Menopause and Hormone Therapy

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					Menopause and Hormonal Therapy
Steven Wilson, M.D.

Epidemiology:                                                                     The average age at menopause is 51 years, with about 5% of women
                                                                                  experiencing premature menopause before the age 40. Menopause occurs
The mean age of menopause is 51; it occurs before age 40 in 5% of women           earlier in women who live at high altitudes and women who smoke. About 15%
                                                                                  of women go through surgical menopause. The average length of menopause is
Average length of perimenopause 4 years
                                                                                  4 years so this is a long process and unfortunately it is difficult to predict in an
Earlier menopause is seen in cigarette smokers, those living at higher altitude   individual woman how long it will take to get through menopause. Generally,
                                                                                  women will experience a shortening of the intermenstrual interval then
Physiology:                                                                       lengthening, then has cessation of menopause, and then they have waxing and
                                                                                  waning periods through this period of time. Symptoms of estrogen lack occur
Premenopausal women after age 40 often have shorter cycles which lengthen just    prior to the cessation of periods as well.
before menopause.
                                                                                  The physiology of menopause is that of increasing ovarian resistance to FSH,
                                                                                  declining estrogen levels and increasing FSH levels. The classic symptom of
Physiology of menopause
                                                                                  menopause is the hot flash. Hot flashes are very common in menopause. Most
                                                                                  women, but not all women, will experience vasomotor instability. It tends to be
   -   increased ovarian resistance to FSH                                        less severe in obese women likely because they have higher circulating
                                                                                  estrogen levels. It is associated with peripheral vasodilatation.
   -   increased FSH levels (diagnostic level > 40)
                                                                                  Other symptoms of menopause include urogenital atrophy and decreased
   -   decreased estrogen                                                         vaginal lubrication manifested as painful intercourse. Some women may also
                                                                                  experience urinary frequency or urgency. They may experience urinary tract
                                                                                  infections with increased frequency and they may experience urinary
   -   estrone (less potent than estradiol) is the major circulating estrogen
                                                                                  incontinence. There is no increased risk of major depression in menopause but
                                                                                  many women do experience other symptoms. There can certainly be insomnia
Symptoms:                                                                         associated with nocturnal hot flashes that interrupt sleep and there appears to be
                                                                                  a decrease in short-term memory in women who are going through menopause
Vasomotor instability - "hot flashes"                                             and women who are post-menopausal.

   -   affect 80% of women                                                        Management of the symptoms of menopause, it is clear that estrogen is the
                                                                                  most effective therapy for the treatment of the hot flashes and vaginal atrophy
   -   less severe in obese women                                                 of menopause. Provera is an option of progesterone that is in general an option
                                                                                  for women who are intolerant of estrogen or in whom estrogen is
                                                                                  contraindicated. Clonidine orally or as a transdermal patch is less effective than
Urogenital atrophy                                                                estrogen, but better than placebo and can be used in normotensive women
                                                                                  follow up of blood pressure and symptoms to be sure that it is tolerated.
   -   decreased lubrication - dyspareunia
                                                                                  Not listed on the slide are phytoestrogens which are available in plant sources.
   -   UTIs                                                                       Soy is particularly one that women may be using. There is relatively little data
                                                                                  to guide us however in terms of dosing and benefits and actual regimen to
Mood disorders                                                                    prescribe. Suggesting decreased alcohol, caffeine and spicy food intake may be
                                                                                  of benefit.
   -   no increase in major depression, ?mild symptoms of depression may          Hormonal therapy and prevention. The preventive benefits with respect to
       sometimes occur.                                                           hormone therapy are many. The strongest evidence to date exists for preventive
                                                                                  benefits with respect to coronary heart disease and osteoporosis, there is some
   -   hot flashes may interfere with sleep                                       important evidence that using hormonal therapy decreases mortality. There is
                                                                                  less robust evidence with respect to benefits in stroke and colon cancer risk.
Treatment of symptoms:                                                            There is a growing body of evidence with respect to cognitive function delay
   - estrogen 95 % effective                                                      and onset in Alzheimer's disease. Women who are on estrogen lose fewer teeth
                                                                                  than women who are not on estrogen and there may be some cosmetic benefits
                                                                                  with respect to skin appearance as well.
   -   progesterone 10 mg qd 85% effective
                                                                                  With respect to hormone replacement in overall mortality, there does seem to
   -   clonidine 0.1-0.2 mg bid 30-40% effective                                  be a decrease in overall mortality. The benefit appears to decline with greater
                                                                                  duration of use. But it appears that when women are on hormonal therapy for
   -   avoid alcohol, caffeine, spicy foods                                       more than 10 years they may experience increased breast cancer mortality and
                                                                                  that is clearly an issue. The greatest benefit appears to accrue to those women
                                                                                  who have coronary artery disease risk factors or established coronary artery
Hormone Replacement Therapy and Prevention                                                disease.

