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

1 The History of Hormones –

Have we delivered what we promised?

Wulf H. Utian

MB.BCh, PhD, DSc(Med), FRCOG, FACOG, FICS CONSULTANT IN WOMEN’S HEALTH Professor Emeritus, Case Western Reserve University Consultant, The Cleveland Clinic Scientific Director, Rapid Medical Research, Cleveland, OH Executive Director Emeritus and Founding President, NAMS Co-Founder and Honorary Past President, International Menopause Society

NAMS Chicago, Illinois September 26, 2019

THINKING OF HISTORY OUT OF THE BOX

RATHER THAN A CHRONOLOGICAL REHASH OF HISTORY, THIS WILL BE A REVIEW OF THE HISTORY OF MENOPAUSAL HORMONE THERAPIES FROM A PERSONAL PERSPECTIVE TO CONSIDER HOW WE GOT TO WHERE WE ARE

DOCUMENTED PROMISES

 Cessation of aging and longer lives  No more osteoporotic fractures  Over 50% less CHD and heart attacks  No more hot flashes and night sweats  No skin wrinkles  Complete bladder control  No depression and better memory and mood

• No increase in cancer risk

Menopause Milestones

Recognition of reproductive failure Association with disease 1929 estrogen identified 1975 cancer scare 1700 1800 1900 2019 1950’s Beginning of aggressive HRT Negative connotations Adapted from Utian, 1980

2002 EPT Termination 2004 E-only Termination 2007 Combined data analysis 2009 E+P follow-up 2011 E-only follow-up

↓ Anti-aging silver bullets ____________________

WHI Study

Progestin

↓

1978

IMS Launched

1989

NAMS Started WHI 2013 Reanalysis

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SERENDIPITY – JOURNAL CLUB 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!

Groote Schuur Hospital, University of Cape Town, 1967 World’s first Menopause Research Clinic I can best summarize the background to my future studies by quoting from my first published analysis

• f the narrative and non-scientific literature that

existed in 1968. The critical review opened with the observation that “most of what is published is based on emotional and philosophical premises; the ‘change

• f life’ is an emotional subject not only to women,

but to men and doctors.”

Utian WH. Feminine forever? Current concepts on the menopause. A critical review. S Afr J Obstet Gynecol 6:7-10, 1968.

The purpose of the 1968 review was listed as:

“1. To analyze the current thoughts regarding the

menopause.

 2. To draw attention to the paucity of authoritative

research and published data.

 3. To serve as an indication for the urgent need for

research, particularly into the nature of the menopause and the methods for the relief of menopausal symptoms and disorders; the process of ‘ageing’ and, in particular, the

• ccurrence of osteoporosis and atherosclerosis in

postmenopausal women; and the metabolic and vascular changes following acute hormone withdrawal, e.g. after bilateral oophorectomy in the pre- and postmenopausal female.”

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My Assessment of the State of the Art 1968

QUOTE: “Several questions urgently require answers:

Is the climacteric a normal physiologic stage in the life of the human female, or is it a

simple result of ovarian failure and oestrogen deficiency?

Are the manifestations of ageing directly related to diminution of circulating sex

hormones?

Can the administration of exogenous oestrogen or other sex hormones prevent the

manifestations of ageing?

Are the oestrogens at present available for administration equivalent in effect to

circulating endogenous oestrogens?

Does long-term oestrogen administration result in an increased incidence of breast or

uterine carcinoma?

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.

“Ideally these potent hormones should not be administered by medical practitioners in the absence of definite climacteric symptoms until there is a clear evidence of the relationship between the development of carcinoma and the administration of

• estrogens.”

Wulf H. Utian, S Afr J Gynec Obstet, 6:7-10, 1968

MY CONCLUSION - 1968

Geneva May 1973

Perhaps the most pivotal day in the history of menopause-related medicine

van Keep and Utian

An all-day pub crawl leads to:

A menopause club – to become the

International Menopause Society - the first formal platform for scientific discussion

A newsletter – to become Maturitas Meetings in exotic places – to become the

International Menopause Congresses

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Utian WH, Serr D. The climacteric syndrome. In: Consensus on Menopause Research. MTP Press, Lancaster, 1976, pp. 1-4.

Climacteric symptoms and complaints result from:

• 1. Decreased ovarian activity with subsequent hormonal

deficiency causing early symptoms (hot flushes, perspiration, and atrophic vaginitis) and late symptoms related to changes in various end

• rgans.
• 2. Sociocultural factors determined by the woman’s

environment.

• 3. Psychological factors resulting from the individual

woman’s character.

The variety of symptomatology results from interaction between these three components.

1st International Congress on Menopause LaGrande Motte, France, 1976

The Food and Drug Administration believes that the new findings linking postmenopausal estrogen administration to endometrial cancer must be considered carefully by every physician who prescribes these drugs and every patient who takes them. FDA Statement, 1976 INFLUENTIAL MENOPAUSE AND HORMONE THERAPY STUDIES

STUDY FIRST PUBLICATIONS PRIMARY FOCUS Groote Schuur Hospital (UCT) Studies 1970 Menopause specific Rancho Bernado 1972 CHD Nurses Health Study 1976 Multiple Nachtigall NYU Study 1979 Menopause specific Melbourne Women’s Healthy Aging 1990 Multiple/menopause Million Women Study 1996 Breast cancer PEPI 1997 CHD HERS 1998 CHD SWAN 2000 Multiple/menopause Cache County 2002 Alzheimer's WHI 2002 CHD, BC, Osteo. E3N EPIC 2005 CHD, VTE ESTHER 2007 HRT, VTE KEEPS 2009 CHD DOPS 2012 Osteoporosis ELITE 2016 CHD/vascular

Utian, 2019

THE TWO MOST NEFARIOUS MISDIRECTIONS IN THE HISTORY OF WOMEN’S HEALTH

1960 Onwards – The Feminine Forever Gang > Too many prescriptions for the wrong reasons 2002 Onwards – The WHI false reporting > Too few prescriptions for the wrong reasons

Utian 2019

5 Menopause Management Editorial, July 2002  “While the merits and demerits of the

data and the wisdom of the decision to terminate this arm of the WHI study will be debated for years, the manner in which the study was terminated was poorly planned, abrupt and

• inhumane. Predictably, the media

response was enormous, ranging 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.

What Has Been Changing?

 Knowledge about physio-pathology of

menopause

 The Health System  Women’s attitudes and awareness  Decline in appeal of MHT  Alterations in MHT usage  Development of pharmaceutical alternates  Mega marketing of compounded drugs, herbs,

“food supplements” etc.

 Menopause and public health policy

ONE MORE LOOK AT THOSE DOCUMENTED PROMISES

 Cessation of aging and longer lives  No more osteoporotic fractures  Over 50% less CHD and heart attacks  No more hot flashes and night sweats  No skin wrinkles  Complete bladder control  No depression and better memory

• No increase in cancer risk

DO YOU THINK THAT THESE PROMISES HAVE BEEN FULFILLED?

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Finally, have my 1968 questions been answered?

QUOTE: “Several questions urgently require answers:

1.Is the climacteric a normal physiologic stage in the life of the human 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? 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

• f breast or uterine carcinoma?

6.Do oestrogens have a direct effect on the psychological state and sense

• f 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

“Most of the time in our world truth is just opinion.”

Michael Ondaatje, Anil’s Ghost. 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!!