Post-Menopausal Hormone Replacement Therapy in 2007

Background:

Estrogen Replacement Therapy, commonly referred to as Hormone

Replacement Therapy (HRT) has been around in one way or another for
over a century, but “modern” HRT as we now know it has only existed for
the past 40 years. Initially, estrogen alone was used to control
postmenopausal vasomotor symptoms until it was noticed that endometrial
cancer could result from its prolonged use. In the 1960s, it was found that
the addition of a progestogen could counteract the negative effect of
estrogen on the uterus, thus preventing endometrial cancer.
Since then, HRT gained tremendous popularity, with reports about its safety
and beneficial effects abounding; so much so that it was considered by some
to be able to restore youth and femininity to all post-menopausal women. As
a result, its use became widespread and for a whole generation, taking HRT
post-menopausally became the norm rather than the exception, regardless of
symptoms or indications.
Studies in the 1980s and 1990s showed that the lipid profile in women who
used HRT would improve, with the levels of total serum cholesterol and
Low Density Lipoprotein (LDL) dropping and High Density Lipoprotein
(HDL) rising. This naturally led to the conclusion that HRT could protect the
heart and blood vessels from atherosclerosis and coronary heart disease
(CHD).
It was also thought that the effect of Estrogen on the breasts was
insignificant and that the addition of a progestogen would counteract any
possibly deleterious effect.
In the last few years however, doubt was cast regarding both the safety and
alleged benefits of HRT. Notably, three large recent studies suggested that
HRT could in fact be dangerous, leading to the recent public scare and
mistrust of all HRT – even in those cases where its use is indicated.

Recent Studies:

The first of these studies to be published, the “Heart and Estrogen/Progestin

Replacement Study” (HERS) and its extension known as HERS II, was
performed on a group of older women (average age 71) all known to have
pre-existing CHD who were given a combination of estrogen (Conjugated
Equine Estrogens (CEE)) and progestin (Medroxyprogesterone Acetate
(MPA)). The study revealed an increase in the incidence of CHD, especially
in the first 1-2 years of use, leading to the conclusion that “Postmenopausal
HRT should not be used to reduce the risk of coronary events in women with
existing CHD”.
Shortly thereafter came the highly publicized study known as the “Women’s
Health Initiative”. It had two main “arms” or components, one using a
combination of “Estrogen” (Conjugated Equine Estrogen or CEE) and
“Progesterone” (Medroxyprogesterone Acetate) and the other using
“Estrogen” (CEE) only. The primary end-points were coronary heart disease
(death and non-fatal myocardial infarction) and invasive breast cancer. The
“Estrogen/Progesterone” arm of the study was stopped after an average of
5.2 years because of a similar finding of an increase in CHD as well as a rise
in the relative risk of invasive breast cancer, especially after several years of
HRT use.
It is noteworthy that the WHI was a randomized controlled trial (RCT)
involving over 16,000 post-menopausal women half of whom received CEE
+ MPA and the other half taking a placebo. This was the first RCT of such
magnitude, making its findings more credible than previous less rigorously
performed studies. It should be noted however that the average age of the
women enrolled in the WHI was 63 years.
The “Estrogen” only arm which involved over 10,000 women who had
previously undergone hysterectomy for various reasons was continued for
6.8 years before being stopped. Contrary to the E/P arm of the study, here
there was no increase in the incidence of breast cancer or coronary events.
As a matter of fact, a recently published analysis of the data on this group of
women showed a statistically significant decrease in the incidence of
coronary events in those aged 50-59 years.
The third study is the “Million Women Study” (MWS) carried out in Britain
and published in August 2003. This was not a RCT but an observational
study relying on information gathered from questionnaires based on the
recall of information by participating women. Like the WHI, it also showed
an increase in relative risk of CHD and invasive breast cancer, with minor
differences in figures and conclusions.
Both the WMS and WHI also showed an increase in the relative risk of gall
bladder disease, deep vein thrombosis (DVT), pulmonary embolism (PE)
and strokes.
The previously reported improvement in memory and risk of Alzheimer’s
disease could not be corroborated.
On the positive side, the studies showed a decrease in the relative risk of
colon cancer and osteoporotic fractures of the spine and hip. The sum total
of the overall risks however surpassed these potential benefits.
The difference between increased relative risk (RR) and absolute risk should
be clarified at this point. In the studies mentioned above, the increase in RR
for CHD, breast cancer, DVT, PE, strokes, etc., is roughly in the magnitude
of a 50% increase. This means that if the risk of a certain condition is 10
occurrences per 1,000 women not using HRT, a 50% increase in RR
incurred by women taking HRT raises that figure to 15 (out of 1,000). Thus
the absolute risk increase is 5 additional cases per 1,000 women.
For the individual woman considering taking HRT, that increase in risk is
actually quite small, but when large populations are involved any (small)
increase gains significance.
Which brings us to the following questions?
Should we still use HRT, especially in the management of Osteoporosis?
If so, how and for whom?
Otherwise, why not and what are the alternatives?

