Menopause Management for the MillenniumCME
Abstract
In the year 2000, an estimated 31.2 million women will be undergoing the menopausal transition.
Although menopause is a normal developmental process, the resulting decline in endogenous estrogen
levels can have serious clinical sequelae. Estrogen deficiency has been implicated in an increased risk
for vasomotor symptoms, osteoporosis, cardiovascular disease, urogenital atrophy, cognitive decline,
and Alzheimer's disease. This clinical management module provides an overview of the physiology of
menopause, considers women's perceptions of menopause, and presents a detailed review of available
and coming therapeutic options for the management of menopausal symptoms and the long-term effects
of estrogen deficiency. A critical and individualized approach to menopause management is
emphasized, because no intervention is suitable for every woman, and each option has a different
risk/benefit profile.
Introduction
The age of menopause has not changed over the past few centuries, but there has been a gradual
increase in life expectancy. Whereas in previous centuries women were not expected to live beyond
menopause, women now spend one third to one half of their life after menopause. The total group of
postmenopausal women in the United States is increasing. In the year 2000, there will be an estimated
31.2 million women older than 55 years, compared with 28.7 in 1990. By the year 2020, the size of this
group is estimated to be 45.9 million.
This clinical management module presents a comprehensive overview of the most current data,
thinking, and therapeutic strategies relating to the principal clinical consequence of menopause,
estrogen deficiency.
The Physiology of Menopause
Clinically, menopause is defined as the cessation of menstrual cycles and results from either follicular
depletion ("natural" menopause) or surgical removal of the ovaries ("induced," or "surgical,"
menopause). The secretion of the ovarian hormones estrogen and progesterone ends with menopause.
However, menstrual cycles seldom cease abruptly; there is an interval termed the "perimenopause" or
"menopausal transition," during which there are considerable hormonal fluctuations. The perimenopause
usually begins a few years before the last menstrual cycle; the cycles become irregular, and there are
often symptoms suggesting a decline in estrogen concentration. Estrogen levels can even swing higher
than normal early in the perimenopause, but an abrupt decline in estrogen occurs 6 months before
menopause. The perimenopause also extends for a few years after the last menstrual cycle; during this
time, transient and episodic bursts of ovarian activity may occur, which may result in some vaginal
bleeding.
Natural menopause occurs at a median age of 51.4 years, with a Gaussian distribution ranging from 4058 years. A number of factors appear to determine the onset of menopause. The age at onset of natural
menopause and the risk for surgical menopause both seem to be determined by familial factors as well
as by genetic polymorphisms of the estrogen receptor (ER).[1] There also appears to be a relation
between childhood cognitive function and the timing of natural menopause. [2] Multiparity and increased
body mass index (BMI) are associated with later onset,[3,4] whereas smoking,[3,5,6] nulliparity,[3] medically
treated depression,[7] toxic chemical exposure,[8] and treatment of childhood cancer with abdominalpelvic radiation and alkylating agents[9] have been associated with a younger age at onset. Premature,
or early, menopause (age < 40 years) has been linked to both familial and nonfamilial X-chromosome
abnormalities.[10-13]
Reproductive Decline and Menopause
The time from the decline in reproductive capacity onward is often referred to as the climacteric.
Reproductive aging occurs rapidly after the third decade, and fecundity is extremely low before
menopause. Follicular atresia accelerates at about 37.5 years. [14] Thus, reproductive aging precedes
menopause by 5-10 years, at a "young" chronologic age. This is signified by an increase in the serum
follicle-stimulating hormone (FSH) level in the early follicular phase of regular cycles and a decrease in
the circulating inhibin B level. The elevation in FSH drives the accelerated follicle depletion. [15] In late
perimenopause, levels of estradiol (E2) and inhibin A also decrease, inhibin B levels remain low, and
FSH is markedly increased.[16]
Hormonal Changes With Established Menopause
The typical hormonal changes in the early follicular phase of postmenopausal women compared with
those of ovulatory women are shown in Figure 1. Compared with the typical hormonal changes in the
early follicular phase of ovulatory women, in postmenopausal women, the most significant findings are
the marked reductions in E2 and estrone (E1) levels. The serum E2 level is lower than the serum E1
level. Serum E1 is produced primarily by peripheral aromatization of androgens, which are not as
dramatically affected by menopause. Postmenopausal levels of E2 average 15 pg/mL and range from
10-25 pg/mL. In oophorectomized women, levels are usually 10 pg/mL or lower. Serum E1 values
average 30 pg/mL but may be higher in obese women, because aromatization increases as a function of
the mass of adipose tissue. Estrone sulfate (E1S), an estrogen conjugate that serves as a stable
circulating reservoir of estrogen, has the highest levels of any estrogen. In premenopausal women, E1S
is usually above 1000 pg/mL; in postmenopausal women, levels average 350 pg/mL.
Figure 1. Circulating levels of pituitary and steroid hormones in postmenopausal
women compared with levels in premenopausal women studied during the first week
(days 2 to 4 [D2-4]) of the menstrual cycle. FSH = follicle-stimulating hormone; LH =
luteinizing hormone; PRL = prolactin; TSH = thyroid-stimulating hormone; GH =
growth hormone; E2 = estradiol; E1 = estrone; A = androstenedione; T = testosterone;
DHEA = dehydroepiandrosterone. From Yen SS. The biology of menopause. J
Reprod Med. 1977;18:287. Reprinted with permission.
Apart from elevations in FSH and luteinizing hormone (LH), pituitary hormones are not affected.
Specifically, growth hormone, thyroid-stimulating hormone, and adrenocorticotropic hormone levels are
normal. Serum prolactin levels may be very slightly decreased because prolactin is somewhat
influenced by estrogen status. Both the postmenopausal ovary and the adrenal gland continue to
produce androgen. The ovary continues to produce androstenedione and testosterone (levels are about
20 ng/dL) but not E2, and this production is at least partly dependent on LH. Androstenedione and
testosterone levels are lower in women who have undergone bilateral oophorectomy, with values
averaging 0.8 ng/mL and 10 ng/dL, respectively. The adrenal also continues to produce
androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS);
primarily as a function of aging, their levels decrease somewhat (adrenopause), although cortisol
secretion remains unaffected.
Whether an androgen "deficiency" occurs after menopause is still debated. One view is that a drop in
serum androgen levels may be more a function of aging than specifically the occurrence of
menopause.[16] Cross-sectional data obtained across the perimenopause have suggested very little
early change in levels of secreted androstenedione and testosterone. However, the results of a 5-year
prospective study of 59 women undergoing the transition from pre- to postmenopause indicate that
androgen hormonal changes do occur with the menopausal transition. [17] Specifically, both
androstenedione and testosterone declined 3 years before menopause in these women, and
fluctuations in the testosterone levels occurred after menopause. However, immediately after
menopause, the decline in androstenedione is greater than that of testosterone; that is, in early
postmenopause, testosterone levels may be indistinguishable from those in premenopausal women. [18]
Ultimately, several years after the menopause, the levels of androstenedione and testosterone are
significantly lower than levels measured in premenopausal women.
The Effects of Declining Estrogen
Two estrogen receptors exist: ER-alpha and ER-beta. Although the DNA-binding domains of the 2
receptors are almost identical (about 97% homology), the ligand-binding domains are different and have
only 60% homology.[19] Various estrogens have different affinities for ER-alpha and ER-beta, which, in
turn, have different tissue distributions in the body. For example, preliminary evidence suggests that in
certain regions of the brain (eg, frontal cortex), ER-beta predominates over ER-alpha. In the cerebellum,
only ER-beta is expressed.[20,21] Because ERs are abundant throughout the body, the menopausal
decline of estrogen potentially affects virtually all organ systems.
Brain and Central Nervous System
Estrogen receptors are abundant in the brain. Estrogen is known to have a role in many brain
processes, and the absence of estrogen can result in physiologic and symptomatic changes. Estrogen is
important for cerebral blood flow, cerebral glucose administration, synaptic activity, neuronal growth, the
survival of cholinergic neurons, as well as such complex functions as cognition.
Hot Flushes
Hot flushes are an early and acute symptom of estrogen deficiency. They often begin in the
perimenopause when estrogen levels characteristically fluctuate widely. It is the rapid fall in estrogen
level that precipitates the symptoms. Hot flushes typically last from 0.5 to 5 years after natural
menopause but may persist as long as 15 years. They tend to last longer and be more severe with
surgically induced menopause.[22]
Although the proximate cause of flushes remains illusive, the episodes result from a hypothalamic
response (probably mediated by catecholamines) induced by a change in estrogen status. The flush has
been well characterized physiologically: heat dissipation occurs through an increase in peripheral
temperature (eg, in the fingers and toes); a decrease in skin resistance, associated with diaphoresis;
and a reduction in core body temperature. There are hormonal correlates of flush activity, such as an
increase in serum LH and plasma propiomelanocortin peptides (adrenocorticotropic hormone, betaendorphin) at the time of the flush; however, these occurrences are thought to be epiphenomena that
result as a consequence of the flush and are not related to its etiology.
Hot flushes can cause insomnia,[22,23] which contributes to fatigue, irritability, and a reduced ability to
concentrate. However, a recent study suggests that psychological changes attributable to chronic sleep
disturbance may be more than side effects of hot flushes -- a direct effect of changing hormonal status
may also play a role.[24]
Mood Changes and Cognitive Function
In general, estrogen has a positive effect on mood and contributes to a sense of well-being,[25] which
may be due to its stimulation of the adrenergic and serotoninergic systems. The role of estrogen
deficiency in postmenopausal depression, declining cognitive function, dementia, and Alzheimer's
disease is not clear and is an area of intensive debate and research. [26-33] For example, one study found
a positive correlation between perimenopause and depressive symptoms (although a prior history of
depression may have been a factor).[27] By contrast, another study found that only a decreased level of
DHEAS, and not other sex hormones (including E2 and E1), was significantly associated with depressed
mood in a cohort of community-dwelling postmenopausal women.[34] A companion study also found only
weak or absent gender differences in the decline in cognitive function with age.[35]
Migraines
Estrogens and progestins affect central serotoninergic and opioid neurons.[36] Alterations in the level and
cycling of these hormones may cause a change in the prevalence or intensity of headaches. Because
the orderly pattern of estrogen and progesterone secretion is lost as menopause approaches,
perimenopausal women with a history of menstrual migraines may experience an exacerbation. [37]
Vision
There are numerous data indicating an increased incidence of some vision-threatening conditions in
postmenopausal women.[38] For example, idiopathic full-thickness macular degeneration predominantly
affects women older than 60 years. There appears to be a hormonal component, because symptoms
become more severe with menopause.[38] Changes in hormonal status may thus affect the physiology of
the eye. This hypothesis was tested by Ogueta and colleagues[39] in their analysis of ER-alpha
expression in human eye tissue. They found gender and age differences in ER-alpha expression in the
retina. ER-alpha was detected in the retina and retinal pigment of young female eyes but not in the eye
tissues of postmenopausal women.
Collagen
Estrogen has a positive effect on collagen, which is important for bone and skin. Both estrogen and
androgen receptors have been identified in skin fibroblasts. The loss of collagen is more rapid in the first
few years after menopause, and 30% of skin collagen is lost within the first 5 years after menopause.
The rate of collagen decrease is approximately 2% per year for the first 10 years after menopause. This
statistic, which is similar to that of bone loss after menopause, strongly suggests a link between skin
thickness, bone loss, and the risk of osteoporosis. In addition, reductions in collagen support and
atrophy of the vaginal and urethral mucosa have been associated with a variety of symptoms, including
uterine prolapse and urinary incontinence.
