Menopausal hormone therapy and

menopausal symptoms
Zain A. Al-Sa, M.D., and Nanette Santoro, M.D.
Division of Reproductive Endocrinology and Infertility, University of Colorado, Aurora, Colorado

A majority of women will experience bothersome symptoms related to declining and/or uctuating levels of estrogen during their
menopausal transition. Vasomotor symptoms, vaginal dryness, poor sleep, and depressed mood have all been found to worsen during
the menopausal transition. While vasomotor symptoms gradually improve after menopause, the time course can be many years. Vaginal
dryness does not improve without treatment, while the long-term course of sleep and mood deterioration is not clearly dened at this
time. A small minority of women have vasomotor symptoms that persist throughout the remainder of their lives. These common meno-
pausal symptoms all improve with estrogen treatment. Over the last 10 years, we have witnessed a dramatic reduction in enthusiasm for
menopausal hormone therapy, despite its high efcacy relative to other treatments. We have also seen the emergence of sound,
evidence-based clinical trials of non-hormonal alternatives that can control the common menopausal symptoms. Understanding the
natural history of menopausal symptoms, and the risks and benets of both hormonal and
non-hormonal alternatives, helps the clinician individualize management plans to improve
quality of life. (Fertil Steril 2014;101:90515. 2014 by American Society for Reproductive Use your smartphone
Medicine.) to scan this QR code
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W
omen nowadays spend more mood (36). This review will focus on night sweats are sometimes considered
than a third of their lifetime the common menopausal symptoms, unusually intense hot ashes that occur
beyond the menopausal along with hormonal and non- at night, it is not clear that they differ in
transition (1). With the progressive ag- hormonal treatments targeting these their pathophysiology or treatment
ing of the population, the proportion of conditions. from less intense hot ashes. It is
women who are menopausal is ex- Throughout this review, we will be believed that hot ashes and night
pected to continue to rise (2). Thus, referring to the Stages of Reproductive sweats interrupt sleep, as women
reducing the burden of menopause- Aging Workshop 10 staging system frequently subjectively cite VMS at
related health conditions and (7) for various stages of reproductive night as the source of this sleep distur-
improving overall quality of life aging (Fig. 1). bance (8), however, some laboratory
become increasingly important. studies do not support this notion (9).
Declining and/or uctuating levels of Between 60% to 80% of women
estrogen are associated with the meno- VASOMOTOR SYMPTOMS will experience VMS at some point dur-
pausal transition and may result in Vasomotor symptoms (VMS), ing their menopausal transition (3). The
bothersome symptoms. Those meno- commonly known as hot ashes/ frequency and severity of VMS peak in
pausal symptoms that have been shown ushes and night sweats, are sudden the late perimenopause and early post-
to be associated with the onset of the episodes of intense heat that usually menopausal years, with large ethnic
menopausal transition and to improve begin in the face or chest and spread and racial variation in prevalence, fre-
with hormones are vasomotor symp- throughout the body, accompanied by quency, and severity of symptoms (3).
toms, vulvovaginal atrophy/dyspareu- sweating and ushing that typically African-American women are most
nia, sleep disturbance, and adverse last 1 minute to 5 minutes (8). Although likely to report VMS and are also
more likely to describe them as bother-
Received December 2, 2013; revised and accepted February 18, 2014; published online March 6, 2014.
N.S. reports stock options with Menogenix and investigator-initiated grants from Bayer, Inc. Z.A.A.-S
some (10), whereas women of Asian
has nothing to disclose. background (Japanese and Chinese-
Reprint requests: Zain A. Al-Sa, M.D., Division of Reproductive Endocrinology and Infertility, Univer- American) are least likely to report
sity of Colorado School of Medicine, 12631 East 17th Avenue, Mail Stop B-198, Aurora,
Colorado 80045 (E-mail: zain.al-sa@ucdenver.edu). VMS, and are less likely to describe
them as bothersome (3, 10). These
Fertility and Sterility Vol. 101, No. 4, April 2014 0015-0282/$36.00
Copyright 2014 American Society for Reproductive Medicine, Published by Elsevier Inc.
racial/ethnic differences in VMS in the
http://dx.doi.org/10.1016/j.fertnstert.2014.02.032 Study of Women's Health Across the

