Menopause is the permanent cessation of menstru-

ation that results from loss of ovarian follicular

function. By definition menopause has occurred
after the passage of 12 months of amenorrhea.
Therefore, the timing of menopause (ie, the final
menstrual period) can only be known in retrospect.
The average age at which menopause occurs is
between 48 and 52 years.
1
Menopause (the termination of ovulation)
does not happen abruptly. Rather, current theory
holds that the menopause transition, also called per-
imenopause, begins between 2 and 8 years before
the final menses. In general, this transition is char-
acterized by changes in ovarian follicular function
and associated hormonal feedback loops. At present
our knowledge of the hormonal and clinical details
of perimenopause is rudimentary. A three-staged
theoretic model is reviewed briefly here; ongoing
studies will elucidate this process more clearly.
In early perimenopause menstrual cycle lengths
appear normal or can be abbreviated due to a short-
ened follicular phase. Follicle stimulating hormone
(FSH) levels are higher than are those of younger
women,
2,3
perhaps due to the presence of fewer folli-
cles or decreased secretion of inhibin.
4,5
Middle peri-
menopause is characterized by a less predictable
menstrual cycle pattern.
6
One such pattern is
marked by short cycles interspersed with long
amenorrheic intervals. Some perimenopausal cycles
are ovulatory, whereas others are anovulatory
(estrogen levels rise and fall without progesterone
secretion).
7
In middle perimenopause FSH values
can be markedly higher than are those of younger
cycling women (ie, in what is commonly thought of
as the postmenopausal range). Therefore meno-
pause is not diagnosed by a high FSH value in a
woman who is still menstruating. Women may
experience hot flashes, breast tenderness, and
menorrhagia during middle perimenopause.
8
The
year after the final menstrual period is designated
late perimenopause.
There are probably many patterns of meno-
pause transitions. The percentage of women who
manifest changes in cycle length, perimenopausal
symptoms and the relation between symptoms,
menstrual cycle characteristics, and hormonal cor-
relates are presently unknown but are areas of inten-
sive investigation.
SYMPTOMS AND TREATMENTS
The hot flash is a definite symptom of perimeno-
pause and postmenopause. Hot flashes range from a
sense of warmth to drenching sweats. Skin flushing,
heart pounding or palpitations, and a sense of full-
ness in the head are common accompanying fea-
tures of the hot flash. A chill may follow, if core tem-
perature drops after the sweating phase. Flashes may
last seconds to hours and may be innocuous or
extremely disruptive of daily function or sleep. In
the majority of women, hot flashes begin in the few
years prior to the final period, and they abate in a
similar amount of time after menopause;
6
however,
the persistence of hot flashes varies greatly. Ethnic
variation in hot flash experience is also large, with
up to 80% of women from Western countries but as
few as 10% of women from Eastern countries
reporting them.
9,10
Hot flashes respond to estrogen therapy in a
dose-dependent manner. Using standard dosages
4
APPROACH TO
THE MENOPAUSAL PATIENT
Gail A. Greendale, MD
1
(see Postmenopausal Hormone Therapy), hot
flashes are reduced by about 70 to 80% within
6 weeks of initiating treatment. Women with a sub-
optimal response to standard doses may benefit
from a higher dose (eg, 1.25 mg of conjugated
equine estrogens instead of 0.625 mg). Downward
titration should be attempted within 1 to 2 years,
however, to reduce the risk of long-term exposure to
high estrogen doses. Methyldopa, clonidine,
medroxyprogesterone acetate (MPA), and megestrol
acetate are nonestrogen treatments for hot flash-
es.
11,12
Of these, megestrol acetate is most effective,
resulting in a 70% decrease in hot flashes.
Vaginal atrophy is a well-known clinical corre-
late of the postmenopause, but careful epidemiolog-
ic studies of this syndrome are lacking. Women who
experience vaginal dryness, itching, irritation, and
dyspareunia may have accompanying vaginal exam-
ination findings of atrophy such as epithelial pallor,
friability, and diminished rugae. However, women
may also have vaginal symptoms without these
physical findings, and they may have atrophic exam-
ination findings without any symptoms.
