Hormonal Replacement Therapy for postmenopausal females: To give or not to give?
Amna B. Buttar, MD, MS
Assistant Professor of Clinical Medicine Indiana University School of Medicine Scientist, Indiana University Center for Aging Research
Introduction
• Hormonal Replacement Therapy (HRT) is one of the most commonly prescribed treatments in the USA • HRT is also one of the most controversial topics in modern history of medicine • Increasing use reflects increasing no. of postmenopausal women • Controversy is due to the balance between benefits and risks
Clinical Scenario 1
• 52 years old woman asks you regarding HRT. – Irregular menstrual periods for one year – Hot flashes – Sleep disturbance – Emotional lability – Otherwise healthy – Non-smoker – No family history of cancer or cardiovascular disease – Mother and aunty have osteoporosis
Clinical Scenario 2
• 72 years old woman has been taking estrogen daily for 24 years asks you whether she should continue or not. – HRT initially used for hot flashes when she underwent hysterectomy and oophorectomy – She continued to use it as she had heard it was good for heart and bones – Hx of increased cholesterol, and Diabetes controlled by oral hypoglycemics – Complains of chronic low back pain
Clinical Scenario 3
• 55 years old woman who has been receiving HRT for 5 years since natural menopause. • Seeks your opinion regarding continuation as her 64 years old sister was just diagnosed with breast cancer. They also tell you that one aunt and a cousin died of breast cancer. • Annual mammograms have been normal.
Clinical Scenario 4
• 62 years old woman receiving HRT since menopause had her first heart attack. • Cardiac catheterization revealed 2 vessel disease and patient treated medically. • Should she continue to get HRT?
Landmark studies to date
• Nurse’s Health Study (Goodstein et al. NEJM 1997)
– 17 year follow-up of 91,523 women – Current HRT users had a 37% lower risk of death than women who had never taken HRT – In those using HRT for > 10 years, risk of death was 20% lower. – Among women with a first degree relative with breast cancer, the risk of death was 35% lower in HRT users than in non users.
Landmark studies to date
• Post menopausal Estrogen/Progestin Intervention (PEPI) trial • 3 year multicentered randomized, double blind placebo controlled trial • 875 healthy post menopausal women aged 4564 years • Randomized to: placebo, CEE, CEE + cyclic MPA , CEE + continuous MPA, • All HRT arms lowered LDL-C significantly compared to placebo • Modest increase in HDL-C
Landmark studies to date
• Heart and Estrogen/Progestin Replacement Study (HERS), Hullley et al. JAMA 1998 • Randomized, blinded, placebo controlled trial (2763) of the effect of combined HRT on coronary heart disease event risk among 2763 postmenopausal women with documented CHD • Overall, during 4.1 years of follow-up, there were no significant differences between the HRT and placebo groups in the primary outcome of CHD events (nonfatal MI + CHD related death). • Post-hoc analysis showed a significant trend with more CHD events in the HRT group than placebo during first year of treatment
Landmark studies to date
• Women’s Health Initiative, JAMA 2002 • Multicenter trial of 16,608 women randomized to combined HRT or placebo for women with intact uterus, and to Estrogen or placebo for women without a uterus • The study began in 1991, and was expected to go on till 2006, however, the combined HRT was stopped early after a mean follow-up of 5.2 years because of increased rates of CAD (HR 1.29), Breast Cancer (1.26), Stroke (1.41), PE (2.1). • Risk of colon cancer, and hip fracture were significantly reduced in the HRT group. • Overall, there was no increase in cancer deaths or total mortality
Landmark studies to date
• Scientific review for recommendations for USPSTF, Nelson et al. JAMA 2002. • No Coronary Heart Disease Protective effect • No mortality reduction • Increased incidence of Stroke (RR, 1.12), and thromboembolic stroke (RR, 1.20) • Increased risk for DVT and PE (RR, 2.14), During first year (3.49), and after first year (1.91)
Landmark studies to date
• Scientific review for recommendations for USPSTF, Nelson et al. JAMA 2002. • Reduction of hip fracture risk (RR, 0.64), and vertebral fractures (RR, 0.60) • Increased risk of breast cancer (RR, 1.21 – 1.40) • Risk of breast cancer increases with increasing duration • No effect on breast cancer mortality • Increased risk of endometrial cancer for unopposed estrogen users (RR, 2.3) • Increased risk with increasing duration and remained elevated 5 or more years after discontinuation of RX. • Combined HRT decreased risk of endometrial CA (RR, 0.8)
Landmark studies to date
• Scientific review for recommendations for USPSTF, Nelson et al. JAMA 2002. • 20% reduction in colon cancer risk in ever users • 34% reduction in colon cancer risk in current users • HRT was found to be associated with decreased risk of dementia (RR, 0.66) • Increased risk of cholecystitis (RR, 1.8)
– Risk increased after 5 years of use
Potential benefits of HRT
• Short term benefits: • alleviate perimenopausal symptoms
– – – – hot flashes urogenital atrophy Depressed mood Insomnia
• Improve or maintain bone density (short term use does not prevent fractures in the future)
Potential benefits of HRT
• Reduction in vertebral and hip fracture rate, and increase in Bone Mineral Density
• Prevention of colon cancer
Potential benefits/Harms of HRT
• Does HRT help cognition? Or Not?
