REVIEWS

Symptoms of menopause —
global prevalence, physiology
and implications
Patrizia Monteleone, Giulia Mascagni, Andrea Giannini, Andrea R. Genazzani
and Tommaso Simoncini
Abstract | The symptoms of menopause can be distressing, particularly as they occur at a time
when women have important roles in society, within the family and at the workplace. Hormonal
changes that begin during the menopausal transition affect many biological systems.
Accordingly, the signs and symptoms of menopause include central nervous system-related
disorders; metabolic, weight, cardiovascular and musculoskeletal changes; urogenital and skin
atrophy; and sexual dysfunction. The physiological basis of these manifestations is emerging as
complex and related, but not limited to, oestrogen deprivation. Findings generated mainly
from longitudinal population studies have shown that ethnic, geographical and individual
factors affect symptom prevalence and severity. Moreover, and of great importance to clinical
practice, the latest research has highlighted how certain menopausal symptoms can be
associated with the onset of other disorders and might therefore serve as predictors of future
health risks in postmenopausal women. The goal of this Review is to describe in a timely
manner new research findings on the global prevalence and physiology of menopausal
symptoms and their impact on future health.

Hot flashes
A sudden wave of body heat
accompanied by reddening of
the face and neck and profuse
sweating, sometimes
followed by a feeling of cold
and shivering.
Ovarian failure
The definite loss of function of
the ovaries.
Division of Obstetrics and
Gynecology, Department of
Clinical and Experimental
Medicine, University of Pisa,
Via Savi 10, Pisa 56126,
Italy.
Correspondence to A.R.G. 
andrea.genazzani@med.
unipi.it
doi:10.1038/nrendo.2017.180
Published online 2 Feb 2018
In common belief, the symptoms of menopause arise
from the permanent cessation of menstrual periods,
which defines this condition1. However, hot flashes and
night sweats, insomnia and mood instability might
actually begin before the cessation of menses and are
the manifestation of incipient ovarian failure1. The tran-
sition from the reproductive period to the first year
of postmenopause, termed perimenopause, occurs over
several years and is characterized by substantial bio-
logical change. According to the widely accepted Stages
of Reproductive Ageing Workshop (STRAW) staging
system, perimenopause encompasses three stages: early
menopausal transition (also known as early perimen-
opause), characterized by persistent irregularity of the
menstrual cycle; late menopausal transition (also known
as late perimenopause), characterized by an interval of
amenorrhoea of ≥60 days in the prior 12 months; and
early postmenopause, which is the first year following
the final menstrual period (FMP)1. Perimenopause is
characterized by marked fluctuations in levels of sex
hormones, which are greater than those that occur
during the follicular and luteal phases of the menstrual
cycle during premenopause, and is associated with
the worst menopausal symptom burden, arising from
neurochemical changes within the central nervous sys-
tem (CNS)2. In postmenopause, long-term manifesta-
tions of definite oestrogen deprivation ensue, such as
urogenital atrophy and ageing of the skin, and osteopo-
rosis might develop during this time. In addition, a shift
towards central body fat distribution and the consequent
metabolic alterations might occur as a result of increases
in the androgen:oestrogen ratio3, which is also driven by
increased insulin resistance4.
The symptoms of menopause can be very distress-
ing and can considerably affect the personal, social
and work lives of women. Owing to the heterogeneous
nature of menopausal symptoms, a firm understanding
of their physiological basis has been established only
following many years of investigation. The development
of the STRAW staging system1 (TABLE 1), which is based
on the menstrual patterns of women, has allowed inves-
tigators to generate more uniform scientific data regard-
ing events correlated with menopause and has prompted
research on the assessment of trajectories of hormonal
changes and their clinical correlates1. Moreover, over
the past decade, data from epidemiological studies
involving many women have been made available to
investigators in the field of menopause. These large

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Key points Central nervous system-related symptoms

• Menopausal symptoms have a substantial effect on the quality of life of women and
on performance at the workplace; increased awareness of symptoms and acquisition
of coping strategies might help
• Certain menopausal symptoms might serve as markers for future health; severe
vasomotor symptoms and sleep disorders might increase cardiovascular risk,
whereas severe vasomotor symptoms and depression might affect cognitive
function
• The nature of menopausal symptoms is common to all women; however, geographical
location and ethnicity influence the prevalence of certain symptoms
• Individual factors such as personal history, current health status (particularly
obesity) and socioeconomic status considerably worsen a woman’s experience
of menopause
• Health-care providers should offer education to women on improving modifiable
lifestyle factors to reduce the risk of future illness
• Menopause seems to accelerate the ageing process; therefore, the manifestation of
menopausal symptoms might be in part due to ageing
population studies have not only increased the robust-
ness of research conclusions but have also incorporated
different ethnicities, allowing between-group obser-
vations. Importantly, in contrast to the cross-sectional
studies that were performed in the past, new data have
been generated from longitudinal studies and therefore
provide important insight into the temporal pattern
of the development of menopausal symptoms and the
associated hormonal changes.
The scope of this Review is to describe symptoms of
menopause in light of new findings generated from the
study of ethnicity and geographical location, personal
history and individual characteristics as factors influ-
encing a woman’s experience of menopause and the
impact of these symptoms on her social and personal
life. Up‑to‑date evidence on the complex physiology
of menopausal symptoms is provided. Moreover, as an
important contribution to modern clinical practice, this
Review offers insight into the associations between cer-
tain menopausal symptoms and other disorders and the
implications of these associations for future health in
postmenopausal women5.
Menopause and its symptoms
Menopause, with its signs and symptoms, occurs at a
time in a woman’s life when she is often actively engaged
in family upbringing and/or handling a full-time job,
Postmenopause during which time she might also have the responsibil-
The period of a woman’s life ity of caring for ageing parents. Women are often puz-
that follows the final menstrual
period.
zled by the remarkable changes in mood, sleep patterns,
memory and body shape that occur, as well as the onset
Perimenopause of vasomotor and urogenital symptoms. As menopau-
The period of a woman’s life sal symptoms can be very distressing and considerably
that encompasses the
affect a woman’s personal and social life, health-care
menopausal transition and the
first year following the final providers caring for women at all levels of the health-
menstrual period. care system must be well prepared to guide patients
through this transition and provide advice to improve
Amenorrhoea quality of life. In this section, a detailed description of
The absence of menstrual
periods for 3 or more
the wide range of symptoms experienced by women at
consecutive months in a menopause, in relation to the affected biological system,
woman of reproductive age. is provided (FIG. 1).
CNS-related symptoms are those arising as a conse-
quence of the neurobiochemical changes that occur after
ovarian failure, such as vasomotor symptoms, sleep dis-
turbances, anxiety and depression, migraine and changes
in cognitive performance.
Vasomotor symptoms. Approximately 75% of women
experience vasomotor symptoms during menopause2.
Vasomotor symptoms are the hallmark of menopause
and are defined as hot flashes and sweating, sometimes
followed by trembling and a feeling of coldness (FIG. 1).
These are typically the most frequent and bothersome
symptoms associated with menopause due to their sud-
den and seemingly random onset during the day and
even at night. Vasomotor symptoms can begin as early
as 2 years before the FMP, peak 1 year after the FMP and
continue for 4 years after the FMP in approximately half
of women6. Approximately 12% of women will continue
reporting symptoms as far as 11–12 years after the FMP6,7.
In fact, one study reported that approximately one-third
of women aged 65–79 years still report vasomotor symp-
toms8. It seems that women who begin to experience
vasomotor symptoms earlier with respect to the FMP
will experience these symptoms for longer periods in
postmenopause, with a median time of 7.4 years9.
Although vasomotor symptoms influence the quality
of life of women during daytime, they also greatly alter
the quality of sleep. Indeed, women with nocturnal vaso-
motor symptoms have greater motor restlessness in bed,
less efficient sleep and a reduced feeling of restedness in
the morning compared to women without night-time
symptoms10. Nocturnal hot flashes are more common
during the first 4 hours of sleep and are associated with
a greater number of episodes of waking after the onset
of sleep, whereas later rapid-eye-movement (REM)
sleep suppresses hot flashes, arousals and awakenings11.
Furthermore, following pharmacological induction of
temporary menopause using gonadotropin-releasing
hormone (GnRH)-analogue administration in pre-
menopausal volunteers, vasomotor symptoms arise
most commonly during the first stage of sleep and wake,
typically preceding or occurring simultaneously with
wake episodes12.
Sleep disruption. Sleep difficulties, particularly nocturnal
awakenings, are major complaints and are reported by
40–60% of menopausal women13,14 (FIG. 1). The increased
occurrence of sleep disruptions has been clearly demon-
strated among perimenopausal and postmenopau-
sal women compared with premenopausal women in
the multiethnic, community-based Study of Women’s
Health Across the Nation (SWAN)15,16. Data from the
Penn Ovarian Ageing Study collected over an 8‑year
period have suggested that the decline of sleep quality in
menopausal women might be due to menopause-related
symptoms, namely, hot flashes and depressive symp-
toms17. Moreover, a recent polysomnography study found
that self-reported and physiological hot flashes are more
common in menopausal women with insomnia than in
women who do not develop clinical insomnia and that

