Download 1) PRESENTATION: Cynthia A. Stuenkel

UCSD Biomedical Ethics Seminar Series
Hormone Replacement Therapy: What Went Wrong?
Jan. 21, 2003
Cynthia A. Stuenkel, MD,
Clinical Professor of Medicine, Endocrine and Metabolism
Mary Devereaux, Ph. D.,
Ethicist and Director for the Biomedical Ethics Seminars, UCSD Research Ethics Program
What follows is a synopsis of the discussion that followed Dr. Stuenkel and Dr. Devereaux’s Jan. 21 st, 2003
presentation. It aims to summarize the range of views expressed following their talk. Not all of these views
represent Dr. Stuenkel or Dr. Devereaux’s own thinking on the topic. Nor of course do they necessarily
represent the views of everyone present at the discussion.
1) PRESENTATION: Cynthia A. Stuenkel
Key points in Hormone Replacement Therapy Trials History:

PEPI: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial was
the first large randomized trial conducted on HRT, which results were published
in 1995: HRT was found to have beneficial effects on bone mineral density
and heart disease risk factors. However, the study also found estrogen had
negative effects on the uterine lining, unless progesterone was used in
combination.

HERS: Heart and Estrogen-Progestin Replacement Study was the first largescale randomized, double-blind, placebo-controlled clinical trial evaluating the
efficacy of HRT on postmenopausal women with coronary heart disease over a
period of 4 to 5 years. It unexpectedly found that hormone therapy presented
no overall benefit over placebos in preventing heart attacks and that
women in the first year of the study were actually at increased risk for
heart attacks and blood clotting.

The results of HERS called into question the conclusions of observational studies and
brought to the foreground issues of hierarchies of evidence for therapeutic studies.
If the ideal is evidence-based medicine, what are the ideal research methods to prove
the efficacy of therapy regimens?

The Oxford Centre for Evidence-based Medicine defines the ‘Levels of Evidence’ that
can be assigned to therapeutic studies as follows: (May 2001)
http://www.cebm.net/levels_of_evidence.asp
HIGHEST: Meta-Analysis of RCTs Systematic Review of RCTs
↓
Individual RCT Individual RCT
↓
Observational Studies (Cohort and Case-Control Studies)
↓
Basic Research (Test Tube, Animal, Human Physiology)
↓
WEAKEST: Clinical Experience Expert Opinions, Consensus Opinions

WHI: The Women's Health Initiative (WHI) is a large-scale, 5-year NIH research
program on cardiovascular disease, cancer, osteoporosis, mental health and quality of
life related factors in postmenopausal women. It studied the effects of HRT on Fracture
Risk and Bone Mineral Density (October 2003), Gynecologic Cancers and Diagnostic
Procedures (October 2003), Coronary Heart Disease Risk (August 2003), Breast
Cancer Risk (June 2003), Dementia and Cognitive Function -- WHI Memory Study
(May 2003), Stroke Risk (May 2003) and Quality of Life (March 2003.)
o The ‘Combination Therapy’ part of the study was stopped in July 2002 by the
investigators, when it was found that HRT put healthy women at an increased risk
for breast cancer and heart disease and lacked overall benefit for prevention. The
estrogen-only study is still ongoing. (Addendum: On March 4, 2004, WHI
participants in the estrogen only arm were notified that the study had been halted
due to an increase in stroke risk. According to the press release, there was also a
trend for an increase in dementia, a reduction in fractures, and no increase or
decrease in coronary heart disease, and no increase in breast cancer).
o For fracture risk and bone mineral density, HRT was found to have positive effects.
However the associated risks outweighed the benefits, even in the subgroup of
women at increased risk for bone fracture.
o For gynecologic cancers, women taking HRT were found at similar or slightly
smaller risk of endometrial cancer than women taking placebo, and at similar risk for
ovarian cancer.
o For coronary heart disease and breast cancer, HRT in combination was found to
have no positive effects and to increase their incidence.
o HRT was found to increase the risk for probable dementia and contributed to a
significant decline in the score used to evaluate cognitive function (Modified MiniMental State Exam total score) Increased risks of strokes were also found for
estrogen/ progestin combination. In terms of quality of life, HRT was found to have
no significant effects on general health, vitality, mental health, depressive
symptoms, or sexual satisfaction.
In conclusion, the associated risks of HRT outweighed the benefits in terms of
prevention. The effects of estrogen alone should be published soon.
How can we reconcile the divergent results of observational studies and
Randomized Controlled Trials?