(Shumaker et al. JAMA, 2003, May 28: 289:2651-62)
– Women’s Health Initiative Memory Study (WHIMS) • 4532 women (age >65) were tested annually with the Modified Mini Mental State Examination • Probable dementia was diagnosed in 40 women who received HRT and in 21 women on placebo (HR, 2.05) after average 4 years of follow-up
Potential benefits/Harms of HRT
• Does HRT help cognition? Or Not?
(Rapp et al. JAMA, 2003, May 28: 289:2663-72)
– Women’s Health Initiative Memory Study (WHIMS)
• 6.7% of women who took HRT had decrease of more than 2 standard deviations in their Mental Status Scores after a mean of 4 years as compared to 4.8% of women on placebo.
Potential benefits/Harms of HRT
• More about stroke!
(Wassertheil-Smoller et al. JAMA, 2003, May 28: 289:2673-84) – Women’s Health Initiative (N = 16,608) • 151 women who took HRT (1.8%) and 107 on placebo (1.3%) suffered strokes within mean 5.2 years follow-up. • 31% increased stroke risk for HRT group.
Potential Harms of HRT
• Stroke • Increased incidence of Coronary Heart Disease events • Thromboembolic events • Increased risk of Breast Cancer • Cholecystitis • Increased risk of endometrial cancer
Clinical Scenario 1
• 52 years old woman asks you regarding HRT. – Irregular menstrual periods for one year – Hot flashes – Sleep disturbance – Emotional lability – Otherwise healthy – Non-smoker – No family history of cancer or cardiovascular disease – Mother and aunty have osteoporosis
Clinical Scenario 1
• 52 years old woman asks you regarding HRT.
– Improvement of menopausal symptoms – 1.8 fold increased risk for cholecystitis – 3.5 fold increased risk for thromboembolic event in the first year – Increased risk for stroke and MI
Clinical Scenario 2
• 72 years old woman has been taking estrogen daily for 24 years asks you whether she should continue or not.
– HRT initially used for hot flashes when she underwent hysterectomy and oophorectomy – She continued to use it as she had heard it was good for heart and bones – Hx of increased cholesterol, and Diabetes controlled by oral hypoglycemics – Complains of chronic low back pain
Clinical Scenario 2
• 72 years old woman has been taking estrogen daily for 24 years asks you whether she should continue or not.
– High risk for stroke due to risk factors like Diabetes, increased cholesterol and continued estrogen use – Estrogen should be discontinued – Bone mineral density should be obtained to assess severity of osteoporosis – Allendronate or other treatments can be used if osteoporosis is present
Clinical Scenario 3
• 55 years old woman who has been receiving HRT for 5 years since natural menopause. • Seeks your opinion regarding continuation as her 64 years old sister was just diagnosed with breast cancer. They also tell you that one aunt and a cousin died of breast cancer. • Annual mammograms have been normal. – Her breast cancer risk is 2.2% compared to 1.4% for a woman with no risk factors
Clinical Scenario 4
• 62 years old woman receiving HRT since menopause had her first heart attack. • Cardiac catheterization revealed 2 vessel disease and patient treated medically • Should she continue to get HRT? • American Heart Association recommends discontinuation after an acute event