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Table 1 | The Stages of Reproductive Ageing Workshop staging system

Stage Duration Terminology Menstrual cycle characteristics
Menarche
−5 Variable Reproductive: early Variable to regular
−4 Variable Reproductive: peak Regular
−3b Variable Reproductive: late Regular
−3a Variable Reproductive: late Subtle changes in flow length
−2 Variable Menopausal transition: early Variable length: persistent ≥7 day difference
in length of consecutive cycles
−1 1–3 years Menopausal transition: late Interval of amenorrhea of ≥60 days
Final menstrual period
+1a 2 years Postmenopause: early –
+1b 3–6 years Postmenopause: early –
+1c 3–6 years Postmenopause: early –
+2 Remaining Postmenopause: late –
lifespan
Adapted with permission from REF. 208, Elsevier.

Obstructive sleep apnoea
A sleeping disorder caused by
repetitive upper airway
collapse during sleep, leading
to intermittent hypoxia and
characterized by loud snoring,
apnoea during sleep, insomnia,
excessive daytime sleepiness,
morning headache and fatigue.
the presence of objective hot flashes predicts the num-
ber of awakenings, indicating a clear contribution for
hot flashes in sleep disturbance18. Sleep electroenceph-
alography has demonstrated that the underlying cause
of impaired sleep quality in late perimenopausal and
postmenopausal women might be related to a change in
arousal levels during both REM and non-REM sleep19.
Sleep disruption in menopause might be exacerbated
by disordered breathing due to obstructive sleep apnoea,
independent of body weight and age 20. Moreover,
obstructive sleep apnoea affects more women in post-
menopause than in premenopause20. Data have emerged
in the literature linking sleep disorders with an increased
risk of cognitive decline in menopausal women, particu-
larly with respect to attention, episodic memory and
executive function21. Furthermore, cognitive function
was found to be worse in early postmenopausal women
at high risk of obstructive sleep apnoea compared to
those at low risk of sleep apnoea22.
Depression and anxiety. The menopausal transition is
a vulnerable period for the onset of depressive symp-
toms (FIG. 1). Longitudinal studies and meta-analyses
have shown that women in the menopausal transition
and early postmenopausal years are more likely to report
a depressed mood than premenopausal women23–26. In
the SWAN cohort, data collected from the Center for
Epidemiological Studies Depression Scale (CES‑D) ques-
tionnaire — which evaluated sadness, loss of interest,
appetite, sleep, concentration, feelings of guilt, tiredness,
agitation and suicidal ideation24 — showed that across
5 years, women were substantially more likely to report
a high symptom score during early perimenopause, late
perimenopause and postmenopause compared with
premenopause, and also during late perimenopause
compared with early perimenopause25. Extended lon-
gitudinal data from this same cohort confirmed these
observations27. With respect to major depression, the
lifetime prevalence of this disorder is >20% in women
and twice that in men28. Women with a personal history
of major depression are at risk of relapse during peri-
menopause23,25,29 and in the first 2 years of postmeno-
pause but not beyond30. However, it is unclear whether
women who have never experienced major depression in
their premenopausal years are at increased risk during or
after menopausal transition31,32. Regarding anxiety, data
from the SWAN cohort have indicated that women with
high levels of anxiety premenopausally continue to expe-
rience such anxiety through the menopausal transition,
whereas women with low anxiety premenopausally are at
increased risk of developing high levels of anxiety during
and after the menopausal transition32. Thus, the meno-
pausal transition might be a critical time for women who
are susceptible to anxiety disorders32.
Cognitive changes. Perimenopausal women often report
a decline in memory and concentration (FIG. 1), which
might be distressing and is clinically relevant 33. Data
from the SWAN cohort analysing cognitive function
longitudinally over a 4‑year period have demonstrated
that there is a reduction in cognitive performance, spe-
cifically a lack of learning, but that it is isolated to the
perimenopausal stage of the transition34. More specif-
ically, a lack of improvement in verbal memory was
reported in the early and late perimenopausal stages, and
deficits in processing speed with repeated testing were
seen in the late perimenopausal stage compared with
the premenopausal and postmenopausal stages34. These
data suggest that the detrimental effect of menopause
on cognitive performance is transient and limited to the
perimenopausal stage. In addition, other longitudinal
studies examining women in the menopausal transi-
tion have indicated modest declines in processing speed
and verbal episodic memory (delayed recall)24,35,36. In a
study published in 2017, the estimated rates of cognitive
decline over a 10 year period were reported as 4.9% of
the mean baseline score for processing speed and 2%
of the mean baseline score for delayed recall37.

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Central nervous system Skin, mucosal and hair changes Moreover, the presence of moderate to severe vasomotor
• Vasomotor symptoms • Reduced skin thickness symptoms has been associated with a greater number of
• Sleep disruption • Reduced elasticity complaints of poor memory function41. Finally, as sleep
• Depression and anxiety • Reduced hydration
• Cognitive changes • Increased wrinkling is important for learning and memory consolidation42,
• Migraine • Hair loss it is very plausible that disordered sleeping, particularly
sleep apnoea22, contributes substantially to the memory
lapses reported by many perimenopausal women.

