Department of Obstetrics and Gynecology, The University
of Tokushima School of Medicine, Tokushima, Japan
Abstract:Hormone replacement therapy (HRT) is effective
for relieving vasomotor symptoms such as hot flash and vaginal
atrophy and for preventing bone loss in postmenopausal and
bilaterally ovariectomized women. However, compliance with
HRT was reported to be low despite the benefits of HRT.
In addition, results of several recent large-scale randomized
clinical trials have demonstrated that protection from cardiovascular
disease is not an indication for treatment with estrogen
and progestin in postmenopausal women.
Recent studies have demonstrated that low-dose HRT is safe
and effective for prevention of postmenopausal bone loss.
Low-dose HRT has also been shown to be effective for reducing
the number and severity of hot flashes, improving vaginal
atrophy, and inducing favorable changes in lipids, lipoproteins
and hemostatic factors. Moreover, low-dose regimens of CEE
(conjugated equine estrogen) and MPA (medroxyprogesterone
acetate) result in higher rates of amenorrhea and endometrial
protection compared with the conventional dose of HRT. Low-dose
HRT may improve the compliance rate and may be more effective
than conventional-dose HRT for reducing the risk of breast
cancer. On the other hand, it has been shown that transdermal
estrogen treatment reduces the incidence and severity of
hot flashes and that long-term treatment with transdermally
administered estrogen is effective for protection against
osteoporosis. Transdermal administration of estrogen is
recommended in postmenopausal women with hypertriglycemia
because this treatment has little effect on lipid metabolism.
The serum estradiol level was reported to be closely related
to estrogenic effects on various tissues. An HRT regimen
should be based on the needs of each patient. Serum estradiol
levels in women should be maintained at appropriate levels
for benefits and not be excessively high in order to prevent
side effects. Selection of the most appropriate regimen
of HRT (dose, route of administration and schedule) for
the needs of the individual are important factors to increase
the rate of continuation with HRT. J. Med. Invest. 50:136-145,
2003
Keywords:hormone replacement therapy (HRT), low-dose HRT,
transdermal estrogen, estrogen threshold
BENEFITS AND RISKS IN HRT
The effectiveness of estrogen replacement therapy (ERT)
for relief of vasomotor symptoms such as hot flash and vaginal
atrophy and for prevention of bone loss in postmenopausal
and bilaterally ovariectomized women is well established
(1-3). In postmenopausal women with hypercholesterolemia,
estrogen is effective for reducing the levels of total cholesterol
and low-density lipoprotein - cholesterol (LDL-C) and for
increasing the level of high - density lipoprotein - cholesterol
(HDL- C)(4, 5). Supplementation of estrogen was also demonstrated
to improve endothelium - dependent vasodilatation in postmenopausal
women due to augmentation of nitric oxide production (6).
In addition, estrogen was reported to be associated with
reduced risk of Alzheimer's disease (7). In women with an
intact uterus, treatment with estrogen and progestin as
hormone replacement therapy (HRT) is needed to reduce the
incidence of endometrial hyperplasia observed with unopposed
estrogen and to reduce the risk of endometrial cancer.
In USA and several countries in Europe, more than30%of postmenopausal
women are receiving HRT. However, compliance with HRT has
been reported to be low despite the various benefits of
HRT. Many studies have shown that a large percentage of
postmenopausal women receiving HRT discontinue treatment
within5years. Thorp et al. reported that only42%of new HRT
drug users continuously took HRT drugs during the first
year (8). Ettinger et al. demonstrated that the probability
of continuation in older women aged65years or older was
only 38% after 12 months treatment (9). MacLennan et al.
reported that the ratio of current and past use of HRT drugs
in South Australian women was 50 to 60% (10). In addition,
the rate of long-term compliance was shown to be lower.
Purdie reported that only 48% of women who started HRT were
continuing2years later (11). Coope et al. reported that
only 15% of women had continued HRT for over5years (12).
The most common reasons for discontinuation of HRT have
been reported to be side effects such as uterine bleeding,
breast tenderness, fear of cancer and anxiety about thrombosis
(9, 13).
In Japan, the total sales of estrogen products have increased
threefold over the past decade. However, the percentage
of postmenopausal women receiving HRT is still smaller than
the percentages in Europe and USA. In the Department of
Obstetrics and Gynecology of Tokushima University Hospital,
the rates of compliance with HRT after one, three and five
years in postmenopausal and bilaterally ovariectomized women
treated with HRT were 65.4%, 48.5% and 36.9%, respect-ively
(14). The compliance rate was significantly lower in women
with an intact uterus than in hysterectomized women. In
addition, the rate of early discontinuation of HRT was high
; 43% of the women discontinued HRT after only one visit
to our out-patient clinic. Anxiety about HRT and no relief
of symptoms were the major reasons for stopping HRT in the
first year after beginning HRT, while the percentage of
women who discontinued HRT due to side effects such as unacceptable
uterine bleeding and breast tenderness increased after one
year of HRT.