13
Unlike
hot flashes, vaginal atrophy tends to become more
pronounced with increasing time after menopause.
Usual systemic doses of estrogen are generally
effective for the treatment of vaginal atrophic symp-
toms; however, it is sometimes necessary to add
additional local therapy in those women who do not
obtain adequate symptom relief. Options include
local topical estrogen or vaginal moisturizers (such
as Astroglide, Moist Again, Replens (polycarbophil),
and Gyne-moistrin).
The relation between menopause and urinary
tract pathology remains uncertain, but several
anatomic and physiologic alterations in the urinary
tract that accompany menopause suggest a plausible
association.
14
After menopause, several changes
occur in the urinary tract that may lead to inconti-
nence or irritative voiding symptoms (frequency
and urgency). These include atrophy of the bladder
trigone, thinning of the urethral mucosa, and
diminished sensitivity of the bladder neck and ure-
thral sphincter a-adrenergic receptors. In addition,
menopause may be a risk factor for urinary tract
infection due to the presence of a higher vaginal pH
and to vaginal colonization with gram-negative
organisms.
Studies using estrogen to treat urinary incon-
tinence have had positive and negative results.
1517
However, most studies have been done in small
samples, types of incontinence have been heteroge-
neous, and forms and doses of estrogen have varied.
Thus, many clinicians offer a trial of estrogen treat-
ment (systemic or topical) for irritative voiding
symptoms, stress incontinence, and urge inconti-
nence. Although based on limited data, evidence for
a beneficial effect of estrogen on recurrent urinary
tract infection is striking; one randomized trial
reported almost complete prevention of recur-
rences in women treated with vaginal estriol com-
pared with recurrences in those women given
placebo.
18
Whether menopause-related changes affect
sexual function remains unclear. In cross-sectional
studies, women report diminishing desire and
intercourse frequency with increasing chronologic
age, but the role of menopause per se as well as the
impact of other important factors such as partners
sexual capability and relationship quality as etiolo-
gies of sexual dysfunction are poorly under-
stood.
19,20
Despite the absence of formal studies, few
would argue that dyspareunia is likely to benefit
from systemic or vaginal estrogen therapy. Less cer-
tain is whether sexual desire, orgasm, or arousal will
improve similarly with estrogen treatment, although
an estrogen trial for these conditions is reasonable.
Controversy surrounds the use of testosterone to
enhance sexual desire in postmenopausal women. In
randomized placebo-controlled studies, women
who have undergone oophorectomy and treatment
with high doses of testosterone report increased
desire,
21
whether these results can be generalized to
naturally menopausal women and whether the high-
dose testosterone used is safe are debated.
22
Although
there are minimal supporting data,
23
a trial of low-
dose oral methyltestosterone (1.25 to 2.50 mg daily)
may be considered for women whose major com-
plaint is decreased desire. Although even low doses
of oral methyltestosterone can lead to acne, hir-
sutism, or virilization, it is relatively safe, especially if
used for less than 2 years.
24
Several population-based longitudinal studies
find no relation between menopause and depres-
sion.
25
However, one subgroup of women appear
more vulnerable to affective disorders during the
transition to menopause: cohort studies show that
women with a prior history of depressive illness are
at risk for a recurrence of depression during the
2 Principles of Womens Health
perimenopause.
26,27
However, the prevalence of clin-
ical depression in women presenting for medical
care around the time of the menopause is quite
high45% of the women attending one meno-
pause clinic.
28
The striking contrast between the
results of population-based research (concluding
no association between menopause and depression)
compared with rate of depression in clinical
samples seeking menopause care suggests a high
degree of self-selection on the part of women with
depressive symptoms.
Estrogen should not be used as monotherapy
for peri- and postmenopausal women with clinical
depression. However, a secondary analysis of a large
clinical trial suggested that estrogen augments
responsiveness to fluoxetine;
29
results of ongoing
studies attempting to replicate this finding are
awaited.
