Hormonal Replacement Therapy for postmenopausal

females: To give or not to give?

Amna B. Buttar, MD, MSAssistant 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 45-64 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