A meta-analysis of observational studies adjusted for socioeconomic status or
education and other CHD risks, found no benefit in the secondary or primary prevention
of CVD events, consistent with the findings of recent RCTs
(Annals of Internal Medicine: Linda L. Humphrey, MD, MPH; Benjamin K.S. Chan, MS; and Harold C. Sox, MD,
Editor, August 2002: http://www.annals.org/cgi/content/abstract/137/4/273)

In an article in the New England Journal of Medicine, Francine Grodstein, Thomas B.
Clarkson and Jo Ann E. Manson set out to explore the differences in results between
RCTs and observational studies for HRT. (“Understanding the Divergent Data on
Postmenopausal Hormone Therapy” February 2003)
http://content.nejm.org/cgi/content/extract/348/7/645
o “In randomized clinical trials, subjects are randomly assigned to treatments, thereby
minimizing possible differences between the groups in lifestyle or health-related
factors. In observational studies, by contrast, subjects who choose to take a given
agent may be very different from those who do not.”
o They found methodological differences:
- Confounding bias: “healthy user”
- Compliance bias
- Incomplete capture of early events
o And postulated biological differences:
- Hormone regimen (formulation and dose)
- Characteristics of study population: endogenous estrogen level, time since
menopause, stage of atherosclerosis
What is the role of hormone therapy in postmenopausal women?

The FDA issued New Labels for Estrogen and Estrogen with Progestin Therapy:
o Highlighting the increased risks for heart disease, heart attacks, strokes, and breast
cancer
o Emphasizing that these products are not approved for heart disease prevention
o Requesting similar label changes for all other manufacturers of estrogen and
estrogen with a progestin because all products are believed to have similar risks

The FDA also modified its approved indications for HRT, now only to include:
o Treatment of moderate to severe vasomotor symptoms associated with
menopause: - Prescribe at the lowest dose and for the shortest duration for the
individual woman.
o Treatment of moderate to severe symptoms of vulvar and vaginal atrophy (dryness
and irritation) associated with menopause.
o When prescribed solely for the treatment of symptoms of vulvar and vaginal
atrophy, consider topical vaginal products.Prevention of postmenopausal
osteoporosis
o When ET or EPT prescribed solely for prevention of osteoporosis, approved nonestrogen treatments should be carefully considered.
o ET and EPT products should only be considered for women with significant risk of
osteoporosis that outweighs the risks of the drug.
In Summary:
o Consider lower dose hormone therapy for symptom relief at menopause in
symptomatic women
o Women should be counseled about the small but real increased risk of CHD, stroke,
VTE, and breast cancer
o The CEE arm of the WHI will help to answer questions about unopposed estrogen
risks/benefits
o At least annually, reassess, and consider preventive strategies with safer risk
profiles that target benefits to specific individual risks: SERMs, bisphosphonates,
statins, etc.
o More research on different doses, modes of administration, and type of hormone
therapy will be important in the future.
2) PRESENTATION: Mary Devereaux
What are the ethical considerations involved in hormone replacement therapy?

For years doctors prescribed powerful drugs (HRT) to a large patient population in the
belief that estrogen alone, or in combination, would protect against heart disease,
osteoporosis and other diseases. Recent studies (e.g., The Women's Health Initiative)
fail to support such claims. What aspects of medical practice led so many doctors to
"get it wrong for so long"?
o Existing guidelines should have helped avoid this kind of episode. Why didn’t
they?
 Ethical principles: ‘Do not harm’; Informed Consent.
 Scientific Principle: Evidence-based medicine.
 Medical Principle: ‘Only prescribe what works’
o Need prophylactic regimens be evaluated more conservatively than therapeutic
ones, before being approved?

What role did pharmaceutical interests play in encouraging the widespread use of
HRT for menopausal and post-menopausal women?
o The FDA survives at the will of Congress, which gets lobbied by pharmaceutical
companies.
o Who sponsors the studies?
 HERS study was sponsored by a pharmaceutical company: WyethAyerst Research, an affiliate of American Home Products Corp. SR
 WHI was NIH-sponsored.
 PEPI was sponsored by various national institutes (National Heart, Lung,
and Blood Institute (NHLBI) National Institute on Aging (NIA) National
Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) National Institute of Child Health and Human Development
(NICHD))

Were there clinical warning signs that should have gained greater attention earlier, but
didn't? And if so, what happened?
o Disregard of low compliance rate (large numbers of women would quit regimen
within a year)
o Conventional wisdom, “the old story” versus “the new story”

What role did cultural views about women, female reproduction and aging play in
contributing to this outcome?
o Does medicine, as historically a “predominantly male field” tend to dismiss or
under treat women’s health concerns? Studies focusing on female populations
alone are rare, as is funding for such studies.
o The marketing of HRT drugs relies heavily on selling youth and beauty (better
skin, delayed signs of aging) as well as purported health benefits. Aging itself
treated as a disease.
o Assumption that women aren’t in a position to make medical decisions for
themselves. “Physicians know best what’s good for me”

Is menopause (male or female) in need of medical treatment?
o Female menopause has gone from being seen as a natural life event to
“estrogen deficiency” and pathology.
o Developing market for symptoms of “male menopause” -- hormone therapies
(testosterone) and sexual enhancement drugs (Viagra, etc) – support the view
that male aging is also a disease in need of treatment.

