----Francois de la Rochefoucauld
T. WATSON JERNIGAN, MD MA NMCP
PROFESSOR AND CHAIRMAN
DEPARTMENT OF OB/GYN
QUILLEN COLLEGE OF MEDICINE
DO NOT have a financial interest/arrangement or
affiliation with one or more organizations that could
be perceived as a real or apparent conflict of interest in
the context of the subject of this presentation.
OBJECTIVES
 “As a result of participating in this activity, the
participant will be able to…”
 Demonstrate an understanding of the intent and focus
of the Women’s Health Initiative (W.H.I.)
 Demonstrate an appreciation for the outcomes of the
W. H. I.
OBJECTIVES
 Demonstrate an understanding of the format of the
Kronos Early Estrogen Prevention Study
 Demonstrate the similarities and differences between
the outcomes of the two studies
INTENT OF THE PRESENTATION
 As health care providers, all of us here are affected by
the changing world outside of our care areas. Every
year/month/day, there is new information to process
and to implement into our day-to-day practices. This
presentation attempts to add to the information about
treatment of patients in early menopause especially in
contrast to previous information.
LESSONS LEARNED ABOUT ESTROGEN
 Use of estrogens improve menopausal symptoms such
as hot flashes and night sweats (1940s)
 Use of estrogens can cause thromboembolic
phenomenon (1950s)
 Use of unopposed estrogen can lead to endometrial
hyperplasia or even endometrial cancer (1970s)
 Use of estrogens can reduce incidence of Coronary
Heart Disease (CAD) (1990s)
IMPACT OF CARDIOVASCULAR DISEASE
(CVD) ON WOMEN
 In 2012, CVD will impact approximately 515,000
American women
 CVD claims more female lives than all forms of female
cancer COMBINED
 64% of women who died suddenly of CVD had NO
previous symptoms
 While incidence of new breast cancers cases has
leveled, the number of deaths from breast cancer has
decreased
MENOPAUSE
 According to records of prescriptions, there were 129
million prescriptions for Hormonal Therapy (HT)
including estrogen in the year 2000
 In 2001, a Women’s Health Initiative (WHI) study was
undertaken to evaluate the efficacy of Estrogen and
Progestin as well as Estrogen alone in preventing heart
disease in postmenopausal women
RESULTS OF E2+P4 TRIAL OF W.H.I.
 The study was halted after 5.2 years because the test
statistic for invasive breast cancer exceeded the
stopping boundary for this adverse effect
 BREAST CANCER
HAZARD RATIOS (HRs) 1.26 (1.00-1.59)
ABSOLUTE EXCESS RISKS PER 10,000 PERSONYEARS WAS 8 MORE INVASIVE CANCERS
RESULTS OF E2 + P4 TRIAL OF W.H.I.
 The HRs for CHD, Stroke, Pulmonary Embolus (PE),
and Total Cardiovascular Disease (CVD) were all
elevated:
CHD: 1.29 (1.02-1.63)
STROKE: 1.41 (1.07-1.85)
PE: 2.13 (1.39-3.25)
TOTAL CVD: 1.22 (1.09-1.36)
POST-WHI MENOPAUSE
 After the 2002 WHI study was published
approximately 65% of women on HT stopped therapy
 In 2003, there were just over 76 million HT
prescriptions dispensed
 By 2008, this number had dropped to approximately
42 million prescriptions for HT in USA (29 million
were for estrogen only RXs)
POST W.H.I. EFFECT
 “Trends in hormone therapy use before and after
publication of the Women’s Health Initiative trial: 10
years of follow-up”
 Published 2009 but showed the impact of the W.H.I.
on European prescribing of estrogen in Barcelona,
Spain
 By 2007, there was a peak reduction of 89% in
percentage of overall prevalence
 Barbaglia, Gabriela MD, et al, Menopause Vol. 16, No. 9, 2009; 1061-
1064
RESULTS OF E2 ALONE TRIAL OF W.H.I.
 In 2004, the NIH decided to end the intervention
phase of the trial early after 6.8 years of observation
 Breast Cancer HRs were NOT elevated as
anticipated…neither were they statistically significant
for reduction
BREAST CANCER: 0.77 (0.59-1.01)
RESULTS OF E2 ALONE TRIAL OF W.H.I.