Urogenital Atrophy
Estrogen deficiency has deleterious affects on the urogenital system. It has been reported that as many
as one third of women aged 50 years and older experience urogenital problems. [40] Estrogen deficiency
results in a thin and paler vaginal mucosa; the moisture content is low, the pH increases (usually pH >
5), and it may exhibit inflammation and small petechiae. Cytology reveals a loss in superficial cells and
an increase of basal and parabasal cells. In reproductive-age women, the vaginal flora is dominated by
lactobacilli. In postmenopausal women, the vagina is gradually repopulated with diverse flora, including
pathogenic organisms commonly found in urinary tract infections (eg, coliform bacteria[41]), as a result of
the reduced acidity. The decrease in lactobacilli, yeast, and bacterial vaginosis-associated bacteria also
may explain the lower incidence of bacterial vaginosis and yeast vaginitis in postmenopausal women
than in women of reproductive age.[41]
Dry and atrophied vaginal and urethral epithelium can cause vaginal discomfort, itching, dyspareunia,
and recurrent vaginitis as well as such urinary symptoms as frequency and dysuria.. Estrogen deficiency
in periurethral tissues is also a factor in pelvic laxity and stress incontinence, which is common in
postmenopausal women.[42]
Bone Loss
In industrialized western countries, more than one third of women older than 65 years suffer from
symptoms of osteopenia/osteoporosis, a disorder characterized by low bone mass. Estrogen deficiency
is a dominant pathogenic factor in bone loss. This can be noted for the first time during perimenopause.
From 1.5 years before menopause to 1.5 years after menopause, spine bone mineral density (BMD)
decreases by 2.5% per year, compared with a premenopausal loss rate of 0.13% per year. [43] Loss of
trabecular bone (spine) with estrogen deficiency is greater than cortical bone (femoral neck) loss.
Estrogen deficiency is also a risk factor for alveolar (oral) bone loss in postmenopausal women with a
history of periodontitis.[44] In addition, there is an association between reduced BMD and both
cardiovascular (CV) mortality[45] and cognitive decline.[32]
In women, peak bone mass is achieved by the second decade and begins to decrease thereafter. At
menopause, an accelerated loss of bone occurs, which results in a 3% reduction in bone mass per year
for the first 5 years; thereafter, the rate of loss of bone ranges from 1%-2% per year. Dramatic changes
in bone architecture accompany this loss in bone, greatly increasing the risk of fracture. Every standard
deviation of reduction in bone mass results in a 2-fold or greater risk of fracture. The rate at which a
woman reaches the fracture threshold depends on many factors, such as genetics, nutrition, activity
level, and lifestyle; also extremely important is the total amount of bone a woman has at the time of
menopause.
Estrogen action on bone is mediated by direct effects on bone through the estrogen receptor and by
effects on collagen. The accelerated decline in bone mass that occurs with estrogen deficiency is
mediated by a variety of mechanisms, but the primary event is increased resorption (osteoclastic
activity), which becomes uncoupled from bone formation (osteoblastic activity). There are also indirect
effects mediated by parathyroid hormone and cytokines, which oppose the resorptive effects. [46,47]
Osteoprotegin (OPG), for example, a member of the TNF-receptor family, is a soluble protein that
inhibits osteoclastic bone resorption. OPG is secreted by osteoblasts and binds to OPG ligand, a factor
necessary for osteoclastogenesis. Serum levels of OPG appear to be significantly elevated in
postmenopausal women with osteoporosis.[48] In addition, estrogen enhances OPG secretion by
osteoblasts in vitro, suggesting that OPG may have an important role in the antiresorptive action of
estrogen on bone.[49]
In postmenopause, the positive effects of estrogen on growth factors, calcitonin, vitamin D metabolism,
and calcium absorption are also diminished.
Cardiovascular Effects
The degree to which estrogen deficiency increases the risk of cardiovascular disease (CVD) in women
has not been definitively established and is a subject of intense debate and research. [50] The
Framingham Heart Study[51] found that 10-year incidence of CVD in postmenopausal women aged 5059 was 4-fold higher than in premenopausal women of the same age range (although the results were
not were not adjusted for smoking[52]). The Nurse's Health Study[53] found a higher risk of CVD in
postmenopausal women compared with premenopausal women. However, the relative risk (RR) of CVD
depended on the interval that age was adjusted for (ie, for a 5-year interval, the RR was1.7; for a 1-year
interval, the RR was 1.2) as well as on adjustment for smoking.[52] In addition, although the largest
increase in coronary mortality in women appears to coincide with menopause, vital statistics data do not
support that menopause apart from chronologic aging increases the risk of CVD.[54] These data do not
rule out a role of estrogen deficiency in increased CVD risk; the age of onset of natural menopause is
quite variable and estrogen levels decline gradually over time. What does seem likely is that aging and
gradual estrogen deficiency contribute to the increased risk of CVD in older women.
On the other hand, there does seem to be a relation between premature menopause, or surgically
induced menopause (ie, hysterectomy with bilateral oophorectomy), and increased incidence of CVD
morbidity and mortality.[54,55] Premature menopause, occurring before age 35, has been associated with
a 2- to 3-fold increased risk of myocardial infarction; oophorectomy (before age 35) increases the risk 7fold.[56]
When the possible reasons for the increase in CVD in postmenopausal women are examined, the most
prevalent finding is that total cholesterol rises at an accelerated rate after menopause. Whereas agerelated changes in weight, blood pressure, and blood glucose levels are not thought to be substantially
different in men and women, the rate of elevation in total cholesterol after menopause is significantly
different. This increase in total cholesterol results from increases in levels of low-density lipoprotein
cholesterol (LDL-C), with the more dense forms predominating, and increases in very-low-density
lipoprotein (VLDL) and lipoprotein a (LP(a)). The oxidation of LDL-C is also enhanced. High-density
lipoprotein cholesterol (HDL-C) levels may decrease over time, but these changes are small and
insignificant relative to the increases in LDL-C.
A European study just published reports the results of a cross-sectional analysis of 9309 women (neverusers of hormone replacement therapy [HRT]) that quantified the effect of menopause on blood lipid and
lipoprotein levels.[57] After adjustment for covariates (age, educational level, study center, BMI, smoking,
hypertension, diabetes, previous contraceptive use, and time since menopause), the increase in total
cholesterol, LDL-C, and triglycerides from premenopause to postmenopause was 4.4%, 4.0%, and
3.2%, respectively; without adjustment, the increases are higher -- 6.9%, 7.5%, and 9.0%, respectively.
Coagulation balance is not altered significantly with menopause because a counterbalance of changes
occurs; some procoagulation factors increase (factor VII, fibrinogen), but so do certain fibrinolytic factors
such as antithrombin III and plasminogen. Blood flow in all vascular beds decreases after menopause;
prostacyclin production decreases, endothelin levels increase, and vasomotor responses to
acetylcholine challenges are constrictive. Further, circulating plasma levels of nitric oxide increase, and
levels of angiotensin-converting enzyme decrease. Estrogen and progesterone receptors have been
found in vascular tissues, including coronary arteries. Overall, the direct vascular effects that occur after
menopause are considered as important as, or more important than, the changes in lipid and
lipoproteins in terms of CVD risk.
In healthy, nonobese, postmenopausal women, carbohydrate tolerance decreases as a result of an
increase in insulin resistance. Biophysical and neurohormonal responses to stress (stress reactivity) are
exaggerated in postmenopausal women compared with premenopausal women. However, the role of
estrogen deficiency in these CVD risk factors has not been elucidated.
Estrogen deficiency probably has subtle effects on the musculoskeletal system, the eyes (see above),
ears, and sensory organs, but these systems have been incompletely studied. Similarly, the effect of
declining estrogen on immune function warrants further investigation.
How Do Women Perceive Menopause?
More than half (51%) of 752 postmenopausal women participating in the North American Menopause
Society (NAMS) 1998 menopause survey reported that they were happier and more fulfilled in their
postmenopausal years than in their 20s (10%), 30s (17%), or 40s (16%). [58] They reported that many
areas of their lives had improved since menopause, and almost 75% had made some health-related
lifestyle change at midlife (eg, smoking cessation). More than half reported that their sexual relationship
was unchanged at menopause, and women who had undergone hysterectomy expressed that they had
improved sexual relationships and spouse/partner relationships, a sense of personal fulfillment, and
improved physical health.
Women's perception of menopause is derived from a number of sources, including their peers, relatives,
the media, and health professionals.[58-60] The Seattle Midlife Women's Health study[61] found that a
cohort of well-educated, middle-aged women defined menopause as a normal developmental process
(Table 1). These women did not consider menopause primarily as a time of symptoms and increased
disease risk or a time for medical care. In fact, they were uncertain of their expectations regarding
menopause.
Table 1. Women’s Perceptions of Menopause







Cessation of menstrual cycles
End of reproductive ability
A time of hormonal changes
A change of life
A changing body
A time of changing emotions
An aging process
Adapted from Menopause. 1999;6:167-173.[61]
The previous year, the NAMS 1997 survey found that overall, women are divided in their views of
menopause, with some considering menopause a medical condition requiring treatment and others
considering it a natural transition that should be managed by "natural" means. [62] The survey also found
that many women who were already menopausal or perimenopausal expressed a neutral or positive
attitude toward menopause. The women surveyed were more likely to believe that menopause is
associated with depression and irritability rather than heart disease, and few were aware of an
association between menopause and increasing risk for memory loss or Alzheimer's disease.
When Do Women Perceive They Are Undergoing Menopause?
Garamszegi and colleagues[63] investigated the relation between how women themselves perceived
their menopausal status and their clinically defined menopausal status (ie, menstrual and hormonal
status). Interestingly, they found that women's perceptions of having begun menopause were based on
symptoms and related more closely to their endocrine status than to their menstrual status. The NAMS
1997 survey also found that the decision to commence HRT was more often made on the basis of
physical symptom relief rather than as protection against osteoporosis or prevention of stroke or heart
attack.
How Do We Manage Menopause Today?
It is the approach to management of menopause that is critical. Assessment of symptoms, if present, the
needs of the woman, her specific risk factors, and her family history are fundamental. It is only in this
context that the various options should be considered and choices made. The ultimate question at the
end of the assessment should be, Will any of the available options improve the overall quality of life for
the woman?
Preventive Medicine for Postmenopausal Women
How can we modify the increased mortality rates in our older women patients? Smoking cessation to
prevent lung cancer should be the emphatic message of all health providers. Postmenopausal women
should be carefully screened for breast cancer risk factors. Risk can be assessed on the basis of family
history; fertility or infertility history, and age at menarche, menopause, and first pregnancy. Preventive
measures necessitate frequent self-examination and provider examinations; annual mammography in
women older than 40 years should be encouraged. For CVD, it is important to assess family history and
such modifiable risk factors as blood pressure, cholesterol level, diabetes, smoking, poor diet, and lack
of exercise. We need to assess women in totality and not ignore surveillance for cancers of the colon,
ovary, and uterus.
It is also important to evaluate bone mass, particularly in the woman who is undecided about therapeutic
intervention. Performing bone mass screening has proved to be very useful for decision making and
follow-up, particularly because we have nonhormonal as well as many hormonal options for the
prevention and treatment of osteoporosis. The only way to accurately assess bone mass is by direct
measurements. Historic information about risk factors and biochemical urinary analyses are only partly
helpful. Dual x-ray absorptiometry, which has high precision and reproducibility and results in low
radiation exposure, remains the best approach.
Diet and Exercise
Such lifestyle factors as diet, exercise, and weight control are important in determining a woman's risks
for CVD, osteoporosis, diabetes, breast cancer, and depression. In most developed countries, women
have a higher prevalence of obesity than men.[64] Menopause is a high-risk time for weight gain.
