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and epidemiologic studies, clarify the favorable benet-risk prole for MHT use by
recently menopausal women with bothersome vasomotor and related menopausal
symptoms.
• A Cochrane review of double-blind, randomized, placebo-controlled trials of
oral MHT concluded that estrogen therapy, alone or in combination with proges-
togens, is highly effective in alleviating hot ushes and night sweats. Hot ush
frequency was reduced 75%, and severity decreased as well [16]. The dropout
rate due to side effects was only marginally increased in the MHT groups.
22.4.1 Tibolone
Tibolone is a drug with complex tissue-specic action that exhibits a combination
of estrogenic, progestogenic, and slight androgenic activity. Its variable prole
explains its clinical effects, depending on the target tissue where it is metabolized,
its metabolites’ afnity for and potency in hormone receptors, and probable enzy-
matic activity modulation. Tibolone, used at the daily dose of 2.5mg, may be less
effective than combined MHT in alleviating menopausal symptoms although it
reduced the incidence of vaginal bleeding [17]. There are the same concerns about
their long-term safety as with estroprogestins [18].
22.4.2 Conjugated Estrogen-Bazedoxifene
The combination of conjugated estrogen with a selective estrogen receptor modula-
tor (SERM), bazedoxifene, also called tissue-selective estrogen complex (TSEC),
is projected as a progestogen-free option for the treatment of estrogen deciency
symptoms in postmenopausal, non-hysterectomized women. A combination con-
jugated estrogen 0.45 and 20mg bazedoxifene tablet is effective in reducing VMS
frequency and severity, as well as sleep parameters when compared to placebo [19].
In addition, TSEC has shown improvements in quality of life and vaginal atrophy.
In respect to MHT using progestogens, the benets of TSEC are found mainly in
the bleeding pattern, amenorrhea rate, and reduction in mammary repercussion (i.e.,
breast tenderness and radiological density) [20]. It can be an alternative to conven-
tional combined estrogen-progestin therapy. Its efcacy and safety have been evalu-
ated in randomized controlled trials (RCT) compared with placebo or menopausal
hormone therapy (MHT) [21], but long-term data are lacking.
22.5 MHT andOther Menopause-Related Symptoms
Other menopause-related symptoms including mood swings, sleep disturbance,
sexual dysfunction, and myalgia may improve with MHT [22].
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22.5.1 Sleep Disturbance
Poor sleep quality is common in recently menopausal women. Sleep quality
improved with MHT formulations. The relationship of VMS with domains of sleep
suggests that assessing severity of symptoms and domains of sleep may help direct
therapy to improve sleep for postmenopausal women [23].
22.5.2 Mood Lability/Depression
During the menopausal transition, there is an increased risk of depressive symp-
toms and depressive disorders. Although there are few trials, it seems that treat-
ment with estrogens, alone [24] or combined with progesterone [25, 26], which
could minimize estradiol (E2) uctuation and/or withdrawal, is an effective
treatment for perimenopausal depression. MHT, alone or in combination with
an antidepressant as a selective serotonin reuptake inhibitor (SSRI), is effective
for women who experience lability or depression of mood during the perimeno-
pause [27].
22.5.3 Joint Aches andPains
It is unclear whether the pain is related to estrogen deciency or a rheumatologic
disorder, but MHT has been shown to have some benet in alleviating arthral-
gia associated with menopausal transition and can be considered in women who
report distressing vasomotor symptoms [28, 29]. SERMs and estrogen may rep-
resent therapeutic options to treat joint diseases in the future [30]. A new group
of estrogen- related drugs, TSECs, may have the potential to protect other joint
tissues [31].
22.5.4 Sexual Function
The perimenopausal and postmenopausal periods are associated with many symp-
toms, including sexual complaints. MHT treatment with estrogens alone or in com-
bination with progestogens was associated with a small to moderate improvement
in sexual function, particularly in pain, when used in women with menopausal
symptoms or in early postmenopause (within 5years of amenorrhoea), but not in
unselected postmenopausal women. Since oral estrogen increases the liver’s pro-
duction of sex hormone-binding globulin, resulting in lower free (bioavailable)
testosterone, sexuality concerns may represent a reason to prefer the use of trans-
dermal as opposed to oral estrogen [32].