HRT may have a role in prevention of:                                                     The benefits of estrogen in coronary heart disease are likely mediated through a
                                                                                          variety of mechanisms. One very important mechanism is the beneficial effects
                                                                                          on the lipid profile and other benefits.
   Overall mortality
                                                                                          The cohort studies today, have consistently shown a substantial reduction in
   Osteoporosis                                                                           relative risk of coronary heart disease. Some of the numbers from this body of
                                                                                          evidence is there is about a 0.5 relative risk reduction. Longer therapy confers
   Coronary Heart Disease                                                                 greater benefit. The addition of progesterone is not harmful with respect to the
                                                                                          cardiac risk reduction.
                                                                                          Coronary heart disease and HRT. Clearly, again we know that there is known
                                                                                          protection from endogenous estrogens. The weight of evidence suggests that
   Cognitive function decline                                                             we reduce the risk of coronary heart disease in half. It is very clear that
                                                                                          estrogen is of benefit in women who have established coronary heart disease.
   Colon cancer                                                                           What is not so clear is how important it is to start estrogen therapy at the time of
                                                                                          menopause and how long one needs to continue that benefit and whether
   Tooth loss                                                                             benefit persists after discontinuing estrogen should one do so.

Overall Mortality                                                                         Osteoporosis is common in postmenopausal women. Other risk factors for
                                                                                          osteoporosis include smoking and alcohol. They include low peak bone mass,
                                                                                          low calcium intake, family history or osteoporosis and steroids and
   Users of HRT have a 0.63 relative risk of death
                                                                                          hyperthyroidism. Sedentary life style is also on the list. So, those are things to
                                                                                          consider in seeing an individual woman. Use of estrogen clearly decreases the
   Benefit decreases to 0.8 relative risk with more than 10 years of HRT due to           risk of hip fracture. Remote use of estrogen does not confer the same benefit. If
   increased risk of breast cancer mortality.                                             one looks at a woman who is on estrogen and examines her bone density 10
                                                                                          years after she stopped estrogen, she looks very much like a woman who never
   Greatest benefit accrues in those with risk factors for coronary artery disease.       took estrogen at all.

Coronary Heart Disease:                                                                   Historically, it has been thought that it is best to start estrogen right at the time
                                                                                          of menopause because the period of peak bone loss occurs in the
                                                                                          perimenopausal and immediately postmenopausal period. There is some recent
   Known protective effect of endogenous estrogen                                         evidence that suggests however that if you start estrogen in a woman 10 or 20
                                                                                          years out from menopause, she doesn't look all that different from a woman
   Observational cohort studies relative risk -0.5                                        who has been on it since the time that menopause started. The addition of
                                                                                          progesterone does not appear to confer added benefit but also does not reduce
   Benefit as secondary prevention in women after CABG and angioplasty                    the benefit with respect to osteoporosis. It is thought that the minimum
                                                                                          effective dose of Premarin or conjugated estrogen is 0.625 mg/day. There is
   Mechanism of benefit attributed to lipid effects, thrombotic mediators, vascular       probably some benefit from lower doses, particularly if they are used in
                                                                                          combination with other protective therapies like calcium and vitamin D.
   endothelium, platelets.
                                                                                          Transdermal estrogen has similar efficacy with respect to osteoporosis
   Timing and duration of benefit not clear; there may be increasing benefit with         protection, and that is in contrast to coronary artery disease where it is likely
   longer duration of use. (Helbert Arch Int Med 1997;157:1330).                          transdermal estrogen does not have the same beneficial impact as does oral
   Other studies suggest that increased triglycerides attenuated with transdermal
   estrogen Osteoporosis:                                                                 Stroke. Recent studies suggest that estrogen may decrease the risk of stroke.
   Epidemiology: vertebral fractures 25% women > age 60 hip fractures 25 %                Similarly, a smaller number of studies done in Alzheimer's disease but with
                                                                                          somewhat more impressive endpoints, particularly in recent studies. Hormone
   women > age 80
                                                                                          therapy tends to delay the onset of Alzheimer's disease and also improves
                                                                                          function on complex neuropsychiatric testing and improves short-term
Significant functional impact                                                             memory. A small number of studies suggest that one decreases the risk of colon
   Risk factors: lower peak bone mass, smoking, alcohol, lack of exercise, family
   history, low calcium intake, steroids, hyperthyroidism                                 There are reports that estrogen increases the risk of breast cancer. It is clear that
                                                                                          unopposed estrogen increases the risk of endometrial hyperplasia and
HRT and osteoporosis:                                                                     endometrial cancer with a 40% risk of endometrial hyperplasia after just two
                                                                                          years of unopposed estrogen. The effect increases with increasing dose and
                                                                                          increasing duration of estrogen therapy. The risk of death appears to be lower
   Observational cohort studies relative risk of hip fracture 0.6-1.0 ever use, 0.3-0.8   in women who develop endometrial cancer on estrogen than in women who
   current use                                                                            develop it without estrogen.

