Position Statements: Hormone Replacement Therapy
Current clinical practice must continually be reevaluated in view of new evidence. The current clinical practice of oestrogen replacement therapy (ERT) and hormone replacement therapy (HRT) for the short-term alleviation of menopausal symptoms is unchallenged. Numerous randomized controlled trials (RCTs) agree on benefit, without any reason to expect unacceptable risk, if therapy is instituted shortly after the start of menopause and discontinued after 5 years.
The rationale of initiation of ERT or HRT after age 55, or continuation after 5 years, relies heavily on observational data indicating a risk reduction of 50% in coronary heart disease (CHD). The observational data has been consistent and backed by plausible biological explanations. As CHD is the main cause of death in postmenopausal women, the potential benefit of ERT/HRT outweighed the possible small increase in breast cancer as seen in observational studies. It has previously been proposed that the observational data may be flawed by a healthy users effect. This suspicion was supported by results of the HERS study, a RCT which failed to show secondary protection of HRT in elderly cardio-symptomatic patients after 4 years' use.
In order to assess the long-term benefits and risks of ERT/ HRT, the National Institute of Health (USA) launched the Women's Health Initiative (WHI). In a large RCT the effect of daily oral conjugated equine estrogen (CEE) 0.625 mg alone (ERT study arm), or daily oral continuous combined CEE and medroxy-progesterone acetate 2.5 mg (HRT study arm) were evaluated against placebo for the outcome of coronary heart disease (CHD), breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer and death due to other causes.
On the 31 May 2002, the HRT arm was prematurely discontinued after 5.2 years, as the incidence of breast cancer in the HRT arm exceeded a predetermined "hazard" level. Furthermore, risk exceeded benefits. The ERT arm was not stopped. Publication of the results on 17 July caused great concern amongst patients and health care providers.(1)
It is recommended that all members of SASOG study the original paper in depth. The following discussion is aimed at providing some help in the interpretation. Members are encouraged to attend the 3 rd annual congress of the South African Menopause Society in Durban on 30/8-1/9/2002, where international experts will address the issue.
Results:
| Outcome | Number | Relative risk(RR) |
Increased absolute risk per 10 000 w/y |
Increased absolute benefit per 10 000 w/y |
| Myocardial infarction | 286 | 1.29 | 7 | |
| Stroke | 212 | 1.41 | 8 | |
| Breast cancer | 290 | 1.26 | 8 | |
| Thrombo embolism | 101 | 2.11 | 18 | |
| Hip fracture | 106 | 0.66 | 5 | |
| Colon ca | 112 | 0.63 | 6 | |
| Risk / benefit | 41 | 11 |
W/y=women per year
Interpretation
of results:
General:
Conclusions
are only valid for continuous combined HRT, and
not for unopposed ERT.
Conclusions are not valid
for other hormone regimes or different drugs.
Conclusions may not be valid for low dose HRT.
Breast cancer:
Although the trial was stopped primarily because
the risk of incident breast cancer crossed a predetermined
value, this is surprising as the increased incidence
was consistent with available epidemiological studies
(2). Breast cancer in patients on HRT is generally
accepted as having a better prognosis than cases
diagnosed in non-users. This may happen as a result
of oestrogen promoting growth in pre-existing cancers
and thus allowing earlier diagnosis and treatment.
Tumours in the WHI study have not yet been analyzed
in this regard. The results are consistent with
two recent trials indicating risk only when progestin
is added. The WHI results do not significantly change
present thinking on breast cancer risk.
Cardiovascular Disease:
The lack
of cardiovascular protection in a primary prevention
study is the most significant finding of this study.
As in HERS, the increased risk of cardiac events
was mostly confined to the first year of treatment.
Increases in thromboembolism though occurred during
all 5 years of the study. As myocardial infarction
is the main cause of death in menopausal patients,
the WHI results are very significant for long-term
use of HRT.
Fracture prevention
The WHI paper is the first trial with definitive
data to support the ability of HRT to significantly
prevent osteoporotic fractures. The magnitude of
this effect will obviously be much greater in a
population at high risk for fracture.
Bowel cancer
WHI is the first large study
to support the beneficial effect as seen in observational
studies
Risk/Benefits
When
assessing the risk/benefit ratio of HRT use, it
is important to note that the WHI study did not
include the following proven HRT benefits:
Alleviation
of menopausal vasomotor symptoms.
Overall quality
of life assessment.
Effects on cognitive function
and brain dementia
Conclusion reached
by the authors
In healthy asymptomatic
postmenopausal women with an intact uterus, this
particular regime of HRT should not be initiated
or continued for the sole purpose of primary prevention
of CHD.
Suggested clinical guidelines
It is important to understand that there is
no need for panic. Patients must be assured that
they can continue with their present medication,
but be encouraged to consult their health care provider,
when convenient, to assess their individual indication
for HRT. This should be reassessed annually.
Although the risk and benefits of HRT given
for the treatment of acute menopausal symptoms were
not addressed in this study, there is still good
reason to suspect that risk in the first 5 years
after menopause is small. Undisputed scientific
evidence supports the fact that only ERT/HRT is
successful in the alleviation of vasomotor symptoms.
There is no evidence to support the use of alternate
medication such as phyto-oestrogens. It is concluded
that present practice as regards the management
of acute symptoms of menopause be unchanged.
A decision to continue with HRT after 5 years
will have to be based on an individual assessment
of risk and benefit. The WHI results make this task
easier than before. The difficult part remains the
value placed on the improvement of quality of life.
This has not been quantified and will differ between
individuals. For many patients at present, this
constitutes the only reason why they persist with
the use of HRT. The patient must understand that
the absolute risks as found in the WHI study. It
is expected that patients will be most concerned
by the breast cancer results. It is important to
be prepared to spend some time to explain that the
increased diagnosis does not necessarily imply causality.
Furthermore, neither in this nor in other studies
has mortality been shown to be increased.
The suggestion not to use HRT for the sole purpose
of prevention of CHD should be strictly observed.
The beneficial effect of lifestyle changes on the
prevention of CHD must be stressed. Optimal medical
treatment of hypertension, diabetes and hypercholesterolemia
must be assured.
There is evidence from observational
data to suspect that the results of the ERT arm
of WHI study may differ significantly. This issue
will be resolved in 2005. In the meantime, it is
recommended that the results of this WHI study and
suggested guidelines be applied to ERT and HRT users.
The medical profession must put pressure on companies
providing other drugs and routes of administration
of HRT to undertake appropriate clinical trials.
Without such evidence, we simply have no other choice
but to apply the results of the WHI study to all
methods of prescribing ERT/HRT when assessing the
need of individual patients. This is recommended
not only on a scientific basis, but also from a
medico-legal point of view.
References
- Writing group for the Women's Health Initiative
Investigators. Risk and benefit of estrogen
plus progestin in healthy postmenopausal women
JAMA 2002; 288: 321-333.
- Collaborative group on hormonal factors
in breast cancer. Brest cancer and hormone replacement
therapy: collaborative re-analysis of data from
51 epidemiological studies of 52705 women with
breast cancer and 108411 women without breast
cancer. Lancet 1997; 350: 1047-1059.
Compiled By Dr Tobie de Villiers
Edited by Prof Gerhard Lindeque
August 2002