VOL. 101 NO. 4 / APRIL 2014 905

VIEWS AND REVIEWS
FIGURE 1
The Stages of Reproductive Aging Workshop 10 staging system for reproductive aging in women. (Taken from Harlow. STRAW 10: staging
reproductive aging. Fertil Steril 2012.)
Al-Sa. Menopausal symptoms and hormone therapy. Fertil Steril 2014.
Nation (SWAN) persisted even after controlling for key
factors like body mass index, estradiol level, hormone use,
smoking, education and economic strain (difculty paying
for basic necessities) (3).
Obesity has been found to be a key risk factor for peri-
menopausal, but not postmenopausal, VMS. Women with
higher abdominal adiposity, particularly subcutaneous
adiposity, are more likely to report VMS in the early and
late perimenopause (11). Smoking has also been associated
with VMS, while other health behaviors such as dietary
composition, has weaker and less consistent associations
(3). While unadjusted data from SWAN showed association
of VMS with lower physical activity scores, no such associa-
tion existed after adjustment for other factors (3).
Women who experience premenstrual symptoms are at a
higher risk for VMS when they traverse the menopause (3).
VMS have been associated with all aspects of perceived
sleep disturbance that contribute to the subjective complaint
of poor sleep. These include falling asleep, staying asleep, and
early morning awakening (5).
Quality of life can be negatively affected by VMS, yet
remarkably little is known about their pathophysiology (12).
906
The main factors thought to inuence VMS occurrence and
severity include reproductive hormones, particularly estra-
diol, inherent thermoregulatory process within the individual,
and genetics (1318). Reproductive hormones are believed to
play an integral role as evidenced by the onset of VMS
occurring in the context of the dramatic reproductive
hormone changes of the menopausal transition and by the
therapeutic role of exogenous estrogen in their treatment.
Data from Penn Ovarian Aging Study showed that
uctuations of estradiol, decreased levels of inhibin B, and
increased FSH levels, were signicantly and independently
associated with menopausal symptoms (13). VMS are
believed to be thermoregulatory heat dissipation events,
although the exact mechanisms underlying VMS are not
entirely known. The thermoneutral zone in the
hypothalamus is narrowed in women with VMS (14). This is
believed to be the area of the brain in which core body
temperature is maintained without triggering
thermoregulatory homeostatic mechanisms such as
sweating or shivering. In symptomatic women, small
uctuations in core body temperature can exceed this zone
and trigger heat dissipation mechanism, such as sweating
VOL. 101 NO. 4 / APRIL 2014

and peripheral vasodilation (which is experienced as a hot
ash). Estrogen appears to widen this thermoneutral zone,
thus reducing VMS (15).
Finally, studies suggest a possible link between genetic
polymorphisms and prevalence and severity of VMS. These
involve variants in genes encoding estrogen receptor alpha
(16, 17) and single nucleotide polymorphisms involved in
the synthesis and metabolism of estrogens, such as those
affecting enzymes (like sulfotransferase and aromatase)
related to synthesis of and conversion to more or less potent
estrogens (18). These polymorphisms may alter sex steroid
hormone activity, but it is unknown whether these genetic
determinants exert their effects centrally or peripherally (12).
Longitudinal studies of the duration of women's experi-
ence of VMS have observed a median duration between 5
years to 10 years (19, 20). A small but signicant
percentage of women still report bothersome hot ashes 8
years after their nal menstrual period (21). The identied
predictors for VMS duration include earlier menopausal
stage at onset of VMS, younger age at onset of VMS, and/
or being African American. They were all associated with
longer duration of VMS, while obesity was associated with
a shorter duration (20).
Emerging data from SWAN have suggested a possible link
between VMS and adverse physical health outcomes such as
cardiovascular disease (CVD), as persistent VMS have been
associated with measures of subclinical CVD indicating higher
CVD risk, especially when associated with other CVD risk
factors, such as obesity (22, 23). VMS were also linked to
lower bone mineral density (24) and higher bone turnover (25).
In contrast, other population based studies indicate that
hot ashes with night sweats were associated with a reduced
risk of death over the following 20 years (26). Further inves-
tigation is required to explore the precise nature and reasons