Although the average weight gain during the menopausal transition is 2-5 pounds, it can be much
greater. In addition, the hormonally driven shift in fat distribution from peripheral to abdominal, which
may begin even before menopause,[65] may increase health risks.[65-67] Burghardt reports that although
physical fitness at menopause can reduce these risks, only 38% of women older than 19 years exercise
regularly.[68] Together, diet and exercise are crucial components of preventive medicine for women pre-,
peri-, and postmenopause.
A Diet Fit for Menopause
A diet rich in fruits, vegetables, whole grains,[69,70] nuts, and low-fat dairy products; low in saturated fat,
cholesterol, sugar, and refined carbohydrates (eg, the DASH diet [71]); and emphasizing chicken and fish
rather than red meat can reduce BMI, increase HDL-C levels, and lower LDL-C, triglycerides, blood
pressure, and blood glucose.[71-73] Data from the Dietary Approaches to Stop Hypertension (DASH)
study showed that this kind of diet not only significantly reduced systolic blood pressure -- suggesting
that the DASH diet may offer an alternative to drug therapy for hypertension[71-73] -- but also improved
the perception of health-related quality of life.[74]
A trial of dietary intervention in women with extensive areas of radiologically dense breast tissue (a risk
factor for breast cancer) is under way. Thus far, it has shown that after 2 years on a low-fat, highcarbohydrate diet, there is a significant reduction in the area of dense breast tissue, particularly in
women going through menopause.[75] Recent data suggest that isoflavones and other phytoestrogens
(found in soybeans), as well as flaxseed, have beneficial effects on vasomotor symptoms and bone
health.[76-79] However, it appears that isoflavones do not exert clinically important estrogenic effects on
vaginal epithelium or endometrium.[80]
Nutritional Supplements
Adequate calcium and vitamin D are important adjuncts to treatment and preventive health programs for
postmenopausal women. Vitamin D deficiency in postmenopausal women, particularly those who live in
northern latitudes, may be significant, as LeBoff and colleagues[81] have reported. These investigators
found that a cohort of postmenopausal community-dwelling women who presented with hip fracture
showed occult vitamin D deficiency. However, it should be noted that vitamin D supplementation alone
does not appear to prevent lumbar bone loss.[82,83] The results of some small studies have also
suggested that vitamin D together with HRT, and possibly vitamin K2, [84] may provide a bone-sparing
effect that is superior to that of HRT alone.[83,85]
Calcium supplementation should begin before menopause. At the 21 st annual meeting of the American
Society of Bone and Mineral Research (ASBMR) in St. Louis, Missouri, Dr. DT Baran[86] of the University
of Massachusetts at Worcester reported the results of a 3-year placebo-controlled trial of the effects of
calcium supplementation on BMD in 98 premenopausal women (average age 39 years). In the 44
women who received oral calcium carbonate (500 mg daily), BMD in the total hip was maintained,
whereas it decreased by 0.4% per year in the 54 women taking placebo. Calcium supplementation in
premenopausal women thus appears to prevent bone loss, allowing them to enter menopause with
greater bone mass, which may reduce the risk of later bone fracture.
Estimating the appropriate amount of calcium to be added to dietary sources for optimal
supplementation is difficult, however, because calcium intake varies with race and with environmental
and dietary conditions.[87] Long-term ingestion of very high doses poses a risk of hypercalciuria and
kidney stones and an imbalance in the calcium-magesium ratio. The current recommendation is that
postmenopausal women consume at least 1000 mg of calcium through diet and supplementation.
Antioxidants, particularly vitamins E and C, have been shown to be beneficial in prevention of bone loss
and CVD.[70,88-91]
DHEA supplementation may eventually be recommended for some postmenopausal women who have
particular concerns such as depressive symptoms and lack of energy. Short-term DHEA
supplementation has been shown to restore impaired pituitary beta-endorphin response to clonidine,
indicating that DHEA may restore neuroendocrine control of anteropituitary beta-endorphin secretion
and thus restore psychological and physical well being. [92] There is accumulating evidence that DHEA/S
is a neuroactive steroid, but long-term clinical trials are needed to determine the safety and benefit of
DHEA therapy in postmenopausal women with depressed mood. [34,93] In addition, DHEA may have
some beneficial actions on vaginal epithelium and bone.[94] However, oral DHEA doses of 50 mg or
more exert an androgenic effect and lower HDL-C, resulting in supraphysiologic levels of free
testosterone. Thus, only lower doses (eg, 25 mg) should be considered, but they may be sufficient to
achieve the desired effect in some women.
Exercise: A Must for Menopause
Aerobic exercise can modify lipoprotein levels in postmenopausal women. [72,95-98] A large 8-year
prospective study involving 72,488 female nurses aged 40-65 years (The Nurses' Health Study) has
shown that brisk walking and vigorous exercise are strongly associated with a reduced risk for coronary
events (fatal and nonfatal myocardial infarction).[99] In this study, even sedentary women who became
active in midlife or later had a reduced risk of coronary events compared with their sedentary
counterparts.
Weight training is also beneficial for postmenopausal women. Progessive resistance training [100] and
weight-bearing exercise[101-103] have been shown to be effective in increasing BMD, reducing
osteoporotic fracture risk, and preventing falls in older women.
Therapeutic Intervention in Menopause: What Are the Options?
The first question to address is, What is the reason to intervene? Are there symptoms such as hot
flushes? For a woman suffering from hot flushes, there need not be a commitment to long-term therapy;
a short-term approach may be embarked upon. A more difficult question arises in the older
postmenopausal woman who has no major complaints but is concerned about osteoporosis, for
example. Her family history, risk profile, and bone-mass assessment are valuable adjuncts to help
decision making. Depending on these variables, the choice of intervention may be one of natural
supplements, nonhormonal treatments (eg, a bisphosphonate), a selective estrogen receptor modulator
(SERM), or HRT. The wide array of options now available allows many women to make decisions they
are comfortable with.
Overall, there are sufficient data in my view to suggest that all-cause mortality is reduced in women who
receive estrogen replacement therapy, principally because of a reduction in CVD. [104-106] This large effect
counterbalances any potential increase in breast cancer mortality, even if the RR is 1.6 or greater. [104,107109] These are data that also suggest that even in women with a family history of breast cancer, the risk
is not increased further by HRT; all-cause mortality is decreased in these women to a similar degree as
that reported in the several observational cohorts.[110] Yet, a woman who has seen her mother suffer
from breast cancer will probably choose not to use estrogen. A number of models are available to help
clinicians individualize therapy to prevent the long-term effects of estrogen deficiency.[111-113]
Natural Estrogen Supplements for Vasomotor Symptoms
In my clinical experience, natural estrogen supplements are popular. However, few have proven
sustained benefit for symptoms. Among those that have received the scrutiny of controlled trials, only
black kohosh, genistein, and soy-based products have been shown to be effective for hot flushes. [77,114]
Although some data are available for soy-based products, there are no convincing data about efficacy
for vaginal health,[80] lowering CVD risk, or improving brain function. Because phytoestrogens bind to
ERs (ER-beta > ER-alpha), large doses (which are needed to achieve benefit on a statistical basis) may
pose some risk for estrogen-responsive cancers, such as breast cancer; although, conventional thinking
is that these products are protective for the breast.
Bisphosphonates for Prevention and Treatment of Osteoporosis
Bisphosphonate therapy may be appropriate for women with or at risk for osteoporosis who cannot or
choose not to use HRT. Bisphosphonates adsorb to bone mineral and inhibit bone resorption.[115]
Etidronate and alendronate are approved for the prevention and treatment of osteoporosis. Although the
relative efficacy of these 2 agents has not been directly compared, alendronate appears to be the
bisphosphonate of choice on the basis of clinical trials using fracture as an end point. [116] In addition,
alendronate has a more favorable side-effect profile.
Alendronate (5 mg/day for prevention; 10 mg/day for treatment) significantly increases bone mass
compared with placebo at any studied skeletal site in recipients, regardless of age, race, baseline rate of
bone turnover, or baseline BMD. It is the only agent that has been shown to positively affect
symptomatic and asymptomatic vertebral fracture and nonvertebral fracture rates.[117] Indeed, the
International Committee for Osteoporosis clinical guidelines for osteoporosis state that on the basis of
accumulated evidence, alendronate appears to be the most effective antifracture agent. [118] However,
the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group warn that a cautionary note is in
order. One trial[119,120] reported that in postmenopausal women with low BMD and no vertebral fracture,
alendronate did not significantly reduce the incidence of all clinical fractures, except in a subset of
women with low hip BMD.[121] Alendronate can produce gastrointestinal side effects (abdominal pain,
esophagitis, dyspepsia, peptic ulceration). Esophagitis, which has been reported to occur in about 1% of
patients, in many cases results because the medication had been ingested incorrectly. [117] Patients must
be reminded that alendronate tablets have to be taken in a fasting state, at least a half hour before
breakfast, with a full glass of water.
Third-generation bisphosphonates with a milder side-effect profile are under investigation for the
prevention and treatment of osteoporosis. Risedronate, for example, is being evaluated for use as longterm therapy for the prevention and treatment of osteoporosis. It can be administered orally in lower
dosages than earlier-generation bisphosphonates and has a side-effect profile similar to placebo in
clinical trials.[121,122] In a trial involving postmenopausal women with low or normal bone mass, oral
risedronate at 5 mg/day increased bone mass within 2 years.[122] The VERT Study Group has just
published the results of their 3-year trial on the efficacy and safety of daily treatment with risedronate to
reduce the risk of vertebral and nonvertebral fractures in postmenopausal women with established
osteoporosis.[121] This randomized, double-blind, placebo-controlled trial enrolled 2458 women younger
than 85 years who had at least 1 vertebral fracture at baseline. Treatment with 5 mg/day risedronate
plus calcium 1000 mg/day (a subset of women with low 25-hydroxyvitamin D levels received vitamin D,
up to 500 IU/day) reduced fracture risk by 65% after 1 year. It also decreased the cumulative incidence
of new vertebral and nonvertebral fractures by 41% and 39%, respectively, over 3 years. Compared with
placebo, risedronate produced significant increases in BMD at the lumbar spine (5.4% with risedronate
vs 1.1% with placebo), femoral neck (1.6% vs -1.2%), femoral trochanter (3.3% vs -0.7%), and midshaft
of the radius (0.2% vs -1.4%). These data suggest that risedronate therapy is an effective and welltolerated treatment for postmenopausal osteoporosis. Of note is that a new formulation -- a cellulose
film-coated tablet -- has been developed to optimize esophageal transit of risedronate. [123]
New Treatments for Osteoporosis in the Pipeline
Osteoprotegerin
This naturally occurring protein is a negative regulator of osteoclast formation that has shown promise
as a potential treatment for osteoporosis. At the 21st annual meeting of the ASBMR, Dr. P.J. Bekker and
his group[124] from Amgen Inc., Thousand Oaks, California, presented the results of a small, randomized,
double-blind study involving 52 postmenopausal women who were given a single subcutaneous
injection of OPG or placebo in the abdomen. An 80% reduction in N-telopeptide/creatinine levels
occurred within 5 days in women who received OPG at a dose of 3 mg/kg, which remained below
baseline levels for about 4 weeks. The investigators described the tolerability profile as excellent, with
mild pruritis at the injection site as the notable adverse event. These initial results are encouraging, and
larger clinical trials are under consideration.
Parathyroid Hormone
Bisphosphonates, estrogen, and SERMs slow or stop bone loss but they do not replace bone that has
already been lost. Currently in clinical development are a group of bone-building peptides -- native
parathyroid hormone, its 34- to 38-amino acid N-terminal fragments, and a group of molecules known as
second-generation mini-PTHs.[125]
SERMs: A Mini Course
As we have seen, estrogen deficiency manifests in many organ systems, indicating that ERs are
ubiquitous and that estrogen exerts effects throughout the body. Although all of these effects are
desirable in normal premenopausal women, some estrogenic effects should be avoided during disease
states and after menopause. For example, the addition of estrogen should be avoided in premenopausal
women with estrogen-sensitive neoplasia or with such disorders as leiomyomata and endometriosis. In
postmenopausal women, estrogenic stimulation of the breast and uterus increases the risk for breast
and uterine cancers.
