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