Story of HRTStory of HRT

Irina ProskorovskyIrina Proskorovsky

TimelineTimeline 1821- French physician de Gardanne 1821- French physician de Gardanne

invented the term menopause to describe the invented the term menopause to describe the phenomenon of transition phase in a phenomenon of transition phase in a woman’s life and the problems thereofwoman’s life and the problems thereof

1890 - doctors start to experimented with 1890 - doctors start to experimented with testicular extracts for men and ovarian testicular extracts for men and ovarian extracts for women extracts for women

1923-1938 Research leads to identifying 1923-1938 Research leads to identifying estrogen and other hormonesestrogen and other hormones

TimelineTimeline 1941 – FDA approves estrogen for treatment of 1941 – FDA approves estrogen for treatment of

menopausal symptomsmenopausal symptoms 1942 - First estrogen pill (Premarin) was introduced 1942 - First estrogen pill (Premarin) was introduced

in USin US In the 1950s, Ayerst Laboratories funded a massive In the 1950s, Ayerst Laboratories funded a massive

campaign to educate doctors on menopause, campaign to educate doctors on menopause, menopausal symptoms, and the consequences of menopausal symptoms, and the consequences of estrogen loss—and on the use of its product estrogen loss—and on the use of its product Premarin to treat menopausal symptomsPremarin to treat menopausal symptoms

1966 - Robert Wilson (Brooklyn gynecologist) 1966 - Robert Wilson (Brooklyn gynecologist) published his best seller “Feminine Forever”published his best seller “Feminine Forever”

Timeline (Con’t)Timeline (Con’t) 1975 - New England Journal of Medicine published two 1975 - New England Journal of Medicine published two

articles that found an increase risk of endometrial cancerarticles that found an increase risk of endometrial cancer 1980 - Few studies show HRT prevents Osteoporosis1980 - Few studies show HRT prevents Osteoporosis 1985 - Nurses’ Health Study showed a protective effect 1985 - Nurses’ Health Study showed a protective effect

of HRT on CVDof HRT on CVD 1991 – Meta-Analysis of the effect of estrogen 1991 – Meta-Analysis of the effect of estrogen

replacement therapy showed increase risk of breast replacement therapy showed increase risk of breast cancercancer

1998 – Results of Heart and Estrogen/Progestin 1998 – Results of Heart and Estrogen/Progestin Replacement Study (HERS) publishedReplacement Study (HERS) published

2001 – Risk and Benefits of Estrogen Plus Progestin in 2001 – Risk and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women-Women’s Health Healthy Postmenopausal Women-Women’s Health Initiative Initiative

MenopauseMenopause Menopause is the permanent cessation of menstruation due Menopause is the permanent cessation of menstruation due

to loss of ovarian activity and the depletion of follicles to loss of ovarian activity and the depletion of follicles During menopause women produces less hormones During menopause women produces less hormones

(estrogen and progesterone)(estrogen and progesterone) Symptoms include changes in the menstrual cycle, hot Symptoms include changes in the menstrual cycle, hot

fleshes, night sweats, dryness, itching, burning, or thinning fleshes, night sweats, dryness, itching, burning, or thinning of the vaginaof the vagina

Quote from Egyptian medical text, 2000 B.C.: “If a Quote from Egyptian medical text, 2000 B.C.: “If a menopausal woman has pain or makes trouble, pound her menopausal woman has pain or makes trouble, pound her hard on the jaw”.hard on the jaw”.