Migraine. The prevalence of migraine during meno-

pause ranges from 10% to 29%43 (FIG. 1). It seems that
women who are susceptible, particularly those with
Weight and metabolic changes
premenstrual migraine during fertile years, have more
• Weight gain migraine headaches as they transition through meno-
• Increased visceral adiposity pause44. In community-based studies, the prevalence
• Increased waist circumference
Sexual function of migraine headache in women migraineurs has been
• Decreased sexual desire reported to increase in perimenopause and decrease in
• Dyspareunia
post­menopause44. Importantly, a study that enrolled a
large number of women reported that the risk of high fre-
quency headache was markedly increased in women dur-
Urogenital system ing perimenopause compared with premenopause34,45;
• Vaginal dryness high frequency headaches affected 8% of premenopau-
• Vulvar itching and burning
• Dysuria sal women, compared with 12.2% of perimenopausal
• Urinary frequency women and 12% of postmenopausal women.
• Urgency
• Recurrent lower urinary Musculoskeletal system
tract infections • Joint pain Weight and metabolic changes
• Sarcopenia
One of the main complaints from women at midlife
is increased weight 46 (FIG. 1). Indeed, the prevalence of
obesity is higher in postmenopausal women than in pre-
menopausal women46. Absolute weight gain in women
at midlife seems to be fundamentally related to age-
ing rather than to menopause itself 46. In women aged
40–55 years, the average weight gain was reported by
one study to be 2.1 kilograms over 3 years47. What seems
to be menopause-dependent is a redistribution of body
Nature Reviews | Endocrinology fat 47,48 characterized by accumulation of mostly visceral
Figure 1 | Overview of menopausal symptoms. Symptoms of menopause include
central nervous system (CNS)-related disorders, bodily alterations related to adiposity at the trunk, leading to an increase in waist cir-
cardio-metabolic changes, musculoskeletal alterations, urogenital and skin atrophy and cumference and an obvious change in body shape47. In
sexual dysfunction. Perimenopause is associated with the worst menopausal symptom addition, studies using techniques such as dual-energy
burden, arising from neurochemical changes within the CNS leading to severe X‑ray absorptiometry (DXA), CT and MRI have docu-
vasomotor symptoms, sleep disorders and depression, which might affect cognitive mented the increase in visceral abdominal fat deposi-
function. Long-term manifestations of definite oestrogen decline result in urogenital tion in postmenopause compared with premenopause48.
atrophy and ageing of the skin, whereas osteoporosis and sarcopenia might develop
Visceral adipose tissue poses a greater health risk than
during the postmenopausal period.
subcutaneous fat and, in general, is an independent
cause of cardiovascular disease (CVD), primarily due to
Surgical menopause has more severe consequences the increase in insulin resistance and the consequent risk
on cognitive functions than natural menopause and is of developing diabetes mellitus and the metabolic syn-
associated with an increased risk of cognitive impair- drome36. Furthermore, evidence that ovarian failure is
ment or dementia in later life38. One study reported that causative of visceral fat accumulation during menopause
surgical menopause after 45 years of age was associated has come from cross-sectional49,50 and longitudinal stud-
with lower performance in verbal learning and a decline ies51,52. In support of this hypothesis, surgically induced
in visual memory compared with natural menopause, menopause seems to accelerate weight gain in the years
whereas a decrease in semantic memory was observed in following surgery compared with ovarian-sparing
women who underwent oophorectomy before 45 years hysterectomy or natural menopause53.
of age39. Interestingly, oophorectomy after natural meno­
Surgical menopause pause is not associated with alterations in cognitive Cardiovascular changes
Menopause induced by the performance39. Atherosclerosis and the risk of cardiovascular adverse
surgical removal of the ovaries. In the SWAN cohort, although the cognitive deficits events increase in women after menopause, which might
observed during perimenopause are independent of be due in part to the production of pro-inflammatory
Visceral adiposity
Accumulation of adipose tissue
mood symptoms, women with more depressive symp- cytokines and adipokines in visceral adipose tissue54,55.
in the abdomen and around toms displayed a worse processing speed, and those with Increased deposition of visceral fat in postmenopau-
internal organs. higher degrees of anxiety had a poorer verbal memory 40. sal women might be associated with fat accumulation

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in other visceral tissues such as the heart 56. Indeed, it
has been reported that late perimenopausal and post­
menopausal women have markedly greater volumes
of heart fat than premenopausal women independ-
ent of age, race, obesity or other covariates57. Notably,
blood lipid profiles tend to become atherogenic in
women within the year following the FMP, with major
increases in total cholesterol, LDL cholesterol and apo-
lipoprotein B (APOB), independent of ethnicity, age or
weight 58. Moreover, the anti-atherogenic effect of HDL
cholesterol seems to be abolished as women transition
through menopause; increases in HDL cholesterol levels
are, at this stage, independently associated with greater
progression of carotid intima–media thickness59. The
markedly reduced exposure to oestrogen during meno­
pause might have a negative effect on endothelial cell
growth and reduce the inhibitory effect of female sex
hormones on the growth and proliferation of vascular
smooth muscle cells60. Moreover, although blood pres-
sure levels seem to be lower on average in premeno-
pausal women than in their male counterparts, this
advantage is lost around the time of menopause, and
blood pressure levels start to rise in women, reaching
levels similar to those of men of the same age group61.
The prevalence of salt sensitivity also increases in post-
menopausal women and doubles as early as 4 months
after surgical menopause, therefore contributing to
their increased risk of developing hypertension 61.
Taken together, these negative changes in cardiovascu-
lar features increase the risk of adverse cardiovascular
events, a risk that is even greater in women younger
than 45 years who experience premature or early-onset
menopause62 (FIG. 1).
Box 1 | Origin and clinical characteristics of genitourinary syndrome
Oestrogen receptors (ERα, ERβ) are present in the vagina, vestibule of the vulva,
urethra and trigone of the bladder; in different myofascial structures and ligaments
such as utero-sacral ligaments, levator ani muscles and pubo-cervical fascia; and also
on autonomic and sensory neurons in the vagina and vulva68,162. The highest
concentration of ERs is in the vagina, with ERα being the only active form
after menopause.
Genitourinary syndrome symptoms are manifestations of the changes that occur at
menopause due to oestrogen withdrawal. Loss of lubrication, burning, dryness,
itching and entry dyspareunia with fissuring are some of the vulvovaginal
symptoms64,68. Urinary symptoms include recurrent urinary tract infections, urgency
and urge incontinence, stress incontinence, dysuria and voiding issues67,68. These
might enhance loss of libido and sexual dysfunction in terms of arousal and orgasm.
Signs of genitourinary syndrome are numerous and heterogeneous and consist of
decreased elasticity and moisture, labia minora resorption, pallor, erythema,
loss of vaginal rugae, tissue fragility, loss of hymenal remnants, introital retraction,
urethral eversion or prolapse, prominence of urethral meatus and recurrent urinary
tract infections64,68,160.
The aim of management and treatment of genitourinary syndrome is to provide
symptom relief. However, counselling for genitourinary syndrome symptoms is also
an appropriate time to discuss lifestyle, diet and exercise, smoking cessation and
appropriate alcohol consumption. Treatment will depend on the signs and symptoms
and degree of severity. Nonhormonal therapies include personal lubricants, vaginal
moisturizers and vaginal laser treatment (of which the long-term safety and
effectiveness have not been established). Hormonal therapies include vaginal oestriol
cream or pessaries, vaginal oestradiol tablets or systemic hormone therapy
(menopause hormone therapy).
Urogenital symptoms
Although they are not frequently reported, urogenital
symptoms are often present after menopause63 (FIG. 1)
and include vaginal dryness, dyspareunia, vulvar
itching and burning, dysuria, urinary frequency and
urgency and recurrent lower urinary tract infections64.
The US Real Women’s Views of Treatment Options for
Menopausal Vaginal Changes (REVIVE) survey high-
lighted a reluctance among postmenopausal women to
address these symptoms with their health-care provid-
ers, causing a delay in their management 65. The inter-
national Vaginal Health: Insights, Views and Attitudes
(VIVA) study reported the prevalence of individual
urogenital symptoms in a large cohort of women with
vaginal discomfort as 83% for vaginal dryness, 42% for
pain during intercourse, 30% for involuntary urination,
27% for soreness, 26% for itching, 14% for burning and
11% for pain when touching the vagina66. In the same
study, 62% of women with vaginal discomfort reported
the severity of these symptoms as moderate or severe66.
The recent European REVIVE survey — which included
the largest cohort of postmenopausal women studied
to date — confirmed that vulvovaginal atrophy is still
underdiagnosed and undertreated67. It is widely accepted
that this group of symptoms — now termed genitouri-
nary syndrome68 (BOX 1) — typically manifests 4–5 years
after menopause in the presence of stably low levels of
oestrogen. Longitudinal studies have also reported an
increase in urinary incontinence symptoms with meno­
pause69,70; however, it is unclear whether this change
is attributable to the menopausal transition itself or to
the concomitant weight gain that typically occurs dur-
ing this time69. Indeed, it has been demonstrated that
an increase in body weight of 1 kg is associated with a
higher incidence of urinary incontinence in women at
midlife70. Furthermore, cross-sectional studies have also
affirmed that menopausal status per se is not a determi-
nant of urinary incontinence71; the risk of developing
stress incontinence increases with obesity and parity,
whereas the risk of urge urinary incontinence increases
with age. Moreover, mixed incontinence is positively
correlated with higher BMI and hysterectomy 71.
Sexual dysfunction
Longitudinal and cross-sectional studies have reported
that the menopausal transition is associated with a
decrease in sexual desire, independent of ageing 72 (FIG. 1).
Specifically, the menopausal transition is characterized
by a change in hormone-driven sexual desire73. The
decline in sexual function in perimenopausal women is
greatest between 20 months before the FMP and 1 year
after the FMP74, and women seem to exhibit a decrease
in sexual desire and an increase in painful intercourse
beginning in late perimenopause72. Curiously, masturba-
tion — a behaviour that is not dependent on partner sta-
tus — increases temporarily in early perimenopause and
declines thereafter in postmenopause72. Sexual activity
continues to decrease, but at a slower rate, throughout
the 5 years following the FMP, independently of vaginal
dryness, lubricant use or mood disorders74. Further on,
vulvovaginal symptoms can add to sexual dysfunction

