Story of HRT Irina Proskorovsky

Timeline 1821- French physician de Gardanne invented the term menopause to describe the phenomenon of transition phase in a woman’s life and the problems thereof 1890 - doctors start to experimented with testicular extracts for men and ovarian extracts for women 1923-1938 Research leads to identifying estrogen and other hormones

Timeline 1941 – FDA approves estrogen for treatment of menopausal symptoms 1942 - First estrogen pill (Premarin) was introduced in US In the 1950s, Ayerst Laboratories funded a massive campaign to educate doctors on menopause, menopausal symptoms, and the consequences of estrogen loss—and on the use of its product Premarin to treat menopausal symptoms 1966 - Robert Wilson (Brooklyn gynecologist) published his best seller “Feminine Forever”

Timeline (Con’t) 1975 - New England Journal of Medicine published two articles that found an increase risk of endometrial cancer 1980 - Few studies show HRT prevents Osteoporosis 1985 - Nurses’ Health Study showed a protective effect of HRT on CVD 1991 – Meta-Analysis of the effect of estrogen replacement therapy showed increase risk of breast cancer 1998 – Results of Heart and Estrogen/Progestin Replacement Study (HERS) published 2001 – Risk and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women-Women’s Health Initiative

Menopause Menopause is the permanent cessation of menstruation due to loss of ovarian activity and the depletion of follicles During menopause women produces less hormones (estrogen and progesterone) Symptoms include changes in the menstrual cycle, hot fleshes, night sweats, dryness, itching, burning, or thinning of the vagina Quote from Egyptian medical text, 2000 B.C.: “If a menopausal woman has pain or makes trouble, pound her hard on the jaw”.

Development of HRT Before 1880 treatments for menopausal symptoms had primarily consisted of herbals: a selection of belladonna, cannabis, or opium In 1889, Dr. Brown-Sequard's made the following announcement: "I sent to the Society of Biology a communication, which was followed by several others, showing the remarkable effects produced on myself by 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 one has added a little water" (Medvei 1982:289) In the 1890's Merck offered flavored powder made by drying and pulverizing cow ovaries called Ovariin, that may have been the first substance commercially available for treatment of menopausal symptoms that was derived from animal sources Research by Dr. Allen and Dr. Doisy between 1923-1938 led to discovery of estrogen and all other hormones

Development of HRT Emminen, the first replacement therapy to contain conjugated estrogens, was extracted in Ayerst Laboratories from the urine of pregnant women and became commercially available in 1933 1942 Premarine (PREgnant MARes’s urINe) available in US 1938 English chemists, including Charles Dodds, developed powerful synthetic, nonsteroidal estrogen diethylstilbestrol (“DES”), that had the same effects as estrogens but 3 time more powerful (pulled from the market in 1971 when babies born to DES users were found to have increased incidence of cancer of the reproductive organs) 1980 Progestin developed to balance estrogen

Marketing HRT In the 1950s, Ayerst Laboratories funded a massive campaign to educate doctors on menopause, menopausal symptoms, and the consequences of estrogen loss—and on the use of its product Premarin to treat menopausal symptoms 1966 Robert Wilson argued in his book “Feminine Forever” that menopause was not natural age-related condition and estrogen become long-term treatment for chronic ills of aging

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

Nurses' Health Study Design: Prospective, observational Cohort Setting: Nurses health study with follow up from 1976 to 1996 Participants: postmenopausal women with no hx of CVD in whom major coronary events and strokes were identified Comparisons: Current HRT Users, Past Users, Never Main Outcomes: CVD

Results of NHS (JAMA 1985) During 105,786 person-years of observation among 32,317 postmenopausal women who were initially free of coronary disease, 90 women had either nonfatal myocardial infarctions (65 cases) or fatal coronary heart disease (25 cases). 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) The relative risks were similar for fatal and nonfatal disease and were unaltered after adjustment for cigarette smoking, hypertension, diabetes, high cholesterol levels, a parental history of myocardial infarction, past use of oral contraceptives, and obesity. These data support the hypothesis that the postmenopausal use of estrogen reduces the risk of severe coronary heart disease.