REPORTS OF THE WOMEN'S HEALTH INITIATIVE
Several recent large - scale randomized clinical trials
such as the Heart and Estrogen/Progestin Replacement Study
(HERS) and the Estrogen Replacement and Atherosclerosis
(ERA) trial have shown that there is no apparent benefit
of HRT for risk of atherosclerosis and that protection from
cardiovascular disease is not an indication for the use
of HRT in postmenopausal women(15, 16). The Women's Health
Initiative (WHI) trial, a randomized controlled primary
prevention trial in which16,608 postmenopausal women (50
-79 yr. old) with intact uteri participated, was stopped
in July, 2002 on the basis of assessment that the overall
health risks exceeded health benefits after an average follow-up
period of5.2years (17). As shown in Table1, this planned
8.5 -year randomized clinical trial showed that women taking
estrogen (conjugated equine estrogen : CEE) at a dosage
of 0.625mg/day and progestin (medroxyprogesterone acetate:
MPA) at a dosage of 2.5mg/day were at increased risk for
myocardial infarction, stroke, venous thromboembolism and
breast cancer compared with women taking a placebo. Although
there were decreased risks of osteoporotic fractures and
colorectal cancer in the hormone treatment group, an unfavorable
global risk-benefit profile was found in this group. The
estrogen-alone trial is scheduled to continue until March,
2005.Moreover, the UK Medical Research Council announced
that the Women's International Study of long Duration Oestrogen
after Menopause (WISDOM) had to be stopped in October, 2002
for scientific and practical reasons (18).
In the WHI trial, only one drug regimen, CEE at a dosage
of 0.625mg/day and MPA at a dosage of 2.5mg/day, was tested
in postmenopausal women. In the report presenting results
of the WHI, it was stated as a limitation of the study that
the results do not necessarily apply to lower dosages of
these drugs or to estrogens and progestins administered
through the transdermal route. Several problems characteristic
of the subjects in this trial were also discussed in that
report. The women who enrolled in the WHI trial were 50
to 79 years old at the time of recruitment, but participants
were not typical users of HRT drugs. In the WHI trial, 36%
of the women who underwent HRT had hypertension, 49% were
current or past smokers and 34% were obese (body mass index>30kg/m2).
Therefore, not all women were healthy. Further analysis
of the WHI data may be necessary.
LOW-DOSE HRT
The most commonly prescribed estrogen for HRT is conjugated
equine estrogen (CEE : Premarin?, Wyeth), which is usually
taken orally at a dosage of 0.625mg/day. Medroxyprogesterone
acetate (MPA : Provera?,Upjohn) for endometrial protection
is the most commonly used progestin for HRT, with typical
dosages of 2.5mg/day when taken daily and 5 to 10mg/day
for a cycle of 10 to 14 days when administered sequentially.
CEE was reported to be effective in preventing bone loss
and reducing fracture rates when given orally at a daily
dose of 0.625mg, and relatively small doses of CEE (less
than 0.625mg/day) were originally found to be ineffective
in preventing osteoporosis (19). However, recent studies
have demonstrated that low- dose HRT is safe and effective
for prevention of postmenopausal bone loss (20, 21). Dosages
of estrogens that are considered to be low are shown in
Table 2 (20). Ettinger et al. and Webber et al. demonstrated
that CEE at a daily dose of 0.31mg with calcium supplementation
of 1,000mg/day was effective in preventing postmenopausal
bone loss (22, 23). Mizunuma et al. reported that HRT using0.31mg
of CEE can increase lumbar bone mineral density (BMD) in
Japanese postmenopausal women(24). Recker et al. demonstrated
that continuous low-dose HRT with CEE (0.3mg) and MPA (2.5mg)
combined with adequate calcium and vitamin D supplementation
provides a bone - sparing effect that is similar or superior
to that provided by higher- dose HRT regimens in elderly
postmenopausal women (25). Prestwood et al. also reported
that low-dose estrogen treatment with calcium and vitamin
D decreased bone resorption and increased bone mass in older
women (26). As shown in Figure1, Lindsay et al., who recently
carried out a large-scale, randomized, placebo - controlled
study, demonstrated that lower doses of CEEs (0.45 and 0.3mg/day)
prevented the loss of spine and hip BMD and reduced bone
turnover (27).