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and interfere with social, interpersonal and psycho­
logical well-being as the consequent dyspareunia can
lead to avoidance of sexual intimacy with a partner 73.
Indeed, the European REVIVE study reported that pain
during intercourse has a substantially negative influence
on sexual satisfaction67. In addition, a decline in general
self-esteem and well-being after menopause might also
contribute to the loss in sexual intimacy with a partner 75.
Nonetheless, being in a long-lasting relationship seems
to preserve a satisfying sexual life, even in older late
menopausal women73.
Musculoskeletal symptoms
A major concern in menopausal women is a decline in
bone health. Postmenopausal osteoporosis is a degen-
erative bone disorder characterized by reduced BMD
(FIG. 1) and altered bone structure, such as thinning and
increased porosity of the cortex and decreased connec-
tivity of trabeculae76. Osteoporosis increases the risk
of fractures76 — which occur most frequently in the
spine, hip and wrist in postmenopausal women with
osteoporosis77 — and might lead to long-term disability.
Although there are minimal changes in BMD during
premenopause or early perimenopause, BMD sharply
declines during late perimenopause78. The annual rates
of bone loss after the FMP are estimated to be 1.8–2.3%
in the spine and 1.0–1.4% in the hip78. Epidemiological
studies have shown that the incidence of wrist and spine
fractures in postmenopausal women rises before hip frac-
tures77; this observation seems to be related to the rapid
bone loss that occurs in the first 3–5 years after meno­
pause, which primarily affects trabecular bone tissue,
whereas that which occurs in the following 10–20 years
involves both trabecular and cortical bone76.
Changes in body composition that occur in women
at midlife also affect lean muscle mass (FIG. 1), which,
as opposed to fat mass, seems to decrease79. Although
sarcopenia cannot be currently attributed to meno-
pause, this degenerative process is more evident in age-
ing women than ageing men and seems to occur more
rapidly after menopause80,81. Resistance exercise82 and
adequate dietary protein intake70 are important lifestyle
factors that help to maintain lean muscle mass and
consequently preserve mobility and postural stability,
reducing the risk of falls and bone fractures.
In addition, the prevalence of osteoarthritis increases
greatly after the FMP83, and pain specifically affecting
the distal interphalangeal joints of the fingers and
base of the thumb due to osteoarthritis of the hand is
a commonly reported symptom in the perimenopau-
sal period73. Although osteoarthritis of the hand dur-
ing perimenopause usually subsides within 2–3 years,
it is predictive of successive joint disease in the knee
and spine84. With respect to knee osteoarthritis, most
affected women report the onset of symptoms during
perimenopause or within 5 years of the FMP85.
Skin, mucosal and hair changes
Menopause reduces skin thickness, elasticity and
hydration and leads to an increase in wrinkling 86 (FIG. 1).
Structural changes occur mainly in the dermis where
there is a loss of collagen-producing dermal fibroblasts
and reduced elastin proteoglycan content and water
retention87. Moreover, similar changes occur in the
mucosa of the orogastrointestinal and urinary tracts,
which also become more fragile. Moreover, menopause
seems to increase susceptibility to mucosal injury and
delay mucosal healing owing to a less robust humoral
and cellular immune response and to increased per-
meability of the mucosa to pathogens in the presence
of oestrogen deficiency 88. Changes in hair distribution
might also occur at menopause with the appearance of
facial terminal hairs and a decrease in body and scalp
hair 89 (FIG. 1). Hair loss in perimenopausal women usu-
ally appears as a dispersed thinning of hair, primarily in
the central and forehead region, and can also occur
in parietal and occipital regions89.
Personal and social impact
Midlife is a time of profound personal and social change
for women. The perception and interpretation of meno-
pausal symptoms, and therefore their interference with
day‑to‑day life, are influenced by social and cultural
beliefs90. On an international level, ~20% of women
perceive menopause as a disease, even if they are not
necessarily fully aware of its symptoms and health
implications90,91. Depending on personal and working
characteristics, even mild menopausal symptoms can be
distressing for some women, and most women with per-
vasive menopausal symptoms will experience profound
trouble in coping with daily life.
The personal experience of menopausal symptoms,
particularly bodily changes that occur related to ageing
and the awareness of the loss of fertility, can alter self-­
image. Life events might produce a change of role and/or
identity around the time of the menopausal transition.
The empty nest syndrome, retirement from work, hav-
ing frail or ill parents and the loss of a parent or partner
are all conditions that frequently occur at midlife. These
new conditions imply a depletion of personal and social
networks, a repositioning towards a less prestigious sta-
tus, an increase in caregiving activities, with an overall
decline in quality of life91. Thus, midlife and the meno-
pausal transition are often perceived as a time of crisis
by women, and the presence of distressing menopausal
symptoms adds to the perception of deteriorating mental
and physical well-being with indirect consequences on
health92. Nonetheless, many women perceive menopause
as a natural phase of life without negative implications93.
The reasons for this interpersonal variability in the per-
ception of menopause might be attributable to the rela-
tive intensity of symptoms but might also depend on how
women interpret and manage these symtoms94 according
to their social position and cultural inclination95,96.
Approximately 30–40% of women report that men-
opausal symptoms reduce performance in the work-
place94, and the most disruptive symptoms are hot
flashes, insomnia, a feeling of tiredness and poor concen-
tration96. Even in women who are not heavily burdened
by menopausal symptoms, the cost is often paid in terms
of perception of worsened social desirability and feel-
ings of shame or embarrassment, which are sometimes