Development of HRTDevelopment of HRT Before 1880 treatments for menopausal symptoms had Before 1880 treatments for menopausal symptoms had

primarily consisted of herbals: a selection of belladonna, primarily consisted of herbals: a selection of belladonna, cannabis, or opiumcannabis, or opium

In 1889, Dr. Brown-Sequard's made the following In 1889, Dr. Brown-Sequard's made the following announcement: "I sent to the Society of Biology a announcement: "I sent to the Society of Biology a communication, which was followed by several others, communication, which was followed by several others, showing the remarkable effects produced on myself by showing the remarkable effects produced on myself by subcutaneous injection of a liquid obtained by the maceration subcutaneous injection of a liquid obtained by the maceration on a mortar of the testicle of a dog or of a guinea pig to which on a mortar of the testicle of a dog or of a guinea pig to which one has added a little water" (Medvei 1982:289)one has added a little water" (Medvei 1982:289)

In the 1890's Merck offered flavored powder made by drying In the 1890's Merck offered flavored powder made by drying and pulverizing cow ovaries called Ovariin, that may have and pulverizing cow ovaries called Ovariin, that may have been the first substance commercially available for treatment been the first substance commercially available for treatment of menopausal symptoms that was derived from animal of menopausal symptoms that was derived from animal sources sources

Research by Dr. Allen and Dr. Doisy between 1923-1938 led Research by Dr. Allen and Dr. Doisy between 1923-1938 led to discovery of estrogen and all other hormonesto discovery of estrogen and all other hormones

Development of HRTDevelopment of HRT Emminen, the first replacement therapy to contain Emminen, the first replacement therapy to contain

conjugated estrogens, was extracted in Ayerst Laboratories conjugated estrogens, was extracted in Ayerst Laboratories from the urine of pregnant women and became from the urine of pregnant women and became commercially available in 1933commercially available in 1933

1942 Premarine (PREgnant MARes’s urINe) available in 1942 Premarine (PREgnant MARes’s urINe) available in USUS

1938 English chemists, including Charles Dodds, 1938 English chemists, including Charles Dodds, developed powerful synthetic, nonsteroidal estrogen developed powerful synthetic, nonsteroidal estrogen diethylstilbestrol (“DES”), that had the same effects as diethylstilbestrol (“DES”), that had the same effects as estrogens but 3 time more powerful (pulled from the market estrogens but 3 time more powerful (pulled from the market in 1971 when babies born to DES users were found to have in 1971 when babies born to DES users were found to have increased incidence of cancer of the reproductive organs) increased incidence of cancer of the reproductive organs)

1980 Progestin developed to balance estrogen1980 Progestin developed to balance estrogen

Marketing HRTMarketing HRT In the 1950s, Ayerst Laboratories funded a massive In the 1950s, Ayerst Laboratories funded a massive

campaign to educate doctors on menopause, campaign to educate doctors on menopause, menopausal symptoms, and the consequences of menopausal symptoms, and the consequences of estrogen loss—and on the use of its product estrogen loss—and on the use of its product Premarin to treat menopausal symptomsPremarin to treat menopausal symptoms

1966 Robert Wilson argued in his book “Feminine 1966 Robert Wilson argued in his book “Feminine Forever” that menopause was not natural age-Forever” that menopause was not natural age-related condition and estrogen become long-term related condition and estrogen become long-term treatment for chronic ills of aging treatment for chronic ills of aging

Scientific EvidenceScientific Evidence

1976 -The Nurses' Health Study was 1976 -The Nurses' Health Study was established by Dr. Frank Speizer with funding established by Dr. Frank Speizer with funding from the National Institutes of Health. The from the National Institutes of Health. The primary motivation in starting the NHS was to primary motivation in starting the NHS was to investigate the potential long term investigate the potential long term consequences of the use of oral contraceptives, consequences of the use of oral contraceptives, a potent drug that was being prescribed to a potent drug that was being prescribed to hundreds of millions of normal women. hundreds of millions of normal women.

