The Women's Health Initiative (WHI) was a 15-year study from 1991-2010 that examined the effects of postmenopausal hormone therapy (HT) and lifestyle interventions on health outcomes in postmenopausal women. The WHI hormone therapy trials found that estrogen plus progestin therapy modestly increased risks of heart disease, stroke, blood clots and breast cancer. Estrogen-alone therapy increased risks of stroke and blood clots but did not change heart disease risk. Subsequent research has found that risks may depend on factors like age at start of therapy, duration of use, and type of progestin used. Current recommendations are to use the lowest effective dose of HT for the shortest time to treat

1. Menopause - Post WHI
Jessie Chan
27th Sept 2012

2. Women’s Health
Initiative
15 year project - 1991-2010
3 components:
Randomized clinical trial
68,132 postmenopausal women between the ages of 50-79.
Hormone Therapy (HT): Effect of HT on the prevention of heart disease and osteoporosis, and
any associated risk for breast cancer. Women participating in this component took hormone pills
or a placebo (inactive pill).
Dietary Modification: Effect of a low-fat, high fruit, vegetable and grain diet on the prevention of
breast and colorectal cancer and heart disease. Study participants followed either their usual
eating pattern or a low-fat eating program.
Calcium/Vitamin D: Effect of calcium and vitamin D supplementation on the prevention of
osteoporosis-related fractures and colorectal cancer. Women in this component took calcium and
vitamin D pills or a placebo.
Observational study
examined the relationship between lifestyle, health and risk factors and specific disease outcomes
Community prevention study

3. WHI - Hormone trial
Two studies
The estrogen-plus-
progestin study
(women with a uterus)
The estrogen-alone study
(women without a uterus)

4. WHI - Hormone trial
Compared with the placebo, Compared with the placebo,
estrogen plus progestin resulted in: estrogen alone resulted in:
Increased risk of heart attack
No difference in risk for heart
Increased risk of stroke attack
Increased risk of blood clots
Increased risk of stroke
Increased risk of breast cancer
Increased risk of blood clots
Reduced risk of colorectal cancer
Fewer fractures Uncertain effect for breast cancer
No protection against mild cognitive No difference in risk for colorectal
impairment and increased risk of dementia
cancer
(study included only women 65 and older)
Reduced risk of fracture
(Findings about memory and

6. WHI - Limitations
Addressed the value of long-term HT in the prevention of major chronic conditions of
women after menopause, not intended to explore treatment of menopausal symptoms.
E+P trial was stopped after 5.6 years because of an increased risk of breast cancer and
because overall risks, including increased risks for heart attack, stroke, and blood clots,
outnumbered benefits
The E-alone study was stopped after 6.8 years because of an increased risk of stroke and
no reduction in risk of CHD. The estrogen-alone study also found an increased risk of
blood clots.
Difference between results of E+P and E-alone, progestin (medroxyprogesterone
acetate) may be responsible?
Two trials populations dissimilar - E-alone participants had a higher mean body mass
index and more years of prior exposure to HT than E + P participants, so interpretation
of trial differences must be cautious.

7. Recent Debates:
HRT and CVD
HRT and CVD
Women’s Health Initiative (WHI) (Rossouw et al, JAMA 2007; 297: 1465-77)
Younger women (50 -59) taking HRT over a period of 10 years have shown no
increased risk of developing CVD - previous WHI study which stated an
opposite finding
The women's international study of long duration estrogen and progestin
after menopause (WISDOM)
Women starting or restarting combined HRT have increased cardiovascular and
thromboembolic risk when treatment begins many years after the menopause
(Vickers et al, BMJ, July 2007, doi:10.1136/bmj.39266.425069.AD)
Decreased risk of osteoporotic fracture and no difference in the risk of stroke or
cancers.

8. Recent Debates:
HRT and Breast Ca
HRT and Breast Ca
Studies have shown an association between E+P with breast cancer - but related to certain
types of HRT and certain types of breast cancer for women of a particular age group.
The recorded risks are statistically small and appear to be linked with the duration of therapy
(Ravdin et al, NEJM 2007; 356: 1670-4)
Postmenopausal women who take E+P for at least 5 years are increasing their risk of breast
cancer. Researchers also found that women can quickly reduce their risk of breast cancer
by stopping HRT (Chlebowski et al., NEJM 2009; 360(6): 573-587).
In considering these findings, women should be aware that only a small percentage of
combined estrogen plus progestin users continue use for more than five years (Brett &
Reuben, Obstet Gynecol 2003; 102:1240-9).
The Society of Obstetricians and Gynaecologists of Canada has noted that risk factors for
breast cancer, such as hormones, should be evaluated in light of equally important risk
factors related to lifestyle (Reid et al, JOGC 2009; 31(1): S5-S8)
Research suggests that 34% of breast cancers could be avoided by making lifestyle
changes at the time of menopause (Sprague et al, Am J Epidemiol 2008; 168(4): 404-11).

