HORMONE REPLACEMMENT

THERAPY(HRT)
THE OESTROGEN ELIXIR

• 60 years
• First : PREMARIN (Combined equine oestrogen)
• 1960-1975 : prescriptions doubled
• 1975 : clinical studies showed an increase in endometrial cancer
BUT

• 1992 : the most prescribed drug in the US

BENEFITS OF HRT
Established Benefits

• Eliminates hot flushes, night sweats, dry vagina, and

palpitations.

• Reduces osteoporotic bone fracture (?P)

• Reduces colorectal cancer (?P)

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Possible Benefits

• May increase mood and feeling of well-being –quality of life

• May reduce risk of Alzheimer’s disease

• May reduce arthritis

• May maintain dental health

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RISKS OF HRT
Established Risks

• HRT increases the risk of VTE (?P)

• HRT increases the risk of non-fatal stroke (?P)

• HRT increases the rate of non-fatal MI (?P).

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Established Risks 2

• Estrogen increases the risk of endometrial cancer when it is

taken without a progestin.

• HRT increases the incidence of gallbladder disease in some

women

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Possible Risks

• There may be an increased risk of breast cancer after taking

HRT for five years or more (?P)

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WOMEN’S HEALTH
INITIATIVE
 WHI Clinical Trials
Postmenopausal Women, aged 50-79; Not moving < 3
yrs
Diet Modification (DM) Design
Trial ~ 9 years
Diet (DM) average
Primary Outcomes: follow-up
Breast & Colorectal Cancer 48,836
(40:60)

11.8%
Secondary Outcome: Overlap
Coronary Heart Disease(CHD) Hormone
Hormone Trials 27, 347
Primary Outcome: CHD (50:50)
Secondary Outcomes:
Hip Fracture, Breast Cancer
Ancillary Study: Memory (Dementia)Total CT = 68,133
 Women’s Health Initiative (WHI)
Hormone Therapy (HT) Trials

E+P Trial
Generally Healthy
Postmenopausal NO CEE + MPA (medroxy-
Women N= 16,608
aged 50-79 years progesterone acetate, 2.5
mg/d) = Prempro®
Placebo
Hysterectomy
E-alone Trial
CEE (Conjugated equine
YES estrogens, 0.625 mg/d)
N= 10,739
Placebo = Premarin®

*Initially: CEE only (N=331), CEE+MPA, or Placebo

(Post-PEPI: CEE only were converted to CEE+MPA)
Current HT required 3-month wash-out before baseline testing.
 WHI HT Trials: Sample Size, Outcomes,
Follow-up

Women, aged 50-79 Total HT trials = 27,347

Hormone Trials
Primary Outcome:
Coronary Heart Disease E+P
Average
Follow-up
Secondary Outcomes: 16,608 5.6 years*
Stroke, Blood Clots
Lungs (PE, pulmonary emboli)
Legs (DVT, deep vein thrombosis)
Average
Breast, Colorectal, Uterine Cancers E-Alone 7.1
10,739
Hip Fracture; Other Deaths years*
WHI Memory Study (WHIMS)
- for women aged ≥ 65: Dementia
*design ~ 8.5 years
 WHI Memory Study (WHIMS) - ancillary study

(Postmenopausal Women, aged 65-79)

WHIMS E+P and E-only trials = 7,479

Primary Outcome: E+P Average

 Probable Dementia (PD)
(women with Follow-up
a uterus)
4.1 years*
Secondary Outcomes: 4532
 Combined PD & Mild Cognitive
E-Alone Average
Impairment (MCI) (post-hystX) 5.2
- Supporting Data: 2947 years*
Global Cognitive Function
(by annual Modified Mini-mental
State Examination, 3MSE)) *design ~ 7 years
 WHI Hormone Trials: Baseline (1993-1998) Hypotheses

Anticipated Expected
Risk Benefit
Coronary Artery Disease
(Heart Attacks)
Stroke?
Breast Cancer

Threshold Level Threshold Level

Early STOPPING Early STOPPING
for HARM for BENEFIT
Additional Risks: Additional Benefits:
• Blood Clots, VTE Plan to follow to 2005 • Hip (Bone) Fractures
Lungs=PE; Legs=DVT (average 8.5 years) • Overall Mortality

• Colon Cancer
• Global Index: overall balance of benefits and risks
Earliest occurrence of CHD, Stroke, PE, Breast Cancer, Hip Fracture,
Colorectal Cancer, Death from other causes, Endometrial Cancer
 Results from the WHI trial
JAMA 2002;288:321-33

HR for HRT Events per Events per Excess

vs. Placebo 10,000py 10,000py events per
(95%CI) for placebo for HRT 10,000 py
CHD 1.29 (1.02-1.63) 30 37 7
(non-fatal MI &
CHD death)
Stroke 1.41 (1.07-1.85) 21 29 8
Breast cancer 1.26 (1.00-1.59) 30 38 8
VTE 2.11 (1.58-2.82) 16 34 18
Hip fracture 0.66 (0.45-0.98) 15 10 -5
Colorectal 0.63 (0.43-0.92) 16 10 -6
cancer
Total mortality 0.98 (0.82-1.18) 53 52 NS
Discussion points (WHI)

• Significant study
• Breast cancer “strong trend” as rates not statistically significant
• Study stopped on breast Ca, and global trend not CHD events
• Trial could not distinguish the effects of oestrogen from progestin

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Discussion points

• Older women – average age 63 years

• Not taking HRT for symptoms
• Large dropout rate – 42 % HRT group and 38% of placebo
• What is the significance of Progestin?