Nurses' Health StudyNurses' Health Study Design: Prospective, observational CohortDesign: Prospective, observational Cohort Setting: Nurses health study with follow up Setting: Nurses health study with follow up

from 1976 to 1996from 1976 to 1996 Participants: postmenopausal women with no Participants: postmenopausal women with no

hx of CVD in whom major coronary events hx of CVD in whom major coronary events and strokes were identifiedand strokes were identified

Comparisons: Current HRT Users, Past Users, Comparisons: Current HRT Users, Past Users, Never Never

Main Outcomes: CVDMain Outcomes: CVD

Results of NHS (JAMA 1985)Results of NHS (JAMA 1985) During 105,786 person-years of observation among 32,317 During 105,786 person-years of observation among 32,317

postmenopausal women who were initially free of coronary postmenopausal women who were initially free of coronary disease, 90 women had either nonfatal myocardial infarctions disease, 90 women had either nonfatal myocardial infarctions (65 cases) or fatal coronary heart disease (25 cases). (65 cases) or fatal coronary heart disease (25 cases).

Ever vs. never RR= 0.5 (95% CI; 0.3 -0.8; P = 0.007)Ever vs. never RR= 0.5 (95% CI; 0.3 -0.8; P = 0.007) Current vs. never RR= 0.3 (95% CI, 0.2 - 0.6; P = 0.001)Current vs. never RR= 0.3 (95% CI, 0.2 - 0.6; P = 0.001) The relative risks were similar for fatal and nonfatal disease The relative risks were similar for fatal and nonfatal disease

and were unaltered after adjustment for cigarette smoking, and were unaltered after adjustment for cigarette smoking, hypertension, diabetes, high cholesterol levels, a parental hypertension, diabetes, high cholesterol levels, a parental history of myocardial infarction, past use of oral history of myocardial infarction, past use of oral contraceptives, and obesity. contraceptives, and obesity.

These data support the hypothesis that the postmenopausal use These data support the hypothesis that the postmenopausal use of estrogen reduces the risk of severe coronary heart disease. of estrogen reduces the risk of severe coronary heart disease.

Use of HRT in CanadaUse of HRT in Canada

Ilona Csizmadi, Andrea Benedetti, Jean-François Boivin, James A. Hanley, and Jean-Paul Collet Use of postmenopausal estrogen replacement therapy from 1981 to 1997 CMAJ. 2002 January 22; 166(2): 187–188

Walnut Creek Study (1987)Walnut Creek Study (1987) Walnut Creek Study (N=16,500)Walnut Creek Study (N=16,500) Diana Petitti also found a reduced risk of Diana Petitti also found a reduced risk of

CHD among women taking HRTCHD among women taking HRT But!!! She also found an even more But!!! She also found an even more

dramatic reduction in death from dramatic reduction in death from homocide, suicide and accidents homocide, suicide and accidents

Her conclusion: something else appear to Her conclusion: something else appear to be confounding the observed association be confounding the observed association

HERS Trial (HERS Trial (JAMA 1998)JAMA 1998)   Design: Randomized, blinded, placebo-controlled secondary Design: Randomized, blinded, placebo-controlled secondary

prevention trialprevention trial Setting: Outpatient and community settings at 20 US clinical Setting: Outpatient and community settings at 20 US clinical

centerscenters Participants: 2,763 Women with CHD, < 80 years, Participants: 2,763 Women with CHD, < 80 years,

postmenopausal with an intact uteruspostmenopausal with an intact uterus Intervention: Either 0.625 mg of conjugated equine estrogens Intervention: Either 0.625 mg of conjugated equine estrogens

plus 2.5 mg medroxyprogesterone daily or placeboplus 2.5 mg medroxyprogesterone daily or placebo Compliance: 82% of those assign to HRT at 1 year, 75% at Compliance: 82% of those assign to HRT at 1 year, 75% at

end of year 3end of year 3 Main Outcomes: Main Outcomes:

Primary: Non-fatal MI or CHD Primary: Non-fatal MI or CHD Secondary: Coronary revascularization, unstable angina, Secondary: Coronary revascularization, unstable angina,

congestive heart failure, stroke, TIA, PAD, cardiac arrest congestive heart failure, stroke, TIA, PAD, cardiac arrest