Evidence regarding other MHTs (synthetic steroids and SERMs) is of low qual-
ity, and we are uncertain of their effect on sexual function. The current evidence
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does not suggest an important effect of tibolone or of SERMs alone or combined
with estrogens on sexual function [33]. Available data are not adequate to pro-
vide counseling by the physicians in menopausal women regarding the efcacy
of vaginal therapies as an alternative to estrogens, on all parameters of sexual
function [34].
22.6 Urogenital Atrophy
The female genital and lower urinary tracts share a common embryological origin,
arising from the urogenital sinus, and both are sensitive to the effects of the female
sex steroid hormones, which may be the reason for frequent symptoms related to
the lower urinary tract in menopause [35]. Recently, a panel of experts incorporated
this increased frequency of urinary tract symptoms into a unifying concept called
“genitourinary syndrome of menopause” (GSM) [36]. While the creation of a new
medical entity has been widely debated and criticized, it highlights how menopause
does not affect solely vaginal tissues.
The benecial effects of estrogen therapy include both the improvement of symp-
toms associated with vaginal atrophy and the restoration of the vaginal anatomy
[37]. Both systemic estrogen and vaginal estrogen are effective for the symptoms
of genitourinary atrophy, although in women who only have GSM with no other
menopausal symptoms (e.g., ashes), vaginal estrogens are more efcient. Vaginal
estrogens can be used at any age, and progestogens typically are not prescribed to
women using any of these products [38].
• A Cochrane review of 30 randomized, controlled trials involving 6235 women
reported that the efcacy of any estrogenic formulation in relieving symptoms of
VVA was similar [39].
22.6.1 Promestriene
Promestriene is an analogue of estradiol which is minimally absorbed, and it has
been shown to be effective in reversing atrophic changes caused by estrogen de-
ciency in women undergoing natural or surgically induced menopause. Given the
absence of systemic activity, promestriene may be a good choice in women requir-
ing purely locally estrogen and those who have survived or who are at risk of breast
cancer and who have severe vulvovaginal symptoms [35]. There are little data avail-
able in the literature, mostly consisting of small, open-label, short duration studies
and few RCTs. After a long-term market experience (almost 40 years), the side
effects were very rarely reported in pharmacovigilance data, whereas the effective-
ness to relieve atrophy was good [40].
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22.6.2 Ospemifene
Ospemifene is a systemic selective estrogen receptor modulator (SERM) that acts as an
estrogen agonist in the vagina and appears to have no clinically signicant estrogenic
effect on the endometrium or breast. A 1-year clinical trial did not identify endome-
trial safety concerns [41]. However, hot ushes were reported by 7.2% of participants
randomized to ospemifene 60mg vs. 2.0% of those randomized to placebo. Although
there may be the possibility of its use in breast cancer survivors who are disease-free
and who have completed their anticancer treatment, as with systemic MHT and low-
dose vaginal ET, package labelling for ospemifene cautions against using this medica-
tion in women with a personal history of breast cancer or thromboembolic disease.
The International Society for the Study of Women’s Sexual Health (ISSWSH)
stressed the importance of androgens for women with GSM as they support genito-
urinary tissue structure and function. In the vagina, androgens and estrogens regulate
vaginal mucin production in epithelial cells, and sex steroid hormones may regulate
androgen and estrogen expression in genitourinary tissues. Although positive immu-
nostaining for estrogen and androgen has been demonstrated in human vulvar tissue,
estrogen was less prevalent, and androgen was more prevalent when compared with
vaginal tissue. Clitoral hypertrophy is considered one of the most sensitive markers
for excess androgen production in women through menopause [42].
22.6.3 Transdermal Testosterone
Transdermal testosterone has shown efcacy for the treatment of hypoactive sex-
ual desire disorder (HSDD) in both naturally and surgically postmenopausal women,
either alone or in combination with estrogen [43]. In RCTs at 24weeks in women
with natural or surgical menopause and referring HSDD, a 300μg/day testosterone
patch signicantly improved the measures of primary efcacy of sexual desire and
the frequency of satisfying sexual events (measured by patented instruments) versus
placebo [44, 45]. Levels of sexually related distress also decreased signicantly com-
pared to placebo. However, given the concern about the long-term safety of the use of
testosterone in postmenopausal women [46], their use has been declining.