It would be ideal therefore to "design" an estrogen-like compound for the treatment of specific
conditions. Such a compound would have selective agonistic or stimulatory effects (ie, estrogenic) on
one organ system and neutral or antagonistic (ie, antiestrogenic) effects on other organ systems. At
least 2 approaches could be adapted to design such a compound. The first would involve targeted
delivery of native E2 with a vehicle or modified molecule such that E2 could enter one organ and not
another. The second approach would be to use an estrogen analogue that would selectively modulate
receptors to express agonistic, neutral, or antagonistic activities in different tissues.
An example of the first approach is to couple E2 to a quaternary salt that would not have systemic
effects but which could pass through the blood-brain barrier. In the brain, the molecule could be
modified to release E2 for direct action.[126] Although this is an appealing approach, currently there are
no clinical data to support its use.
The second approach involves a group of compounds called SERMs (see Table 2 for a partial listing).
Several SERMs are available for clinical use, others are in development,[127] and phytoestrogens, such
as isoflavones, are under investigation.[77,79] How SERMs "selectively" influence different tissues is not
completely understood, but what is known is briefly reviewed here.
Table 2. Selective Estrogen Receptor Modulators (SERMs)
Triphenylethylenes


Clomiphene
Tamoxifen



Toremifene
Droloxifene
Idoxifene
Benzothiophenes


Raloxifene
LY353381
Naphthalenes

CP336,156
Chromans

Levormeloxifene
Phytoestrogens


Genistein
Daidzein
Conjugated Estrogens

Delta8,9-Dehydroestrone sulfate
Our understanding of ligand binding to the ER has changed over the past few years. SERMs may be
classified according to their antagonistic and agonistic activities, which relate to how they bind to the ER.
This has been modeled after knowledge of the progesterone receptor. [128,129] Compounds that prevent
receptor-DNA interactions are called type I antiestrogens. There are no known pure type 1
antiestrogens. A type II antiestrogen is one that induces a conformation that is closest to that of an
inactive receptor. An example of this is the pure estrogen antagonist, ICI 164, 384. A compound that
exhibits partial agonistic effects is considered a type III antiestrogen -- raloxifene, which acts as an
agonist in bone and an antagonist in breast, for example (see below). A compound that stabilizes the
ER in a conformation allowing transcription on only certain ER-responsive genes is a type IV
antiestrogen; tamoxifen, which is used in the prevention and treatment of breast cancer, is an example
(see below).
How do type III or IV antiestrogens exert agonistic versus antagonistic activities? The ER contains
different transcription activating factors (TAF). TAF1, or AF1, is located near the N-terminus of the ER,
and TAF2, or AF2, is at the C-terminus. Different tissues have different AF1 and AF2 activities. Thus far,
tamoxifen is known to interact with AF2 to effect antagonistic activity and with AF1 to effect agonistic
activity. In the breast, a tissue exhibiting much AF2 activity, tamoxifen thus acts as an antagonist.
Raloxifene (see below) may induce a different and unique receptor conformation, which explains its
antagonistic activity in the breast.[129,130] In addition, 1 of 2 types of proteins are recruited to the ER:
coactivators, which enhance ER activity, and corepressors, which inhibit ER activity.
The Ideal SERM for Menopause
Ideally, the use of SERMs should fall into 2 categories (Table 3). The first would be to relieve symptoms
associated with estrogenic deficiency and so improve the quality of life for postmenopausal women. The
second, more selective use would be to target the antiestrogenic effects of a SERM to 1 organ system
(eg, the breast). For postmenopausal health, the following would be the ideal scenario for SERM action:
agonistic activity in the brain, bone, CV system (not necessarily the liver), vagina, and urinary system,
and antagonistic activity in the breast and uterus.
Table 3. Effects of Estradiol and SERMs on Various Organ Systems as Pertinent to
Postmenopause Use
Brain Uterus Vagina Breast Bone Cardiovascular System
Estradiol
++
++
++
++
++
++
Pure antiestrogen —
—
—
—
—
—
Ideal SERM
++
—
++
—
++
++
Tamoxifen
—
+
—
—
+
+
Raloxifene
—
—
—
—
+
+
Isoflavones
+
—
+—
—
+
+
Theoretically, the ideal SERM's estrogenic activity in the brain, bone, and CV system would reduce the
risk of morbidity and mortality in postmenopausal women by improving cognitive function and reducing
the risks for osteoporotic fractures, Alzheimer's disease, CVD, and stroke.[131,132] The ideal SERM would
increase HDL-C levels and reduce LDL-C and total cholesterol. The hepatic effects of a SERM, if
excessive, however, increase the risk of venous thromboembolism. Of note is that although at least 60%
of the total effect of estrogen on the CV system involves direct vascular effects, such effects may not
occur with certain SERMs because of differential binding avidity to ER-alpha and ER-beta,[133] both of
which are expressed on coronary vessels.[134]
Age increases the risk of breast cancer, independent of the effects of estrogen. Many lines of evidence
suggest that a reduction in estrogen status decreases the risk of breast cancer. [135] Thus, whether or not
prolonged estrogen use increases the risk of breast cancer, any SERM ideally would lower this risk for
postmenopausal women. Although not pathologic, uterine withdrawal bleeding that occurs with HRT is
unacceptable to most postmenopausal women. Accordingly, a SERM that exerts agonist effects on
systems such as bone but does not result in uterine/endometrial stimulation would be ideal.
The SERMs We Have Now: Clinical Effects
We do have considerable experience with several SERMs, including clomiphene, which is used for
ovulation; tamoxifen, used for the treatment of ER-positive breast cancer and chemoprotection for
women at risk of breast cancer[136]; the tamoxifen derivative, toremifene, indicated for the treatment of
ER-positive breast cancer; and raloxifene, used for the prevention and treatment of osteoporosis.
Tamoxifen. This triphenylethylene acts as an antiestrogen in breast tissue, but it exerts an estrogenic
effect on the uterus, which can lead to endometrial disease (polyps and cancers). [137] These effects are
inconsistent, exhibit an unusual pattern of expression, and are not predictable, possibly because of the
activation of a spectrum of ligand-receptor interactions in tissues of different women. Tamoxifen is
agonistic (to variable degrees) in bone and liver but antagonistic in the vagina and certain brain regions.
Of interest is that in the cynamologous monkey model, tamoxifen reduces the coronary artery
atherosclerosis extent almost as much as conjugated equine estrogens (CEE) do[138]; however,
tamoxifen does not appear to affect coronary vasodilation, a characteristic feature of estrogen. In trials
of healthy women, tamoxifen exhibited a protective effect for osteoporosis and a beneficial lipid profile
but increased the risk of uterine cancer and venous thrombosis.[139-142] The long-term effect of tamoxifen
on the risk of osteoporotic fractures has not been determined. [141]
Thus, tamoxifen is protective to some degree against osteoporosis [140] and induces some CV protection
by reducing LDL-C and total cholesterol levels,[139] but it also increases the risk of venous thrombosis[142]
and tends to precipitate vaginal atrophy and hot flushes. [143]
Toremifene. This triphenylethylene is a chlorinated derivative of tamoxifen and is indicated for the
treatment of breast cancer in postmenopausal women with ER-positive or receptor-unknown status
tumors. It is used as an alternative to tamoxifen. The clinical experience with toremifene is limited.
Toremifene has bone antiresorption effects comparable to those of tamoxifen and appears to have little
impact on bone turnover markers.[144,145] It also may have similar effects on lipid profile to those of
tamoxifen.[146] The effect of toremifene on the uterus and endometrium has not been clearly defined in
clinical trials, but hot flushes, vaginal discharge, and nausea are the most common adverse effects of
toremifene.[147] The risk of venous thrombosis is probably comparable to that for tamoxifen, but again,
clinical trials are needed to answer this definitively.
Raloxifene. In head-to-head comparisons, this benzothiophene prevents bone loss and reduces
fracture risk in a superior fashion to placebo but not as well as CEE. [148] The effects of raloxifene (60
mg/day) are approximately 50%-60% those of CEE (0.625 mg/day) on the basis of BMD measurements.
However, raloxifene has been shown to significantly reduce vertebral fractures.[149] Raloxifene has a
beneficial effect on the liver by lowering total cholesterol, LDL-C, and triglycerides, but it does not
increase HDL-C.[150] However, these lipid effects cannot be equated with significant CV protection or a
reduction in atherosclerosis. In the cynamologous monkey model, raloxifene did not reduce coronary
atherosclerosis extent despite lowering total cholesterol and LDL-C.[151] These data are controversial, as
studies with rabbits have suggested that raloxifene exerts a CV benefit. A benefit for women with a
uterus is that raloxifene does not stimulate endometrial proliferation.
Raloxifene is not beneficial for hot flushes (and may induce these symptoms), [152] nor is it beneficial for
vaginal atrophy. Raloxifene may also induce leg cramps, although one study showed that this effect did
not cause participants to discontinue taking this SERM.[152] We do not know whether there are any
beneficial effects on the brain, such as the cognitive benefits associated with estrogen use, although
raloxifene does not appear to impair cognition or affect mood in postmenopausal women. [153] There is a
small increase in the risk for venous thrombosis with raloxifene, which is similar to that of tamoxifen.
Nevertheless, given that women have different needs, raloxifene remains an option for some women,
particularly those who are at high risk for osteoporosis or who have had breast cancer in the past and
are not bothered by hot flushes.
Phytoestrogens. Although human data are limited, certain phytoestrogens, particularly isoflavones,
might also be considered SERMs.[77] Although isoflavones have some positive effects on the brain,
bone, and the CV system, they may not have appreciable stimulatory effects on the breast or uterus.[154]
Soy-based estrogens have also been shown to be beneficial for hot flushes, although there is a strong
dose effect, with higher doses being required to achieve a statistically significant beneficial effect. As a
class, all phytoestrogens appear to have a greater affinity for ER-beta. This has particular relevance to
areas in the body that are rich in ER-beta, such as the brain and coronary arteries.
Hormone Replacement Therapy: Status in 1999
Whether or not HRT should be considered is a very individual decision, which must take into account
symptoms, risk factors, and individual preferences and needs. Alternatives should also be carefully
considered. If hormonal therapy is chosen, there should be flexibility in prescribing -- there is no ideal
regimen for every woman. It should be emphasized that the decision to use estrogen need not be a
long-term commitment. Estrogen can be used for short-term treatment of symptoms at the lowest
dosage that will adequately control hot flushes or vaginal dryness or dyspareunia. Ultimately, the results
of ongoing prospective trials will allow more data-driven decision making. I refer here to the anticipated
results of the Women's Health Initiative, for example, which should begin to be available in 2005.
Although it is my speculation that these results will not alter current recommendations, this study will
provide new and important data for us to reflect on to help our patients.
Women's Perception of HRT
At least 2 recent studies indicate that there are differences in the level of awareness of HRT that are
determined by race, educational level, and the perception of going or having gone through
menopause.[59,155] One study found that women selected or self-selected for long-term HRT use as a
whole tended to be healthy: they were thinner, younger, and physically more active; more were involved
in professional work; and more had oophorectomies and experienced earlier menopause than the
average postmenopausal woman.[156]
Many women express fear regarding HRT, especially because of the associated risk of breast cancer.
Although breast cancer risk is a real and serious concern for all women, this fear drives much decision
making, particularly regarding hormonal options. The decision analysis for HRT largely contrasts the
risks and mortality associated with CVD on the one hand and breast cancer on the other.
