Hormonal Replacement Therapy for postmenopausal females: To give or not to give?

1
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

2
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

3
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

4
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

5
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.

6
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?

7
Landmark studies to date

• Nurses 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 gt 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.

8
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

9
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

10
Landmark studies to date

• Womens 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

11
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)

12
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)

13
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

14
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)

15
Potential benefits of HRT

• Reduction in vertebral and hip fracture rate, and
  increase in Bone Mineral Density
• Prevention of colon cancer

16
Potential benefits/Harms of HRT

• Does HRT help cognition? Or Not?
• (Shumaker et al. JAMA, 2003, May 28 2892651-62)
• Womens Health Initiative Memory Study (WHIMS)
• 4532 women (age gt65) 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

17
Potential benefits/Harms of HRT

• Does HRT help cognition? Or Not?
• (Rapp et al. JAMA, 2003, May 28 2892663-72)
• Womens 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.

18
Potential benefits/Harms of HRT

• More about stroke!
• (Wassertheil-Smoller et al. JAMA, 2003, May 28
  2892673-84)
• Womens 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.

19
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

20
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

21
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

22
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

23
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

24
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

25
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