Treatments for GSM should combine both androgenic and estrogenic actions,
such as seen with esteried estrogens with methyltestosterone and tibolone, which
exerts estrogenic, progestogenic, and androgenic effects.
22.6.4 Vaginal Prasterone
Vaginal prasterone, another name for dehydroepiandrosterone (DHEA), an andro-
gen derivative, has shown effectiveness in treating GSM [47]. In placebo-controlled
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clinical trials, daily insertion of dehydroepiandrosterone vaginal ovules decreased
vaginal pH, improved the vaginal epithelial maturation index and vaginal epithelial
thickness and integrity, and increased vaginal secretions resulting in improvement
in dyspareunia.
Clinical trial data addressing the use of vaginal testosterone are limited; longer as
well as larger studies are needed to assess efcacy and safety. Information related to
systemic testosterone therapy and low testosterone therapy for GSM is insufcient;
more trials are needed in a postmenopausal population to determine whether testos-
terone therapies are benecial.
Several RCTs have demonstrated that low-dose vaginal estrogen, intravaginal
prasterone, and oral ospemifene effectively treat GSM and related dyspareunia.
Although libido can improve with adequate treatment of dyspareunia, these biologi-
cal improvements alone do not guarantee a good sexual response. However, DHEA
has showed that all the six domains of the Female Sexual Function Index (FSFI)
are improved over placebo (from P=0.047 to 0.0005), by an action exerted exclu-
sively at the level of the vagina, in the absence of biologically signicant changes
of serum steroids levels [48]. A study evaluated the long-term (52weeks) effect of
treatment with daily intravaginal 0.50% (6.5mg) DHEA on the various domains
of female sexual function using a questionnaire at baseline, week 26 and week 52
[49]. Postmenopausal women with at least one mild to severe symptom of VVA and
who had completed the questionnaire at baseline and at least one post-baseline time
point were included in the analysis (n=154). All domains of sexual function ana-
lyzed increased as well as the total score [49]. Also, a randomized trial found that
ospemifene (60mg/day, 12weeks) resulted in improvements in sexual pain, arousal,
and desire domains of the FSFI, a validated measure of function sexual activity [50].
On the other hand, vaginal estrogens reduce irritative urinary symptoms, such
as frequency and urgency, and have been demonstrated to reduce the likelihood of
recurrent urinary tract infections in postmenopausal women [51]. Although incon-
tinence is a signicant problem for aging women, the effect of estrogen deciency
remains unclear [
52].
• In a Cochrane review, 34 trials were identied which included approximately
19,676 incontinent women of whom 9599 received estrogen therapy (1464
involved in trials of local vaginal estrogen administration). Urinary incontinence
may be improved with the use of local estrogen treatment. However, there was
little evidence from the trials on the period after estrogen treatment had nished
and no information about the long-term effects of this therapy was given.
Conversely, systemic MHT using conjugated equine estrogen may worsen incon-
tinence [53]. There were too few data to reliably address other aspects of estro-
gen therapy, such as estrogen type and dose, and no direct evidence comparing
routes of administration.
Menopause is reckoned to be a key event associated with the emergence or a
worsening of pelvic organ prolapse (POP). Symptoms and severity increase sig-
nicantly across the menopausal transition [54]. Despite this, it is difcult to
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differentiate the specic contribution of estrogen withdrawal from that of the aging
process per se. Pelvic organs, and their muscular and connective tissue supports,
are estrogen- responsive. The use of postmenopausal systemic hormone therapy also
stimulates steroid hormone receptors in the pelvic oor [55]. Based on the Cochrane
analysis, the impact of postmenopausal hormone therapy on the pelvic oor support
is, however, still unclear [56]. Controversy remains as to whether the use of local
estrogens before and/or after vaginal surgery is benecial. The use of local estro-
gens improves the rate of vaginal maturation at the time of surgery and increases the
thickness of the vaginal epithelium, but this does not translate into increased vaginal
subepithelial/muscularis thickness [57], and, therefore, possible surgical advantages
still need to be demonstrated.