In the United States, many women believe that the leading cause of death in women is breast cancer
(Table 4).[157] Many also believe that only a small percentage of deaths are attributable to CVD. The
truth, of course, is the reverse. One in 3 women older than 65 years has some evidence of CVD, and
the risk of breast cancer after age 65 is 1 in 36.[158] Although it has been widely asserted that the
incidence of breast cancer in women is approximately 1 in 8 women, this is the lifetime risk. [158] Agespecific data are quite different, and the risk is 1 in 77 in the fourth decade, 1 in 42 in the fifth decade,
and 1 in 45 in the eighth decade (Table 5).[158] In terms of mortality, the case fatality rate of CVD is
several times greater than that of breast cancer; thus, even if the incidence rates of these 2 diseases
were similar, many more women would die of CVD. Figure 2 shows the mortality rates according to
different age groups.[158] Soon after menopause, at age 50-54, breast cancer mortality decreases while
CVD mortality rises steadily.[158] As noted in the figure, the leading cause of cancer death in
postmenopausal women is lung cancer. Overall, however, 30%-40% of women die of CVD, and by age
55, 20% of all deaths result from CVD.
Figure 2. Percentages of women who died of breast cancer, lung cancer, or
cardiovascular disease (including cerebrovascular causes) in Ontario in 1995,
according to age. For each group, the value is expressed as a percentage of the total
number of deaths among women in that age group. The proportion of deaths due to
breast cancer never exceeded 20%. Data were obtained from the Ontario Cancer
Registry. From Phillips KA, Glendon G, Knight JA. Putting the risk of breast cancer in
perspective. N Engl J Med. 1999;340:141-144. Reprinted with permission.
Table 4. Women’s Top Health Risks and Causes of Death
Perception
Reality
Breast cancer
46%
Heart disease 34%
Unspecified cancer
16%
Other cancers 12%
Heart disease
4%
Lung cancer
5%
AIDS
4%
Stroke
8%
Uterine/ovarian cancer 3%
Breast cancer 4%
Adapted from the Gallup Poll for Walnut Marketing Board, National Center for Health
Statistics, 1995.[157]
Table 5. Age-Related Risk of Breast Cancer

Of these factors, age is the
most
significant, with the risk
being
greatest for women in their
70s.

Number of women who will develop breast
cancer
o During their 30s: 1/250
o During their 40s: 1/77
o During their 50s: 1/42
o During their 60s: 1/36
o During their 70s: 1/34
o During their 80s: 1/45
Adapted from N Engl J Med. 1999;340:141-144.[158]
Risk/Benefit Assessment of HRT
HRT is indicated for the relief of vasomotor symptoms associated with menopause, treatment of vaginal
atrophy, and prevention and treatment of osteoporosis. HRT may be prescribed for short-term relief of
symptoms, but clinicians should be prepared to discuss with their patients the use of HRT for long-term
prophylaxis -- not only as protection against osteoporosis but also as potential protection against CVD,
cognitive decline, and Alzheimer's disease. These long-term benefits are sustained as long as HRT is
prescribed; the benefits decrease after cessation of HRT.
The Benefits of HRT
Relief of Vasomotor Symptoms
It is well established that estrogen replacement provides relief from hot flushes. The questions
investigators are asking now relate to the most effective form of estrogen replacement. For example,
Simon and colleagues[159] recently compared estrogen-androgen therapy with estrogen-only therapy for
efficacy in relieving vasomotor symptoms. In their trial, 93 patients were randomized to receive 1 of 5
daily regimens for 3 months: oral CEE (0.625 mg or 1.25 mg), oral CEE combined with
methyltestosterone (0.625 mg and 1.25 mg or 1.25 mg and 2.5 mg), or placebo. These investigators
found that the extent of relief with the lower-dose estrogen-androgen treatment was similar to that
achieved with the higher-dose estrogen-only treatment. The data also suggested that 1.25 mg/day oral
CEE can produce a hypoandrogenic state because of the induced rise of sex hormone-binding globulin
(SHBG), which reduces the bioavailable testosterone. This may have implications for sexual function.
Currently, estrogen replacement is delivered orally or transdermally; both means have disadvantages,
including variable bioavailability, intestinal and hepatic first-pass effects (oral), and dermatologic
reactions (transdermal). Studd and coworkers[160] studied the efficacy and acceptability of intranasal E2
(S21400), which was designed to bypass these drawbacks. In a 3-month, double-blind study, 420
women were randomized to receive 1 of 4 daily dosage regimens of intranasal S21400 (100, 200, 300,
or 400 mcg), intranasal placebo, or oral E2 valerate (1 or 2 mg). The incidence of hot flushes decreased
by 75% with 200 mcg/day S21400 at 4 weeks. Except for a greater incidence of sneezing and
application-site reaction (99% mild or moderate), there were no significant effects on ear, nose, or throat
function or adverse events, compared with placebo and oral E2. Overall, the study found that intranasal
E2 was significantly more effective than placebo and about as effective as oral E2 in relieving
menopausal symptoms and was well tolerated. Another recent study showed that intranasal E2 (300
mcg/day) normalized bone turnover to premenopausal levels within 3 months. [161] Thus, it appears that
we may have a new option for HRT, one that avoids first-pass metabolism and provides a reproducible
and easily adjustable dosing mechanism.
Of note are recent findings that women who have no vasomotor symptoms when they begin HRT do not
develop such symptoms when treatment is first instituted and then abruptly stopped after 3 months. [162]
This may be useful information for a clinician to provide a patient who is undecided about whether to
begin HRT when she is not experiencing vasomotor symptoms.
Prevention and Treatment of Osteoporosis
Estrogen replacement clearly decreases bone turnover and prevents postmenopausal bone loss. A
dosage regimen equivalent to 0.625 mg/day oral CEE reduces the risk for osteoporosis and fractures by
30%-60% (RR 0.4-0.7).[163]
Estrogen delivered transdermally is also effective in preventing bone loss in postmenopausal women.
Data from a recent randomized, controlled trial showed that transdermal E2 at a dosage as low as 0.025
mg/day is effective.[164] However, a slightly higher dosage (0.05 mg/day) produced larger increases in
mean BMD of the lumbar spine and total hip. This result was corroborated in a 2-year randomized,
controlled trial of a matrix transdermal E2 delivery system. [165] The most frequent adverse effects in both
studies were local reactions attributed to the delivery system, side effects of estrogen, and menopausal
symptoms.
Although HRT reduces the risk for osteoporotic hip fractures, are there other factors that modify this risk
reduction? Michaelsson and coworkers[166] addressed this question in a population-based case-control
study conducted in Sweden. They found a significant relation between HRT and both weight and
physical activity (P = .05). The protective effect of HRT was most pronounced in lean women and in
women with low recent leisure physical activity (< 1 hr/wk), indicating that HRT is most protective
against hip fracture in high-risk women.
A positive correlation exists between systemic osteoporosis and oral alveolar bone resorption.[167,168]
(Alveolar bone in the maxilla and mandible provides the framework for tooth support.) Estrogen
replacement reduces oral alveolar bone loss, increasing the probability of better tooth retention in
postmenopausal women.[168] HRT has also been associated with reduced gingival inflammation and
progression of periodontitis in osteopenic/osteoporotic women in early menopause. [169]
However, Orwoll and Nelson[170] caution us not to consider HRT the end of osteoporosis management
for postmenopausal women. Low bone mass and fractures are serious threats in older women, even
those taking HRT. The National Osteoporosis Foundation has recommended that older women undergo
BMD testing, regardless of estrogen status.[171] Women on HRT who have low BMD require further
therapeutic attention, with the aim of further reducing fracture risk. For example, the addition of a
bisphosphonate to the HRT regimen may be appropriate. In fact, our recent work has suggested a
synergism between HRT and alendronate. In postmenopausal women with low bone mass in spite of
being on HRT for at least 1 year, the addition of alendronate (5 mg/day) to HRT produced significant
increases in the BMD of lumbar spine (2.7% vs 0.5 % for women taking HRT only, P < .001) and hip
trochanter (1.7% vs 0.8%, P < .001) after 1 year of treatment.[172] The change in BMD at the femoral
neck, however, was not significantly different between the 2 groups.
Biochemical markers of bone turnover also decreased significantly with the addition of alendronate and
remained within premenopausal levels. In this study,[173] which enrolled 428 women, the addition of
alendronate to the HRT regimen was generally well tolerated. In particular, gastrointestinal side effects
were not significantly different between the 2 groups. This study corroborates results of an earlier study
showing the additive effect of etidronate on hip and spine BMD in postmenopausal women with
established osteoporosis.
The addition of fluoride to HRT regimens is also under investigation. In an 8-month, randomized,
placebo-controlled study,[174] women assigned to HRT plus monofluorophosphate (equivalent to fluoride,
20 mg/day) had a significant increase in spine BMD during treatment compared with women on HRT
alone (11.8% vs 4.0%, P < .05). The decrease in markers of bone formation was also more pronounced
in the HRT plus fluoride group. Adverse events were reported to be rare and mild when they occurred.
Reversal of Urogenital Atrophy
With estrogen treatment, vaginal cytology can change from a profile of predominantly parabasal cells to
one with an increased number of superficial cells.[175] Along with this change, vaginal pH decreases,
vaginal blood flow increases, and the electropotential difference across the vaginal mucosa increases to
premenopausal levels. Estrogen delivery by the vaginal route is most effective for treatment. [176] The
17beta-E2-releasing ring, which delivers 2 mg/day E2 over 12 weeks, is safe and effective and is
associated with high compliance because of its ease of use. [177-179] The E2-releasing ring decreases
vaginal epithelial pH, induces maturation of vaginal and urethral mucosal cells, prolongs the time to
recurrence of urinary tract infection, and decreases the frequency of urinary tract infection. [178,179]
Cardiovascular Disease Prevention
On the basis of accumulated epidemiologic data, HRT is estimated to reduce the occurrence of CVD,
and possibly cerebrovascular disease, by 25%-50% compared with no treatment.[180,181] This protective
effect of estrogen is partly due to improvements in cholesterol metabolism, which have been estimated
to account for about 25% of estrogen's beneficial effect.[181] New data suggest that HRT enhances
postprandial lipid metabolism[182] and inhibits lipid peroxidation..[183] Estrogen raises HDL-C by about
10% and lowers LDL-C by about 10%.[184] Estrogen may also positively influence carbohydrate
metabolism, atheroma formation, and cardiovascular hemodynamics. [180,181] Estrogen restores
endothelial function, increases cardiac output, increases arterial flow velocity, decreases vascular
resistance, and decreases systolic and diastolic blood pressure. [181] Quantitative ultrasound studies of
carotid atherosclerosis in women who have used HRT compared with nonusers showed that HRT users
developed less severe disease, an effect the investigators suggest may be due to direct hormonal
effects on the carotid wall and indirect influence of the hormones on lipoproteins. [185]
In addition, estrogen may favorably affect fibrinolysis and reduce plasma fibrinogen to premenopausal
levels,[181] although one study reported no differences in fibrinogen levels after treatment with oral or
transdermal estrogen for 6 months.[186] However, the investigators of this study did find that oral
estrogen plus progesterone significantly reduced the level of plasma-soluble intracellular adhesion
molecule 1, a marker of vascular inflammation.. On the other hand, the Postmenopausal
Estrogen/Progestin Intervention (PEPI) investigators[187] found that HRT rapidly increases the level of
inflammation factor C-reactive protein while reducing the soluble E-selectin level (a possible antiinflammatory effect). As pointed out by these investigators, such data underscore the need to study the
effect of HRT-mediated changes in inflammation on the risk of subsequent coronary events.