   Estrogen actually increases bone density                                               The PEPI studies again shed light on this and it has been the impression from
                                                                                          observation studies for many years that the addition of progesterone essentially
   No demonstrated difference in adding progesterone 0.625 mg Premarin is               eliminates this risk. With respect to the endometrial cancer, most physicians
   minimum dose required for benefit Transdermal estrogen has similar efficacy          would not use unopposed estrogen any longer. If estrogen is used in
                                                                                        combination with progesterone, the concerns about endometrial cancer are
                                                                                        essentially nonexistent.
   Exercise, calcium and vitamin D should also be used
                                                                                        Breast cancers are often estrogen sensitive and have estrogen receptors.
   Timing of use:                                                                       Women with prolonged endogenous estrogen exposure are at increased risk of
                                                                                        breast cancer. We worry about women with early menarche and nulliparous
       -         greatest benefit from prolonged use                                    women and animal models estrogen can induce tumors.

       -         bone loss resumes at accelerated rate when estrogen stopped; risk of   Looking at cohort studies, the suggestion has been that, in fact, estrogen does
                 hip fracture near baseline > 6 years after stopping therapy            increase the risk of breast cancer. The risk appears to be greater with longer
                                                                                        duration of use.
Stroke: relative risk in recent observational studies 0.7-0.85 though older study as    Meta-analyses done of this question have suggested that the risks need not be
high as 2.6 Alzheimer disease: relative risk may be as low as 0.4                       as great as we were initially led to believe but certainly in women who are in
Colon cancer: relative risk 0.5-0.9                                                     particular risk groups - women with family history or women with benign
                                                                                        breast disease - that there may some increased relative risk of breast cancer.
Risks of HRT:
                                                                                        A woman's risk of coronary heart disease is going to have an enormous impact
Endometrial hyperplasia and cancer:                                                     on her risk of mortality.

