HRT – A Changing Philosophy
The
Women’s Health Initiative Study safety committee concluded that
combination estrogen/progestin HRT should
not be initiated or continued for the primary prevention of
coronary heart disease, and there is a substantial risk of breast
cancer.
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July 2002 was an unsettling month
regarding the use of hormone replacement therapy in menopausal women.
On July 9, partial results of the National Institute of Health’s (NIH)
“Women’s Health Initiative” (WHI) were announced prematurely for the
Prempro® arm of the study. This
announcement, together with the announcement regarding menopausal hormone
replacement therapy and the risk of ovarian cancer released by the National
Cancer Institute a week later, have raised questions about the use and safety
of estrogen and progesterone therapy in menopausal women.
Traditionally, women who reach menopause have been encouraged to use
hormone replacement therapy (HRT) for the primary prevention
of several diseases. HRT means
any combination of the two hormones, estrogen and progestin.
It does not refer to the use of estrogen replacement alone in women
who have had their uterus removed. It
is known that HRT helps to prevent hotflashes, night sweats, and vaginal
dryness, common menopausal symptoms that occur in up to 80% of women after
loss of ovarian function. It has
long been postulated that HRT also helps to prevent osteoporosis, colon cancer
and heart disease in this same population.
For the last few years
we have accepted that there may be a slight increased risk of breast cancer in
women using HRT, but that the overall risk of taking HRT in the menopause was
outweighed by the potential benefit to the heart, bone and colon. And
in July, the NHI released information on a study involving 16,000 women that
stated the combined estrogen-progesterone HRT (PremPro®) caused an
increased number of women in the study to have a heart attack.
The PremProÒ
arm of the WHI study divided women into two groups: those on PremPro® and
those on a placebo. The data and
safety monitoring board of the WHI decided on May 31, 2002 to recommend
discontinuing the PremPro® arm of the study because the number of breast
cancer cases in the HRT group was approaching a predetermined cutoff for the
number. The committee further noticed a trend that the risk of heart attack
was greater in the HRT group than in the placebo group.
These two trends taken together led the committee to determine that it
was no longer safe for the HRT group to continue taking hormones because
the risk of PremPro® therapy outweighed the potential benefit.
The new data suggest that HRT in
some combinations is not protective from cardiovascular disease and indeed
increases risk of heart attack. This discovery will lead to a
fundamental shift in our philosophy about who should use HRT and for how long
they should use it. This
means that the future emphasis will probably be short-term use of HRT for
relief of menopausal symptoms and not long-term use as a preventative
medicine.
Relative and Absolute Risk or Benefit Seen in Estrogen Plus Progesterone
Arm of WNI
(N=16,608,
placebo and study drug)
| Health
Event |
Relative
Risk for HRT user vs Placebo (sugar pill
user) Group At 5.2 years |
Increased
Absolute (your) risk
per 10,000 Women/Year |
Increased
Absolute (your) benefit
per 10,000 Women/Year |
| Heart
Attacks |
1.29* |
7** |
|
| Strokes |
1.41 |
8 |
|
| Breast Cancer |
1.26 |
8 |
|
| Thromboembolic Events |
2.11 |
18 |
|
| Colorectal Cancer |
0.63 |
|
6 |
| Hip Fracture |
0.66 |
|
5 |
*
This means a user’s risk compared to a non-users risk, e.g. a
29% increased risk of heart
attacks in a user. The risk are
cumulative over time and do not occur day one.
** This means there
were 7 more heart attacks in 10,000 women on PremPro® than in 10,000 women on
a placebo over a period of 5 years.
Adapted from WHI HRT Update, June 2002
The actual risk for an individual is very small. The increase risk of a
heart attack in a user of HRT computes to 0.007% over a five-year period.
However, the risk to the total group (several million women in the
U.S.
) is significant. It
is this finding that will lead to a fundamental change in the way HRT is used.