for these associations.
VULVOVAGINAL ATROPHY
Vulvovaginal atrophy with its symptoms of vaginal dryness,
itching, dyspareunia, and irritation, is strongly and consis-
tently linked to estrogen deciency (27, 28). Similar to
VMS, vulvovaginal atrophy is highly prevalent in
menopausal and perimenopausal women. One survey study
observed a prevalence rate of 45% among a large sample of
women over the age of 45, progressing from 4% in early
perimenopause to 21% in late perimenopause to 47% by 3
years after the nal menstrual period (4). On the other hand,
data from the observational cohort of the Women's Health
Initiative (WHI) Study indicated a vulvovaginal atrophy
prevalence of 27% (29). Among Hispanic women within the
SWAN cohort, Central American women reported vaginal
dryness more frequently than Puerto Rican/Dominican,
South American, or Cuban women (30). Painful urination
and frequent urinary tract infections can also occur in
association with vulvovaginal atrophy. Unlike VMS,
vulvovaginal atrophy does not improve without treatment.
Other non-estrogen related etiologies for vulvovaginal
complaints need to be ruled out, as various inammatory
conditions of the vulva like contact dermatitis, squamous
VOL. 101 NO. 4 / APRIL 2014
Fertility and Sterility
hyperplasia, or lichen sclerosis can also cause such complaints
(31). Evaluation should include inquiring about the use of
exogenous agents like soaps, perfumes, powders, or panty
liners, as these may mimic or exacerbate vulvovaginal irritation
due to atrophy. Physical examination should include inspec-
tion of the vulva for obvious lesions, dermatoses, erythema,
or inammation, as well as signs of vaginal atrophy. Micro-
scopic examination of vaginal smears can be used to assess
the vaginal maturation index, which is the ratio of parabasal,
intermediate, and supercial squamous cells. Vaginal pH can
also be clinically useful to determine hormonal inuence (31).
SLEEP DISTURBANCES
Sleep quality declines with age, but the menopausal transition
appears to contribute to this decline in women (32). Virtually
all markers of subjective sleep quality seem to be impacted by
the process of menopause. Self-reported measures of sleep
quality include assessments of sleep latency, sleep duration,
and wakefulness (33), while objectively measured sleep
quality assesses sleep continuity, duration, and architecture
as well as measures of sleep apnea (34, 35). Self-reported
poor sleep increases as women traverse the menopause, it
was reported in 38% of the 12,603 women who participated
in the cross-sectional survey of the SWAN Study (32). As
with most menopausal symptoms, severity and prevalence
seem to peak during the late menopausal transition, when
women are undergoing prolonged amenorrhea (32).
Mechanisms through which VMS inuence reports of
poor sleep are not entirely known. It was found that hot
ashes occurring in the rst half of the night were associated
with more awakenings and arousals than those occurring in
the second half, possibly because rapid eye movement sleep,
which is more frequent in the second half of the night, sup-
presses thermoregulation (36).
A signicant proportion of women nd perimenopause as
a particularly challenging period of life for preserving good
sleep (37). SWAN data indicate that the menopausal transition
is related to self-reported sleep difculty, independent of age
(32), indicating that age is not the primary determinant of
the perimenopausesleep relationship. Likewise, it was found
that the perimenopause-sleep relationship is not entirely ex-
plained by VMS, as subgroup analyses restricted to women
without VMS continue to nd an association between the peri-
menopause and poor sleep quality (32). A number of additional
variables that were associated with sleep difculty included
psychological (depression, anxiety) symptoms, self-perceived
health, quality of life, less physical activity, current smoking
and arthritis (32). Prevalence of sleep difculty increased
from premenopause to late perimenopause and plateaued
through postmenopause, decreasing slightly in age-adjusted
analyses from 45% in late perimenopause to 43% in postmen-
opause (32). Primary sleep disorders, such as sleep apnea and
periodic limb movement disorder were also common at this
age group, with 53% of women having either one or both in
one cross-sectional study of women who reported disturbed
sleep (35), and a lower prevalence in other studies (34). Beyond
quality of life, sleep disturbances may increase the risk for
developing adverse health conditions such as the metabolic
907
VIEWS AND REVIEWS