Low- dose HRT was also effective in decreasing the number
and severity of hot flashes and in improving vaginal atrophy
in postmenopausal women (Fig.2)(28) in addition to inducing
favorable changes in lipids, lipoproteins and hemostatic
factors (Fig.3)(29). A recent Nurses Health Study report
noted that administration of low- dose HRT reduced the incidence
of cardiovascular disease (30). Sanada et al. reported that
low- dose CEE plus MPA similar to conventional - dose CEE
plus MPA augmented endothelial function in forearm resistance
arteries and decreased malondialdehyde -modified LDL levels
(31). Goudev et al. revealed that low- dose HRT with 17β
- estradiol and norethisterone acetate reduced the serum
levels of intercellular adhesion molecules, vascular cell
adhesion molecules and P-selectin, which are associated
with cardiovascular risk (32). Moreover, low-dose regimens
of CEE and MPA result in higher rates of amenorrhea, no
bleeding and endometrial protection compared with 0.625mg
CEE and 2.5mg MPA per day (33, 34). These findings suggest
that low-dose HRT may improve the compliance rate because
low-dose HRT causes minimal spotting and breast tenderness
and less progestogen -related adverse effects and possibly
reduces the risk of cancer. The establishment of low-dose
formulaions with potentially fewer side effects is important
for enhancing patient acceptance and continuance of HRT.
Recently, low- dose HRT has also been shown to result in
a better quality of life (35).
In Japan, CEE at a dosage of 0.3125mg was not available
in principle. Serum estradiol levels in subjects in the
present study who were treated with CEE and MPA every other
day were found to be significantly lower than those in subjects
who were treated every day (36),and treatment with CEE and
MPA every other day could be regarded as low-dose HRT. We
showed that HRT with CEE and MPA every other day was effective
for relieving vasomotor symptoms and preventing bone loss
and was associated with fewer side effects, such as unscheduled
bleeding or breast tenderness, while it showed no beneficial
effects on lipid profile (36). HRT administered every other
day at a low dose is also a choice of treatment for preventing
unscheduled uterine bleeding and breast tenderness.
TRANSDERMAL ESTROGEN TREATMENT
Estrogen administered transdermally has been shown to reduce
the incidence and severity of hot flashes (37).Long-term
treatment with transdermal estrogen has been effective for
preventing osteoporosis (38). However, the effect of transdermal
estrogen therapy on lipid metabolism was reported to be
weak because estrogen administered transdermally is absorbed
directly into the systemic circulation, avoiding hepatic
first-pass metabolism, while estrogen administered orally
directly enters hepatic circulation and affects lipid metabolism
in the liver. Thus, changes in lipid profiles in the case
of treatment with transdermal estrogen are smaller than
those in the case of treatment with oral estrogen.
On the other hand, hypertriglyceridemia is also a risk factor
for coronary heart disease. McNamara et al. suggested that
the plasma triglyceride level is the single most important
factor affecting the size of LDL particles (39). Oral estrogen
therapy with CEE was reported to increase the plasma concentration
of triglyceride and reduce the size of LDL particles, while
transdermal estrogen therapy was demonstrated to decrease
the plasma concentration of triglyceride and increase the
size of LDL particles (40). Small sizes of LDL particles
are associated with increased risk of coronary heart disease
because they are more susceptible to oxidative modification,
an initial step in the atherosclerotic process. Thus, transdermal
estrogen treatment is recommended for postmenopausal women
with hypertriglyceridemia.
ESTROGEN THRESHOLD HYPOTHESIS
The serum estradiol level was reported to be closely related
to the estrogenic effects on various tissues(41, 42). As
shown in Fig.4, the hierarchy of the most-sensitive to least-sensitive
estrogen -responsive process is in the order of calcium
turnover, gonadotropin secretion, vasomotor symptoms, vaginal
epithelial growth, lipid production and liver protein production
such as sex hormone -binding globulin production (41). In
a similar manner, estradiol - dependent disease processes
also appear to have a hierarchy of responsiveness to estradiol.
Breast cancer can be very sensitive to the growth-promoting
effect of estradiol at concentrations as low as 10 to 20pg/ml.
To reduce myoma volume in premenopausal women by 50%, serum
estradiol concentrations in the range of 15 to 25pg/ml must
be achieved. A serum estradiol level about 30pg/ml induces
regression of endometriotic lesions. The hierarchy of the
most-sensitive to least-sensitive estrogen -response disease
processes appears to be in order of breast cancer, myomas
and endometriosis.