CHRONIC DISEASES
The occurrence of several major chronic diseases
may have a temporal relation to menopause
(Table 41). Rates of cardiovascular disease and
osteoporosis increase. There are proposed relations
between numerous other illnesses and menopause,
including osteoarthritis, cataracts, periidontal dis-
ease and tooth loss, colon cancer, and dementia. An
extensive review of the data supporting these associ-
ations is beyond the scope of this chapter. The read-
er is referred to recent reviews and manuscripts for
further information.
3037
POSTMENOPAUSAL HORMONE
THERAPY
In formulating a treatment plan for menopause, it is
critical to establish each patients objectives. If hor-
mone therapy is directed primarily at symptom
relief, it can usually be given for a relatively short
time or as local treatment, therefore obviating
potential concerns about long-termrisks. In contrast
estrogen for chronic disease prevention or treatment
generally is ongoing, thus requiring detailed consid-
eration of long-termbenefits and risks of treatment.
Postmenopausal hormones are recommended wide-
ly for primary prevention of cardiovascular disease.
38
This is described further in Chapter 33, Coronary
Artery Disease, and Chapter 46, Osteoporosis.
However, results of randomized controlled trials
with clinical heart disease and fracture outcomes are
not yet available.
A second overall consideration is that doses
and routes of hormone treatment for the menopause
vary according to indication. For example, peri-
menopausal hot flashes may temporarily need high
systemic doses of estrogen, whereas vaginal atrophy
may respond to very-low-dose local treatment.
Examples of commonly used systemic estro-
gen and progestin doses and regimens are summa-
rized in Table 42. These are considered standard, as
the estrogen doses are those shown to preserve bone
density in clinical trials, and the progestin doses and
regimens are those that prevent endometrial hyper-
plasia (evidenced by endometrial biopsy). Random-
ized controlled trials show that unopposed estrogen
causes endometrial hyperplasia,
39
a precursor to
cancer. Observational studies demonstrate a link
Approach to the Menopausal Patient 3
TABLE 41. Symptoms and syndromes that May Be Associated with Menopause and Postmenopause*
Perimenopause and Early
Postmenopause

Mid-postmenopause

Later Menopause

Irregular menses Stress incontinence Cardiovascular disease

Hot flashes Sensory-urge incontinence Osteoporosis
Dysphoric mood Urinary urgency Cognitive impairment
Interrupted sleep Dysuria Cataracts
Self-reported memory problems Dyspareunia Tooth loss
Atrophic vaginitis
* Associations between menopause and many of these symptoms and diseases are not definitive. Please see text and references.
5 years before to 5 years after onset of menopause.
5 to 10 years after onset of menopause.
10 or more years after onset of menopause.
between unopposed estrogen to endometrial can-
cer,
40
and also find that this risk is obviated by prop-
er use of progestins.
41
Continuous (daily) administration of estrogen
is recommended because daily use is easy to remem-
ber and avoids symptom breakthrough. Monthly
cyclic (progestogen used on calendar days 1 to 12
monthly) or daily continuous progestogen schedules
are recommended. These facilitate adherence and
also make it easy to characterize onset and duration
of vaginal bleeding related to cyclical progestogen
use. Am quarterly progestogen regimen (progesto-
gen given four times per year) is not recommended,
as this schedule has been associated with an unac-
ceptably high incidence of hyperplasia.
42
Each of the progestogen dose-duration regi-
mens shown in Table 42 has undergone testing in
clinical trials that used biopsy-based assessments of
the endometrium. However, the sample sizes and
lengths of studies have varied. For example, the safe-
ty of the cyclic 5-mg dose of MPA was tested in a
1-year study,
43
whereas that of the 10-mg dose has
been tested for up to 3 years.
