Gail A Greendale, Nancy P Lee, Edgar R Arriola
Menopause is diagnosed after 12 months of amenorrhoea resulting from the permanent cessation of ovarian function.
The mean age at menopause is 51 years. The perimenopause, a time of changing ovarian function, precedes the finalmenses by several years. The physiology and clinical manifestations of this transition to menopause are not wellunderstood; however, some symptoms, such as hot flashes, certainly begin in the perimenopause. Causalassociations between menopause and several symptoms and diseases are proposed. The evidence for theseassociations varies and is reviewed. Hormone replacement therapy can be directed at symptom relief or at preventionor treatment of chronic diseases. Doses and routes of hormone replacement therapy vary by indication. Complicationsof hormone replacment therapy depend on the regimen used. Knowing the expected vaginal bleeding pattern for eachhormone replacement therapy regimen is important, since unexpected bleeding may signal endometrial hyperplasia.
Postmenopausal hormone therapy is a complex intervention that produces positive and negative specific healtheffects. Overall, based on observational studies, postmenopausal women who use hormones have a 30–50% lower all-cause mortality rate than those who do not use hormones. It is important to recognise that the value that individualwomen place on various health outcomes associated with hormone replacement therapy may differ. Thus, thedecision to use hormone replacement therapy should be made jointly by each woman and her health-care provider,after careful consideration of possible benefits, risks, and her personal preferences.
menstrual cycle that may occur in perimenopause, some
women have classic postmenopausal symptoms, for
M e n o p a u s e
—The menopause is the permanent cessation
example, hot flashes (we do not use the term flushes
of menstruation due to loss of ovarian follicular function.
because not all women flush as part of their hot flash
Clinically, menopause is diagnosed after 12 months of
experience). Furthermore, indicators of risk for chronic
amenorrhoea, so the time of the final menses is
disease, such as lipid profiles, may become less favourable
during the perimenopause. Therefore, we describe
perimenopause and postmenopausal presentations of
P e r i m e n o p a u s e
—Although a discrete point in time (the
symptoms and changes in risk factors for chronic disease.
final menses) is designated as the beginning of thepostmenopausal period, the transition to postmenopausal
status is not abrupt. Current theory holds that theperimenopause, a period of changing ovarian function,
precedes the final menses by between 2 and 8 years. The
The unequivocal, temporal relation between hot flashes
physiology and clinical presentations of perimenopause
and the menopause transition justifies this designation as
are not well understood, but one model proposes that it
a definite perimenopausal and postmenopausal symptom.
occurs in stages. Early perimenopause occurs when the
Hot flashes are a sensation of warmth, frequently
neurohormonal systems that govern ovulation begin to
accompanied by skin flushing and perspiration. A chill
may follow as core body temperature drops. Hot flashes
vary: they can be occasional or frequent, or last from
perimenopause may be characterised by irregular
seconds to an hour, and are characterised by mild warmth
menstrual cycles, particularly by short cycles intermingled
to profuse sweating. Some women perceive hot flashes as
with longer time between menstruation.
a minor nuisance, whereas in other women this symptom
During perimenopause, concentrations of follicle-
disrupts work, sleep, or daily activities.
stimulating hormone (FSH) may be raised to the
Hot flashes commonly start during perimenopause.
postmenopause range during some cycles, but return to
McKinlay and colleagues2 reported that 58% of women
premenopausal concentrations during subsequent cycles.
i n their study had hot flashes in the 2 years around
Gonadotropins and oestrogen may also be high during the
t h e i r final menses. The proportion of women who report
transition to menopause.1 Thus, high concentrations of
hot flashes may be as great as 80% in western countries,3
FSH should not be used to diagnose menopause in
but as low as 10% in some East Asian countries.4 T h e
menstruating women. In addition to such variability in
causes of this variation are not known. Hot flashesdiminish spontaneously as time from menopause
Although there is some evidence that hot flashes
Division of Geriatrics, School of Medicine (Prof G A Greendale MD)
r e s u l t in adverse biological consequences, for example,
and Department of Pharmaceutical Services (N P Lee, E R Arriola),Center for Health Sciences, University of California, Los Angeles,
h y p e r t r i g l y c e r i d a e m i a ,5
flashes and negative metabolic profiles requires furtherstudy. The major reason to treat hot flashes continues to
Correspondence to: Dr Gail A Greendale, Division of Geriatrics,University of California, Los Angeles, 2339 PVUB, Box 951687,
be their effect on the woman’s comfort and ability to
THE LANCET • Vol 353 • February 13, 1999
Panel 1: Vaginal oestrogen preparations and indices to assess safety
Oestradiol tablet (Vagifem) Each table contains 25 ug oestradiol 1 tablet twice weekly
Low serum concentrations of E1 and E2.