22.7 Cardiovascular Effects
The effect of MHT on cardiovascular health remains unclear and controversial. The
many of the apparent benets of MHT observed in epidemiologic studies were not
found in the randomized trials. Rather than a reduction in risk of CHD events, an
increase was seen [58, 59]. Possible methodologic explanations for the striking dif-
ference in CHD data include “healthy user” bias, older age of the study population,
and timing of initiation of therapy.
The impact of age and years since menopause on the relationship between MHT
initiation and health outcomes, also known as the timing hypothesis, has been identi-
ed as one of the important factors explaining the complex, and sometimes discrepant,
ndings. Specically, it has been found that women who were less than 10years from
menopause or aged between 50 and 59years at baseline when MHT was started had
lower hazard ratios (HR) for CHD than women initiating MHT at an older age [60],
which in turn would be related to the health of the underlying vascular tissue or other
factors, such as the reduction in or downregulation of estrogen receptors (ER) [61].
In fact, available scientic evidence supports the hypothesis that MHT halts pro-
gression of atherosclerosis in women whose menopause is of recent onset but that
it would have a neutral or adverse effect in older women or if it is started more than
10years after onset of the menopause. In addition, when initiated late in the athero-
sclerotic process, MHT could have adverse effects, potentially destabilizing exist-
ing plaques and triggering a coronary event [62, 63]. There is greater support for the
possibility that the metabolic effects of estrogens can vary with age and time since
onset of the menopause, and there is evidence that ER may be more functional and
sensitive at the initiation of the menopause than afterward. As a result, any preven-
tive treatment for CHD, including MHT, is more effective in younger women with
less established atherosclerosis.
However, although there is biological plausibility, the “timing” hypothesis has
not been tested in an RCT as hard endpoints of myocardial infarction or CVD mor-
tality are not possible in a young healthy population. Use of “intermediate” end-
points with a high correlation to CHD has been proposed and has been incorporated
into the design of ongoing RCTs, namely, KEEPS and ELITE.
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• The Early versus Late Intervention Trial with Estradiol (ELITE) attempted to dem-
onstrate the timing hypothesis for atherosclerosis progression [64]. The main nd-
ing was that women who started MHT within 6 years of menopause had a
signicantly lower atheroma progression than those who initiated it beyond 10years
past of menopause. These ndings support a benet of MHT in the primary preven-
tion of CHD, particularly when it begins near the onset of menopause.
• Kronos Early Estrogen Prevention Study (KEEPS) is a multicenter, randomized,
double-blinded, placebo-controlled trial, designed to test the hypothesis that
low-dose MHT, either oral or transdermal, along with oral micronized progester-
one, initiated in recently postmenopausal women will reduce the progression of
subclinical atherosclerosis, dened by carotid artery intima-media thickness and
coronary artery calcication.
After 4 years of early use of MHT, the progression of atherosclerosis was not
affected despite improving some markers of cardiovascular disease risk [65]. At rst
glance, the rst KEEPS results were frustrating, since many expected to see clear car-
dioprotective outcomes in hormone users, which apparently was not the case. However,
these KEEPS results are not surprising, since they reect the almost nil expected pro-
gression of atherosclerosis during 4years of follow-up in recently menopausal healthy
women who had no atherosclerotic burden at the beginning of the study [66].
In addition, there is evidence that factors related to the type, the dose, and the
route of delivery of MHT affect the risk of cardiovascular disease. Not only that,
but there is strong suggestion that low-dose MHT via the transdermal route does not
increase the risk of VTE, and biological data support this difference between oral
and transdermal estrogens [64, 67]. However, KEEPS did not nd any meaningful
differences between transdermal and oral MHT with regard to effects on thrombo-
embolic and cardiovascular markers (VTE and CVD events were not assessed) [65].
The use of a progestogen and its type most probably has an impact on cardiovas-
cular risk: norpregnane derivatives are associated with higher risk of VTE, whereas
micronized progesterone appears safe [
68, 69]. In conclusion, transdermal estro-
gens alone or combined with micronized progesterone may represent the safest
alternative for women who require MHT [67].