Use 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 (N=16,500) Diana Petitti also found a reduced risk of CHD among women taking HRT But!!! She also found an even more dramatic reduction in death from homocide, suicide and accidents Her conclusion: something else appear to be confounding the observed association

HERS Trial (JAMA 1998)  Design: Randomized, blinded, placebo-controlled secondary prevention trial Setting: Outpatient and community settings at 20 US clinical centers Participants: 2,763 Women with CHD, < 80 years, postmenopausal with an intact uterus Intervention: Either 0.625 mg of conjugated equine estrogens plus 2.5 mg medroxyprogesterone daily or placebo Compliance: 82% of those assign to HRT at 1 year, 75% at end of year 3 Main Outcomes: Primary: Non-fatal MI or CHD Secondary: Coronary revascularization, unstable angina, congestive heart failure, stroke, TIA, PAD, cardiac arrest

HERS Trial Results Figure 3.—Kaplan-Meier estimates of the cumulative incidence of primary coronary 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 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 P values are .91 for primary CHD events, .46 for nonfatal MI, and .23 for CHD death.

HERS Conclusions In postmenopausal women with established coronary disease and an average age of 66.7 years, daily use of conjugated equine estrogens and medroxyprogesterone acetate did not reduce the overall risk for MI and CHD death or any other cardiovascular outcome during an average of 4.1 years of follow-up This therapy did increase the risk of venous thromboembolic events and gallbladder disease Extended follow-up of the HERS cohort and additional randomized trials are needed to clarify the cardiovascular effects of postmenopausal hormone therapy

Woman’s Health Initiative RCT (JAMA-2002) Design: Randomized Controlled double blind primary prevention Trial Settings: most women recruited by population-based direct mailing campaign in conjunction with media awareness campaign Participants: postmenopausal women age 50-79 with intact uterus at baseline Intervention: Either 0.625 mg of conjugated equine estrogens plus 2.5 mg medroxyprogesterone daily or placebo 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 respectively Main Outcomes: Primary: Non-fatal MI, CHD and CHD Death and Cancer (AE) Global Index: 2 primary outcomes plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture and death due to other causes

WHI Results After 5.2 years of follow up trial of estrogen plus progestin vs. placebo was stopped because the test statistic for invasive breast cancer exceeded the stopping boundary and an overall balance of harm was found to be greater than benefit with respect to 8 prespecified outcomes WHI-ET, the estrogen-only trial stopped 2 years prematurely in 2004, after an average of 6.6 years. The main reason for stopping this trial early was a 39% increased incidence of stroke among ET users and a very low likelihood for future cardiac benefit.

Results of HERS and WHI Hazard Ratio (95% CI) Clinical event HERS (estrogen + progestin) WHI (estrogen + WHI (estrogen) CHD events 0.99 (0.80–1.22) 1.29 (1.02–1.63) 0.91 (0.75–1.12) Stroke 1.23 (0.89–1.70) 1.41 (1.07–1.85) 1.39 (1.10–1.77) Pulmonary embolism 2.79 (0.89–8.75) 2.13 (1.39–3.25) 1.34 (0.87–2.06) Breast cancer 1.30 (0.77–2.19) 1.26 (1.00–1.59) 0.77 (0.59–1.01) Colon cancer 0.69 (0.32–1.49) 0.63 (0.43–0.92) 1.08 (0.75–1.55) Hip fracture 1.10 (0.49–2.50) 0.66 (0.45–0.98) 0.61 (0.41–0.91) Death 1.08 (0.84–1.38) 0.98 (0.82–1.18) 1.04 (0.88–1.22) Global index NA 1.15 (1.03–1.28) 1.01 (0.91–1.12)

USE 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. National use of postmenopausal hormone therapy. JAMA 291:47–53 (43, figure 3, p. 50)

Why Results of NHS and 3 Trials are So Different Bias of Healthy Users: people who are taking drugs as prescribed, or eating healthy diet are fundamentally different from those who don’t Women who take HRT are more thinner, have fewer risk factors for heart disease, more educated and wealthier, generally more health conscious Prescriber Effect: The reasons a physician will prescribe one medication to one patient and none to other are often complex and subtle

Why Results of NHS and 3 Trials are So Different Measurement Error: In NHS study women were asked if they were taking HRT every two years Timing Clinical Trials: What happens if older women gets HRT years after menopause Observational Studies: What happens to women taking HRT near onset of menopause