Progestagin challenge, endometrial ultrasoundand in some cases endometrial biopsy.
Progestagin challenge, endometrial ultrasound
and in some cases endometrial biopsy.
No change in SHBG or other liver markers.
0·5 mg oestriol twice weekly Low serum concentrations of E1 and E2.
No change in SHBG or other liver markers.
E1=oestrine; E2=17␤-oestradiol; E3=oestriol. SHBG=sex hormone binding globulin.
*Although E1 and E2 concentrations are unaffected by low-dose oestriol, E3 concentrations increase.
Treatment of hot flashes
—Oestrogens diminish hot
genitourinary response to usual systemic oestrogen
flashes, and there is a dose-dependent relation between
regimens, vaginal therapy may be added rather than an
oestrogen dose and suppression of hot flashes. To achieve
increase of the systemic dose. Some examples of vaginally
satisfactory control of this symptom, women with severe
administered oestrogens are shown in panel 1. The
or frequent flashes may require higher than standard
availability of the vaginal oestrogen preparations varies by
oestrogen doses (see menopause treatments). For
example, in a woman who continues to have hot flashesafter the start of 0·625 mg conjugated equine oestrogens
daily, the dose can be increased to 1·25 daily. Higher than
Although there is no definite causal link between urinary
standard doses of oestrogen should be reduced if possible
tract infection and menopause, physiological changes that
to keep to a minimum potential long-term risks.
occur after the menopause may lead to increased
Alternatives to oestrogen for treatment of hot flashes
susceptibility to such infection. These changes include
include methyldopa, clonidine, medroxyprogesterone
increased vaginal pH and an alteration in the vaginal flora
acetate, and megestrol acetate. Of these, megestrol
to predominantly gram-negative organisms.
acetate (20 mg twice daily) is most effective, and
Treatment of urinary tract infection
produces a 71% reduction in the frequence of hot flashes.
intervention with vaginal oestriol in women with recurrent
Moderate reductions in hot-flash frequency (about 20%)
urinary tract infection resulted in 0·5 episodes of infection
have been obtained with oral or transdermal clonidine;
per patient-year in the treated group, compared with 5·9
however, adverse effects such as dry mouth, constipation,
episodes per patient-year in the controls.1 2 C o r r e s p o n d i n g
local skin irritation, and drowsiness limit its usefulness.
improvements in risk factors (pH, bacterial flora) forurinary tract infection were seen.1 2
Some studies report an association between menopause
and increased prevalence of urinary incontinence, whereas
In clinical samples, women who present with symptoms
others do not.6 , 7 Postmenopausal changes in the urinary
of dyspareunia, vaginal dryness, itching, and irritation
tract that may account for irritative voiding symptoms
frequently have signs of vaginal atrophy on physical
(frequency and urgency) and incontinence include:
examination. These signs can include epithelial pallor,
atrophy of the bladder trigone; decreased sensitivity of
petechiae, friability, and absence of rugae. Signs
␣-adrenergic receptors of the bladder neck and urethral
consistent with atrophy may be present on examination in
sphincter; and thinning of the urethral mucosa.
the absence of symptoms; coversely, women may have
Use of oestrogens for stress and urge urinary
symptoms but no atrophy. The maturation index, a
incontinence have mixed results. Individual studies have
measurement of vaginal parabasal (least mature),
reported up to a 50% reduction in stress urinary
intermediate, and superficial (most mature), cells shifts
incontinence with combination ␣ agonist and oestrogen
towards less mature cell types after menopause. In small
studies, however, an immature maturation index has not
incontinence with oestrogen use.9 However, Frantl and
correlated with symptoms.1 3 Thus, the syndrome known
c o l l e a g u e s1 0 showed no symptomatic benefit of oestrogens
as atrophic vaginitis is ill-defined and can include
for stress or urge urinary incontinence.1 0 A meta-analysis
symptoms only; symptoms and signs; or signs on
concluded that oestrogens had only a small effect on
urinary incontinence.1 1 The reliability of this summaryestimate is limited by small and heterogenous samples,
Treatment of vaginal atrophy—
Usual systemic doses of
varied forms of incontinence, and use of different
oestrogen can be used for therapy of vaginal atrophy,
oestrogens. In the face of such conflicting results, many
atrophic symtoms, or both. As with urinary tract
clinicians use a trial treatment of oestrogen for stress and
infection, additional vaginal therapy (hormonal or non-
hormonal) is sometimes required for women who don o t respond adequately to systemic oestrogen; this
Treatment of urinary incontinence
—Oral oestrogens can
o p t i o n is preferable to an increase in the systemic dose.