syndrome and prelude to cardiometabolic disease (38). When Non-Hormonal. When menopausal hormone therapy (MHT)
evaluating women with sleep disturbances, it is important to is contraindicated (e.g. a history of breast cancer) (Table 2),
exclude other medical (e.g. chronic obstructive pulmonary dis- or by patient preference after counseling on the risks and
ease, hyperthyroidism), and psychiatric disorders (e.g. depres- benets of MHT, non-hormonal medications can be used
sion, anxiety), or medications (e.g. decongestants) that can to alleviate menopausal symptoms. Trials for these medica-
contribute to sleep difculty (39). tions provide evidence for efcacy, although they are less
effective than estrogen (52), which often makes them subop-
timal for the most severely affected women. With the excep-
MANAGEMENT OF MENOPAUSAL tion of the low-dose paroxetine 7.5 mg for treatment of
SYMPTOMS VMS, non-hormonal alternatives are not approved by the
Vasomotor Symptoms Food and Drug Administration (FDA) for this indication,
Lifestyle modications are an appropriate rst step to consider and thus prescribing them is off-label. A list of these med-
before initiating, or in conjunction with, pharmacologic thera- ications, with their common doses and side effects is sum-
pies for VMS. These include avoiding smoking, and moderate marized in Table 3.
alcohol use, as they were associated with VMS (3, 40). Selective Serotonin Reuptake Inhibitors and Serotonin
Despite limited supporting data, common sense lifestyle Norepinephrine Reuptake Inhibitors. Selective serotonin re-
solutions such as dressing in layers, maintaining a low uptake inhibitors (SSRIs) have been found efcacious in the
ambient temperature, and consuming cool drinks are treatment of VMS based on a number of randomized clinical
reasonable measures for managing VMS (41). Aerobic trials (5355). Once initiated, VMS relief usually occurs within
exercise has not been associated with a consistent reduction a week (53), a far more rapid effect than the relief of
in VMS (42), however, it favorably affects mood, perceived depressive symptoms, which usually takes 6 weeks or
stress, and body image (19), and also decreases body weight, longer. Paroxetine and uoxetine are among the rst SSRIs
all of which may render VMS less bothersome. The WHI's that have been used to treat hot ashes. Doses of either 12.5
dietary intervention trial indicated that weight loss was mg/day or 25 mg/day of paroxetine were studied in a
associated with a decreased prevalence of VMS among randomized, controlled trial of 165 women who were
postmenopausal women (43). Other non-pharmacologic thera- treated for 6 weeks. Both doses signicantly reduced hot
pies that have been studied for treatment of VMS and showed ashes composite scores (62.2% and 64.6%) when
possible benet include paced respiration, a type of slow, deep compared with placebo (37.8%) (53). Paroxetine was
breathing that requires training (44), clinical hypnosis (45), recently approved by the FDA in a 7.5 mg formulation for
cognitive behavioral therapy (46), and mindfulness based stress the treatment of VMS. Furthermore, a randomized, placebo-
reduction (47). These are summarized in Table 1. Most of these controlled trial of 20 mg uoxetine administration in 81
interventions are useful for mild-moderate symptoms as the ef- breast cancer survivors showed a reduction in hot ashes
fect is small and study designs frequently preclude denitive by 20% in women treated with uoxetine for 4 weeks when
conclusions. These treatments have essentially no harm associ- compared to the placebo treated group (54). Escitalopram,
ated with their use, and thus they are very attractive to patients.
Although not widely used at this time due to limited efcacy for
severe symptoms, further studies may prove some of these in- TABLE 2
terventions to be effective for the more bothersome VMS.
Acupuncture was not shown to have benet over placebo for Contraindications for menopausal hormone therapy.
VMS in a meta-analysis (48). A similar lack of efcacy was
Condition Reason for contraindication
observed for yoga (49) and omega-3 supplementation (50).
Other causes of ushing need to be ruled out in these History of breast or May be exacerbated with hormones
endometrial cancer
women, such as emotional ushing, autonomic epilepsy, hy- Porphyria May be exacerbated with hormones
perthyroidism, medications (e.g. calcium channel blockers), History of thromboembolic May increase risk for
alcohol related ushing, pheocromocytoma, and carcinoid disease thromboembolism
syndrome (51). Unexplained vaginal bleeding Need to rule out neoplasia, as it may
be exacerbated with hormones
Active liver disease Estrogen is metabolized in the liver
Acute cardiovascular disease May be exacerbated with hormones
TABLE 1 Immobilization May increase risk for
thromboembolism
History of coronary artery May be exacerbated with hormones
Nonpharmacologic interventions that have been studied and showed disease or stroke
possible benet for treatment of vasomotor symptoms. Hypertriglyceridemia May increase risk for
Intervention Reference thromboembolism
Atypical ductal hyperplasia May increase risk of progression to
Stellate ganglion blockade 109 of the breast malignancy
Paced respiration 44 Uncontrolled hypertension May increase risk of cardiovascular
Clinical hypnosis 45 disease
Cognitive behavioral therapy 46 Active gallbladder disease May be exacerbated with hormones
Mindfulness based stress reduction 47 Migraine headaches May increase risk of stroke
Al-Sa. Menopausal symptoms and hormone therapy. Fertil Steril 2014. Al-Sa. Menopausal symptoms and hormone therapy. Fertil Steril 2014.

