Intended for healthcare professionals

Rapid response to:


Hormone replacement therapy

BMJ 2002; 325 doi: (Published 20 July 2002) Cite this as: BMJ 2002;325:113

Rapid Response:

Hormone replacement therapy

The Women’s Health Initiative (WHI) randomised trial of HRT has
resulted in two contrasting leaders, one
in the BMJ by Stevenson and Whitehead (1) and the other in JAMA by Fletch
and Colditz (2). Stevenson
and Whitehead point out that the increased risks of breast cancer are
small but they do not mention that
during the study 42% of women taking active drug and 38% of those
receiving placebo stopped the assigned
medication, whereas Fletcher and Colditz report that the intention to
treat analysis “may have
underestimated the true effects and that if the duration of treatment is
important as appears to be the case
with breast cancer and if compliance decreases over time then five year
results may underestimate long
term treatment effects”. Stevenson and Whitehead state because the risk
of breast cancer is not
appreciably increased within the first few years of use women with short
term menopausal symptoms
should be reassured but there must be an interval between applying an
agent which increases breast cancer
risk and to cancer manifesting clinically so the four year gap may well
represent a period during which
cancers caused by the oestrogen take to develop and become clinically
apparent. Both leading articles point
out that the number of adverse events were small although Fletcher and
Colditz do note that the adverse
events add up and over the 5.2 years of the trial the excess numbers of
events in the active drug group was
approximately one for ever 100 women.

The BMJ editorial states “long term HRT therapy could still be
considered for prevention of osteoporosis”
whereas the JAMA editorial finishes with the definitive statement “do not
use oestrogen/progestin to
prevent chronic disease”.

The leader in the BMJ states “we do not yet know the effects if any
of HRT for the prevention of dementia
although preliminary evidence is encouraging”. This contrasts with a
review published only last year by
Manson and Martin in the New England Journal of Medicine (3) who state
“although a number of early
observational studies suggest that the cognitive dysfunction or
Alzheimer’s disease is less likely to develop in
women who take estrogen after menopause, more recent observational studies
have failed to support this
hypothesis (4) and a recent randomized clinical trial failed to
demonstrate any benefit of estrogen therapy as
treatment for mild-to-moderate Alzheimer’s disease (5)”. Further
randomized data from the HERS study
(6) also failed to show any benefit of HRT on cognitive function. I am
surprised that Stevenson and
Whitehead believe that these data are encouraging. We await with interest
further information from the
Women’s Health Initiative which is evaluating the role of HRT in the
prevention of memory loss and
cognitive decline.

Both Smith in his editor’s choice (7) and Stevenson and Whitehead
point out that in the WHI study there has
been no effect as yet on mortality but as the authors of the original
paper report the WHI study “could not
address the risk due to breast cancer due to the relatively short follow
up time”. Statements on mortality
are therefore of questionable value. .

As the JAMA leader points out “the results of the WHI study are
consistent with the growing body of
literature on the effects of the combination of estrogen and progestin”.
Stevenson and Whitehead may be
correct that the dose (and possibly type) of oestrogen and the type of
progestogen may be crucial in
determining the effects of combined preparations but as stated so
eloquently by Ross and Pike “the burden
of proof should no longer be on the epidemiologists and other
investigators to demonstrate that it (combined
HRT) increases the risk of breast cancer, rather it should shift to the
proponents of their use to demonstrate
that they do not” (8).

There remains much that is uncertain in this area and contrasting
views in two leading articles in two major
journals one week apart make it even more difficult to put forward a
coherent and consistent message
following the WHI study to our patients.

1. Stevenson JC, Whitehead MI. Hormone replacement
therapy. BMJ 2002; 325: 113-114.

2. Fletcher SW, Colditz GA. Failure of estrogen
plus progestin therapy for prevention. JAMA 2002;

3. Manson JE, Martin KA. Postmenopausal hormone
replacement therapy. N Eng J Med 2001; 345:

4. Grodstein F, Shen J, Pollen DA et al.
Postmenopausal hormone therapy and cognitive function in
healthy older women. J Am Geriatr Soc 2000; 48: 746-752.

5. Mulnard RA, Cotman CW, Kawas C et al. Estrogen
replacement therapy for treatment of mild to
moderate Alzheimer disease: a randomized controlled trial: Alzheimer’s
Disease Cooperative Study. JAMA
2000; 283: 1007-1015.

6. Grady D, Herrington D, Bittner V et al for the
HERS Research Group. Cardiovascular disease
outcomes during 6.8 years of hormone therapy: Heart and Estrogen-progestin
Replacement Study Follow-up
(HERS II). JAMA 2002; 288: 49-57.

7. Smith R. Editor’s choice. BMJ 2002; 325 (20th

8. Ross R, Pike MC. Effect of hormone replacement
therapy on breast cancer risk: estrogen versus
estrogen plus progestin (response). J Natl Cancer Institute 2000; 92:

Competing interests: No competing interests

25 July 2002
Mike Dixon
Consultant Surgeon and Senior Lecturer
Edinburgh Breast Unit, Western General Hospital, Edinburgh, EH4 2XU