So far, there is no rm support for the use of MHT solely for the prevention of
CHD, but evidence of the use of MHT in the primary prevention of CHD in post-
menopausal women continues to accumulate.
22.8 Cognition, Mood, andPsychosocial Functioning
Although a relationship between the development of cognitive impairment and
lifestyle- related risk factors, such as obesity, tobacco, and alcohol use, has been
reported, age is still the strongest risk factor for dementia and other neurodegenerative
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disorders [70]. Estrogen has an array of action mechanisms underlying cognitive
benets [71]. Recently, some studies reported a signicant effect of estrogen on
DNA repair enzymes in the brain [72]. However, research on this issue and the
related mechanisms are still scarce.
Many observational studies and meta-analyses agree that the use of estrogens in
mid-life reduces a woman’s risk of subsequent dementia, whereas MHT initiation
in late life could have deleterious effects [73]. Regarding the impact of estrogen on
cognition, the effects of timing, route of administration, and dosage remain to be
claried. The timing hypothesis for dementia has been recently challenged by RCT
[74] assessing the impact of oral estrogen on cognition.
Three large randomized trials found that MHT initiated early in menopause
and continued for less than 7 years had no impact on cognitive function [26,
74, 75]. The Cache County (Utah) long-term prospective cohort study, however,
found that MHT started early in menopause and continued for 10years or longer
was associated with a signicant reduction in risk of Alzheimer’s disease (AD) or
other dementia [76].
Of note are results from the 2017 report of 18-year cumulative mortality among
WHI participants [77]. In that study, mortality from AD and other dementia was
lower among participants who were randomly assigned to treatment with estrogen
alone versus placebo (HR, 0.74; 95% condence interval [CI], 0.59–0.94). With
estrogen-progestin therapy, the HR was 0.93 (95% CI, 0.77–1.11), and the pooled
HR for the 2 trials was 0.85 (95% CI, 0.74–0.98) [77].
Cognitive impacts of progestogen differ widely by preparation. Analogous to
estrogen, natural progesterone (P4) could be neuroprotective, stimulate synap-
tic plasticity, and enhance hippocampal neurogenesis [78]. Moreover, P4 might
improve cholinergic neurotransmission. In animal and invitro experiments, syner-
gistic effects of E
2
and P4 have been reported [79]. Small, short-term clinical trials
of progesterone show no meaningful effect on cognition. The quality of evidence
is low, but overall ndings do not reveal consistent, clinically important effects of
progesterone on cognitive function in women [80].
Although MHT should not be considered in the prevention of dementia, these
new studies reinforce the “critical window” hypothesis [81], leaving open the possi-
bility that initiating systemic MHT soon after the onset of menopause (especially in
surgical menopause) and continuing it in the long term may have positive cognitive
benets and may decrease the risk of AD.It is necessary to evaluate the individual
characteristics of the patients, the possible benets and risks, and ongoing assess-
ment over time.
Based on ndings from observational studies, the timing hypothesis posits that
estrogen may preserve neurologic function and decrease the risk of dementia when
administered early in menopause; however, the effects may be neutral or even harm-
ful if estrogen is initiated later in life [75, 76].
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22.9 Cancer
Sex steroids are not known to damage DNA directly. They can stimulate or inhibit
cell proliferation and thus can modulate tumor developmental progression. However,
it is important to consider that not all estrogens and progestins are used with the
same dosage and route of administration (for oral, transdermal, and estradiol intra-
nasal) and, mostly, different estrogens do not show the same bioavailability and
tissue effects. The available data do not allow to discriminate for all these variables,
and therefore it is inappropriate to consider jointly all forms of hormonal therapy.
During the 18 years of follow-up Women’s Health Initiative (WHI) studies,
cancer mortality rates were almost identical between hormone users and nonusers
(8.2% vs. 8.0%; HR, 1.03 [95% CI, 0.95–1.12]) [77].