A relation between estradiol level and BMD of the lumbar
spine in postmenopausal women who have been continuously
taking esterified estrogen medication has been demonstrated
(43). However, it is not known whether there is a relation
between serum estradiol level and BMD in women treated with
CEE. CEE, which is the most commonly prescribed drug for
HRT worldwide, is a unique complex of at least 10natural
estrogens. Thus, precise measurement of serum estradiol
levels in women receiving oral CEE is difficult. For postmenopausal
women receiving CEE for HRT, extraction of sex steroid hormones
from serum before the assay is needed for measurement of
serum levels of estradiol. We have developed a highly sensitive
and specific assay using high-performance liquid chromatography
(HPLC) for purification and a radioimmunoassay (RIA) for
measurement of serum estrone and estradiol levels, and reported
the precise levels of estrone and estradiol in women undergoing
oral CEE treatment (44). The mean serum estradiol level
measured by HPLC -RIA was 22.8pg/ml, while that measured
using a conventional RIA kit was76.2pg/ml. We also measured
serum levels of estradiol in postmenopausal women receiving
CEE(0.625mg) and MPA (2.5mg) every other day and every day,
and we showed that there was a relation between serum estradiol
level and BMD of the lumbar spine(45).
ENDOGENOUS ESTROGEN
The need for estrogen replacement therapy may depend on
the amount of endogenous estrogen being synthesized and
estrogen threshold for a relevant organ (e.g., brain, bone
and heart). Thus, the level of endogenous estrogen is also
an important factor in the administration of exogenous estrogen
such as HRT. Endogenous estrogen level is known to be closely
related with body mass index (46). Women who are heavier
or who have a greater body mass index have been reported
to have higher levels of estrogen, due to the aromatization
of gonadal steroid hormone precursors in fat and muscle
tissue(47-50).
Recent studies using highly sensitive methods to measure
serum estradiol levels have provided evidence of beneficial
effects of very low levels of circulating estrogens on bone.
Cummings et al. found that women 65years of age or older
with low but detectable levels of serum estradiol (ranging
from 5 to 9 pg/ml) had a significantly lower risk of hip
or vertebral fractures than did women with undetectable
levels (less than 5pg/ml)(51). In a different sample of
women randomly selected from the same cohort, Ettinger et
al. found that women with estradiol levels below 5pg/ml
had substantially less BMD at all sites measured than did
women with levels in the range of 10 to 25pg/ml (52). Thus,
higher endogenous estradiol levels are associated with increased
bone density, reduced bone loss and reduced fracture incidence
in elderly women. In addition, low endogenous estradiol
levels in postmenopausal women were found to be related
to appearance of hot flash (53). On the other hand, the
relative risk for breast cancer in women with very high
endogenous estradiol levels was significantly higher than
that in women with very low estradiol levels (54). The results
of the MORE trial showed that the risk of breast cancer
in women with an endogenous estradiol level of greater than
10pmol/l was higher than that in women with an undetectable
estradiol level (55).
The relation between endogenous estrogen and its effect
on various tissues in Japanese postmenopausal women is not
clear. We precisely measured the level of endogenous estrogen
by the HPLC-RIA method whose sensitivity of estrone and
estradiol levels was5and 2pg/ml, respectively. A study of
the relation between endogenous estrogen level and BMD of
the lumbar spine in postmenopausal women revealed that women
with estradiol levels below 2pg/ml for whom more than 5years
had passed since menopause had less spine BMD than did women
with levels in the range of10to 20pg/ml (Fig.5)(56).
INDIVIDUALIZED HRT
It was reported that ERT reduces the risk of edentulism
and protects against loss of teeth (57). ERT was also reported
to have a protective effect on lenses in postmenopausal
women (58). In addition, Zandi et al. suggested that the
higher risk of Alzheimer's disease for women than for men
in old age might disappear if women were to undergo long-
term postmenpausal HRT (Fig.6)(59). Thus, there is great
interest in further development of low- dose HRT and transdermal
estrogen therapy. These regimens with fewer side effects
in addition to various effects on several tissues, will
be important for the future of HRT.
An appropriate HRT regimen should be selected to suit the
individual in terms of risks, benefits and preferences (60).
Various basic characteristics of individuals such as endogenous
estrogen level, BMI, smoking and the state of glucose metabolism
are important, and selection of the most appropriate regimen
of HRT (dose, route of administration and schedule) for
the needs of the individual are important factors for continuation
of HRT. Alternative treatments, such as herbal medicines
and soy proteins for improvement of vasomotor symptoms and
selective estrogen receptor modulators and bisphosphonate
for maintenance of bone mineral density, may be also selected.
A plan for treatment over a 1-year period should be made,
and adjustments may be made after1year with consideration
given to individual needs, benefits and risks based on results
of examination. Clinicians should become experts in tailoring
HRT to accord with the characteristics and needs of each
woman.
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