Some of the news is good, a decrease in colorectal cancer and hip
fracture. The study does not
address the role played in decreasing the symptoms hot flushes, insomnia,
decreased sex drive or vaginal atrophy. As
stated, these symptoms occur in 80% of women to some degree at the time of
menopause. Fortunately, the
symptoms are self limited in most women and will disappear over time. There
are non-hormonal treatments available to treat menopausal symptoms. These
treatments are successful in some but not all women and some treatments, such
as soy, are not well tested and may have harmful side effects themselves.
Some women may choose to continue HRT once the risk are explained
because of the unacceptable loss of quality of life do to hot flushes,
insomnia, mood swing and other estrogen deficiency symptoms.
The WHI concluded that combination estrogen/progestin HRT
should not be initiated or continued for the primary prevention of coronary
heart disease, and there is a substantial risk of breast cancer.
(Writing Group for the WHI Investigators, JAMA 2002; 288:321-333)
On
August 9th, 2002
, the
American
College
of Obstetricians and Gynecologist released a response to the news from the
Women’s Health Initiative Study.
The ACOG report noted: “to date, this is the largest, most
statistically valid, and well-analyzed research to
evaluate the use of HRT in healthy postmenopausal women.”
The ACOG review panel concluded that while this study looked only at
the drug PremProÒ,
other data suggested caution with the use of any estrogen
progesterone combination HRT. It
recommended that women on combination HRT be advised of the increased risk
noted in the WHI study. They recommend that a decision be made by that patient
and her physician about continuation or discontinuation of HRT.
That decision should based on an individual assessment of the reason
she is using HRT and evaluation of potential risk, benefits and alternative
treatments. For most women,
the potential risk will outweigh the potential benefit.
For women choosing to discontinue hormone use, there is no
recommendation about how best to do this.
The response noted, some women will develop
menopausal symptoms that will necessitate restarting HRT to maintain quality
of life. They stressed the
dose should be the lowest that gives symptomatic relief.
…the
estrogen only arm of the WHI study continues because no increase in
breast cancer incidence has been noted to this point in the study.
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It is important to note that the estrogen only arm of the WHI study
continues because no increase in breast cancer incidence had been noted.
We do not yet know what incidence of heart disease there is in women in
this arm. This study is to be completed in 2005 and will provide additional
important information.
The WHI study did not look at
the effect of estrogen replacement on ovarian cancer.
The
American
College
of Obstetrics and Gynecology did not make a comment on this issue in its
report of August 2002. On
July 16, 2002
, the National Cancer Institute released a statement regarding increased risk
of Ovarian Cancer in women on Estrogen therapy.
This study, “Menopausal hormone replacement
therapy and risk of ovarian cancer.” JAMA 2002; 288:334-341,
involved over 44,000 women followed over 20 years and concluded:
1.
The main finding of our study was that postmenopausal women who
used estrogen replacement therapy for 10 or more years were at significantly
higher risk of developing ovarian cancer than women who never used hormone
replacement therapy.
2
. The risk for developing ovarian cancer in women on estrogen
only was 80% greater with 10 years of use and 220% greater with 20 or more
years of use. The risk of any
American female for ovarian cancer is one in seventy in her lifetime. This
study estimated a 1 in 39 chance of cancer with estrogen use for more than 10
years and a one in 32 chance for estrogen use over 20 years.
This assumes a woman has not had her ovaries removed.
Women with no ovaries do not
have these risks.
3.
Even though our data showed that women who took estrogen
combined with progestin were not at
increased risk for ovarian cancer, only a few women in our study who developed
ovarian cancer had used estrogen-progesterone therapy for more than four
years. So, at this point, there
simply aren’t enough data to say whether taking the combined therapy has any
effect on ovarian cancer.
Two other recent studies have
found a link between hormone use and ovarian cancer. The message is that if
you are taking HRT and have ovaries you are at increased risk for breast
cancer, heart disease and maybe ovarian cancer.
We do not yet know about the effect of estrogen therapy alone on breast
cancer and heart disease.
If you are taking HRT,
do not panic! As stated, the
consensus is that short-term (amount of time is not defined) use of HRT for
the relief of symptoms of the menopause is safe. As
stated, the individual risk is small. Please,
discuss your individual risks and potential benefits of starting or continuing
HRT with your doctor.
Charles R. Jaynes, MD
August 2002