be used for urinary incontinence. Alternatively, local
For women who cannot or do not wish to use systemic
therapy with oestrogen vaginal creams, tablets, and rings
oestrogen, vaginal atrophy can be treated with vaginal
can be used. For a woman who has an incomplete
moisturisers (proprietary names include Astroglide,
THE LANCET • Vol 353 • February 13, 1999
hormone is fairly safe, low-dose testosterone may be tried
Panel 2: Some testosterone preparations used
in women whose main sexual complaint is diminished
for diminished sexual function in postmenopausal
arousal. Some testosterone compounds and doses are
Several longitudinal population-based studies report no
Esterified oestrogens/ 0·625–1·25 mg Alopecia, acne, hirsutism,
association between the menopause transition and
d e p r e s s i o n .2 3 By contrast, one Canadian cohort study did
show high rates of depressive symptoms among
menopausal women: 51% of women screened positive on
the Centers for Epidemiologic Studies Depression Scale
at least once during 3 years of observation, but high
scores were related to poor perceived health and not to
the menopause per se.2 4 Two other cohorts, from the
perimenopausal depression, mostly in women who had
had a history of depression. These studies lend support to
a vulnerability theory—women who have previously had
affective disorders may be at increased risk of
*Increase risk of long durations of use or high doses virilisation.
m o o d disturbance during the menopausal transition.
B y contrast, women who present for care at menopause
clinics have rates of clinical depression as high as 45%.2 7
(Replens) decreases vaginal pH and reduces symptoms of
Oestrogen treatment of mood disturbance
of oestrogens and oestrogen/progestagen combinations onmood and wellbeing in women without clinical depression
is unsettled. Some studies showed improvements and
The prevalence of sexual activity in one US sample1 1 o f
others no benefit.2 3 There are few placebo-controlled
875 women was 70% among those aged 45–54 years and
studies of monotherapy with oestrogen for clinical
60% among those aged 55–64 years,1 5 which is similar to
depression. In a post-hoc analysis of a large clinical trial,
the prevalence reported in community-based surveys from
Europe and the USA.1 6 , 1 7 Although studies are limited by
augmented the patients’ response to fluoxitene. Oestrogen
cross-sectional design, narrow definitions of sexual
should not be relied on to treat menopausal women with
behaviour (usually frequency of intercourse), and
clinically significant signs of major depression; these
incomplete control for the multiple determinants of
women should be assessed and treated with standard
sexuality, there seems to be a trend toward declining
frequency of sexual intercourse and decreased sexualdesire with increasing age. Whether part of the age-relatedreduction in sexual behaviour is related to menopause per
se is uncertain, but there is reason to believe that some
menopause-related symptoms interfere with sexuality. For
An aetiological relation between menopause and
example, vaginal atrophy can lead to vaginal dryness and
increased risk of cardiac disease is corroborated by a
friability which causes dyspareunia, and in some women
higher age-adjusted rate of this disease among women
who have had an ooporechtomy than among those who
Hormone therapy for sexual complaints
—There is no
have not, and by the finding that postmenopausal women
controversy about treatment of overt dyspareunia in a
have a two-fold higher risk of developing the disease than
postmenopausal women with vaginal atrophy. However,
premenopausal women, after adjustment for age.
whether diminished sexual desire, arousal, orgasm, or
In longitudinal studies that have accounted for
satisfaction benefit from oestrogen treatment is not
ageing and the menopause transition, age-adjusted
known. Since oestrogen improves the integrity of vaginal
concentrations of lipids and lipoproteins become less
tissue, beneficial effects on sensation, vasocongestion, and
favourable after the menopause.2 9 Scores of intervention
vaginal secretions may occur, leading to enhanced arousal.
studies reported beneficial effects of various oestrogens
The role of testosterone for sexual dysfunction,
o n lipid indices. When oestrogens are combined with
particularly for decreased desire, is uncertain. Findings
progestagens, some degree of mitigation of the lipid
that testosterone improves sexual desire come from
benefit is seen, depending on the dose and type of
studies of women who have oophorectomy and received
high doses of testosterone.1 9 , 2 0 Whether such findings can
Progestins Intervention Trial,3 1 with the longest follow-up
be applied to naturally menopausal women is debatable
and the advisability and safety of the very high
replacement therapy, conjugated equine oestrogens
testosterone doses used have been questioned.2 1 M o r e
produced the greatest increase in HDL. Combination
commonly, a trial of low-dose oral methyltestosterone
treatment with conjugated equine oestrogens and cyclical
(1·25–5 mg daily) is used for postmenopausal women
micronised progesterone resulted in slightly less increase
who report low sexual desire. One study2 2 of 5 mg
in HDL, compared with conjugated equine oestrogen
methyltestosterone (together with conjugated equine
alone. This combination regimen (2·5 mg daily or
oestrogens) showed an increase in self-stimulation but
cyclically) produced the third highest increase in HDL
n o t in self-reported arousal. Nonetheless, because this
THE LANCET • Vol 353 • February 13, 1999
Adverse changes in other factors that mediate the risk of
discrepancies partly arise from inexact definitions of
coronary heart disease, such as insulin resistance, increased
perimenopause and early menopause and inprecision
thrombotic tendency, and less favourable haemodynamic
i n some measurements of bone mineral density and
profiles, may also lead to increased cardiac risk with the
b o n e markers. Evidence for varying rates of bone loss
menopause. However, menopause-associated longitudinal
after menopause3 8 raises the question of whether there is a
patterns of these risk indicators await detailed description.