HERS Trial ResultsHERS Trial Results

Figure 3.—Kaplan-Meier estimates of the cumulative incidence of primary coronary Figure 3.—Kaplan-Meier estimates of the cumulative incidence of primary coronary heart disease (CHD) events (left) and to its constituents: nonfatal myocardial infarction heart disease (CHD) events (left) and to its constituents: nonfatal myocardial infarction (MI) (center) and CHD death (right). The number of women observed at each year of (MI) (center) and CHD death (right). The number of women observed at each year of follow-up and still free of an event are provided in parentheses, and the curves become follow-up and still free of an event are provided in parentheses, and the curves become fainter when this number drops below half of the cohort. Log rank fainter when this number drops below half of the cohort. Log rank PP values are .91 for values are .91 for primary CHD events, .46 for nonfatal MI, and .23 for CHD death. primary CHD events, .46 for nonfatal MI, and .23 for CHD death.

HERS ConclusionsHERS Conclusions In postmenopausal women with established coronary In postmenopausal women with established coronary

disease and an average age of 66.7 years, daily use of disease and an average age of 66.7 years, daily use of conjugated equine estrogens and conjugated equine estrogens and medroxyprogesterone acetate did not reduce the medroxyprogesterone acetate did not reduce the overall risk for MI and CHD death or any other overall risk for MI and CHD death or any other cardiovascular outcome during an average of 4.1 cardiovascular outcome during an average of 4.1 years of follow-upyears of follow-up

This therapy did increase the risk of venous This therapy did increase the risk of venous thromboembolic events and gallbladder diseasethromboembolic events and gallbladder disease

Extended follow-up of the HERS cohort and Extended follow-up of the HERS cohort and additional randomized trials are needed to clarify the additional randomized trials are needed to clarify the cardiovascular effects of postmenopausal hormone cardiovascular effects of postmenopausal hormone therapy therapy

Woman’s Health Initiative RCT (JAMA-2002)Woman’s Health Initiative RCT (JAMA-2002) Design: Randomized Controlled double blind primary Design: Randomized Controlled double blind primary

prevention Trialprevention Trial Settings: most women recruited by population-based direct Settings: most women recruited by population-based direct

mailing campaign in conjunction with media awareness mailing campaign in conjunction with media awareness campaigncampaign

Participants: postmenopausal women age 50-79 with intact Participants: postmenopausal women age 50-79 with intact uterus at baselineuterus at baseline

Intervention: Either 0.625 mg of conjugated equine estrogens Intervention: Either 0.625 mg of conjugated equine estrogens plus 2.5 mg medroxyprogesterone daily or placeboplus 2.5 mg medroxyprogesterone daily or placebo

Compliance: 90% and 95% at year 1, 80% and 85% at year 3, Compliance: 90% and 95% at year 1, 80% and 85% at year 3, 69% and 74% at year 5 for women on HRT and placebo 69% and 74% at year 5 for women on HRT and placebo respectivelyrespectively

Main Outcomes: Main Outcomes: Primary: Non-fatal MI, CHD and CHD Death and Cancer Primary: Non-fatal MI, CHD and CHD Death and Cancer

(AE)(AE) Global Index: 2 primary outcomes plus stroke, pulmonary Global Index: 2 primary outcomes plus stroke, pulmonary

embolism, endometrial cancer, colorectal cancer, hip embolism, endometrial cancer, colorectal cancer, hip fracture and death due to other causes fracture and death due to other causes

WHI ResultsWHI Results After 5.2 years of follow up trial of estrogen plus After 5.2 years of follow up trial of estrogen plus

progestin vs. placebo was stopped because the test progestin vs. placebo was stopped because the test statistic for invasive breast cancer exceeded the statistic for invasive breast cancer exceeded the stopping boundary and an overall balance of harm stopping boundary and an overall balance of harm was found to be greater than benefit with respect to 8 was found to be greater than benefit with respect to 8 prespecified outcomesprespecified outcomes

WHI-ET, the estrogen-only trial stopped 2 years WHI-ET, the estrogen-only trial stopped 2 years prematurely in 2004, after an average of 6.6 years. prematurely in 2004, after an average of 6.6 years. The main reason for stopping this trial early was a The main reason for stopping this trial early was a 39% increased incidence of stroke among ET users 39% increased incidence of stroke among ET users and a very low likelihood for future cardiac benefit. and a very low likelihood for future cardiac benefit.