9. Recent Debates:
HRT and Ovarian Ca
HRT and Ovarian Ca
Million Women Study - increased incidence of developing ovarian cancer in
women on HRT, compared to women who have never used HRT (Million
Women Study Collaborators, Lancet 2007; 369:1703-10). However, these
risks are statistically small. Researchers report that the risk of developing
ovarian cancer returns to pre-use levels once users stop using HRT.

10. Recent Debates:
HRT and Colon Ca
HRT and Colon Ca
Small reduction in the risk of colonic cancer (Johnson JR et al, Cancer
Epidemiology Biomarkers Prev 2009;18(1):196-203).
Evidence from the WHI and other trials suggests that current HRT users
have a 40% reduction in colorectal cancers.
? too early to consider HRT use in the prevention of colon cancer (Barnes
and Long)

11. Recent Debates:
HRT and VTE
HRT and VTE
There is an increased risk of venous thromboembolism with oral HRT. This
may be increased with age and obesity, and may vary by the progestogen
used. Observational studies suggest that it may not be associated with
transdermal HRTs (patches), but this needs confirmation (Archer and Ogar).

12. Recent Debates:
HRT and stroke
HRT and stroke
There is a modest increase in stroke risk with HRT use if stated near the
menopause. This risk rises considerably in women who start at older ages.
There is some evidence that use of HRT patches (as opposed to pills) may
not increase stroke risk, but this needs to be confirmed (Henderson and
Lobo).

13. Recent Debates:
HRT and bone
HRT and bone
Taking HRT confers some benefit to bone strength (Farquhar C et al,
Cochrane Database Syst Rev. 2009 Apr 15;(2):CD004143)
Fractures The WHI "Global Index", which looked at the balance of risks and
benefits, inappropriately downgraded the importance of fractures.
HRT gives more bone benefits than many other drugs (e.g.
bisphosphonates), and so restrictions on HRT use as a first-line therapy are
not appropriate (de Villiers and Stevenson)

14. HRT and UG + sexual
health
HRT and UG + sexual
health
Around 50% of postmenopausal women will suffer urogenital atrophy.
Studies indicate that locally applied hormone therapy is generally
more effective than systemic HRT for urogenital symptoms, including
dyspareunia, which can be a critical determinant of a woman’s
interest in sex.(Nappi & Davis)
E-P is effective for relief of lower urinary tract symptoms related to
estrogen deficiency
Most studies show that in post menopausal women with urinary
incontinence, E-alone and E-P are not beneficial and may worsen the
condition

15. Recent Debates:
HRT and QoL
HRT and QoL
WHI - HRT use led to minimal improvement in quality
of life
WHI study wasn’t designed to look at wemen going
through the menopause - underestimated the real
extent of effect of HRT on QoL - hence suffering to
many women
Some studies indicate that E-P improves many domain
of QoL - mental health and depressive symptoms,
physical functioning, bodily pain and sleep.

16. Recent Debates:
HRT and dementia
HRT and dementia
Initial WHI results showed an increase in dementia
for both E+P and E alone users.
? may be influenced by the timing of the HRT
initiation, with benefits for those starting nearer
the menopause, but increased risks for women
starting at older ages (Maki and Henderson).

17. Current
recommendations
The risks associated with the use of HRT are low and duration of use may, if necessary, be
extended, as the use of HRT for many women provides welcome relief from distressing
postmenopausal symptoms (Grady & Barrett-Connor, BMJ 2007; 334:860-1).
Start early, use the lowest dose which gives symptom control, for the shortest period of time
(Benefit outweighs the risks)
‘window-of-opportunity' - before the age of 60 and/or within 10 years of the menopause.
This reduces the risk of coronary heart disease and overall mortality. HRT is more effective
for this than other medicines such as statins and aspirin, and is cost-effective. Starting HRT
later than this increases risks to women (Hodis et al).
All women commencing HRT should be advised of type, dose, mode of delivery and
duration
Tailor treatment to individual patients

18. References
Effect of Hormone Therapy on Risk of Heart Disease May Vary by Age and
Years Since Menopause. Additional analyses from the Women’s Health
Initiative. NHI News April 2007
The Women’s Health Initiative study and Hormone Therapy – what have we
learned 10 years on? International Menopause Society. May 2012
Wallace, Robert. The Women’s Health Initiative: The Role of Hormonal
Therapy in Disease Prevention
Women’s Health Initiative. http://www.nhlbi.nih.gov/whi/
Hormone Therapy During Menopause in Malaysian Women. Clinical Practice
Guidelines July 2010.

19. Thank you....