39
Continuous daily reg-
imens of 2.5 mg or 5.0 mg of MPAhave been studied
for 3 years,
39
and each prevents endometrial hyper-
plasia equivalently. Because daily use of 5.0 mg of
MPA militates against estrogens beneficial lipid
effects more than does 2.5 mg of MPA, the lower
daily MPA dose is preferred. However, women who
are experiencing a lot of spotting and bleeding
during the first months of continuous estrogen and
progestin use benefit fromthe higher (5.0 mg) MPA
dose, as it promotes endometrial atrophy more
quickly than does the lower dose. Cyclically pre-
scribed micronized progesterone, 200 mg for 12 days
per month, when used for up to 3 years, does not
cause an excess hyperplasia.
39
Daily use of 100 mg of
micronized progesterone has been studied in only
small numbers of women and for short periods of
time (maximum 6 months); thus it is not recom-
mended at this time.
44,45
Systemic Estrogens
Estrogen can be given orally, transdermally (by
patch or cream), intradermally (by implantable pel-
let), and intramuscularly (by injection) (see
Table 42). The intradermal and intramuscular
modes of administration are not used commonly in
the United States and are not discussed further here.
All transdermal estrogen patches contain 17-
estradiol. There are reservoir systems, which are
alcohol based (eg, Estraderm) and matrix systems
(eg, Climara, Vivelle), in which the estrogen is in the
adhesive. Patches vary in the amount of 17- estra-
diol released, ranging from 0.035 to 1.0 mg per
24
hours. Non-oral estrogen administration circum-
vents first-pass liver metabolism and is therefore
particularly appropriate for women with high serum
triglycerides, with liver function abnormalities, or
who are at high risk for cholelithiasis. Skin rash
4 Principles of Womens Health
TABLE 42. Systemic Estrogen and Progestogen Doses and Regimens Used for Postmenopausal Hormone
Therapy
Generic Name Dose and Route Regimen
Estrogens
Conjugated equine estrogens 0.625 mg, PO Daily
Estropipate 0.625 mg, PO Daily
17- estradiol valerate 2.0 mg, PO Daily
17- estradiol patch 0.5 mg, topical Change 2 times/wk
17- estradiol gel 1.0 mg, topical Daily
Progestogens
Medroxyprogesterone acetate 510 mg, PO Calendar days 112
2.55.0 mg, PO Daily
Micronized progesterone 200 mg,PO Calendar days 112
Norethisterone 0.72.0 mg, PO Calendar days 112
0.350.5 mg, PO Daily
PO = per os (by mouth).
occurs in 10%of reservoir-based and 5%of matrix-
based patch users; these reactions occur more often
in tropical climates, likely due to high humidity.
46
Cutaneous 17- estradiol cream is available in
Europe; its main shortcoming has been difficulty
standardizing the amount applied. New metered-
dose measurement systems circumvent this prob-
lem; we may therefore see approval of this form of
administration in the United States. Creams may be
of use in those women who desire non-oral admin-
istration but prefer not to wear a patch or who are
intolerant to it.
Vaginal Estrogens
Vaginal estrogens are intended to have a local effect
on vaginal epithelial tissues without stimulation of
other estrogen-responsive tissues (eg, the endo-
metrium or the liver) or production of measurable
increases in estradiol or estrone levels as a result of
treatment. In recent years new methods of vaginal
delivery of estrogens have undergone careful testing
and appear to achieve some or all of these safety
goals; examples are listed in Table 43.
Because patients and physicians often raise
questions about the whether vaginal estrogen
administration is truly local treatment, some topical
vaginal estrogen studies are detailed. A 1-year trial of
low-dose (25 g) 17- estradiol vaginal tablets
resulted in no biopsy-assessed endometrial hyper-
plasia in 43 treated women,
47
although 3 women
developed weakly proliferative endometrial histol-
ogy. Estradiol, FSH, and luteinizing hormone were
unchanged. A 22-week intervention in 20 women
using 25-g 17- estradiol tablets similarly found no
endometrial hyperplasia.
48
Pooled data from12 stud-
ies of low-dose estriol vaginal cream (0.5 mg daily
for 2 to 3 weeks followed by 0.5 mg twice weekly) did
not demonstrate any endometrial proliferation in 61
biopsies taken after 6 months or in 58 additional
biopsies performed after 12 months.