subset of women who lose bone substantially more rapidly
After adjustment for age and body-mass index, menopause
than others, and whether this group can be identified. If
alone does not cause increased blood pressure.3 2 I n
so, such women might be targeted for screening and
normotensive women, unopposed oestrogen or combined
counselling about osteoporosis prevention, and might also
hormone therapy does not raise blood pressure.3 1 S i m i l a r l y ,
require unique therapeutic interventions. Although the
blood pressure does not increase as a result of hormone
postmenopausal rapid bone loss raise important research
Hormone therapy and events from coronary heart
issues, it is too early to define a distinctive clinical
d i s e a s e
—Observational studies of the relation between
approach for these theoretical subgroups of women.
unopposed postmenopausal use of oestrogen and risk of
Hormone therapy and osteoporotic fracture
events from coronary heart disease consistently show
small-scale randomised trials showed a reduction in risk
lower rates of events among postmenopausal women
of fracture as a result of use of oestrogen or oestrogen
w h o use oestrogen than among non-users. Meta-analyses
estimate that the relative risk of coronary heart disease in
prevention of fractures and postmenopausal use of
users versus non-users of oestrogen is about 6 for ever-
hormones comes from observational studies. Cohort
users and 0·5 for current users.3 4 , 3 5 There have been only
studies are, of course, open to bias that may overestimate
a few cohort studies of the effects of oestrogen in
the protective effect of hormone therapy on osteoporosis.
combination with a progestagen, but the magnitude of
Despite this bias, the large number of cohort studies that
protection against coronary heart disease seems to be
consistently report fracture prevention, the evidence of
similar to that found with oestrogen alone.3 6 D e s p i t e
strong effects, and the biological plausibility of this effect
controlling for known confounders, these observational
all point to a protective effect of hormone therapy
studies are limited by a degree of residual selection bias.
o n fracture. Grady and colleagues’ meta-analysis4 1 o f
However, the magnitude, consistency, and biological
observational studies in which most women used
plausibility of protection against coronary heart disease
unopposed oestrogen calculated a summary risk estimate
associated with use of postmenopausal hormones suggest
of hip fracture of 0·50 among current users and 0·75
in ever-users of oestrogen. Later cohort studies, in
The apparent cardioprotection by oestrogen evident in
w h i c h women who used oestrogen plus progestagen
these observational studies led to a recently completed,
combinations are well represented, report similar degrees
large randomised trial, in which continuous combined
of protection against fracture risk as a result of
conjugated equine oestrogen plus medroxyprogesterone
acetate or placebo was given to about 2700 women with
The time at which hormone therapy must be initiated
pre-existing coronary disease.3 7 At the average follow-up
in order to protect against osteoporotic fracture is not
duration of 4 years, no overall effect of the intervention
known. The Study of Osteoporotic Fractures4 3 s h o w e d
was found for coronary heart disease events. However, a
that only women whose use of hormones started within
complex temporal pattern emerged. Compared with
5 years of the menopause had a reduced risk of hip
placebo, the intervention group had significantly more
f r a c t u r e ;4 1 former users, even those who used oestrogen
coronary heart disease events in the first year of the trial,
for longer than 10 years and began it soon after
and fewer events during years 4 and 5. Based on these
menopause, were not protected against hip fractures.