Results of HERS and WHIResults of HERS and WHIHazard Ratio (95% CI)Hazard Ratio (95% CI)

Clinical eventClinical event HERS (estrogen +HERS (estrogen +progestin) progestin)

WHI (estrogen +WHI (estrogen +progestin) progestin)

WHI (estrogen) WHI (estrogen)

CHD eventsCHD events 0.99 (0.80–1.22)0.99 (0.80–1.22) 1.29 (1.02–1.63)1.29 (1.02–1.63) 0.91 (0.75–1.12)0.91 (0.75–1.12)

Stroke Stroke 1.23 (0.89–1.70)1.23 (0.89–1.70) 1.41 (1.07–1.85)1.41 (1.07–1.85) 1.39 (1.10–1.77)1.39 (1.10–1.77)

Pulmonary Pulmonary embolism embolism

2.79 (0.89–8.75)2.79 (0.89–8.75) 2.13 (1.39–3.25)2.13 (1.39–3.25) 1.34 (0.87–2.06)1.34 (0.87–2.06)

Breast cancer Breast cancer 1.30 (0.77–2.19)1.30 (0.77–2.19) 1.26 (1.00–1.59)1.26 (1.00–1.59) 0.77 (0.59–1.01)0.77 (0.59–1.01)

Colon cancer Colon cancer 0.69 (0.32–1.49)0.69 (0.32–1.49) 0.63 (0.43–0.92)0.63 (0.43–0.92) 1.08 (0.75–1.55)1.08 (0.75–1.55)

Hip fracture Hip fracture 1.10 (0.49–2.50)1.10 (0.49–2.50) 0.66 (0.45–0.98)0.66 (0.45–0.98) 0.61 (0.41–0.91)0.61 (0.41–0.91)

Death Death 1.08 (0.84–1.38)1.08 (0.84–1.38) 0.98 (0.82–1.18)0.98 (0.82–1.18) 1.04 (0.88–1.22)1.04 (0.88–1.22)

Global indexGlobal index NANA 1.15 (1.03–1.28)1.15 (1.03–1.28) 1.01 (0.91–1.12)1.01 (0.91–1.12)

USE of HRT in USUSE of HRT in US

Figure 3. Annual Number of US Prescriptions for Hormone Therapy by Formulation, 1995-July 2003

Hersch AL, Stefanick ML, Stafford RS. 2004. Nationaluse of postmenopausal hormone therapy. JAMA 291:47–53 (43, figure 3, p. 50)

Why Results of NHS and 3 Trials are So Why Results of NHS and 3 Trials are So DifferentDifferent

Bias of Healthy Users: people who are taking Bias of Healthy Users: people who are taking drugs as prescribed, or eating healthy diet are drugs as prescribed, or eating healthy diet are fundamentally different from those who don’tfundamentally different from those who don’t Women who take HRT are more thinner, have Women who take HRT are more thinner, have

fewer risk factors for heart disease, more educated fewer risk factors for heart disease, more educated and wealthier, generally more health consciousand wealthier, generally more health conscious

Prescriber Effect: The reasons a physician will Prescriber Effect: The reasons a physician will prescribe one medication to one patient and prescribe one medication to one patient and none to other are often complex and subtle none to other are often complex and subtle

Why Results of NHS and 3 Trials are So Why Results of NHS and 3 Trials are So DifferentDifferent

Measurement Error: In NHS study women Measurement Error: In NHS study women were asked if they were taking HRT every two were asked if they were taking HRT every two yearsyears

TimingTiming Clinical Trials: What happens if older women gets Clinical Trials: What happens if older women gets

HRT years after menopauseHRT years after menopause Observational Studies: What happens to women Observational Studies: What happens to women

taking HRT near onset of menopausetaking HRT near onset of menopause