49
Serum estriol
levels did rise, however, with low-dose estriol vaginal
cream.
50
Open-label nonplacebo controlled studies
of Estring, a vaginal ring that releases 17- estradiol,
7.5 g per 24 hours, used a progestin challenge test
(PCT) at 13 weeks to evaluate endometrial safety
(bleeding after administration of progestin indicates
endometrial stimulation).
51
In one study 5 of 122
participants had positive PCTs, and in another trial
2 of 58 challenges were positive. Endometrial biop-
sies performed on 4 of the 7 women with positive
PCTs were negative for hyperplasia. Two other stud-
ies raised some concerns about a possible systemic
effect of the vaginal estrogen ring. Estrone levels
increased to 950 pmol/L after 48 weeks of ring use
(within the postmenopausal range but higher than
baseline);
52
surprisingly, another small trial found
that the vaginal estradiol ring preserved bone densi-
ty.
53
Two older vaginal preparations, conjugated
equine estrogens cream and 17- estradiol vaginal
creamare not discussed here as there are no compre-
hensive data available for low-dose vaginal applica-
tion of these products.
Overall, low-dose estriol vaginal cream, the
17- estradiol vaginal tablet, and the vaginal estro-
gen ring appear safe with respect to the endometri-
um, causing weakly proliferative endometrial tis-
sue, at most. However, mildly increased serum
estrogen levels and estrogen effects on other tissues
such as bone have not been ruled out. Therefore, in
women in whom no systemic exogenous estrogen
exposure is desired, vaginal estrogens should be
used with caution.
Vaginal atrophy also can be managed with
moisturizers, such as Astroglide, Gyne-Moistrin,
Moist Again, and Replens. Replens decreases vaginal
pH and thus may offer some protection against
recurrent urinary tract infections, but it has not
been studied for this indication.
54
Progestogens
Progestogens, when used in appropriate doses and
for adequate duration, prevent endometrial hyper-
plasia; postmenopausal women without a uterus do
not require a progestogen as part of their hormone
Approach to the Menopausal Patient 5
TABLE 43. Vaginal Estrogen Preparations and Regimens
Generic Name Dose and Formulation Regimen
Estradiol ring Elasomer ring releases 7.5 (g estradiol/d Replace every 90 days
Estradiol cream 0.5-mg (0.5 g) cream is 1 mg/g 0.5 mg 2 times/wk
Estradiol tablet 25-g tablet 1 tablet 2 times/wk
therapy. Progestogens can be classifed as the C-21
derivatives of progesterone (eg, MPA and dydroges-
terone), C-19 derivatives of nortestosterone (eg,
norethisterone), and natural progesterone. Although
each of these subgroups differs with respect to effects
on intermediate end points, such as the impact on
serum lipid profiles,
55,56
cohort studies have not cor-
roborated a meaningful difference in clinical out-
comes
57
or risk factor profiles resulting from use of
differing classes of progestins.
58
Bleeding Patterns
The clinician must know the expected bleeding pat-
terns for each type of postmenopausal hormone
regimen, as aberrant bleeding signals the need for
investigation. When monthly cyclic progestogen in
is used, most women (estimates vary between 70 to
90%) have regular bleeding, commencing after the
ninth day of taking the progestogen. If vaginal
bleeding starts earlier than day 9, or if it is more
intense or longer in duration than the individuals
usual pattern, endometrial biopsy is advised.
Continuous combined estrogen-progestogen
regimens cause erratic spotting and bleeding for up
to 12 months after initiation. The higher (5 mg) dose
of daily MPAcauses more rapid cessation of bleeding
than does the 2.5-mg MPA daily dose.
59
Continuous
combined regimens induce endometrial atrophy,
which is the reason that bleeding ceases within the
first year of using this regimen. Because endometrial
atrophy is likely to be present already in older women
who have not used hormones since menopause, they
tend to have little or no bleeding with continuous
combined estrogen-progestin. Although few studies
of bleeding patterns in older women have been done,
one study of women aged 65 years and over when
continuous combined therapy was begun reported
that only 30%experienced any vaginal bleeding dur-
ing the first year.