Elevated plasma total homocysteine levels are a significant risk factor for CVD, and most recently, van
Baal and colleagues[188] reported the results of 12-week study showing that HRT significantly reduced
fasting homocysteine concentrations in postmenopausal women. In this placebo-controlled, randomized
study, 59 postmenopausal women were assigned to 1 of 3 daily regimens: (1) sequentially combined
E2, 2 mg, plus either trimegesterone, 0.5 mg, or dydrogesterone, 10 mg; (2) unopposed E2, 2 mg; or (3)
placebo. The fasting plasma total homocysteine levels decreased in both HRT groups but was greater
for the estrogen-progestin group (9.4% vs 5.1%); women with elevated baseline levels of homocysteine
had the greatest reductions in plasma homocysteine concentration. In women receiving placebo, on the
other hand, the plasma total homocysteine concentration increased 2.4%.
Central body fatness and insulin resistance also increase the risk of CVD. Most interventional studies
indicate that HRT attenuates the accumulation of central body fat in postmenopausal women compared
with control or placebo-controlled women.[189] Oral estrogen increases insulin sensitivity, but oral CEE
doses of more than 0.625 mg further increase insulin resistance.[190] Higher doses of transdermal
estrogen do not have this effect.[191] Although estrogen replacement increases insulin sensitivity in
postmenopausal women, estrogen-progestin regimens may decrease insulin sensitivity. This was
suggested by a series of studies from one group.[190,191] The progestin effect is related to the type and
dose of progestin. In our studies, the addition of 10 mg medroxyprogesterone acetate (MPA) to the
regimen decreased insulin sensitivity.[190,191] A small randomized, double-blind, placebo-controlled trial
assessed the effect of HRT (continuous combined E2, 2 mg/day, and norethindrone acetate (NETA) at
high [1 mg/day] and low [0.5 mg/day] dosages) on insulin sensitivity. The investigators found that over a
period of 3 months, low-dose continuous E2/NETA did not change insulin sensitivity in postmenopausal
women. The data for the high-dose regimen were not conclusive but suggest that a modest decrease in
insulin sensitivity may occur.[192] Another study investigating the effect of transdermal E2 (50 mcg/ day
continuously for 6 months) with and without intrauterine levonorgestrel (20 mcg /day) showed that
transdermal E2 alone improved insulin sensitivity by 22%, whereas the combination reduced this effect
to 3.6%.[193] However, it should be noted that another group of investigators found that transdermal E2
did not significantly increase insulin sensitivity after 6 weeks of treatment, and the addition of oral
norethisterone (1 mg/day) for a further 6 weeks had no detectable effect on insulin sensitivity.[194] Thus,
the effect of HRT on insulin sensitivity is not established.
The only large randomized clinical trial on the benefit of HRT in CVD, the Heart and Estrogen/progestin
Replacement Study (HERS), found no overall effect of HRT on secondary prevention of CVD in
postmenopausal women with established CVD treated for 4 years (RR = 0.99, CI = 0.80-1.22).[112] HRT
was associated with more secondary cardiac events compared with placebo in the first year of treatment
and with a significant trend for fewer events in the fourth and fifth years of treatment. Thus, although
there is significant evidence that HRT is protective in postmenopausal women in the primary prevention
of CVD, further large-scale studies of HRT in women with established CVD are warranted, especially
with other HRT regimens.[181,195-198]
Although at face value the results of HERS are not consistent with our knowledge of estrogen's action
on the CV system and the many observational studies showing estrogen's benefit, it is premature to rely
only on the results of HERS. This was an older cohort of women (mean age, 67 years) with significant
CVD. All women received the standard care (eg, statins and diet modification), and HRT may not be
able to improve on results obtained with this care in the first 2 years of treatment. A significant variable,
however, is that the HRT regimen that was used in this study consisted of a fixed combination estrogen
and progestin, and there was no comparison group taking estrogen alone. Because progestins are
known to attenuate the benefit of estrogen on the CV system, we cannot exclude the possibility that
estrogen alone could be beneficial. At this time, what we have really learned from HERS is that in older
women with severe CVD, a fixed estrogen-progestin regimen should not be prescribed with the notion
that it will improve the patient's condition in the short term. Nevertheless, women who are already on
HRT should continue with the regimen, because there appears to be a protective effect of HRT on the
CV system after the first few years of use.
Finally, it is still unclear whether HRT prevents stroke in older women; a recent study of older,
postmenopausal, community-dwelling women with a high rate of past or current HRT found no
conclusive evidence that HRT prevented stroke, but the confidence intervals in this study were wide. [199]
Other studies that included cohorts of older women have shown that estrogen replacement is associated
with a reduction in stroke mortality as well as stroke incidence.[108,200]
Dr. A. Pines and colleagues[201,202] of Ichilov Medical Center, Tel Aviv, Israel, presented new data on the
angiotensin-converting enzyme inhibitor moexipril at the Third International Workshop on Hypertension
in Postmenopausal Women, held in Rome, October 1999. Results from their ongoing multicenter trial,
Moexipril as Antihypertensive Drug After Menopause (MADAM), which involves more than 3400 women
with mild to moderate hypertension, indicate that moexipril is safe and effective for both users and
nonusers of HRT. To date, this is the largest controlled study of an antihypertensive agent enrolling only
postmenopausal women.
Improvement in Mood and Cognitive Function
Understanding the effects of sex steroids on the brain is emerging as the new frontier in research in
menopause.[203-214] A large body of basic research has definitively demonstrated a positive effect of
estrogen on neuronal function (eg, growth, survival, synaptic activity). [215-219] Estrogen has also been
shown to decrease brain amyloid content and increase cholinergic activity, [220] which is relevant to
Alzheimer's disease risk in women. Because most of these effects are mediated by ER-alpha and ERbeta, they are generally (but not always) opposed by progestins.
Estrogen has a positive effect on mood, memory, and quality of life scales, [31,33,221-228] whereas
progestins may attenuate some of these effects. The effect of estrogen on short-term memory and
cognition has been incompletely studied.[222,227,229-233] Although many studies have shown that estrogen
has a beneficial effect, the data are not consistent. Some of this lack of consistency may have to do with
the instruments used to assess the effects.[233] For example, estrogen appears to have a more beneficial
effect in verbal domains yet not in other areas, such as numerical or spatial domains. In addition,
instruments that test all performance domains may not be sensitive enough to demonstrate a positive
effect on verbal memory.
The data on estrogen reducing the risk of Alzheimer's disease, however, are remarkably consistent (RR,
0.4-0.6) among case-control and cohort studies.[29,234-244] This reduced risk also appears to be greater
with longer duration of estrogen use. Such benefit has been reported for both oral and nonoral estrogen
formulations. No data exist, however, as to the effect on the risk profile of adding progestin.
Although estrogen appears to have a protective effect on the development of Alzheimer's disease, it is
not central to the pathophysiology of the disease, and estrogen is not expected to be involved in the
pathogenesis. Accordingly, the data on the effects of estrogen in the treatment of Alzheimer's disease
are inconsistent and somewhat disappointing.[245-253] Whereas there are several studies indicating that
estrogen retards the progression of Alzheimer's disease (in terms of the mental score), the disease
remains progressive.
The Risks of HRT
HRT is not without risks, including endometrial disease, breast cancer, vaginal bleeding, somatic
complaints (eg, breast soreness), and idiosyncratic reactions (eg, hypertension and venous thrombosis).
Idiosyncratic Reactions
Hypertension, venous thrombosis, and allergic manifestations have been observed in users of estrogen,
particularly oral estrogen. Hypertension with estrogen use, the cause of which is not entirely clear,
occurs in about 5% of oral contraceptive users. Estrogen usually causes no change in blood pressure; it
may actually reduce blood pressure, a finding that has relevance for normotensive as well as
hypertensive women. In some women, however, HRT may increase both diastolic and systolic blood
pressure, but the elevation is rapidly reversible with discontinuation of HRT. Alterations in the route of
estrogen administration and dosage also may alleviate the problem of increased blood pressure in some
women.
Several observational studies indicate that oral estrogen replacement increases the risk of venous
thromboembolic events (VTEs).[254-256] The risk of VTEs was higher in the first year of treatment. There
did not appear to be a dose-response relation with estrogen, and there was no significant difference
between opposed and unopposed regimens with respect to risk for VTE. In addition, VTEs did not
increase mortality. A pooling of data from 7 case-control studies between January 1982 and January
1997 revealed an RR of 2.1 (95% CI, 1.4-3.0) for venous thromboembolism in current users compared
with nonusers (never-users and past-users combined).[257] However, the real risk of an event appears to
be small. With the baseline rate of 11 cases per 100,000 women, a relative increase to 20-30 cases per
100,000 women is still less than half the cases observed in normal pregnancy (60 cases/100,000
women). On the basis of one cohort study, primary pulmonary embolism associated with HRT was
associated with an RR of 2.1 (95% CI, 1.2-3.8).
In women with a history of thrombosis, there is an increased risk of VTEs with estrogen administered
orally, a risk that is not easily identifiable except by reviewing the patient's history and by measuring
coagulation factors. Women who have a family history of thrombosis or had VTEs with oral
contraceptives or other prior estrogen use should be counseled very carefully and monitored closely.
Nonoral estrogen is a consideration for these patients and can be used judiciously.
Vaginal Bleeding
One of the greatest concerns of women taking HRT is the return of vaginal bleeding. Somatic
complaints such as breast tenderness and bloating may also occur but can be alleviated by alterations
in dosage and type of preparation. Such concerns should be discussed with the patient, and the choice
of regimen should remain flexible. It is important for the clinician to know the expected vaginal bleeding
pattern for a given HRT regimen, as unexpected bleeding may be a sign of endometrial hyperplasia. [258]
Unscheduled bleeding in any postmenopausal woman should be investigated regardless of results of
ultrasonographically determined endometrial thickness, because abnormalities may be present when
the endometrial thickness is less than 4 mm.[259]
Recurrent bleeding during sequential HRT regimens causes many patients to stop treatment.
Endometrial ablation, a minimally invasive procedure, appears to be one method of treating women with
recurrent bleeding disorders without intrauterine causes. A small study showed that after endometrial
ablation, combined continuous HRT could be instituted with high compliance. [260]
Endometrial Disease
Endometrial disease occurs with unopposed estrogen therapy in women who have a uterus. A woman's
risk of developing endometrial cancer with unopposed estrogen use is 2- to 8-fold higher than that for
the general population.[261] However, the risk of varying degrees of endometrial hyperplasia is greater
than that for endometrial cancer. One study showed that the risk of endometrial hyperplasia was 20%
after 1 year of use of oral CEE (0.625 mg/day).[262] In the PEPI Trial, this risk was approximately 40% at
the end of 3 years.[263] No cancers were reported in either of these studies, and the addition of a
progestin essentially eliminated the hyperplasia.
It is generally held that the addition of a progestin eliminates the excess risk for endometrial cancer
induced by estrogen. Evaluation of a continuous combined transdermal delivery system containing E2
(50 mcg/day) and NETA (140 mcg/day) showed that it effectively prevented endometrial hyperplasia
while reducing the mean number of hot flushes to fewer than 1 per day. [264] As a cautionary note, at
least 2 reports suggest that other regimens may not prevent endometrial hyperplasia. Gruber and
colleagues[265] report cases of 2 women who developed endometrial cancer after taking continuous
sequential HRT for 15 months. Measurement of serum E2 levels in these women indicated that both had
supraphysiologic levels despite combination with cyclic progestin therapy. The Scandinavian Long Cycle
Study Group[266] reported that long-cycle HRT regimens (progestin administered for 12-week cycles of
estrogen administration) may also increase the risk of endometrial hyperplasia and eventually cancer
compared with conventional HRT on a monthly cycle.