                                                                                        For the average woman with no special risk, one would anticipate that she
Unopposed estrogen:
                                                                                        would have extended life expectancy on hormones as opposed to not on
                                                                                        hormones. Women with established coronary heart disease, women who are at
relative risk endometrial cancer 2.3                                                    risk for coronary heart disease, achieve a greater extension of life expectancy.
                                                                                        A woman who has established coronary heart disease is more apt to benefit
40% incidence endometrial hyperplasia after 2 years of therapy                          than a woman who has risk factors but is not yet known to have coronary heart
dose related                                                                            disease. Women actually did live longer even if they are at some risk for breast
Risk of death not equally increased; 90% 5 year survival vs 70% for cancers in non-
                                                                                        Women who have a number of risk factors for breast cancer, one would project
                                                                                        they would have a decreased life expectancy but for all other women, one
                                                                                        would project an improved life expectancy on hormone replacement therapy.
Breast cancer:                                                                          Women who had coronary heart disease risk factors or coronary heart disease
                                                                                        and breast cancer risk factors still do better on HRT than not. That is I think the
   Physiologic evidence:                                                                best information available to help take this body of data and counsel a woman
                                                                                        as to what she should do.
   estrogen sensitive breast cancers
                                                                                        Estrogen contraindications. Women with undiagnosed vaginal bleeding should
                                                                                        have that vaginal bleeding investigated before starting hormonal therapy and
   prolonged endogenous estrogen exposure increases risk
                                                                                        specifically when it is to exclude endometrial hyperplasia and endometrial
                                                                                        cancer as a source. Active thromboembolic disease. I would say that women
   correlated with higher bone density                                                  who have thromboembolic disease who are on anticoagulation can safely be
                                                                                        treated with estrogen. Women with a history of DVT or pulmonary embolism
   Cohort studies relative risk 0.5-1.9                                                 who are currently not anticoagulated, I would be concerned about starting that
                                                                                        woman on estrogen.
   Meta-analyses relative risks:
                                                                                        Active liver disease has been listed as a contraindication. I would view this as
                                                                                        significant underlying liver disease with cirrhosis, minor LFT abnormalities are
       Ever use                1.0
                                                                                        not considered to be a contraindication. Breast cancer and endometrial cancer
                                                                                        are contraindications.
       Family history          1.25-3.4
                                                                                        There is an increased risk of DVT and pulmonary embolism in women who are
       Benign breast disease           1.2-1.7                                          on these low doses of estrogen. Randomized control trials suggest that there
                                                                                        may be a 2 to 4-fold increased risk of DVT and pulmonary embolus. This risk
       Nulliparity             1.5                                                      disappears when estrogen is discontinued and it appears to be maximal during
                                                                                        the first year of use. So, if you have been on hormones for a year and you
                                                                                        haven't had a clot you are unlikely to develop one.
Other adverse effects of HRT
                                                                                        Relative contraindications. Family history of breast cancer, migraine
increased incidence of cholelithiasis (oral estrogen only) nausea breast pain           headaches. One should follow frequency of the migraines and just be aware
headache mood swings bloating                                                           that migraines can become more frequent with hormonal replacement therapy.

increased incidence of DVT/PE                                                           Hormones are not contraindicated in diabetics. In fact, diabetics should be
   -   perhaps as much as 2-4 fold increased relative risk while on estrogen   treated more aggressively with hormone replacement therapy because of their
                                                                               increased risk of coronary heart disease. Hypertension is not a contraindication.
   -   maximal first year of use.                                              Again, it is a risk factor for coronary heart disease. In the large populations,
                                                                               blood pressure does not appear to increase with low doses of estrogen used in
                                                                               HRT. Endometriosis and uterine fibroids are also not contraindications. Some
Prescribing HRT                                                                would suggest that it is best to delay initiation of hormonal therapy in women
                                                                               with these conditions for a year or potentially more. Patients can develop
Pharmacology:                                                                  recurrent symptoms with estrogen but it is certainly not an absolute
Oral estrogens metabolized in liver (60-90% first pass)
                                                                               Adverse effects of HRT. Oral therapy will increase the risk of cholelithiasis.
Transdermal estrogens have less effect on liver proteins                       Women may experience nausea, breast pain, headache, mood swings and
                                                                               bloating. Many women worry about weight gain. The PEPI trial suggested that
                                                                               women who are on hormonal therapy gain less weight than women who are
Serum levels of estrogens lower in smokers than non-smokers                    menopausal and not on hormonal therapy.

Contraindications:                                                             Practical aspects of prescribing. In a woman who has had a hysterectomy,
                                                                               current wisdom is that estrogen alone is all that one needs. Progesterone is
   undiagnosed vaginal bleeding                                                really a part of regimens to protect against endometrial cancer. There is no
                                                                               body of evidence to date to say that progesterone adds benefit with respect to
   active thromboembolic disease                                               coronary heart disease and bone density to a degree that it should be in these
                                                                               regimens. Women who have a greater risk must be on progesterone to prevent
                                                                               their risk of endometrial cancer. There are two general ways to do that. One is
   active liver disease
                                                                               cyclical therapy which is at the bottom of this slide and the other is continuous
                                                                               daily therapy with the same low dose of progesterone a day.
   breast cancer
                                                                               Premarin is used most commonly as the estrogen. Premarin is conjugated
   uterine cancer                                                              equine estrogen and is obtained from the urine of pregnant mares. In fact, that
                                                                               is the origin of the name Premarin - pregnant mare urine. The standard dose is
Relative contraindications:                                                    0.625 mg/day. The progesterone that is used is Provera or
                                                                               medroxyprogesterone acetate. There are a variety of ways that one can cycle
                                                                               women. The combination pill Premphase contains 0.625 mg/day and 5 mg of
   family history of breast cancer
                                                                               Provera for 14 days. If one is prescribing them separately, most folks would use
                                                                               10 mg of Provera for 10 days. The combination tablet is actually less expensive
   migraine headaches                                                          than the two tablets purchased separately.