908 VOL. 101 NO. 4 / APRIL 2014

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The mechanism of action of SSRIs or SNRIs in relieving

TABLE 3
VMS is not known, it has been hypothesized that temperature
Nonhormonal medications for treatment of vasomotor symptoms.
increases associated with VMS could be linked to an over-
loading of serotonin-receptor sites in the hypothalamus
Common side
Treatment Dose effects (53). SSRIs, especially paroxetine and uoxetine, must be
used with caution in women with breast cancer receiving
Paroxetine 7.5 mg/d25 mg/d Nausea, headache,
insomnia, and
adjuvant tamoxifen therapy since SSRIs reduce the meta-
possible sexual bolism of tamoxifen to its most active metabolite, endoxifen,
dysfunction by inhibition of the cytochrome P450 enzyme, CYP2D6, an
Fluoxetine 20 mg/d Nausea, headache, effect that was not seen with venlafaxine (63).
insomnia, and
possible sexual Sexual dysfunction has been reported with SSRIs and
dysfunction SNRIs when used in treatment for depression, ranging from
Escitalopram 10 mg/d20 mg/d Nausea, headache, 32.5% in one study (64) to 5873% in another (65). However,
insomnia, and
possible sexual
this adverse effect has not been observed in studies assessing
dysfunction the usefulness of lower doses of paroxetine or venlafaxine for
Venlafaxine 37.5 mg/d, 75 mg/d, Nausea or vomiting, treatment of VMS (53, 62, 66). One explanation for this
or 150 mg/d dry mouth, discrepancy, therefore, may be related to dosing. Another
anorexia, and
possible sexual explanation may be that the depression requiring treatment
dysfunction with the SSRI or SNRI is the root cause of the sexual
Clonidine Oral dose: 0.025 mg/ Dry mouth, insomnia, dysfunction (67, 68). When sexual dysfunction occurs,
twice daily0.075 drowsiness, skin management strategies usually include changing to another
mg/twice daily; reaction with the
transdermal dose: transdermal skin medication (69), or adding a sexual stimulant such as
0.1 mg/d patch buspirone (70).
Gabapentin 100 mg/d900 mg/ Dizziness, Although the reduction is not as large as what is seen with
d in divided doses unsteadiness and
drowsiness
MHT (usually 75% to 80%), the SSRIs result in a modest
Al-Sa. Menopausal symptoms and hormone therapy. Fertil Steril 2014.
improvement in symptoms and are acceptable for many
women (51), but adverse effects may prohibit their use for
others. These therapies may be most useful for highly symp-
another SSRI, was found in a randomized controlled trial to be tomatic women who cannot take estrogen (52).
effective in reducing hot ashes when compared to placebo. A
dose of 10 mg/day to 20 mg/day for 8 weeks improved Clonidine. Clonidine, an a2-adrenergic agonist, may resolve
women's quality of life and this benet did not vary by base- VMS by reducing peripheral vascular reactivity. Data also
line demographic, clinical, mood, sleep, or other symptom have shown that clonidine lowers hypothalamic norepineph-
variables (55). The most common side effects of SSRIs are rine levels (71) and raises the sweating threshold in symptom-
nausea, headache, and insomnia. Use of the lowest possible atic postmenopausal women (72) suggesting a possible
dose may minimize these effects. central mechanism of action on thermoregulatory centers.
Ever since the identication of serotonin receptors and Trials of clonidine in doses ranging from 0.025 mg twice daily
transporters in osteoblasts, osteocytes, and osteoclasts (56 to 0.075 mg twice daily for the oral dose and 0.1 mg per day
58), concern has been raised that medications that block for the transdermal dose reported inconsistent results, with
serotonin reuptake may affect bone metabolism, resulting in approximately half of trials demonstrating signicantly
bone loss. Data from one longitudinal study showed an reduced hot ash frequency or severity for up to 38% reduc-
association of increased bone loss with SSRI use in older tion in hot ash frequency compared with 24% for placebo
women (mean age, 80 years) (59), while another one using (73). Although most trials met criteria for poor quality, the 3
data from the WHI did not observe such an association (60). fair quality trials provided a combined estimate of approxi-
Finally, data from SWAN showed that SSRI use does not mately 1 hot ash per day reduction with clonidine (52).
appear to have adverse effects on bone loss during the Main adverse effects included dry mouth, insomnia, drowsi-
menopausal transition (61). ness, and skin reaction with the transdermal skin patch.
Venlafaxine is a combined serotonin and norepinephrine Postural hypotension is also a potential concern with
reuptake inhibitor (SNRI) that has shown promise in reducing clonidine.
the severity of VMS in symptomatic women. A randomized Gabapentin. Gabapentin provides another potential non-
trial was conducted in 229 women for 4 weeks where women hormonal therapeutic option for the treatment of VMS. One
received varying doses of venlafaxine (37.5 mg/day, 75 mg/ randomized controlled trial of gabapentin (900 mg/day)
day, or 150 mg/day) versus placebo. There was a signicant demonstrated a 45% reduction in hot ash frequency and a
reduction in VMS scores in women receiving all doses of ven- 54% reduction in symptom severity compared with 29%
lafaxine in comparison to the placebo (37%, 61%, and 61%, and 31% reductions, respectively, for placebo (74). Another
compared to 27% for placebo) (62). Common side effects randomized, double-blind, placebo-controlled trial (75) was
included nausea, which is temporary in most cases and largely conducted on 197 women aged 45 years to 65 years, all of
resolved with time (62). Other side effects include mouth dry- whom were menopausal and having at least 14 hot ashes
ness, and anorexia. per week. These women were randomized to receive either