results, institution of hormone treatment for secondary
However, in the Rancho Bernardo cohort,4 4 the bone
prevention of coronary heart disease is not recommended,
mineral density of current users who started treatment
but it may be appropriate for women already receiving
after age 60 years was similar to that of women who
treatment to continue. Questions related to the safety of
institution of hormone treatment in women with possible
Hormone therapy and bone mineral density
— M o s t
subclinical coronary heart disease remain unanswered at
studies of the effects of oestrogen or oestrogen plus
progestagen on bone mineral density in postmenopausalwomen have lasted 1–2 years and showed increases in
h i p and spine bone mineral density of 1–4%. The PEPI
A causal relation between menopause and osteoporosis is
s t u d y4 5 showed no significant differences in the percentage
postulated based on the higher rates of osteoporotic
change in bone mineral density as a function of added
fractures in postmenopausal than in premenopausal
progestagen use. In that study, 3 years of treatment with
women, loss of bone mineral density after menopause,
oestrogen or oestrogen plus progestagen produced
preservation of bone mineral density as a result of use of
a n increase in bone mineral density of 3·5–5·0% at the
hormone therapy after the menopause, and evidence
spine and 1·7% at the hip. Trials that have used more
(mainly from cohort studies) that postmenopausal
androgenic progestagens (for example, norethisterone)
hormone users have fewer fractures than non-users.
reported greater gains in bone mineral density at the spine
The timing of onset of bone loss in relation to
menopausal status, bone mineral density, and bone
Epidemiological studies continue to show possible
turnover markers (serum and urine indicators of bone
associations between menopause, hormone therapy, and
the occurrence of various chronic diseases and
THE LANCET • Vol 353 • February 13, 1999
oestrogen by injection causes wide variation in
Panel 3: Some oestrogens and doses associated with
concentrations and therefore is a suboptimum method
of administration. Oestradiol implants are crystalline
1 7 -␤ oestradiol pellets that are inserted subcutaneously
into the anterior abdominal wall or buttock. If there are
side-effects, pellets are difficult to remove and because
Micronised 17-␤ oestradiol valerate (Climaval)
implants may continue to release oestradiol for a long
17-␤ oestradiol transdermal patch (Estraderm)
time after insertion, progestagen therapy should be
maintained until bleeding stops (which may take 3
years). Percutaneous gel or cream preparations are
convenient and perhaps particularly well suited to
*Doses are the lowest oestrogen doses that prevent bone loss in randomised trials.
women who live in tropical climates and want to use a
conditions—for example, arthritis, cognitive decline and
transdermal route. High moisture in such climates makes
Alzheimer’s disease, tooth loss and periodontal disease,
local skin irritation from patches troublesome. The major
skin atrophy, cataract formation, ovarian cancer, and
limitation of oestrogen gels and creams is variability in the
amount applied, so metered dose-measurement systemswere developed to standardise the amount used.
Reactions at the application site occur in about 10% and5% of women who use reservoir (alcohol-based) and
Hormone therapy for postmenopausal women can target
matrix (oestrogen in adhesive) patches, respectively.
symptoms or prevention of chronic diseases. Therefore, it
Avoidance of moisture and rotating sites keeps to a
is important to establish each patient’s treatment goals,
minimum patch-related local skin reactions.
because therapy directed at some symptoms, such as hot
—Some oestrogens that are applied
flashes, can be short term, whereas treatment of a chronic
vaginally are listed in panel 1. The absence of endometrial
indication, such as osteoporosis prevention, is usually life-
hyperplasia with some vaginal preparations has been
long. Because many women are concerned about the
shown by endometrial ultrasound or biopsy. Other
potential long-term risks of hormone replacement
therapy, the distinction between short-term, and long-
concentrations of circulating oestrogens or have no effect
term goals is central to the discussion of the benefits and
on salient liver proteins. However, as a safety indicator,
serum concentrations must be interpreted with caution:
Doses and routes of hormone replacement therapy vary
some conjugated oestrogens (such as Premarin) contain
by indication. Some commonly prescribed doses and
multiple compounds that are not tested in serum as
regimens of postmenopausal systemic oestrogens and
estrone or oestradiol. Two older vaginal preparations,
progestagens are shown in panels 3 and 4; these are
conjugated equine oestrogens vaginal cream and 17-␤
judged standard because the oestrogen doses are
oestradiol vaginal cream, are not shown in panel 1 since
associated with preservation of bone mineral density and,
there are no comprehensive data on safety available for
in the case of combined hormone therapy, the added
low-dose applications of these products. Whether the
progestagen regimen prevents endometrial hyperplasia. As
effects of vaginal preparations, including those that do not
noted earlier in the above sections on treatment, higher
lead to endometrial hyperplasia are local is not known.
doses of oestrogen are sometimes warranted (for example,
For example, Estring produces concentrations of
in recalcitrant hot flashes). By contrast, in some
oestradiol that are greater than baseline concentrations,
conditions, topical therapy can keep to a minimum
reported to preserve bone density.4 8 Thus, one should notassume that low serum hormone concentrations or
absence of endometrial hyperplasia are proof of the
absence of any other systemic effect.
transdermally, intradermally (by patch, skin cream, orpellet), vaginally, and by injection. Commonly used
oestrogens are summarised in panel 3; doses shown are
Progestagens are used to prevent endometrial hyperplasia
the lowest doses reported to prevent bone loss in
in women with a uterus. There is no need to prescribe a
randomised clinical trials of at least 1 year’s duration.
progestagen if a woman has had a hysterectomy.