Menopausal Symptoms:

Menopause is defined as the complete cessation of menstrual bleeding in

women usually around the age of 50 years. It can occur at a much earlier age
under certain conditions or may take place after surgical removal of the
ovaries or radio- or chemo-therapy for various malignancies. The
outstanding symptoms are what are referred to as vasomotor symptoms,
namely hot flashes or flushes, which can be associated with insomnia and
night sweats, as well as generalized fatigue and mood disturbances.
Such symptoms will only occur in about one third of women and when they
do, will usually last for somewhere between 1 and 4 years, subsiding
gradually after that.
It has long been known that these symptoms could be well controlled in
most women with Estrogen, hence the wide acceptance of HRT as standard
treatment after menopause.
But for many women, especially those with severe symptoms, control is only
temporary, since a return of hot flashes etc. often occurs immediately after
discontinuation of HRT, whether the latter is used for a few months or
several years. Fortunately, such recurrences are usually short-lived and can
therefore be tolerated.
Along with the amelioration of symptoms, it was found that bone mineral
density (BMD) improved in women on HRT with a resultant reduction in
osteoporotic fractures. This has been corroborated by many studies over the
two decades, resulting in the widespread use of HRT as a primary mode of
preventing and treating osteoporosis. With time, it was found that this
positive effect on bone could be brought about even with miniscule doses of
Estrogen, thus minimizing side effects like nausea and bloating that are
sometimes associated with HRT.
Furthermore, HRT was prescribed for the control of urogenital disorders that
frequently plague aging women, such as urinary incontinence and
dyspareunia (painful intercourse).
Here again, many studies demonstrated the positive effect of estrogen on
these problems and many women today will attest to that.
Inadequately controlled and performed studies led to the conclusion that the
severity and risk of having Alzheimer’s disease, as well as memory loss in
older women could be substantially improved by using HRT. Quality of life
(QOL) became an important consideration and duly emphasized in the
media, but could only be referred to anecdotally, since RCTs could hardly be
conducted on such a subjective issue.

Indications for HRT:

Until quite recently, the indications for using HRT were:

Vasomotor Symptoms
Osteoporosis
Cardiovascular Disease
Genitourinary Dysfunction
Memory loss & Alzheimer
Quality of Life
Except for control of vasomotor symptoms, a shadow has been cast on all
the other indications. Although the improvement in BMD and subsequent
reduction of osteoporotic fracture risk is now well accepted, it is thought that
HRT should only be used for such an indication if it is to be used by women
suffering from severe menopausal symptoms. In other words, if a post-
menopausal woman with severe symptoms happens to have low BMD
(osteopenia or osteoporosis) she will benefit from HRT. But if she has gone
through menopause with minimal or no symptoms and is found to have a
low BMD, then non-hormonal treatment is preferred.
As for the cardioprotective effect of HRT, there seems to be a “window of
opportunity” here. Its use seems to be protective in the early post menopause
especially if estrogen alone is used, with an improvement in lipid profile and
reduction of coronary events. In older women several years after menopause
however, HRT has been shown to be harmful. Similarly, the adverse effect
on blood clotting with the resultant increase in DVT, pulmonary embolism
and strokes should be taken into serious consideration in predisposed women
(previous occurrence or strong family history).
Although only slight in absolute terms, the increased risk of breast cancer
should be a deterrent to the indiscriminate use of HRT. Women at risk
should be well screened before starting and repeatedly while on HRT.

HRT in 2007:

So where does all this leave us? Conventional HRT as we know it has fallen
out of favor especially since the release of these three large studies,
especially since all showed rather similar adverse effects. In the HERS II
and WHI studies, the patients were treated with Conjugated Equine
Estrogens and Medroxyprogesterone Acetate (Premarin and Provera). The
women in both studies were as a whole significantly older (sixties and
seventies) than what most women starting menopause would be (fifties).
Age is a crucial factor here, since the “older” women in the HERS and WHI
studies had more pre-existing diseases and factors predisposing to cardiac
and cerebrovascular events then those just starting menopause in their early
50s. In women who had undergone a hysterectomy and were therefore
receiving Estrogen alone, the risk of breast cancer was significantly lower in
both the WHI and MWS, indicating that the addition of progestins had an
additive adverse effect on the breast, but could not be avoided in the
majority of women since they still had an intact uterus.