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VIEWS AND REVIEWS
gabapentin 900 mg daily or placebo for 4 weeks. Of women
assigned to receive gabapentin, hot ash scores decreased
by 51% as compared with a 26% reduction in the placebo
group, from baseline to week 4. Women randomized to gaba-
pentin reported greater dizziness, unsteadiness and drowsi-
ness at week 1 compared with those taking placebo;
however, these symptoms improved by week 2 and returned
to baseline levels by week 4. A 2009 meta-analysis conrmed
these results (76). Therefore, gabapentin seems to be an effec-
tive and well-tolerated treatment for VMS, and may be espe-
cially helpful for women whose chief complaint is night
sweats and resulting poor sleep. Gabapentin is also effective
in treatment of restless leg syndrome (77), a common disorder
that might be responsible for poor sleep. A gastroretentive
(extended release) form of gabapentin has been studied and
shown to be modestly effective in treatment of VMS
compared to placebo (78), with lower rates of dizziness and
somnolence that decreased throughout the study.
The mechanism of action of gabapentin is unclear.
Increased activity of neurotransmitters in the hypothala-
mus as a consequence of up-regulation of the gabapentin
binding site from estrogen withdrawal has been proposed
(79). Gabapentin might exert its effect on VMS by this
mechanism.
Menopausal Hormonal Therapy. Estrogen, with or without a
progestogen, is the most effective treatment for menopause
related VMS and urogenital atrophy (80, 81). Since the
publication of the WHI trials results, the last 10 years have
witnessed dramatic changes in the approach to the
management of menopause. The lack of effectiveness of
MHT for long-term cardioprotection and a number of small
increases in harms have led to a movement away from this
treatment. The most concerning risk of combined estrogen-
progestin MHT was a small but increasing risk of breast can-
cer over time (82). This risk was not present in women who
have had a hysterectomy and took estrogen alone (83). A
recent analysis of the long-term outcomes of women from
the WHI indicates that short-term use of hormones, as given
in the WHI, is associated with little increased overall risk (84),
and they remain a viable option for symptom relief.
Estrogen reduces the severity and frequency of VMS by
more than 70%, usually within one month (85). However, es-
trogen treatment is associated with a small but signicantly
increased risk of some serious diseases, specically stroke
and venous thromboembolism (VTE) (83, 86). When
combined with a progestin, there is an additional increased
risk of breast cancer (82), and a marginal risk for increased
coronary events, which dissipates over time (87). Breast
tenderness and uterine bleeding are among the most
common adverse effects; others include nausea and
vomiting, headaches, weight change, rash and pruritus, and
cholecystitis.
Vulvovaginal Atrophy
Until very recently, estrogen was the only effective prescrip-
tion treatment for moderate to severe symptoms of vulvar and
vaginal atrophy (e.g., vaginal dryness, dyspareunia, and atro-
phic vaginitis) (88). Over-the-counter lubricants and moistur-
910
izers may be tried, but are seldom benecial for the more
severely affected women. Locally administered estrogen is
available as a cream, gel or pill and can be used to relieve
vaginal dryness and dyspareunia. In the low doses commonly
available, opposing the estrogen with progestin is not neces-
sary; however, endometrial safety should not be assumed and
any abnormal vaginal bleeding should be investigated imme-
diately (80). Some clinicians may prefer to conduct ongoing
endometrial surveillance when low dose vaginal preparations
of estrogen are used for a prolonged period of time, as clinical
trial data supporting endometrial safety beyond 1 year are
lacking (89).
Even though both systemic and local estrogen regimens
are FDA approved for treating symptomatic vaginal atrophy,
some of the very low dose systemic estrogen regimens may be
inadequate for the relief of these symptoms, requiring the
addition of local estrogen. However, if MHT is considered
solely for the treatment of vaginal atrophy, local vaginal es-
trogen is advised over systemic estrogen. Lower doses of
vaginal estrogen therapy than previously used, with less
frequent administration, often yield satisfactory results (90).
Estrogen Receptor Agonist/Antagonist. Ospemifene is a
novel non-steriodal, non-hormonal estrogen receptor
agonist/antagonist, also known as selective estrogen receptor
modulator (SERM), which was recently approved by the FDA
for use in treatment of dyspareunia related to menopausal
vulvovaginal atrophy. A randomized, controlled trial
compared oral 60 mg/day of ospemifene to placebo for 12
weeks and indicated signicant benecial changes in the
vaginal epithelium and reduction in dyspareunia, with hot
ashes as the most frequently reported adverse event that
occurred in 6.6% of participants in the ospemifene group
(91). In this study, all participants that were randomized
had moderate-severe dyspareunia. The percentage of partici-
pants, in the intent to treat analysis, reporting no vaginal pain
or mild vaginal pain with sexual activity on week 12 was
greater in the ospemifene group (38.0%, and 25.1%, respec-
tively) than in the placebo group (28.1% or 19.2%, respec-
tively). Other reported adverse events included urinary tract
infection, vaginal discharge, vulvar and vaginal mycotic in-
fections, nasopharyngitis, and headache. All participants in
that study were provided with non-hormonal lubricants to
be used as needed, with a similar proportions of participants
use in the rst week of the study, and then the percentage
of women using lubricants somewhat decreased for both
groups, but more so in the ospemifene group (91). Ancillary
studies suggest a possible benecial effect of ospemifene on
bone, reducing bone turnover, as was assessed using urinary
markers for bone resorption and formation in one clinical trial
(92). Also, animal studies suggested antiestrogenic activity in
breast cancer models similar to tamoxifen and raloxifene (93).
Further studies will be needed to address these endpoints as
well as dening its safety prole for long-term use.
Sleep Disturbances
As far as the role of MHT in treatment of perimenopausal sleep
disturbances, it was found that MHT alone might be insuf-
cient intervention for improving sleep quality except in
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 Fertility and Sterility