Non-oral administration of oestrogen avoids first-pass
Commonly used progestagens are summarised in panel 4;
liver metabolism and can be particularly useful, for
doses and durations shown are those for which protection
example, for women with significant liver function
from endometrial hyperplasia has been shown.
abnormalities or high triglycerides. Non-oral routes
Progestagens used for hormone replacement therapy
include intramuscular injection, implantation, vaginal
can be devided into subgroups: the C-21 derivatives
cream, skin creams or gels, and patches. Intramuscular
Panel 4: Progestagens used for prevention of endometrial hyperplasia in combination hormone therapy
Medroxyprogesterone acetate (Provera; Cycrin; Amen; Curretab)
Micronised progesterone (Prometrium; Utrogestan)
Norethisterone (Micronor; NorQD; Aygestin; Primolut; Nor)
*Degree of hyperplasia protection achieved varies by dose. †Limited data.
THE LANCET • Vol 353 • February 13, 1999
dydrogesterone); C-19 derivatives of nortestosterone
( 1 0 mg) regions. In PEPI4 4 study at 3 years, ten cases of
(norethisterone); and natural progesterone and similar
cystic or more advanced hyperplasia were distributed
compounds. When appropriate doses and durations are
among the continuous (2·5 mg) and cyclic (10 mg
used, these progestagens prevent endometrial hyperplasia,
but differ in their relative metabolic and androgenic effects.
medroxyprogesterone) regimens; this overall 3-year rate
Medroxyprogesterone acetate is minimally androgenic but
did not differ from that with placebo. This finding
does counteract the rise in HDL produced by unopposed
confirms the safety of 2·5 mg medroxyprogesterone
oestrogen therapy.3 1 Oral micronised progesterone does not
acetate daily; the main reason to use the 5·0 mg daily
mitigate against oestrogen-induced HDL increases.3 1
dose is to reduce bleeding. Similarly, the 3-year safety of
Dydrogesterone has no androgenic and oestrogenic activity
the 10 mg cyclical monthly regimen is well established;4 4
and when 10–20 mg is used cyclically with 2 mg oral 17-␤
the documented safety of 5 mg medroxyprogesterone
oestradiol daily, it does not antagonise the beneficial effects
acetate cycled monthly is limited to 1 year.5 4
of oestrogen on lipids. Although various clinical trials that
Ferenczy and Gelfand5 5 assessed the safety of cyclic 10
use metabolic risk factors as outcome measures report that
mg dydrogesterone, in combination with 2 mg oral 17-␤
some progestagens mitigate against oestrogen-induced
oestradiol daily in a 1-year study among 188
benefits, observational studies have not confirmed a
postmenopausal women and found no endometrial
measurable difference in clinical outcomes3 5 or metabolic
h y p e r p l a s i a .5 5 The same result was reported in a smaller
2-year study of this regimen in 27 women.5 6 There have
Investigational methods to deliver progestagens locally
been no reports of the minimum continuous dose of
include an intrauterine device5 0 and vaginal gel. Suhonen
and colleagues’ study5 0 in 45 women reported no
endometrial hyperplasia after 3 years of using a
In the PEPI trial,4 5 during 3 years, 120 women with an
levonorgestrel-releasing intrauterine device in conjunction
intact uterus were randomly assigned cyclic micronised
with various oestrogens. However, such devices do not
progesterone (200 mg) plus daily conjugated equine
have only a local effect. When combined with oestrogen
oestrogen (0·625 mg). Five women developed cystic
they produce changes in lipids similar to that of 1 mg
hyperplasia and only 1 developed atypical hyperplasia;
this rate did not differ signifcantly from that in the
bioadhesive vaginal gel (Crinone) is also under
placebo group. The safety of a daily dose of 100 mg
investigation for use in hormone replacement therapy and
micronised progesterone with regard to endometrial
was recently licensed in the UK. One 3-month trial
hyperplasia has not been tested widely. In one 12-month
reported that this low-dose sustained-release formulation
uncontrolled study in 40 women, there was a 3% rate of
simple hyperplasia.5 7 Gillet and colleagues5 8 found that a
postmenopausal women receiving oestrogen.5 2
25-day regimen of 100 mg oral micronised progesteroneand 1·5 mg percutaneous 17-␤ oestradiol resulted in no
Oestrogen and progestagen regimens
hyperplasia in 78 women after six cycles of treatment.