60
When continuous estrogen-prog-
estin is prescribed, endometrial assessment is recom-
mended during the first year only if vaginal bleeding
is heavy or extended; this is a rather subjective judg-
ment. If bleeding continues beyond 12 months,
endometrial assessment is recommended.
Rarely, a woman with an intact uterus (eg,
someone who has been intolerant to any progesto-
gen regimen) will want to use unopposed estrogen.
In the longest trial of unopposed estrogen use (with
0.625 mg of conjugated equine estrogens), 62% of
women randomized to this treatment developed
endometrial hyperplasia over the 3 years of the
study; roughly half of the cases of hyperplasia were
complex or atypical.
39
Baseline and annual endome-
trial biopsies are necessary when using unopposed
estrogen, and any vaginal bleeding requires
endometrial biopsy assessment.
Endometrial Monitoring
Endometrial biopsy is necessary for surveillance of
endometrial safety during the use of unopposed
estrogen. Vaginal ultrasound is not helpful, as virtu-
ally all women taking unopposed estrogen develop a
double-layer endometrial thickness greater than
5 mm.
61
Thus, the specificity of vaginal ultrasound to
diagnose endometrial hyperplasia (using a 5-mm
cut point) is only 10%; this increases slightly, to 12%,
if simple hyperplasia is excluded fromconsideration.
Relaxing the abnormal criterion to a 9-mm double-
layer ultrasound thickness increases the positive pre-
dictive value to only 15%. Conversely, the negative
predictive value of a vaginal ultrasound thickness of
less than 5 mmused is 99%. However, because most
women using unopposed estrogen have a measure-
ment of greater than 5 mm, testing women with
ultrasound prior to performing a biopsy would sel-
domprevent the performance of biopsies.
When cyclic or continuous combined estrogen
and progestogen regimens are used, baseline or rou-
tine follow-up assessments of the endometrium are
unnecessary. However, evaluation is recommended
if bleeding does not cease after approximately 12
months of continuous combined hormone use, if
vaginal bleeding occurs prior to day 9 of cyclic
progestogen use, and if the patients bleeding pattern
changes markedly with either regimen. In the case of
continuous or cyclic combined hormone use, the
negative predictive value of a vaginal ultrasound
thickness of less than 5 mmis 99%for any degree of
endometrial hyperplasia.
61
At first it may seem that
vaginal ultrasound testing would be a good first test
to evaluate unscheduled or uncharacteristic bleed-
ing; however, approximately half of women taking
either cyclic or continuous combination therapy
develop an endometrial thickness of greater than
5 mm; thus, this strategy is not efficient one.
Contraindications and Complications
Undiagnosed vaginal bleeding, current breast or
endometrial cancer, and active deep vein thrombosis
are absolute contraindications to estrogen use. Other
6 Principles of Womens Health
medical conditions that require special consideration
with respect to safety, but do not exclude hormone
use, include cured stage 1 endometrial cancer,
melanoma, and breast cancer. Use of estrogen after
low-grade stage 1 endometrial cancer has not been
associated with adverse effects, and most experts find
it acceptable to prescribe hormone replacement in
such cases.
62
Although the data for an association
between melanoma and estrogen treatment are not
strong, the use of estrogen in this instance remains
controversial.
63
Recent years have witnessed contin-
ued debate over the use of postmenopausal hor-
mones by breast cancer survivors;
64
definitive evi-
dence for toxicity or safety does not exist. Oral estro-
gens may pose risks towomenwithhepatobiliary dis-
ease andhypertriglyceridemia. Transdermal estrogen
may be a safer choice, as it avoids first-pass hepatic
metabolism. Recent observational studies and a large
clinical trial have found that estrogens, both oral and
transdermal, increase the risk of deep vein thrombo-
sis by approximately two- to threefold.
6567
Estrogens
shouldtherefore be usedwithcautioninwomenwith
a history of venous thrombosis or in those who are at
high risk for this disease.
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Telephone (440) 442-7550
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Approach to the Menopausal Patient 9