postmenopausal women (5). Nonetheless, the clinician may
decide, in partnership with the patient, to try empiric MHT
along with behavioral methods to improve sleep. Cognitive-
behavioral interventions can be very helpful in treatment of
insomnia, and improve sleep; these may include sleep hygiene
education, stimulus control, and relaxation training. These
methods are comparable with or superior to hypnotic medica-
tions (39). For some women, the consolation that sleep will
improve somewhat after the menopausal transition is
sufcient.
MENOPAUSAL HORMONAL THERAPY
REGIMENS
The symptom relief from MHT is primarily due to the estrogen.
A progestin is added to negate the increased risk of endome-
trial cancer from systemic estrogen use. All women with an
intact uterus need to be prescribed an adequate progestin in
addition to estrogen.
Progestins can be given continuously or in a cyclic
fashion. Cyclic regimens are more likely to cause withdrawal
bleeding than are continuous regimens (94). The cyclic regi-
mens were theoretically aimed at decreasing the duration of
exposure to progestins to mitigate long-term risks associated
with MHT, especially breast cancer. However, in the absence
of evidence that a cyclic regimen is superior, patient prefer-
ence seems like the most reasonable approach. The most
comprehensive data on breast cancer risk with combined
estrogen-progestin come from the WHI (82). It should be
recognized that medroxyprogesterone acetate was given
continuously and it is possible but not proven that other reg-
imens of progestins would have a different breast cancer risk
prole. Progestins may be administered orally, transdermally,
or vaginally. The use of a levonorgestrel-containing intra-
uterine system has also been advocated to minimize systemic
exposure to progestins while providing endometrial protec-
tion, with one small study reporting equivalent endometrial
protection compared to a systemic progestogen (95). Long-
term data, however, are lacking. Vaginal progesterone and
the progestin-containing intrauterine system are FDA
approved for premenopausal women but not for postmeno-
pausal women.
The type of progestin is also being investigated to deter-
mine whether the breast cancer risks of combined estrogen
and progestin MHT can be mitigated. Micronized progester-
one has been suggested to be safer than medroxyprogesterone
acetate used in the WHI trials, based on observational data
(96, 97).
Estrogen dose and routes of administration also vary in
regard to their risks. Lower doses are associated with less
adverse effects like breast tenderness or uterine bleeding,
and may have a more favorable benet-risk ratio than stan-
dard doses. Transdermal estrogen is preferred to the oral
route, as the latter is subject to rst-pass hepatic metabolism
which promotes prothrombotic hemostatic changes in factor
IX, activated protein C resistance, and tissue-plasminogen
activator (98). Furthermore, observational data from the Es-
trogen and Thromboembolism Risk (ESTHER) Study, a

TABLE 4

Menopausal hormone therapy preparations.

Preparation Starting dose Comments
Estrogen
Oral
17 b-Estradiol 0.5 mg/d 1 tablet/d
Ethinyl estradiol 2.5 mcg/d 1 tablet/d
Conjugated estrogen 0.3 mg/d0.45 mg/d 1 tablet/d
Transdermal
17 b-estradiol patch 0.014mg/d0.0375 mg/d 1 patch twice/wk
17 b-estradiol gel 0.25 mg/d or 0.75 mg/d 0.25 g gel daily
1.25 g gel daily
17 b-estradiol spray 1.53 mg/d 1spray daily
17 b-estradiol emulsion 8.7 mg/d 2 foil-laminated pouches/d
Vaginal
17 b-estradiol vaginal cream 0.2 mg (2 g of cream)/d 2 g4 g daily for 2 wk, then taper to
maintenance dose of 1 g 1 to 3 times/wk
Conjugated estrogen vaginal cream 0.3125 mg (0.5 g of cream)/d 0.5 g daily for 21 d on and 7 d off or twice/wk
17 b-estradiol vaginal tablet 10 mcg/d 1 tablet/d for 2 wk, then 1 tablet twice/wk
17 b-estradiol vaginal ring 2 mg/ring (7.5 mcg/d) or 1 ring/90 d
12.4 mg/ring (50 mcg/d)
Progestogen
Oral
Medroxyprgosesterone acetate 1.5 mg/d2.5 mg/d Daily in combination preparations or 14 d/mo; 1.5 mg
with 0.3 mg of conjugated estrogen combination
Norethindrone acetate 0.1 mg/d Daily in combination preparations or 14 d/mo
Drospirenone 0.25 mg/d Daily
Micronized progesterone 100 mg/d200 mg/d 100 mg/d continuously or 200 mg/d for 12 d/mo
Transdermal
Norethindrone acetate 0.14 mg/d 1 patch twice/wk
Levonorgestril 0.015 mg/d 1 patch/wk
Al-Sa. Menopausal symptoms and hormone therapy. Fertil Steril 2014.