From pooled data, the recommended dose for cyclic
administration of oestrogen. This regimen augments
therapy with norethistrone is 0·7–1 mg. Some of the
compliance and avoids breakthrough of symptoms.
earliest continuous combined studies on hormone
Progestagens can be prescribed on a monthly cycle,
replacement therapy were done with norethisterone.
continuously, or four times per year (quarterly regimens).
dose-ranging studies biopsy samples taken at
Some commonly used progestagens for postmenopausal
6 m o n t h s showed complete endometrial atrophy with
therapy are shown in panel 4. When the monthly cycled
norethisterone 0·35–5 mg daily when used in conjunction
regimen is used, the easiest way to prescribe the
with conjugated equine oestrogens (0·625–1·25 mg) or
progestagen is on calendar days 1–12 each month. This
oestradiol implants (50 mg). Biopsy samples in a
regimen allows women to remember which days to use
the hormone and also simplifies reporting the bleeding
0 · 3 5 m g i n conjunction with conjugated equine oestrogen
pattern. When used cyclically, progestagens should be
prescribed for at least 10 days each month; with newer
regimens the progestagen component is given for 12 days.
Longer durations of progestagen therapy is associated
Bleeding patterns and need for endometrial monitoring
with reduced risk of endometrial cancer.5 3 Q u a r t e r l y
Understanding the expected bleeding patterns for each
progestagen regimens are not widely used. Although
type of regimen is critical to their use, since bleeding
initial studies reported that this regimen was safe, a long-
patterns are markers of endometrial safety. Bleeding that
term study was stopped early because of an unacceptably
differs from the expected pattern may signal endometrial
high rate of hyperplasia. Various combinations of
hyperplasia, and warrants investigation. With a monthly
oestrogen plus progestagen are commercially available.
cycled regimen of progestagen, 70–90% of women will
Doses to prevent endometrial hyperplasia
—In one large
have vaginal bleeding (the absence of bleeding is not a
problem). With this regimen, bleeding should start
oestrogen (0·625 mg) combined with continuous
sometime after the ninth day of progestagen use.
( 2 · 5 – 5 · 0 mg) or cyclic (5–10 mg on days 15–28)
Endometrial assessment is recommended if bleeding
medroxyprogesterone acetate resulted in a low rate of
starts before this time or if there is a change in duration or
endometrial hyperplasia (1%) at 1 year.5 4 In that study,
intensity of blood flow compared with what is usual for
cystic hyperplasia occurred rarely with the lower doses of
medroxyprogesterone acetate (2·5 mg daily or 5·0 mg
With continuous progestagen regimens, bleeding is
cyclically), and no hyperplasia occurred at 12 months
light to moderate in amount but its timing is erratic and
with the higher-dose continuous (5·0 mg) or cyclic
unpredictable. After 12 months of continuous combined
THE LANCET • Vol 353 • February 13, 1999
hormone therapy, bleeding stops in about 90% of women.
women taking combined hormone treatment, since about
Older women who have not been taking hormones since
half will have an endometrial thickness greater than
menopause may have less vaginal bleeding than younger
5 mm, which requires follow-up biopsy.6 2
women during the first year of continuous combinedtherapy, probably because their endometrium is already
atrophic. Since older women who have not menstruated
Although the efficacy of testosterone for improved sexual
for many years may find resumption of bleeding difficult,
function is not well-established, the safety of a low-dose
a continuous combined regimen may be better suited to
testosterone makes a trial of therapy acceptable. An
them. With continuous combined hormone replacement
androgen therapy carries the risks of virilisation (alopecia,
therapy, endometrial assessment is recommended during
acne, hirsutism, and deepening of voice). Serious hepatic
the first year only if bleeding is heavy or extended;
toxicity (for example, liver dysfunction, peliosis hepatis)
t h i s subjective judgment is often difficult to make.
Endometrial assessment is also advised if bleeding
methyltestosterones. Virilisation is generally reversible
continues to occur after 12 months of use.
and depends on dose and duration, with frequency
Women with an intact uterus sometimes choose
increasing at dosages of methyltestosterone of 10 mg daily
therapy with unopposed oestrogen. The longest study of
or greater or long duration of use. At 2 years, about a
third of women taking 1·25 mg methyltestosterone report
oestrogen) showed that 62% of women developed
hyperplasia after 3 years of treatment, about half of whom
methyltestosterone (1·25 mg) is lipid neutral when given
had complex hyperplasia or atypia.5 9 Thus, baseline and
with standard doses of oestrogen.6 4 When 2·5 mg
annual endometrial biopsy samples are required when this
methyltestosterone is used with oestrogen, the oestrogen-
dose of unopposed oestrogen is used. Any vaginal
endometrial biopsy. In a 2-year study of 0·3 mg esterified
Contraindications and precautions with hormone
oestrogens given in an unopposed manner, Notelovitz and
colleagues found a rate of hyperplasia of only 1·7%, which
Absolute contraindications to hormone replacement
was similar to that in the control women. However
therapy include undiagnosed vaginal bleeding, breast or
Cushing and colleagues case-control study6 1 showed that
endometrial cancer, and active deep vein thrombosis.