Alternatives:

Among the alternative drugs, Tibolone seems to be promising. It has been

available in Europe since 1988 and in many countries other than the USA
and Canada where it is still awaiting FDA approval. Tibolone is a synthetic
steroid that is itself inactive but whose metabolites have a selective effect on
different tissues. For example it acts like an estrogen on bones, thus
increasing BMD, and on the brain, causing relief of menopausal symptoms.
But it has no estrogenic effect on the breast or endometrial tissue so does not
cause breast tenderness or uterine bleeding. Large trials are now under way
to determine its safety regarding the cardiovascular system and breast. A
recent study in the USA showed a small but significant increase in strokes in
women taking Livial. This resulted in the discontinuation of the study and
was a major setback for the manufacturing company.
Estrogens of plant origin (phytoestrogens) are widely used but there are no
properly conducted RCTs to prove their efficacy and / or safety yet. The
general impression is that they work for some women, but some reports
suggest that they are only as effective as placebo in that respect.
As for antidepressants and tranquilizers, their usefulness is limited and they
certainly cannot provide all the benefits of HRT.

Conclusions:

Despite the recently reported adverse effects of HRT, one must be aware that
in absolute terms, the figures are quite small and that the risk for an
individual woman is not so high.
Until we have evidence to the contrary however, we should use HRT
judiciously and only when indicated - meaning if there are annoying
menopausal symptoms - for a few years only and if no contraindication to
the use of Estrogen exists. This will limit its use to the early postmenopausal
period and only for those suffering from moderate to severe vasomotor
symptom. By so doing, the number of adverse effects will obviously be
reduced. Both the European Menopause Society (EMS) and the North
American Menopause Society (NAMS) have recently modified their earlier
position on HRT and now advise that in the early menopause and when no
contraindication exists, HRT can be used safely and beneficially.

Recommendations:

ƒ In postmenopausal women with osteoporosis, HRT should best be

reserved for such women with severe or persistent menopausal
symptoms, where the primary goal of HRT is symptom control and
improved BMD an added benefit. But when no vasomotor symptoms
exist, especially in older women several years after menopause, non-
hormonal treatment is preferred, such as Bisphosphonates, Strontium
Ranelate or Raloxifene.
ƒ For women with vasomotor symptoms who have undergone
hysterectomy, Estrogen alone is the safer option.
ƒ Care must be used if there is a tendency to venous or arterial
thromboembolism.
ƒ Avoidance of HRT in women at high risk of or with pre-existing
breast cancer is preferred unless symptoms are severe and then only
with extreme care and proper follow-up.
ƒ Older women several years after menopause should not be started on
HRT.
ƒ Tibolone promises to be a good alternative; herbal remedies are not as
effective; psychotropic drugs have limited value.
ƒ Local (vaginal) estrogen therapy can be used for the treatment of
urogenital atrophy. The effect of HRT on quality of life, mood
changes and memory loss is still debatable. Further data analysis and
more investigations will be needed to answer those questions.

No drug in the world can be said to be completely safe. Individualization

of treatment is the key to successful treatment.

References:
ƒ Risks and benefits of Estrogen plus Progestin in healthy postmenopausal women.
JAMA 2002. No. 3, July 17, 2002.
ƒ Editorial: The Million Women Study and breast cancer. L. Speroff, Maturitas 46
(2003) 1-6.
ƒ The EMAS 2006/2007 update on clinical recommendations on postmenopausal
hormone replacement therapy. Maturitas 56 (2007) 227-229.
ƒ Position Statement: Estrogen and Progesterone use in peri- and postmenopausal
women: March 2007 position statement of The North American Menopause
Society. Menopause, Vol. 14. No 2, 2007
ƒ Editorial: HRT and the Young at Heart. M. Mendelsohn, R. Karas. New England
Journal of Medicine 356;2639-2641 June 21, 2007.
ƒ Estrogen Therapy and Coronary-Artery Calcification. J. Manson et. al. New
England Journal of Medicine 356;2591-2602 June 21, 2007.
ƒ Purdie, D. Lecture given in Amman June 7, 2007 during “Practical Aspects of
Bone Health” conference.