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due to unwelcome comments from colleagues94,97–99.
Targeted strategies to make the menopausal transition
and its symptoms recognized socially and accepted
in the workplace94,95,100 — such as promoting self-help
readings, specific training, flexible working hours or
shift changes and reviews of workplace ventilation and
temperature — have proved valuable in helping women
to share their experiences with peers and together seek
solutions and develop coping strategies.
Incidence and prevalence of symptoms
International and interethnic epidemiological studies
have shown that the incidence and prevalence of men-
opausal symptoms might vary according to the study
population. Individual characteristics and comorbidi-
ties also have a role in the manifestation of menopausal
symptoms.
Ethnic differences
Differences in the age of natural menopause have been
reported on a global level. Indeed, a recent meta-­analysis
of 36 international studies evaluating age at natural
meno­pause reported an overall mean of 48.78 years, with
a range of 46 to 52 years101. The age at menopause was
reported to be generally lower in women from African,
Latin American, Asian and Middle Eastern countries
and was the highest in Europe and Australia, followed
by the USA101.
Disparities in reported symptoms of menopause
have been described among women of different eth-
nicities and/or geographical regions. Although the
nature of menopausal symptoms is common to women
of all geographical regions and ethnicities, the preva-
lence of certain symptoms varies considerably. Women
of European and Latin American ethnicity predom-
inantly have CNS-related symptoms, including hot
flashes, sleeplessness, mood changes, irritability and
reduced sex drive102–104. In North America, where the
population is multiethnic and comprises women of
African-American, Asian and Hispanic descent as well
as white women, the SWAN study reported that vaso-
motor symptoms were more prevalent among African-
American and Hispanic women and less prevalent
among Japanese-American and Chinese-American
women than among white women105. However, emerg-
ing analyses of studies performed in Thailand, China
and Singapore report that the prevalence of hot flashes
and/or night sweats in Asian women is similar to those
of Western countries106,107. The prevalence of vasomotor
symptoms was also reported to be lower in India and
in Middle Eastern countries, such as the United Arab
Emirates and Saudi Arabia, with respect to Western
countries108–110. African-American women tend to have
vasomotor symptoms that are particularly persistent
compared with the average 7.4 years20, with a median
total duration of 10.1 years20; however, this might be
due to the higher rate of obesity in African-American
women than in other ethnicities in North America111.
In addition, a multicentre study involving Spain and
Spanish-speaking Latin American countries revealed
that the prevalence of hot flashes and night sweats
was associated with higher climate temperatures, and
these symptoms were more frequent and problematic
for women living in higher temperature and lower alti-
tudes112. However, the frequency and severity of these
symptoms were not influenced by seasonal variation in
temperature112, an observation that was confirmed
in studies involving women from other continents109,110.
As previously stated, menopausal women have an
increased risk of cardiovascular events65,66; however, this
elevated risk seems to be higher in black postmenopau-
sal women with obesity than in white postmenopausal
women with obesity, even in the absence of the metabolic
syndrome113.
Skin ageing at menopause also varies according to
skin colour. In a study that enrolled menopausal women
within 36 months of the FMP, black women were shown
to have lower skin wrinkling scores over a period of
4 years than white women, possibly due to the lower sus-
ceptibility of black women to photoageing 114. Skin rigid-
ity, a measure of collagen and water content in skin that
changes rapidly in response to oestrogen deprivation, was
also positively correlated with the time since menopause,
but only in the white subpopulation of the study 114.
Regarding sexual functioning, African-American
women transitioning through menopause report a
higher frequency of sexual intercourse than other ethnic
groups83. Moreover, North American women of Chinese
and Japanese descent have been reported to be less sex-
ually active and attribute less importance to this aspect
than Western women83. However, data from the pan-
Asian REVIVE survey have revealed that genitourinary
syndrome is underdiagnosed and undertreated in Asian
women and that, when present, vaginal dryness and
irritation have the greatest negative influence on sexual
enjoyment and intimacy in this demographic115.
The prevalence of osteoporotic fracture in postmeno­
pausal women, mostly involving the hip, varies consid-
erably across the world, with the highest prevalence in
Scandinavia and lowest prevalence in Africa116. Within
the European continent, the highest rates of osteoporotic
fracture are recorded in northern countries compared
with the more southern Mediterranean countries,
presumably owing to differences in sun exposure and
therefore endogenous production of vitamin D, which
is essential for calcium absorption and bone mineral-
ization117. Interestingly, the rate of hip fractures has
increased threefold in China over the past 25 years,
which might be attributable to westernization and a shift
towards a more sedentary lifestyle118.
Individual differences
A woman’s experience of menopause is extremely per-
sonal, and therefore the incidence and prevalence of
symptoms, particularly CNS-related symptoms, are
influenced by personal characteristics, personal history
and environmental factors.
Personal history. A strong predictive association has
been described between somatic anxiety and the risk
of menopausal hot flashes119. Anxiety, perceived stress
and depressive symptoms also seem to lead to persistent