the odds of developing endometrial cancer were five-fold
Some other conditions warrant careful consideration, but
higher in women taking 0·3 mg unopposed conjugated
do not preclude hormone use. Most gynaecological
equine oestrogen daily, compared with unexposed
oncologists judge hormone use to be acceptable after
women. Thus, low-dose unopposed oestrogen is not
cured stage I endometrial cancer.6 5 Studies of women
given unopposed oestrogen after low-grade stage I
Methods of endometrial monitoring
—Because of the high
endometrial cancer reported no evidence of cancer
rate of hyperplasia, women taking unopposed oestrogen
progression related to hormone use. A weak association
require routine endometrial surveillance. Measurement of
between melanoma and hormone therapy has been
endometrial thickness (double layer) by means of vaginal
reported; use of hormone therapy after a diagnosis of
ultrasound is not an efficient strategy for safety
melanoma remains controversial. The safety of hormone
surveillance in women taking unopposed oestrogen. The
specificity of ultrasound for hyperplasia detection (with
controversial; available evidence does not assure safety or
a 5 mm cut-point) in women taking conjugated equineoestrogen alone is only 10%; even when simple
prove toxic effects. Uterine leiomyoma may grow slightly
hyperplasia is excluded from the analysis, the positive
with hormone therapy but in general do not pose a major
predictive value for an endometrial thickness of 5 mm or
obstacle to hormone use. The hepatic and biliary effects
greater in these women is only 12% for cystic or a more
of oral oestrogens raise concerns about their use in
serious hyperplasia.6 2 An increase of the double-layer cut-
women with hypertriglyceridaemia, liver disease, and
point to 9 mm or greater increases the positive predictive
previous gallbladder disease (with an intact gallbladder).
value of serious endometrial findings to 15%. Thus, with
Women with these conditions should be monitored
unopposed oestrogen, the endometrial lining thickens in
most women. The negative predictive value of a 5 mm
administration may be a safer approach. Case-control
endometrial measurement in women who use unopposed
studies show that oral oestrogens increase the risk of
conjugated equine oestrogen is 100%; but the occurrence
deep-vein thrombosis by about 2–3 times. A large
of a measurement this thin is extremely rare.6 1 S c r e e n i n g
observational study6 6 showed that the risk increased
by ultrasound before performing an oestrogen-only
similarly with transdermal oestrogen. This increase in risk
surveillance biopsy would exclude few women from a
must be considered in the context of the population
baseline risk of deep-vein thrombosis in women aged
Routine surveillance of the endometrial lining is not
45–64 years, about one per 10 000 women per year.
warranted in women who use combination hormonereplacement therapy. If a woman’s bleeding pattern
Complications of hormone replacement therapy
differs from what is expected with the regimen used,
Endometrial hyperplasia is a proven consequence of
investigation is needed. Should this assesment include an
unopposed oestrogen use. Atypical hyperplasia is an
endometrial biopsy, or is ultrasound alone adequate? An
important risk factor for the development of endometrial
endometrial double layer thickness of less than 5 mm has
cancer. Thus, the observed increase in endometrial cancer
a negative predictive value of 99% for any degree of
with use of unopposed oestrogen (without endometrial
surveillance) is believed to result from induction of
predictive value, ultrasound is an inefficient way to assess
hyperplasia which proceeds to cancer. Endometrial
THE LANCET • Vol 353 • February 13, 1999
hyperplasia can be prevented by use of appropriate doses
Cignarelli M, Cicinelli E, Corso M, et al. Biophysical and endocrine-
of progestagens and by careful attention to bleeding
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3 4 – 3 7 .
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READ BEFORE USING CAUTION: ALLOGRAFT IS FOR SINGLE USE ONLY. ASEPTICALLY PROCESSED. PASSES USP <71> FOR STERILITY. CAUTION: SPECIAL HANDLING INSTRUCTIONS THIS ALLOGRAFT HAS BEEN CRYOPRESERVED AND SHIPPED IN THE VAPOR PHASE OF LIQUID NITROGEN (-100 C TO -196 C). DO NOT STORE THE PACKAGE CONTAINING THE VASCULAR ALLOGRAFT IN LIQUID NITROGEN; THE PACKAGE MUST BE MAI
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