Not contraindicated:                                                           The down side of cyclic therapy is that most women will continue to
                                                                               experience periods and will start to have periods if you initiate hormonal
   diabetes                                                                    therapy many years after menopause. Vaginal bleeding is predictable, in
                                                                               contrast to what one experiences with continuous daily therapy. The bleeding
                                                                               tends to start between days 11 and 20. One should biopsy for unanticipated
                                                                               bleeding that falls outside that time frame.

   endometriosis                                                               The other option is continuous daily therapy. Prempro which is available as a
                                                                               single pill using a combination of these medications is Premarin 0.625 mg/day
   uterine fibroids                                                            and Provera 2.5 mg/day. The advantage of continuous daily therapy is that over
                                                                               the long haul most women will have amenorrhea. 70 to 80% have amenorrhea
Post hysterectomy - estrogen only                                              at the end of the first year. But still in the long term women are less likely to
                                                                               have withdrawal bleeding which would be true if they were on cyclic therapy.
                                                                               Forty to 60% will experience bleeding during the first six months of therapy.
Combination therapy:
                                                                               That bleeding can be unpredictable and that is the downside of continuous
cyclic therapy:
                                                                               Women should make their own decision on which regimen they prefer…
daily conjugated equine estrogen (CEE, Premarin) 0.625 mg/d plus               whether they are willing to put up with six months of erratic bleeding with the
medroxyprogesterone acetate (MPA, Provera) 10 mg/day 1-12                      hope that in the long term they won't experience any, or if they would rather
Premphase has 5 mg medroxyprogesterone for 14 days (d 14-28) most experience   have more predictable periods. They can switch from one regimen to the other
withdrawal bleeding d 11-20; biopsy for unanticipated bleeding before day 6    certainly. In my experience and that of others, women who are put on this
                                                                               continuous daily regimen who are just recently through menopause tend to
                                                                               have more bleeding than women who went through menopause earlier. A
                                                                               biopsy is necessary if a woman is still bleeding after six months of continuous
continuous therapy:                                                            daily therapy.

Premarin 0.625 mg/d plus Provera 2.5 - 5.0 mg/d                                The patch is not recommended because one will not achieve the same
                                                                               cardioprotective benefit with the patch. One of the major down-sides of the
Prempro contains 0.625 mg CEE plus 2.5 mg Provera 40-60% breakthrough bleeding       patch is that women who have not had a hysterectomy still need to be on
in first 6 months                                                                    progesterone so they still need to be on some hormonal therapy.
90% amenorrhea at 1 year
                                                                                     For women who describe decreased libido, some have suggested that the
biopsy for persistent bleeding at 6 months
                                                                                     addition of testosterone may be of benefit. This has really not been studied
                                                                                     intensively but there is a combination medication that is available. The dose of
alternative estrogen:                                                                testosterone in this is quite low and likely it doesn't have significant side
ethinyl estradiol (Estrace) 1 mg equivalent to 0.625 mg Premarin
Estratest HS (CEE 0.625 mg with methyltestosterone 1.25 mg) has been used to treat   Indications of endometrial biopsy. A woman that is not having unexplained
    decreased libido                                                                 vaginal bleeding does not need an endometrial biopsy prior to starting therapy.
                                                                                     A woman who is on unopposed estrogen clearly does need annual endometrial
                                                                                     biopsies. For women on combination therapy, women who are on cyclic
alternative progesterone:
                                                                                     therapy who have unanticipated bleeding or particularly heavy bleeding should
                                                                                     have an endometrial biopsy. Women who have bleeding for more than six
micronized progesterone - difficult to obtain - 100 mg bid or 200 mg qd day 1-12     months on low doses of Provera should also have an endometrial biopsy.
norethindrone 0.35 mg X 28 days or 0.7 mg X 14 days
                                                                                     Summary conclusions. Estrogen is very effective in treating the symptoms of
Transdermal estrogen:                                                                menopause. For short term therapy in a woman who was not interested in the
                                                                                     preventative benefits of estrogen therapy, roughly five years is reasonable,
Must use progesterone in women with uterus avoids first pass effect no increase in   followed by tapering of therapy. Abrupt discontinuation of estrogen may cause
                                                                                     recurrent menopausal symptoms. Estrogen is of benefit in the vast majority of
cholelithiasis attenuated rise in HDL levels no increase in triglycerides
                                                                                     women because of the cardioprotective benefits and because of the decreased
?lower risk thromboembolic disease
                                                                                     incidence of osteoporosis and fractures.