VOL. 101 NO. 4 / APRIL 2014 911

VIEWS AND REVIEWS
multicenter case-control study of thromboembolism among
postmenopausal women, demonstrated an odds ratio for
venous thromboembolism in users of oral estrogen to be
4.2 (95% CI, 1.511.6) and 0.9 (95% CI, 0.42.1) for trans-
dermal estrogen, compared to nonusers (86). This approach
has been endorsed by the American College of Obstetricians
and Gynecologists, as gynecologists were recommended to
take into consideration the possible thrombosis-sparing
properties of transdermal forms of estrogen therapy (99).
Various MHT regimens with dose ranges are summarized
in Table 4.
NEWER TREATMENT MODALITIES
Tissue Selective Estrogen Complex
Tissue selective estrogen complex (TSEC) is a combination of
estrogen and a SERM. In an attempt to mitigate the adverse
effects from combining a progestin with estrogen, specif-
ically breast cancer, TSECs were developed so to retain the
efcacy of estrogens in treating menopausal symptoms
and preventing osteoporosis while ensuring tissue safety
via the non-stimulating effects of a SERM on the uterus
and breast (100). Bazedoxifene is a SERM that acts as an es-
trogen receptor antagonist in the endometrium and on breast
cancer cells treated with estrogen, but acts as an estrogen
agonist on bone (101).
A combination conjugated estrogen 0.45 mg and 20 mg
bazedoxifene tablet has been recently approved by the FDA
for the treatment of menopausal symptoms and the preven-
tion of osteoporosis in non-hysterectomized women, and
was found effective in reducing VMS frequency and severity,
as well as sleep parameters when compared to placebo (100). It
can be an alternative to conventional combined estrogen-
progestin therapy. Its efcacy and safety have been evaluated
in randomized controlled trials (102, 103), but long-term data
are lacking.
DURATION OF MENOPAUSAL HORMONAL
THERAPY AND FOLLOW-UP
The duration of MHT should be based on a woman's symp-
toms, preferences, and her benet-risk prole. The North
American Menopause Society has indicated that extending
estrogen-progestin therapy with the lowest effective
dose is acceptable if it is determined that the benets of
menopausal symptom relief outweigh the risks. Women at
high risk of fracture, for whom alternate therapies are not
appropriate or cause unacceptable adverse effects, may
also choose to continue with MHT (80). Women who
continue MHT well beyond their menopause should be
well aware of the potential benets and risks and have
ongoing clinical supervision (80). It is still agreed upon
that providers should prescribe the lowest dose of MHT
for the shortest duration needed to manage menopausal
symptoms. For combined estrogen and progestin, the dura-
tion is limited by a cumulative risk of breast cancer. This
increased risk becomes detectable by 3 years to 5 years of
use (104, 105). Estrogen only therapy has a more
favorable safety prole. When observed over 7 years of
912
use and over 6 years of follow up, a signicant decrease
in breast cancer was observed (84), allowing more
exibility in duration of use. Thus, because symptoms
can remit over time, periodic weaning is recommended to
assess the need for MHT. There is no documented
schedule for periodic weaning that has been shown to be
better than others. Annual to biannual withdrawal has
been recommended.
DISCONTINUATION OF MENOPAUSAL
HORMONAL THERAPY
VMS have an approximately 50% chance of recurring when
MHT is discontinued, independent of age and duration of
use (106, 107). Bone resorption accelerates when MHT is
discontinued, and vulvovaginal atrophy should be expected
to recur. Other risks and benets return relatively rapidly to
baseline, with the exception of breast cancer, which persists
somewhat longer (a few years) (108).
CONCLUSION
Menopausal symptoms are better understood than ever
before, as we have accumulated a number of cohorts of lon-
gitudinal data to elucidate their natural history. We have a
wider repertoire of agents for successful treatment. The choice
of a particular modality should be guided by the patient's risk
prole, other symptoms and preferences. Although hormones
are overall the most effective for treatment of menopausal
symptoms, some patients may choose non-hormonal treat-
ments or they may be contraindicated. The available
non-hormonal therapies can be individualized based on their
primary mode of action, for example a woman with hot
ashes and restless leg syndrome as her primary complaints
and doesn't wish to take hormones, gabapentin would be a
rst choice, or a hypertensive woman who has vasomotor
symptoms and estrogen is contraindicated, may benet
from clonidine. We have also accrued substantial knowledge
about the risks of MHT which can be mobilized to derive new
agents that avoid or mitigate these risks.
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