Although the risk of developing endometrial cancer is increased significantly in estrogen-only users, the
risk of death from this type of endometrial cancer does not increase proportionately. Endometrial
cancers associated with estrogen use are thought not to be as aggressive as spontaneously occurring
cancers. However, it may be that tumors in women taking estrogen are more likely to be discovered and
treated at an earlier stage, thus improving survival rates.
Breast Cancer
Most controversial is the risk of breast cancer with HRT. In earlier calculations of HRT-related risk of
breast cancer, an RR of 1.1 was ascribed to all estrogen use, suggesting a 10% increase in risk relative
to no estrogen use.[104] Several meta-analyses have suggested either no significantly increased risk (ie,
RR ~ 1.0) or a risk as high as 1.6.[267,268] Recent analysis of 51 epidemiologic studies (including over
90% of the world's data), however, reveals a 2.3% increase of the RR for breast cancer for each year of
HRT use, which levels off after stopping use.[269] It has also been suggested that there is no additional
risk for women with a family history of breast cancer.[110] Admittedly, an increased surveillance bias
exists for women who see their doctors regularly. It is also possible that estrogen use causes breast
cancer to occur earlier in some women, but it is not clear which women are at greatest risk. Chiechi and
Secreto[113] have recently proposed a decision model for the calculation of breast cancer risk on the
basis of 7 risk factors: testosterone levels, BMI, waist-to-hip ratio, alcohol consumption, density to
mammography, previous benign disease, and family history.
Whereas short-term estrogen use (~ 5 years) is not associated with increased breast cancer risk,
controversy surrounds long-term estrogen use (> 10 years). The large epidemiologic study of long-term
HRT use and breast cancer risk, which was conducted in Sweden, demonstrated a trend of increasing
breast-cancer risk with duration of HRT use. The increase was statistically significant for women with a
BMI lower than 27 kg/m2.[270] The odds ratio for women treated at least 10 years was 2.43 (95% CI,
1.79-3.30) compared with never-users. The investigators also noted that the positive association was
especially pronounced with continuously combined estrogen-progestin combinations.
The Iowa Women's Health Study, an 11-year prospective cohort study, assessed HRT and the risk of
the various types of invasive carcinoma: ductal carcinoma in situ (DCIS), invasive carcinoma with a
favorable histology, and invasive ductal or lobular carcinoma.[271] Ever-HRT use was associated with an
RR of 1.81(95% CI, 1.07-3.07) of invasive carcinoma with a favorable histology for HRT use fewer than
5 years; the RR rose to 2.65 (95% CI, 1.34-5.23) for HRT use longer than 5 years. This study found no
association between ever-HRT use and the incidence of DCIS or invasive ductal or lobular carcinoma.
Breast cancer-related mortality, paradoxically, has not consistently been shown to increase with HRT;
indeed, there are data to suggest that it may be lower among estrogen users. For example, Jernstrom
and coworkers[272] discovered that among 984 women with diagnosed breast cancer, those who had
previously used HRT had a significantly longer survival overall than those who had never used HRT.
After adjustment for T-stage, N-stage, M-stage, year of diagnosis, and age at diagnosis, the RR of dying
was 0.78 (95% CI, 0.65-0.93; P = .006). ER-positivity was also independently significantly associated
with overall longer survival (P < .0001), and Cobleigh and coworkers[273] discovered that HRT appears to
stimulate the growth of ER-positive but not ER-negative breast cancer. The prognostic significance of
this latter result, however, is not known.
Also of note is a study of the clinical and biological characteristics of breast cancers in postmenopausal
women who had been taking HRT before breast cancer diagnosis.[274] Salmon and colleagues found
that in 129 women with operable breast cancer who had been on HRT for at least 6 months before
diagnosis, the cancers were smaller than in reference patients and were diagnosed radiologically more
often. In a second group of 420 postmenopausal women with breast cancer analyzed for biologic and
pathologic information, those who had been on HRT tended to have cancers of grade I and seldom had
grade III cancers. Although these data suggest that HRT may be associated with a less aggressive
phenotype for breast cancer, it is not yet clear whether these findings are a consequence only of earlier
detection.
In summary, for moderate doses of estrogen, the risk of breast cancer is probably in the range of 20% to
30% in those women who are susceptible. Unfortunately, such women cannot be identified before
therapy is initiated; thus, evaluation of known risk factors is crucial. Clinicians must also be aware that
HRT reduces mammographic sensitivity,[275,276] because breast parenchymal cell density increases in
some women on HRT.[277] Recent trends in prescribing support lower dosages of estrogen for long-term
use, because dose, in addition to duration, is associated with risk.
HRT in the Context of Disease
An important issue is whether HRT can be prescribed for postmenopausal women who have been
treated for cancers (eg, breast and gynecologic cancer) or who have autoimmune diseases (eg,
systemic lupus erythematosus [SLE] and multiple sclerosis [MS]) or other diseases associated with
aging (eg, osteoarthritis [OA] and Parkinson's disease [PD]) or other chronic conditions (eg, diabetes
and epilepsy). No prospective studies with a large number of patients and a long treatment period have
addressed this question.
Gynecologic Cancer
Burger and colleagues,[278] however, have reviewed available studies of HRT in women treated for
gynecologic malignancies. With respect to endometrial cancer, they conclude that HRT might be used in
women with endometrial cancer stage I or II without increasing the risk for disease recurrence or death,
although the claim can only be made on the basis of circumstantial evidence. They also state that HRT
probably does not affect squamous cell cancers of the cervix, vulva, and vagina, and they found no
evidence that HRT adversely influences survival after treatment for ovarian cancer. However, an Italian
research group also reanalyzed the relation between HRT and ovarian cancer and found that data from
4 European case-control studies indicated a weak promoting effect of HRT in ovarian carcinogenesis.
These investigators allow that the association may reflect selective administration to high-risk
individuals.[279] As for any woman, the decision to prescribe HRT for a woman who has been treated for
gynecologic cancer must be made on the basis of her medical history (and family medical history).
Breast Cancer
It has been estimated that the number of breast cancer survivors in the United States may approach 2.5
million.[280] Moreover, because breast cancer is being detected at an earlier age and adjuvant
chemotherapy can cause ovarian failure, the number of women becoming menopausal at a younger age
after breast cancer treatment is increasing.[280] Given that the risk of suffering a recurrence will be low
for a large percentage of these women, should they consider HRT? At least 1 prospective study of HRT
after localized breast cancer indicates that HRT does not seem to increase breast cancer events. [281]
However, the most reasonable course of action for women who have been treated for breast cancer and
who have menopausal symptoms is to treat the symptoms with alternative therapies. Diet and exercise
are effective for prevention of CVD; weight training and the addition of bisphosphonates or SERMs (eg,
tamoxifen and raloxifene) can reduce the risk for osteoporosis. Certain dosages of progestins can
alleviate hot flushes, although many oncologists believe that use of any sex steroids is contraindicated.
Nevertheless, in those breast-cancer survivors who choose HRT,[282] the lowest effective doses should
be used, and these women must be monitored carefully.
Diabetes
Postmenopausal women with diabetes are at increased risk for CVD. The risk factors for CVD in women
with diabetes are similar to those in nondiabetes, but hypertriglyceridemia appears to be a significant
independent risk factor.[283] Low HDL-C, elevated triglycerides, and a small, dense, more atherogenic
LDL particle comprise dyslipidemia in diabetes. Dyslipidemia together with hemodynamic (hypertension)
and metabolic abnormalities (increased platelet aggregation and PAI-1 levels) increase the CVD risk in
diabetic women.[283] Low to moderate doses of estrogen increase insulin sensitivity, and, therefore,
should be beneficial for patients with type 2 diabetes. Several studies suggest that HRT decreases the
CVD risk in diabetic postmenopausal women.[284-286] In this setting, a nonoral estrogen may be
preferable, particularly if hypertriglyceridemia is present. Again, however, larger prospective trials are
required to definitively determine the effect of estrogen on CVD.
Systemic Lupus Erythematosus
The relative benefit/risk ratio of HRT in women with SLE has not been established. Postmenopausal
women with SLE are at a 10-fold higher risk for myocardial infarction than age- and sex-matched
controls, and the prevalence of nonfatal CVD is 5%-8% in patients with SLE.[287] In addition, the risk for
osteoporosis is elevated by menopause (which may be induced by cyclophosphamide) and glucorticoid
use. A recent study showed that fracture occurrence was 5-fold higher in women with SLE compared
with women in the US population.[288] The Safety of Estrogen in Lupus Erythematosus National
Assessment (SELENA) Trial, begun in 1997, is studying the severe and mild-moderate disease flare
rates in women treated with CEE and medroxyprogesterone acetate (MPA). One small study found no
significant increase in the rate or magnitude of flares in women who received HRT over 35 months,
leading the investigators to conclude that HRT appeared to be well tolerated and safe in this group of
postmenopausal women with SLE.[289]
Multiple Sclerosis
A pilot study of the effects of menopause and HRT in women with MS showed that MS symptoms can
worsen with menopause (which occurred in at least half of the 19 women involved in the study) and that
HRT can alleviate the worsening of symptoms.[290]
Osteoarthritis
After menopause, the prevalence of OA dramatically increases, but whether estrogen deficiency is
responsible is not known. A variety of study designs have produced data suggesting that estrogen
replacement is protective against OA.[291-294] However, one study showed that an increased risk for OA
resulted with short-term HRT.[295] Most recently, a longitudinal study that examined the association
between HRT use and the incidence of self-reported, physician-diagnosed OA found that HRT users
were at a higher risk of developing OA; the longer the use, the higher the risk. [296]
Parkinson's Disease
Estrogens are thought to be associated with either a detrimental antidopinergic effect or a
prodopaminergic effect in patients with PD, depending on the study. [297,298] Two recent studies, however,
suggest that HRT may be beneficial in PD. The first, a retrospective chart review, found a positive
association between estrogen use and symptom severity in women with early PD not yet taking Ldopa.[297] The second was a double-blind, placebo-controlled, 2-arm crossover, short-term study of highdose transdermal 17beta-E2 (0.1 mg/day) therapy in 8 postmenopausal women with mild to moderate
disease; 7 women exhibited levodopa-induced dyskinesias. After 10 days, a significant reduction
occurred in the antiparkinsonian threshold dose of IV levodopa, and no worsening in "on" time or motor
ratings occurred. The study suggests that E2 displays a slight prodopaminergic (antiparkinsonian) effect
without consistently altering dyskinesias. The investigators suggest that standard transdermal HRT with
E2 may be well tolerated by many women with PD.[298]
Epilepsy
There have been no retrospective or prospective published studies of the effect of menopause on
epilepsy.[299] A report on a questionnaire survey of female members of the British Epilepsy Association
stated that 29% of women who had taken HRT in the past reported an increase in seizure frequency,
compared with 18% among current users.[300]
Hormonal Regimens
The aim of HRT is to provide estrogen "replacement" in a fashion that is as physiologic as possible.
Follicular phase levels of serum E2 during the normal menstrual cycle range from 40-100 pg/mL.
Threshold levels of E2 for achieving benefit for osteoporosis and CVD are in the range of 50-60 pg/mL
for most women. Nevertheless, any increment of estrogen levels above baseline is expected to exert a
significant effect.
CEEs are a mixture of at least 10 conjugated estrogens derived from the urine of pregnant mares.
Estrone sulfate is the major component, but the biological activities of equilin, 17alpha-dihydroequilin,
and several other B-ring estrogens, including delta8-9 dihydroestrone, have been documented. A
formulation of synthetic conjugated estrogens derived from soy and yam is also available. Table 6 lists
the standard dosages of the most frequently prescribed oral estrogens and the levels of E1 and E2
achieved.