Preparations: estradiol 0.05 mg qd                                                   If one looks at a woman who was remotely on estrogen and is no longer on
   Climara patches changed weekly                                                    estrogen, her body looks like that of one who was never on estrogen.
   Estraderm patches changed twice a week
                                                                                     For a woman with risk factors for breast cancer and in whom one anticipates a
Indications for endometrial biopsy:                                                  period of therapy for less than 10 years, it probably makes sense to delay
                                                                                     initiation of therapy. If you are using this purely for preventive reasons you
                                                                                     may wish to wait until she is 60 to initiate hormone replacement therapy.
Baseline: No biopsy
Cyclic HRT: Unanticipated bleeding before day 6 progestin and/or bleeding > 10       In the absence of major risk factors for breast cancer, it is useful to initiate a
days Continuous daily therapy: very heavy bleeding or bleeding > 6 months            discussion about the hormone replacement therapy and more likely not to start
Unopposed estrogen: Annual biopsy                                                    it at the time of menopause. We may ultimately learn that it is best to wait
                                                                                     awhile. With the women who opt not to start hormonal therapy at the time of
Conclusions:                                                                         menopause, it may ultimately be better to start a little more in their 60s and 70s.

Estrogen is very effective in treating menopausal symptoms.
Progestins protect against endometrial cancer.
Most women would benefit from cardioprotective effects and reduced osteoporosis.
    minimum 5-10 years to prevent osteoporosis
Short term use ( < 5 years) probably does not increase risk of breast cancer.
Women at increased risk of breast cancer, may wish to limit use to <10 years.
Delayed initiation of HRT (i.e. age 60) may prove to be a useful strategy.

Col NF et al. Patient -specific decisions about hormone replacement therapy in
postmenopausal women. JAMA 1997;277:1140-47.

Evans MP Fleming KC Evans JM. Hormone replacement therapy: management of
common problems. Mayo Clin Proc 1995;70:800-805.

Grady d et al. Hormone therapy to prevent disease and prolong life in
postmenopausal women. Ann Int Med 1992; 117:1016-1037.

Grodstein F et al. Postmenopansal hormone therapy and mortality. NEJM

Guidelines for counseling postmenopausal women about preventive hormone
therapy. Ann Int Med 1992; 117:1038-1041.

Coronary disease and HRT

Grodstein F et al. Postmenopausal estrogen and progestin use and the risk of
cardiovascular disease. NEJM 1996;335:453-61. Most recent f/u from the Nurses'
Health Study.

Manson JEet al. The primary prevention of myocardial infarction. NEJM

The writing group for the PEPI trial. Effects of Estrogen or estrogen/progestin
regimens on heart disease risk factors in postmenopausal women. JAMA

Osteoporosis and HRT

Felson DT et al. The effect of postmenopausal estrogen therapy on bone density in
elderly women. NEJM 1993;329:1141-6..

Cauley JA et al. Estrogen replacement therapy and fractures in older women. Ann Int
Med 1995;122:9.

Tosteson AN et al. Cost effectiveness of screening perimenopausal white women for
osteoporosis: bone densitometry and hormone replacement therapy. Ann Int Med
1990; 113:594-603.

Endometrial cancer

The writing group for the PEPI trial. Effects of hormone replacement therapy on
endometrial histology in postmenopausal women. JAMA 1996;275:370-75.

Breast cancer and HRT

Steinberg et al. A meta-analysis of the effect of estrogen replacement therapy on the
risk of breast cancer. JAMA 1991;265:1985.

Venous Thromboembolism and HRT
Vandenbroucke JP and Helmethorst FM. Risk of venous thrombosis with hormone-
replacement therapy. Lancet 1996;348:972. See 3 accompanying articles same issue.

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