22.9.1 Breast Cancer
The relationship between estrogens to postmenopausal development of breast can-
cer (BC) is controversial, and the results of studies with respect to causality are
mixed. Both in the original WHI study and in the long-term follow-up of this popu-
lation, the incidence of BC increased with combined EP-MHT.The use of estrogen
only was paradoxically associated with a decrease in BC incidence [82, 83].
The slightly increased relative risk of BC could have been related to the duration
of hormone use or the sequential administration of progestin therapy or even the
progestogen formulation itself. In contrast, MHT users had more localized tumors
and better survival rates. Individual risks were very small. Several other studies
have reported differences in risk related to the type of MHT regimen.
• The safer risk prole of natural progesterone and dydrogesterone respects to
other synthetic progestins, as showed in the E3N study, a French observational
study of teachers, on menopausal MHT [84]. The increase in risk of breast cancer
observed with the use of synthetic progestogens seems to apply preferentially to
ER+ carcinomas, especially those ER+/PR−, and to affect both ductal and lobu-
lar carcinomas [85].
• Similarly, a Finnish observational study reported that sequential progestin use
resulted in a smaller increased risk of BC than did continuous progestin use, but
one should note that in this study most patients used NETA [86].
Regarding BC, the time hypothesis is also supported by several studies. Contrary
to what happens in the cardiovascular and cognitive systems, starting therapy later
than 5years after the onset of menopause is associated with a signicant reduction
in BC risk, because the estrogen deprivation associated with menopause determines
a sensitization of breast cancer cells to the proapoptotic effects of estrogen, whereas
immediate initiation has no advantageous effects [87]. Furthermore, hormone
receptor-positive breast cancers in postmenopausal women respond to treatment
with high-dose estrogen therapy, while similar tumors in premenopausal women
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do not. This paradoxical response to addition or deprivation of estrogen can explain
both decrease in BC after initiation of MHT and the decrease following cessation
of treatment [88].
22.9.2 Another Cancer
We do not consider ovarian cancer to be a major consideration when deciding to
take MHT for symptomatic relief, because the absolute risk of ovarian cancer with
MHT is very low. On the other hand, we did not consider in the assessment of the
use of MTH the positive effect on the risk of colorectal cancer seen with combined
conjugated equine estrogen-medroxyprogesterone acetate use [89].
22.10 Osteoporotic Fracture
Numerous studies have shown the effectiveness of MHT in preventing bone loss
in postmenopausal women with and without osteoporosis. From a regulatory per-
spective, it may be rational to separate the indication of MHT for prevention from
treatment of osteoporosis. But both prevention and treatment of osteoporosis share
a common clinical goal, which is prevention of fractures. The efcacy of MHT on
fracture reduction in postmenopausal osteoporotic women has been demonstrated
in some small RCTs [90, 91]; however, there are no large long-term RCTs (i.e.,
more than 2–3years as required by the Regulatory Agencies for bone mineral den-
sity data).
Given that bone mineral density (BMD) is considered a surrogate marker for
osteoporotic fracture and that there are other approved osteoporosis drugs, high-
quality antifracture evidence of MTH in women with postmenopausal osteoporosis
may be forever unavailable.
Although the effect of BMD preservation dissipates rapidly after discontinua-
tion of MHT [92], it seems that there is no accelerated bone loss [93] or rebound
fracture risk after stopping MHT [94]. Limited evidence suggests that the long-
term residual bone preservative benet may extend for years after the interrup-
tion of MHT [94]. Evidence from both human and animal studies suggests that
estrogen can enhance muscle mass and strength [95] and increase collagen con-
tent and preserve the health of collagen-rich tissues, including the intervertebral
discs [96]. Women reporting continuous or remote past MHT use had signicantly
less pronounced kyphosis than never users by their mid-80s [97]. Maintenance of
lean paraspinal muscle mass and intervertebral disc heights is essential to prevent
kyphosis and vertebral fracture.
Along with a “timing hypothesis” supported by a critical mass of data and
emerging evidence of residual skeletal benet after HT discontinuation, MHT as a
bone- sparing agent has a distinct value in treating postmenopausal women with or
without established osteoporosis. It may be considered rst-line therapy for some
patients with appropriate indications mentioned above.
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