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Premenstrual syndrome
A heterogeneous group of
emotional symptoms, such as
irritability and food cravings,
and physical symptoms, such
as bloating, breast tenderness
and abdominal pain, that
precede the menstrual period.
Anovulation
The absence of ovulation.
8 | ADVANCE ONLINE PUBLICATION www.nature.com/nrendo
vasomotor symptoms20. Interestingly, one study120 reported household incomes and social support, poor educa-
that women who have experienced one or more form of tion, fair or poor general health and a history of surgical
abuse over the previous year, mostly verbal and/or emo- menopause and stressful life events132.
tional abuse, have higher scores for menopausal symp-
toms such as sleep disturbances, decline in cognitive Physiology of menopausal symptoms
function, bowel and bladder dysfunction, lower sexual Menopausal symptoms arise from the failure of ovar-
activity and decline in general health but not for hot ian function owing to the depletion of ovarian folli-
flashes and night sweats. In addition, women who have cles5 (FIG. 2). This process involves a series of hormonal
experienced moderate to severe premenstrual syndrome alterations over a period of years, a period known as
have an increased risk of developing depression, poor menopausal transition, beginning with the decline in
quality of sleep, feeling less attractive and, in particu- levels of inhibin B, resulting in a decline in their nega-
lar, memory and concentration problems after meno- tive feedback action on the follicle-stimulating hormone
pause121. Conversely, a history of hypertensive diseases (FSH) release from the pituitary 1,5. Increases in FSH
during pregnancy seems to predispose women to more levels of follow, promoting erratic increases in oestra-
severe and persistent hot flashes and night sweats122. diol secretion. This has been demonstrated in a study
of women classified according to the STRAW staging
Obesity. Excess adiposity is a major factor that influ- system as mid-reproductive age, late-reproductive age,
ences a woman’s quality of life during the menopausal early menopausal transition and late menopausal tran-
transition. Obesity is associated with a longer meno- sition133; in 37% of the ovulatory cycles during men-
pausal transition duration49 and a higher prevalence of strual transition, a second rise and fall in oestradiol
vasomotor symptoms123. In fact, gains in body fat over levels was observed during the mid-luteal and late-­
time are predictive of risk and frequency of vasomo- luteal phase, resembling that of the follicular phase but
tor symptoms124. Moreover, concurrent BMI and waist superimposed on the luteal phase, as well as decreases
circumference measurements are positively related to in progesterone secretion. This luteal out‑of‑phase
incident vasomotor symptoms in early menopause125; increase in oestradiol levels seemed to be triggered by a
on the basis of these data, the SWAN investigators have long-term elevation of FSH levels in the follicular phase
suggested that maintaining a healthy weight during early and lower inhibin B levels early in the cycles. Moreover,
menopause might help prevent vasomotor symptoms. the unopposed oestradiol production that is associated
A SWAN substudy found that a pro-inflammatory adi- with stimulation of follicular development is exacer-
pokine profile is associated with an increased incidence bated by increases in FSH and luteinizing hormone
of vasomotor symptoms, particularly at early stages (LH) levels in response to diminished negative feedback
in the menopausal transition, suggesting that a pro-­ on the FSH–LH release from the pituitary due to loss
inflammatory milieu produced by adipose tissue neg- of inhibin B and progesterone1,5. Eventually, the ovary
atively affects thermoregulatory activity in the CNS126. is less responsive to gonadotropin stimulation during
Overweight also seems to be linked with a twofold to perimenopause, leading to reduced oestradiol produc-
fourfold higher incidence of urogenital symptoms in tion1. In turn, LH stimulation is blunted and insufficient
women with normal weight, including vaginal dis- to elicit ovulation.
charge, itching and irritation127, and increases the risk Anovulation leads to the loss of progesterone produc-
of developing urinary incontinence128. Body weight and tion1,5. Conversely, the postmenopausal ovary continues
body composition are also relevant to the incidence of to contribute substantially to the circulating levels of tes-
osteoporotic fractures. Weight loss in older women is tosterone for years134. Moreover, serum concentrations of
associated with a general increased risk of fracture129, adrenal androgens in midlife women might variably and
whereas weight gain is associated with a reduced risk of transiently increase in the late menopausal transition135.
hip fractures but an increased risk of other peripheral In particular, a rise in mean serum concentrations of
fractures, such as wrist fractures130. dehydroepiandrosterone sulfate (DHEAS) occurs in
most women between the early menopausal transition
HIV infection. HIV infection in menopausal women is and early postmenopause stages135. This changing hor-
associated with more severe hot flashes compared with monal environment produces a cascade of CNS-related
women who are not infected with HIV, independent of and peripheral symptoms of variable severity for an
CD4+ T cell count or duration of HIV positivity, and unpredictable amount of time.
leads to interference with daily activities and a lower
quality of life131. More support should be provided for Vasomotor symptoms and sleep disruption
women who are HIV positive in coping with meno- Alterations in thermoregulation are the leading hypo­
pausal symptoms, as a reduction in quality of life might thesized mechanisms underlying vasomotor symp-
reduce adherence to anti-retroviral therapy 131. toms136. Menopause is associated with a reduction in
the thermoneutral zone of the body, meaning that
Socioeconomic status. Approximately 5% of perimen- minor increases in core body temperature can trigger
opausal women experience symptoms in clusters132. In an excessive thermoregulatory reaction and promote
particular, symptoms related to mood, sleep and sexual heat dissipation by peripheral vasodilation and sweat-
activity arise simultaneously, and factors that favour the ing 137. The thermoregulatory circuit is composed of
emergence of these clustered symptoms include low functional elements that are under catecholaminergic
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and/or serotonergic control138, and the hypothalamus is
ascribed a key role in the integration of thermal informa-
tion and in the control of thermoregulatory reactions138.
During perimenopause, hormonal cycles desynchronize,
leading to erratic levels of sex hormones, which often peak
and plummet133. Thermoregulatory dysfunction might be
a result of a maladaptation of the brain to this acyclicity,
with alterations in the function of noradrenergic and sero-
toninergic pathways137 (FIG. 2) that normally have a decisive
role in stabilizing the thermoneutral zone. Indeed, vas-
omotor phenomena are more common in periods of
amenorrhoea, which are characterized by fluctuations
in oestrogen levels139. The slow progression, reduction
and final disappearance of vasomotor symptoms dur-
ing menopausal transition suggest a readjustment of the
brain to the different concentrations of hormones and
neuro­transmitters, a process that might require a variable
amount of time, depending on the individual.

b
a
Mood and cognitive functions:
Vasomotor symptoms neuroendocrine activity
and sleep disruption ↑ Noradrenaline ↓ GABA-ergic function
↑ Noradrenaline ↓ Dopamine ↓ β-endorphin
↓ Dopamine
↓ Serotonin
↓ Serotonin ↓ Allopregnanolone c
↓ Androstenedione ↓ DHEA Urogenital symptoms,
↑ Neurokinin B ↓ Testosterone ↓ DHEAS
↑ Kisspeptin libido and sexual arousal
↓ E2 ↑ Cortisol ↓ E1
↑ Dynorphin ↑ Amyloid-β ↑ Cortisol:DHEA ratio
↑ Cortisol ↓ E2
↓ Androstenedione
g ↓ Testosterone
↓ Inhibin B ↓ DHEA
Skin ageing ↓ DHEAS
and hair changes ↑ FSH
↓ Oestrogen:androgen ratio ↑ LH
↓ Testosterone ↓ E2
↓ Dihydrotestosterone ↓ Progesterone

d
f Metabolic and cardiovascular changes
Bone remodelling ↑ LDL cholesterol ↓ HDL cholesterol
↓ E2 ↑ IL-1 e ↑ FFA ↓ SHBG
↑ N-telopeptide ↑ IL-6 Muscle changes ↑ Triglycerides ↓ GH
of type 1 collagen ↑ TNFα ↓ GH ↑ Cortisol ↓ IGF1
↑ C-terminal telopeptide ↓ TGFβ ↓ IGF1 ↑ Testosterone ↓ GH:IGF1 ratio
of type 1 collagen ↑ T-cell activation ↓ IGFBP3 ↑ Leptin ↓ Adiponectin
↑ Pyridinoline crosslinks ↓ Testosterone ↑ Renin–angiotensin ↓ NO
system

Figure 2 | Endocrine implications of menopausal symptoms and changes. After menopause, NaturetheReviews | Endocrinology
ovaries are depleted of
follicles, oestradiol (E2) and inhibin B production falls and ovulation and menstruation no longer occur. The loss of ovarian
sensitivity to follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and the loss of negative feedback of E2 and
inhibin B on the hypothalamic–pituitary unit result in increased production and release of gonadotropin release hormone
(GnRH), FSH and LH. Increased FSH levels are particularly specific to postmenopause. a | Modifications of gonadotropins, E2,
alterations in the function of noradrenergic and serotoninergic pathways, and opioid tone in the hypothalamus cause the
onset of vasomotor symptoms and consequent sleep disruption. Thermoregulatory dysfunction might be a result of a
maladaptation of the brain to kisspeptin, neurokinin B and dynorphin (KNDy) neuron hypertrophy, which project to the
preoptic thermoregulatory area. b | Mood, cognitive functions and neuroendocrine activity, which are closely related to
the impairment of GABAergic, opioid and neurosteroid neurotransmitter milieu in the central nervous system (CNS), occur
with ageing. Failure of the main target of neurosteroids, the GABA‑A receptor, to adapt to changes in levels of
allopregnanolone over the course of the menopausal transition might lead to depressive symptoms, mood and cognitive
dysfunctions. c | Peripheral levels of oestrogen (oestrone (E1), and E2) withdrawal affects all the tissue expressing oestrogen
receptors (ERs), such as the epithelial tissues of the bladder trigone, urethra, vaginal mucosa, pelvic muscles, and fascia and
gastrointestinal mucosa, leading to vulvovaginal atrophy and urogenital symptoms, the so-called genitourinary syndrome.
The menopausal condition induces reductions in oestrogens and ovarian and adrenal steroids (testosterone,
androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS)), which might contribute
to the onset of sexual dysfunction. d | Increased levels of LDL cholesterol, triglycerides, free fatty acids (FFA), cortisol and
testosterone, together with the decreased levels of HDL cholesterol, sex hormone-binding globulin (SHBG), growth
hormone (GH), insulin-like growth factor 1 (IGF1) and the GH:IGF1 ratio, facilitate the onset of menopausal metabolic
syndrome, which is characterized by an altered lipid profile, hyperinsulinaemia, increased gluconeogenesis, abdominal
obesity and overweight with a consequent rise in cardiovascular risk. e | Loss of oestrogen exposure leads to a progressive
decline in levels of GH and IGF1 and their binding protein insulin-like growth factor-binding protein 3 (IGFBP3), which
reduces muscle mass. The associated decline in androgen production is responsible for the onset of sarcopenia.
f | Circulating E2 levels decline after menopause, and bone resorption exceeds bone formation. Loss in bone mass is
demonstrated by the rise in circulating levels of bone resorption markers, such as N‑telopeptide of type 1 collagen,
C‑terminal telopeptide of type 1 collagen and pyridinoline crosslinks. In bone, oestrogen deficiency also leads to immune
cell activation, resulting in increased pro-inflammatory cytokine levels. g | Dihydrotestosterone, the peripherally active
form of testosterone, is responsible for the gradual involution of scalp hair follicles in androgenic alopecia and hair
changes. NO, nitric oxide; TGFβ, transforming growth factor-β; TNFα, tumour necrosis factor-α.