What lessons can we learn from the HRT “fiasco”? What conclusions might we draw
from a public health/clinical standpoint?
o How, for example, ought new (and unexpected) medical results best be handled
in the future?
o Inflammatory press, prompting widespread nervousness and panic among
patients immediately followed WHI findings on HRT. Patients assailing their
doctors with questions, to which the doctors didn’t yet have answers.
o To the extent that public trust in researchers and clinicians was harmed by this
episode, what, if anything, can be done to reestablish trust, post WHI?
3) DISCUSSION:

Why is there a practice/ data disconnect about menopause? How do you feel that
doctors in the general community are taking the WHI findings? Are they changing their
clinical treatment? Are there any surveys on how clinicians are prescribing?
o Sales of HRT drugs have dropped and the main HRT drug companies’ stock
market value significantly went down.
o However the clinician consensus remains: 60% pro estrogen. 40% against.
o There are a lot of vested economic and institutionalized interests in continuing to
prescribe HRT despite WHI findings.
o Clinicians and researchers stand to have “reputation damage”
o Pharmaceutical industry interests/ Role of estrogen marketing:
- Best-seller, “Feminine Forever,” praising estrogen as the latest beauty
secret later revealed to have been sponsored by several drug
manufacturers.
o National Institutes rely on donors as well and are not necessarily protected from
conflict of interests in their agendas.

Symptomology of Menopause?
o We went from prescribing HRT for symptomatic causes to prescribing HRT for
prevention reasons. It is this shift that got us into trouble.
o “Grandma didn’t care about hot flashes and didn’t feel bad through menopause”
o Yes, but earlier generations “had valiums, cocktails” and other ways of selfmedicating.
o Are there cultural studies studying symptoms across different cultures?
o There is no word for “hot flash” in Japanese, for instance.
o Women suffering from menopausal symptoms in the US do not care whether or
not other women in other cultures don’t. For an individual, “a hot flash is a hot
flash” no matter why it happens.
o From a medical standpoint, is the physiological response to menopause affected
by different diets, for example?

The question asked by the title of this seminar is “What went wrong?” Members of the
audience felt that it could also have been “What went right?” It is remarkable that a
study like the WHI received funding from the NIH to test “what everybody thought was
true.”

Economic fallout: Birth control pills prices have risen because the drug companies
selling HRT lost money.

Public Health dimension of this episode:
o Many people feel that the release of the WHI findings was poorly handled. The
data came out to the media before it reached the medical community. A media
frenzy immediately ensued provoking high level of anxiety in the population.
What can we learn from this case? How could we have best handled this
clinically?

Is it ethical to prescribe and ignore data?
o The commitment in the medical community to adhere to the “old way” is
worrisome.
o Evidence-based medicine is new. Many old physicians do not operate according
to this new model of evidence-based medicine. Prior to that, medical education
emphasized “clinical judgment.” Such clinical judgment is dependent on the
placebo effect. The very belief in estrogen can have a placebo effect.
o There are also culture differences within medical specialties. For instance,
Cardiology specialists seem very excited to hear about new findings (many well
attended meetings presenting new data) and are ready to change things
accordingly and quickly. In other disciplines, like Obstetrics and Gynecology,
things are slower to change.
o Prescribing patterns HAVE changed though, as sales for HRT have dropped by
30%.

Intersection of Culture and Medicine:
o Helping patients “Feel Good” is a different objective from “Preventing long term
disease.”
- The question becomes: Are you “miserable” enough during your
menopause to be willing to accept the risks associated with HRT?
o A patient today can get medical information from the media or the Internet.
Better-informed patients may feel more comfortable making demands on
physicians. Physicians thus need to be clear about the data and the risks for a
given patient.
:
o Aging, moods, menopause, sexual behavior has all recently been redefined by
medicine (or marketing) as pathological rather than natural.
o
Medicine is increasingly treating non-medical problems. For instance, initially
plastic surgery was only used for gross deformities or potentially medically
problematic issues and evolved to become “cosmetic surgery.”