the menopause. A critical review. S Afr J Obstet Gynecol 6:7-10, 1968 Always remember that life is a journey not a destination…. …it has been my privilege to have met so many of you somewhere along the way! Farewell!! 6