Table 6. Mean Serum Estradiol and Estrone Levels Achieved With Estrogen Replacement
Regimens
Level (pg/mL)
Estrogen Dose (mg)
Estradiol Estrone
Conjugated equine estrogens (0.3)
18
76
Conjugated equine estrogens (0.625) 39
153
Conjugated equine estrogens (1.25)
220
60
Micronized estradiol (1)
35
190
Micronized estradiol (2)
63
300
Estrone sulfate (0.625)
34
125
Estrone sulfate (1.25)
42
220
Note: Conjugated equine estrogens contain biologically active estrogens other than
estradiol and estrone.
Synthetic estrogens, administered orally, are vastly more potent than conjugated estrogens. Standard
dosages of ethinyl E2 used in HRT are at least 5 times lower than those used in oral contraceptives.
Ethinyl E2, 5 mcg/day, produces effects equivalent to those of standard HRT dosages of CEE (0.625 mg
/day) or micronized E2 (1 mg/day).
Oral estrogen has a potent hepatic -- "first-pass" -- effect that results in both the loss of approximately
30% of its activity and the stimulation of hepatic proteins and enzymes. Although this stimulation
increases the levels of procoagulation factors (not a beneficial effect), it also increases HDL-C and
decreases fibrinogen and PAI-1 levels (beneficial).
Nonoral estrogen delivery bypasses the major hepatic affects associated with oral administration. E2
may be administered in patches, gels, and rings, as well as subcutaneously (implants or injections);
nasal sprays are under investigation. Standard dosages of alcohol-based or matrix patches deliver 0.05
or 0.1 mg daily. Lower-dose patches that deliver 0.025 mg/day are also available for administration once
a week or twice a week. Matrix patches are preferable because there is less skin reaction and estrogen
delivery is more reliable. In addition, levels of E2 achieved with transdermal therapy are more consistent
than those achieved with oral HRT in individual women. With the 0.05-mg patch, E2 levels of 40-50
pg/mL are achieved; with the 0.1-mg patch, levels typically reach 70-100 pg/mL. It is not unusual,
however, for some women to have levels in excess of 200 pg/mL. Note that with oral and transdermal
methods, estrogen is administered continuously, although it is still acceptable to consider a cyclic
regimen (eg, a 25-day regimen).
For women with vulvovaginal or urinary symptoms, vaginal therapy is most appropriate. Creams of E2 or
CEE are available. Systemic absorption occurs, but at levels one fourth of that achieved after similar
milligram doses administered orally. In addition, the more estrogenized the mucosa, the lesser is the
degree of absorption. With CEE, dosages ranging from 0.15-0.625 mg/day (0.25-1 g cream) are
sufficient; for micronized E2, dosages as low as 0.25 mg/day are sufficient. Other products that have
been designed to limit systemic absorption are also available. For example, a silicone vaginal ring
delivers E2 (2 mg) to the vagina for 1 month with only minimal systemic absorption.
The Progestogen Question
One of the frontiers in this field is how to adequately "oppose" the proliferative effects of estrogen on the
endometrium with a progestin yet avoid potentially harmful effects. For some women, progestin
treatment dampens enthusiasm for estrogen use. Progestins induce bleeding and premenstrual
syndrome-like symptoms and attenuate some of the CV benefits of estrogen. The attenuating effects are
primarily alterations in HDL-C (total cholesterol and LDL-C are not affected), blood flow, and
vasomotion.[301] The addition of progestin interferes with the improvement in stress reactivity with
estrogen and may also affect carbohydrate metabolism. Although unproven, it is plausible that the lack
of secondary CV protection in the HERS trial[302] was attributable to the initial use of a fixed combination
of estrogen and progestin (ie, MPA) in older women with compromised CV function. It has also been
noted that the antiestrogenic properties of MPA may also have contributed to the results obtained in
HERS.[303] My personal preference has been not to use a fixed combination or high dosages of
progestins in women with CVD.
To counter some of these concerns, various progestin preparations have been studied. Data from the
PEPI trial,[304] which only used surrogate end points of CV function, suggest that oral micronized
progesterone (200 mg/day) is more beneficial in terms of the HDL-C profile. Also, vaginal formulations
enhance uterine delivery while minimizing systemic effects. For example, a transdermal progesterone
cream has been evaluated for its efficacy in controlling vasomotor symptoms and bone loss.[305]
Although this formulation was not protective against bone loss, it did relieve vasomotor symptoms
compared with placebo (P < .001). Specifically, targeting the uterus with a progesterone intrauterine
device (IUD) has also been studied,[306] and newer progestin IUDs for postmenopausal women will be
introduced in the next few years.[307] A new HRT formulation under clinical development consists of
trimegestone, a nonpregnane progestogen, and oral E2. [308] Finally, combinations of estrogen and
antiandrogenic progestins (eg, cyproterone acetate [309]) are also being evaluated as novel HRT
regimens.
Tibolone: Another Progestogenic Form of HRT
Tibolone, a synthetic steroid analogue, is a form of HRT that does not tend to induce bleeding. (Tibolone
is approved for use in many countries but not in the United States.) After ingestion and metabolism, the
progestogenic metabolite predominates, which produces an atrophic endometrium. One study has
shown that tibolone was effective in maintaining an inactive endometrium while providing
estrogenization of the lower genital tract over 6 years. [310] It has been suggested as a useful alternative
in women for whom the nonbleeding effect has appeal, and in women who have had hormonedependent tumors, endometriosis, or benign mastopathies or mammograms showing particular
density.[311-313] Recent data show that tibolone (2.5 mg/day) can safely relieve menopausal
symptoms.[314-317] Tibolone has also been shown to reduce bone resorption and increase lumbar spine
density and cortical bone mass.[317-319] Tibolone may also have certain cardioprotective effects. One
study showed that it decreases endothelin to levels similar to those achieved with estrogen. [320] Other
studies have shown that tibolone treatment is associated with a significant decrease in cholesterol,
VLDL, Lp(a), and triglycerides, but it also causes a reduction in HDL-C.[321,322]
Current Progestin Regimens
The most commonly used oral progestins for sequential regimens are MPA, 5-10 mg/day; NETA, 0.3-1.0
mg/day; and micronized progesterone, 100-300 mg/day. To prevent endometrial hyperplasia, equivalent
daily doses of progestin administered for at least 10 days in women receiving estrogen (equivalent to
0.625 mg/day CEE) are as follows: MPA, 5 mg; NETA, 0.7 mg; and micronized progesterone, 200 mg.
Larger doses are used in fixed combinations of estrogen and progestin. Larger doses of estrogen may
require both larger doses of progestins and more prolonged sequential regimens. With sequential
administration of progestins, the number of days (length of exposure) is more important than the
dosage. Thus, if a woman is receiving oral ERT continuously, a progestin regimen of at least 10-12 days
of exposure is preferable to a 7-day regimen.
When progestins are administered sequentially (10-14 days each month), withdrawal bleeding occurs in
about 80% of women. Continuous administration of both estrogen and progestin (continuous combined
therapy) was developed to achieve amenorrhea. In the first 3-6 months, breakthrough spotting and
bleeding are common. Some women on this regimen never completely achieve amenorrhea, and others
are particularly sensitive to this regimen. Although the endometrium is atrophic, a vascularity pattern
develops, probably induced by the local secretion of vascular endothelial growth factor. This leads to
continuous spotting and bleeding and is alleviated only by a change in the regimen; a continuous
combined regimen for only 25 days each month is an option.
In the United States, the most common estrogen-progestin combination is a single tablet containing
0.625 mg CEE and 2.5 mg MPA. A similar tablet with 5 mg MPA is also available. In other countries,
estradiol is often combined with NETA or levonorgestrel. Currently, the only marketed sequential
regimen is one that contains 0.625 mg CEE and 5 mg MPA, which is added for 14 days each cycle.
Compliance Issues With HRT
Bleeding is one of the most common reasons for discontinuance of HRT. Progestins may also cause
mood alterations. These side effects have to be dealt with effectively and usually require more flexibility
in prescribing habits. It would be prudent to use the lowest dose of progestin necessary to prevent
endometrial hyperplasia until more data are available. Except in rare circumstances (previous
endometrial cancer or recent diagnosis of endometriosis), progestins should not be prescribed in women
who have undergone hysterectomy.
Low-dose estrogen regimens may also improve compliance for long-term continuance of HRT. With
long-term use, low-dose estrogen can relieve vasomotor symptoms, prevent bone loss, and reduce the
risk of CVD while being less likely to cause irregular bleeding, heavy bleeding, or breast tenderness. [323]
One recent study showed that a transdermal system, delivering 0.025 mg/day of E2, relieved vasomotor
symptoms and was associated with less frequent estrogen-related adverse events, particularly irregular
bleeding and endometrial hyperplasia, compared with higher dosages. [324]
Menopause and Sexuality: Is There a Role for Androgen Therapy?
Few studies have comprehensively assessed the effect of menopause on sexuality. However, it is clear
that estrogen deficiency causes urogenital atrophy, which leads to reduced vaginal lubrication and
physical alterations that can affect sexual function. This in itself may lead to a decline in sexual interest,
but the ability to become sexually aroused may also be affected. [325] In a subtle way, postmenopausal
women become relatively androgen deficient; androgen deficiency contributes to reduced libido.
Clinicians have proposed adding androgen to HRT for complaints relating to sexual desire and arousal
and energy level. Although well-controlled trials with parenteral testosterone and estrogen have shown
benefit in younger women who undergo surgical menopause (almost complete elimination of hot
flushes, a healing effect, and increased libido and energy level), [326] there are few randomized clinical
studies of testosterone inclusion in HRT regimens that show any benefit, particularly in older women. As
newer formulations of androgen become available, perhaps more women may benefit from the addition
of androgen therapy. Androgen therapy should be individualized and considered for those women who
have symptoms that are not adequately relieved with traditional HRT. At lower doses, androgenizing
side effects are infrequent but should be discussed before prescribing testosterone. Currently, low
dosages of methyltestosterone (1.25 mg/day and 2.5 mg/day) added to esterified estrogens are
available in tablets. Testosterone patches are available for men and therefore require dose reductions
(achieved by cutting the patches) for use in women; a smaller patch designed for women is being
evaluated. Testosterone is also formulated as a subcutaneous pellet of 50-75 mg.
Although there is considerable unmonitored use of DHEA in the United States, it is currently not
recommended as a therapeutic option in menopause outside of clinical trials.[93] At least one
small 12-month trial of 10% DHEA vaginal cream suggests that DHEA may have beneficial
effects, without significant adverse effects, through the transformation of DHEA into androgens
and/or estrogens in specific peripheral intracrine tissues.[94] In this study, the endometrium
remained atrophic in the 14 postmenopausal women in the trial. Vaginal epithelium maturation
was stimulated, and there were significant increases in BMD at the hip and a marker of bone
formation. Further clinical trials are clearly warranted. Conclusions
Menopause is not a disease, but it does have serious clinical sequelae. It is imperative that any
intervention be effective for specific symptoms and/or risk profiles. It is incumbent on us as clinicians to
teach and guide our female patients through the menopausal transition so that they can enjoy a healthy,
active, and full postmenopausal life. We have witnessed an enormous outpouring of information on
menopause in 1999, but we still have much to learn. We are hopeful that in the third millennium, the
results of large prospective trials will further elucidate the effects of estrogen deficiency and that safe
and effective innovations will provide choice and flexibility in prescribing therapies for the short- and
long-term consequences of estrogen deficiency. In the meantime, we must work together with our
patients to help them decide on which therapies are appropriate for them, and we must consider that
such decisions may often be difficult. Not every woman will have the same response to a given therapy.
Therefore, it is important that clinicians be flexible in their prescribing patterns, whether it is for
traditional HRT or alternative approaches. Moreover, with time, a woman's needs change, so there is
never a need to make a long-term commitment to any one particular type of therapy.
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