 Despite the use of estrogen for greater duration, there
was NOT overall increase in harm ratios as with E2 +
P4:
CHD: 0.91 (0.75-1.12)
PE: 1.34 (0.87-2.06)
STROKE: 1.39 (1.10-1.77)
TOTAL CVD: 1.12 (1.01-1.24)
“TIMING HYPOTHESIS”
 With the results of both arms of the W.H.I., there was
concerns by practicing providers
 The majority of menopausal patients placed on
estrogen had recently undergone menopause
 These patients tended to be younger, more active, and
healthier
 “Window of Opportunity” Hypothesis developed
YEAR 2007
 “Postmenopausal Hormone Therapy and Risk of
Cardiovascular Disease by Age and Years Since
Menopause”
 Rossouw et al reviewed the original data of the WHI
and created a secondary analysis
 The study reviewed both arms of the trials (E2 + P4
and E2 alone)
Rossouw, J. E. et al JAMA 2007; 297: 1465-1477
YEAR 2007
 In the combined trials, there were 396 cases of CVD
and 327 cases of stroke in the hormone treated group
 In the combined trials, there were 379 cases of CVD
and 239 cases of stroke in the placebo group
 For women with less than 10 years since Menopause,
the RR was 0.76 95% CI 0.50-1.16
Rossouw, J. E. et al JAMA 2007; 297: 1465-1477
YEAR 2007
 Conclusion from Rossouw et al’s article: “Sub group
analyses in the 2 WHI trials of HT suggested a nonsignificant reduction in the risk of CHD in women
aged 50-59 years in the trial of CEE or in women with
less than 10 years of menopause in the trial of CEE +
MPA.”
Kronos Longevity Research Institute
 K: KRONOS
 E: EARLY
 E: ESTROGEN
 P: PREVENTION
 S: STUDY
K. E. E. P. S.
 Randomized, double-blinded, placebo-controlled, four
(4) year clinical trial
 Participants: healthy women ages 42-59 (mean age of
52) within three (3) years of menopause
 Lab values of menopausal patients: Plasma FSH > 35
and/or Serum Estradiol level < 40 pg/dl
K. E. E. P. S.
 Patients were excluded for:
…Women with evidence of CVD
…Women with plasma levels of Cholesterol or
triglycerides that would require medical therapy
…severe obesity
…heavy smoking habit
K. E. E. P. S.
 772 participants
 Randomized into three (3) groups of therapy
 Group 1: CEE 0.45 mgs daily orally
+ Micronized Progesterone 200 mgs
for 12 days per month orally
Group 2: Transdermal estradiol patch 50 ugs
daily + Micronized Progesterone 200
mgs for 12 days per month orally
Group 3: Placebo capsule daily
+ Placebo capsule for 12 days per month
KEEPS RANDOMIZED TRIALS
 Effects on Lipids and Lipoproteins in Recently
Menopausal Women
 Carotid Intima Media Thickness and Coronary Artery
Calcium
 KEEPS Cognitive Function Outcomes including Verbal
Learning & Memory; Auditory Attention& Working
Memory; Visual Attention & Executive Function;
Speeded Language
K. E. E. P. S.
 Results after 48 months of treatment:
 As expected with any hormonal therapy, Vasomotor
Symptoms (Hot Flashes & Night Sweats) were
improved
 64% of all participants (466) completed all 4 years of
the trial (WHI compliance 50%-60%)
 another 16% of participants (118) discontinued the
study medication but continued to be followed
throughout study
K. E. E. P. S.
 For CAD: neither 0-CEE nor T-E2 significantly
affected either systolic or diastolic BP
 Yearly ultrasound imaging studies on all participants
to estimate thickening of the wall of the common
carotid arteries
 Carotid Ultrasound studies showed similar rates of
progression of arterial wall thickness in all 3 treatment
groups over 4 years of study
K. E. E. P. S.
 Researches saw no statistically significant differences
in rates of breast cancer, endometrial cancer,
myocardial infarction, TIA, stroke or venous
thromboembolic disease between the three groups
K.E.E.P.S.
 “We conclude that hormone treatment at the doses
employed and in this healthy, recently menopausal
population neither significantly reduced nor
accelerated progression of atherosclerosis as measured
by arterial imaging.”
WHAT DOES THIS MEAN TO
YOU?
HORMONES 2013
 “Times they are a changin’”
 Symptomatic young postmenopausal patients are
candidates for estrogen WITHOUT over concern for
CAD progression
 Controversy remains on Estrogen (Progestin?) impact
on Cardiovascular system of menopausal patients who
have no evidence of pre-existing condition
INDIVIDUALIZATION OF
THERAPY
A FINAL THOUGHT
 RELATIVE RISK
CHARACTERISTIC
 14
2 FAMILY MEMBERS WITH BREAST CA
 2.2
1 FAMILY MEMBER WITH BREAST CA
 1.8
OBESITY
 1.6
YOUNG AGE AT MENARCHE
 1.3
>30 AT BIRTH OF FIRST CHILD
 0.7
MENOPAUSE <49 YEARS OF AGE
 1.3
HORMONE THERAPY (E+P)<5 YEARS
Archer, David. “Postmenopausal HRT: What is fact, what is fiction” OBG
MANAGEMENT; June 2006: 76-85.
“THE ONLY CONSTANT IS CHANGE,
CONTINUING CHANGE, INEVITABLE
CHANGE—THAT IS THE DOMINANT FACTOR
IN SOCIETY TODAY. NO SENSIBLE DECISION
CAN BE MADE ANY LONGER WITHOUT
TAKING INTO ACCOUNT NOT ONLY THE
WORLD AS IT IS, BUT THE WORLD AS IT
WILL BE.”
--ISSAC ASIMOV