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WHI E+P: Post-Intervention Follow-up

After E+P trial was stopped early, WHI followed study

participants through the planned termination of the
trial (March 31, 2005)
Except for stopping the intervention and unmasking, the same
trial protocol was followed, e.g. semi-annual monitoring to
identify and classify study outcomes

Post-intervention information (July 8, 2002 - March 31,

2005) was available on 95% of the women: mean of 2.4
years of follow-up

WHI is continuing to follow the participants.

Heiss et al, JAMA 2008; 299: 1036-1045

WHI E+P: Post-Intervention Follow-up CHD

Heiss et al, JAMA 2008; 299: 1036-1045

WHI E+P: Post-Intervention Follow-up
 Cardiovascular risks disappeared
 CHD, (Stroke ?), Blood Clots – no longer increased
 Fracture benefits disappeared
 Hip Fracture - no longer decreased
 Cancer
 Breast Cancer - 27% (ns) more diagnosed post-Intervention
 Colorectal Cancer - no longer decreased
 TOTAL CANCER - increased 1.24 (1.04-1.48)
 Due to increase in variety of cancers, including

Lung Cancer (E+P: 33 events vs placebo:15)

 All-cause Mortality -15% (ns) higher
 Most due to Cancer (E+P: 101 vs placebo: 69)
 only 27 (E+P) and 16 (placebo) due to pre-specified CA

Heiss et al, JAMA 2008; 299: 1036-1045

WHI Extension Study (ES) - 2005- 2010

Total CT Eligible:
63,331
ES: 52,156 (82.4%)
Diet OS
48,836 93,676
Eligible: 45,560 Eligible: 86,744

ES: 37,844 ES: 63,207

(72.9%)
(83.1%)

Hormone
27,347 Total WHI Sample (CT + OS) = 161,809
Eligible:25,19 Eligible: 150,075
3

ES:20,42 Extension Study = 115,363 (76.8%)

5 (81.1%)
 WHI Estrogen Plus Progestin Trial
First/Second/Third Efficacy Analyses (cutoff
dates 7July2002 / 31March2005 / 14August2009)

First: End of intervention period (Per DSMB)

Second: Original trial completion date
Third: Current pre-planned analysis
(note: re-consent required after original completion date)

• Mean follow-up time: 5.6 / 7.9 / 11.0 years

• Invasive breast cancers (n): 349 / 488 / 678
• Breast cancer mortality information reported for first time

Chlebowski, Anderson, Gass, et al JAMA 2010;304:1684-92

Chlebowski, Hendrix, Langer, et al JAMA 2003;289:3243
Chlebowski, Kuller, Prentice, New Eng J Med 2009;360:573
WHI E+P: Invasive Breast Cancer Incidence
Quintiles for duration of intervention indicated by shaded regions

Hazard ratio (HR) 95% CI and P values from Cox proportional hazards regression models

Chlebowski, Anderson, Gass, et al JAMA 2010;304:1684-92

2ND OCTOBER 2013

• Menopausal Hormone Therapy and Health Outcomes During the

Intervention and Extended Poststopping Phases of The Women’s
Health Initiative Randomized Trial ;
• Manson , Chlebowski, Stefanik
• JAMA 2013;310(13):1353-1368. doi:10.1001/jama.2013.278040
CONCLUSION

• In summary, current WHI findings based on results from the intervention,

postintervention, and cumulative follow-up phases do not support the use of
either CEE plus MPA or CEE alone for chronic disease prevention. The risks of
CEE plus MPA outweigh the benefits irrespective of a woman’s age; however,
a more favorable risk-to-benefit ratio was seen in younger women with prior
hysterectomy who received CEE alone. Increased risks of stroke and venous
thrombosis, as well as gallstones and urinary incontinence, in both younger
and older women remain a concern with both regimens. Even though
hormone therapy is a reasonable option for the management of moderate to
severe menopausal symptoms among generally healthy women during early
menopause, the risks associated with hormone therapy, in conjunction with
the multiple testing limitations attending subgroup analyses, preclude a
recommendation in support of its use for disease prevention even among
younger women. Current findings also suggest caution when considering
hormone therapy treatment in older age groups, even in the presence of
persistent vasomotor symptoms, given the high risk of CHD and other
outcomes associated with hormone therapy use in this setting.
•THANK YOU