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Although initial studies reported that LH pulses occur
during hot flashes in postmenopausal women, a causative
link was never found139. The emerging hypo­thesis link-
ing these two events temporally involves the discovery
that kisspeptin, neurokinin B and dynorphin (KNDy)
neurons, which project to the preoptic thermoregula-
tory area, also regulate the hypothalamic GnRH pulse
generator, most likely by mediating oestrogen-dependent
negative feedback of LH secretion140. At postmenopause,
KNDy neurons undergo hypertrophy, and the expres-
sion of the genes encoding neurokinin B and kisspeptin
increases as a result of oestrogen withdrawal, leading to
increased signalling to heat dissipation effectors in the
CNS and to GnRH neurons140 (FIG. 2).
There is also evidence in the literature that severe
vasomotor symptoms are associated with activation of
the hypothalamus–pituitary–adrenal axis, as increased
urinary cortisol secretion has been reported during the
late menopausal transition stage in women with severe
vasomotor symptoms compared with women who have
mild complaints141, and higher salivary cortisol levels
have also been associated with more frequent, severe
and bothersome daily self-reported hot flashes142. Higher
circulating concentrations of cortisol and noradrenaline
were also reported in women at the menopausal tran-
sition or the early postmenopausal stages who experi-
enced vasomotor symptoms143. Increased cortisol might
activate a stress response with a consequent increase in
catecholamines, adrenaline and noradrenaline, which,
in turn, induce vasodilation141.
The biological mechanisms underlying the sleep dif-
ficulties that develop during menopausal transition are
still unclear. Lower levels of inhibin B, a marker of the
early menopausal transition, have been found to strongly
predict poor sleep quality 39,144 in women at late meno-
pausal transition and at postmenopause, whereas higher
mean urinary FSH levels, the hallmark of ovarian failure,
have been associated with poor sleep quality in premen-
opausal and perimenopausal women50,145. In addition, a
faster rate of increase in FSH levels has been associated
with longer sleep duration, indicative of less restful sleep
and more non-REM sleep24. Postmenopausal women also
show an advanced onset of melatonin release compared
with premenopausal women146; therefore, advanced cir-
cadian phase might contribute to early morning awak-
ening, a common complaint in menopausal women35.
Furthermore, obstructive sleep apnoea might exacerbate
these sleep difficulties in menopausal women. Reduced
levels of progesterone, a respiratory stimulant, in peri-
menopausal woman might be the underlying cause of
this nocturnal breathing disorder 147.
Cognitive changes and migraine
Oestradiol is believed to have a major role in cognitive
performance as anatomical studies have demonstrated
that the hippocampus and prefrontal cortex, which medi-
ate episodic and working memory, express high levels of
oestrogen receptors (ERs)148. In these areas of the CNS,
oestradiol-dependent activation of ERs can modulate the
synthesis, release and metabolism of neurotransmitters
(such as serotonin, dopamine and acetylcholine) and
neuropeptides (such as β‑­endorphin and neurosteroids,
namely, allopregnanolone and dehydroepiandrosterone
(DHEA)) (FIG. 2) and can also influence the electrical
excitability, function and morphological features of the
synapses148. Thus, unstable levels of oestrogen during
perimenopause might cause the transient cognitive defi-
cits that are observed clinically at this time148. However,
the link between circulating levels of oestradiol and cog-
nitive impairment is not well established, and clinical
trials evaluating hormone therapy in women at midlife
have not shown improvements in cognition45. It has been
shown that the concomitant rise in LH levels that occur
with ovarian failure might drive both cognitive dysfunc-
tion and loss of spine density in an independent man-
ner 149. Indeed, animal studies have shown that lowering
the peripheral levels of LH using leuprolide acetate, a
GnRH agonist, improved cognition and spatial memory
and increased spine density 149. Persistently high levels
of FSH and LH have been linked to Alzheimer disease in
postmenopausal women, and it is hypothesized that these
hormones might be responsible for increased production
of amyloid‑­β, a main constituent of senile plaques150.
Indeed, pharmaco­logical suppression of LH and FSH
using leuprolide acetate reduced plaque formation in
animal models of Alzheimer disease151.
According to the oestradiol withdrawal hyp­othesis,
migraine in women are triggered by the sudden decline
in oestrogen levels that occurs immediately before
menses, during the menopausal transition or in the
early postmenopausal period152. There is accumulat-
ing evidence that changes in oestradiol levels in the
brain might precipitate a kind of neurogenic inflam-
mation that is characterized by vasodilation, release
of pro-­inflammatory mediators and plasma extra­
vasation153, leading to the typically reported throbbing
and pulsing pain.
Mood changes
The most accredited likely biological hypothesis under-
lying changes in mood is that fluctuations in levels of
steroid hormones, more than their decline, might trigger
perimenopausal depression154. It seems that the longer
the duration of the menopausal transition, and there-
fore the longer the exposure to fluctuating hormones,
the greater the risk of perimenopausal depression155.
In the Penn Ovarian Ageing Study 156, it was found that
a more rapid rise in FSH levels before the FMP was pre-
dictive of a lower risk of depressive symptoms after the
FMP, suggesting that a shorter menopausal transition
protects against perimenopausal depression. A subset
of perimenopausal women might have an increased
sensitivity to changes in gonadal steroids, specifically
oestrogens and progesterone, which in turn modulate
neuroregulatory systems associated with mood and
behaviour 154. In particular, fluctuating oestrogen levels
might lead to dysregulation of serotonin and noradren-
aline pathways in the CNS as oestrogen facilitates a
number of actions of serotonin and noradrenaline, spe-
cifically by modulating receptor binding and the avail-
ability of these neurohormones at the synaptic level154.
In an interesting theoretical model157, fluctuations in

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Urethral closure pressure
The fluid pressure needed to
open a closed urethra.
Valsalva leak-point pressure
The lowest abdominal pressure
required during a stress activity
that causes the urethra to open
and leak.
Free androgen index
An index that represents the
ratio of bioactive circulating
testosterone.
progesterone-derived neurosteroids, particularly allo-
pregnanolone, caused by changes in oestradiol and pro-
gesterone levels might underlie menopause-­associated
depressive symptoms. In particular, failure of the
GABA-A receptor — the main target of neurosteroids —
to adapt to changes in levels of allopregnanolone (FIG. 2)
over the course of the menopausal transition might lead
to depressive symptoms in vulnerable women, such as
those with a history of premenstrual dysphoric disorder
and/or postpartum depression157. The inability to main-
tain GABAergic homeostatic control might exacerbate
the response of the hypothalamus–pituitary–adrenal
axis to stress. Indeed, there is increasing evidence that
dysregulation of the hypothalamus–pituitary–adrenal
axis, which is correlated with oestradiol fluctuation,
might be implicated in the pathophysiology of peri-
menopausal depression158. Moreover, very stressful life
events seem to contribute greatly to the onset of depres-
sive symptoms during the menopausal transition in the
presence of oestradiol variability 159 (FIG. 2).
Urogenital symptoms and sexual function
The lower genital and lower urinary tracts share a com-
mon embryonic origin in the female and express high
numbers of ERs during the reproductive years160; as a
result, both of these tissues are affected by long-term
hypoestrogenism during menopause. From a histo­logical
point of view, after menopause, these tissues exhibit
reduced collagen content and hyalinization, decreased
elastin content, thinning of the epithelium, altered mor-
phology and function of smooth muscle cells, increased
density of connective tissue and fewer blood vessels160,161.
Vaginal blood flow is reduced, as well as the lubrication
and elasticity of the vagina, leading to shortening and
narrowing of the vagina and, consequently, dyspareunia
and easy fissuring of the vaginal walls160. Approximately
20% of postmenopausal women develop urge inconti-
nence, and ~50% develop stress incontinence75; however,
only the incidence of urge incontinence is affected by
long-term oestrogen depletion. It is hypothesized that
the lack of oestrogenic activity in the trigone of the blad-
der and the urethra might decrease the sensory thresh-
old and lower the urethral closure pressure and Valsalva
leak-point pressure, therefore contributing to urinary
urgency 162 (BOX 1).
Pinpointing a biological cause for sexual dysfunction
in menopausal women is extremely difficult due to the
complexity of this domain; changes in sexual activity
depend on changes in sexual desire and partner satis-
faction, dyspareunia due to vaginal dryness and general
health. Important associations between endogenous
levels of reproductive hormones and sexual function
in women going through the menopausal transition
have been reported. Masturbation, desire and arousal
were positively associated with levels of testosterone
and DHEAS, supporting a role for androgens in female
sexual function163,164 (FIG. 2). Indeed, with the exception
of surgical menopause, after which testosterone lev-
els tend to decrease abruptly, androgen levels do not
decline immediately following natural menopause134.
Masturbation, arousal and the ability to climax with a
partner are negatively associated with FSH levels163, the
summiting of which marks ovarian failure. Moreover,
waning oestrogen levels in the late menopausal transi-
tion lead to decreased vascular congestion and lubrica-
tion of the vagina, resulting in unsatisfactory or painful
intercourse165.
Metabolic and cardiovascular changes
From an endocrinological perspective, longitudinal
studies have revealed that the menopausal transition is
characterized by a shift from a predominately oestro-
genic hormonal state to an androgenic state owing to
an increase in bioavailable testosterone levels3,62,166. The
menopausal ovary continues to produce high amounts
of androgen for years after menopause, and the increase
in gonadotropin levels drives ovarian androgen secretion
despite the substantial decline in oestrogen levels123. Sex
hormone-binding globulin (SHBG) levels decrease with
decreasing oestrogen concentrations, thereby increas-
ing the free androgen index and enhancing the imbal-
ance between oestrogens and androgens3 (FIG. 2). The
increase in bioavailable testosterone can stimulate fat
accumulation in preadipocytes of visceral fat 64. Visceral
fat adipocytes express high levels of androgen receptors
that are downregulated by oestrogens167; therefore, when
oestrogen levels decline, visceral fat might become more
sensitive to the negative effects of androgens. Indeed, it
seems that the change in the bioavailability of androgens
can predict accumulation of visceral fat over a period
of 5 years168. Moreover, menopausal women with more
rapidly increasing levels of bioavailable testosterone
undergo larger increases in adiposity than women with
more stable levels, whereas women with slowly increas-
ing levels of bioavailable testosterone experience smaller
increases in adipose tissue168. Rising FSH levels might
also contribute to this phenomenon, as the FSH receptor
(FSHR) is expressed in visceral fat adipocytes169, and ani-
mal studies have indicated that FSHR signalling might
increase adipocyte lipid synthesis and lead to elevated
levels of leptin and decreased levels of adiponectin in
serum, therefore promoting fat accumulation169.
In postmenopausal women, increasing levels of bio-
available testosterone and decreasing SHBG levels are
exacerbated by insulin resistance, and low SHBG lev-
els are predictive of incident type 2 diabetes mellitus in
postmenopausal women170. Insulin resistance and central
obesity, the hallmarks of the metabolic syndrome, occur
in many postmenopausal women171. Furthermore, the
lack of oestrogens per se seems to favour accumulation
and a central distribution of adipose tissue172. Studies
performed in human and animals have shown that
oestrogens regulate food intake negatively and energy
expenditure positively, promote free fatty acid (FFA)
uptake and triacylglyceride synthesis in gluteofemoral
adipose tissue (rather than in abdominal subcutaneous
adipose tissue) and inhibit adipose tissue depot-specific
pathophysiological processes that lead to morbidity 172.
In addition, lower concentrations of oestradiol were
found to be markedly associated with greater volumes
of paracardial adipose tissue in women at midlife, while
the free androgen index was found to correlate positively

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with fat around the aorta, and SHBG levels were found
to correlate negatively with fat in all evaluated cardio-
vascular depots70. Negative changes in endothelial cell
function might also influence the increased risk of CVD
that is observed in postmenopausal women. Oestrogen
deficiency leads to activation of the renin–angiotensin
system, as well as upregulation of endothelin, a potent
vasoconstrictor 173. Conversely, oestrogen deficiency leads
to impaired oestradiol-induced signalling, resulting in
the reduced release of cardioprotective nitric oxide174.
Together, these changes accelerate atherogenesis in per-
imenopausal women, increasing their susceptibility to
ischaemic heart disease and CVD.
Muscle loss and bone remodelling
Studies indicating the presence of ERs on muscle tis-
sue, particularly on type II muscle fibres, have led to the
hypothesis that a loss of ovarian function might have a
direct negative effect on muscle tissue175. As oestradiol
signalling through ERα and ERβ favours the binding of
myosin to actin during muscle contraction, the loss of
oestrogen exposure might reduce the intrinsic quality
of skeletal muscle whereby muscle fibres have a reduced
capacity to generate force176. Maintenance of muscle
mass is known to depend on growth hormone (GH)
secretion, and GH production decreases gradually with
age in both males and females177. However, menopause
leads to a marked decline in 24‑hour mean serum concen-
trations of GH, insulin-like growth factor 1 (IGF1) and
its binding protein insulin-like growth factor-binding
protein 3 (IGFBP3), which are also involved in mainte-
nance of muscle178 (FIG. 2). Secretion of GH is influenced
considerably by oestrogen levels, which probably occurs
through ERα stimulation in the CNS178. Thus, oestro-
gen deficiency might contribute to the ageing-related
decline in GH concentrations. This decline in GH levels
leads to a 1–1.5% reduction in muscle mass in men and
women from approximately age 40 years onwards179,
which is paralleled by an increase in visceral fat con-
tent180. Visceral adiposity and hyperinsulinaemia, in turn,
can further reduce GH secretion, leading to the devel-
opment of a vicious cycle of muscle loss180. Increasing
body weight with age, along with the increased levels
of pro-inflammatory cytokines and oxidative stress that
occur at menopause, might also favour muscle catabo-
lism181. Together, these changes determine a decrease in
muscle mass, strength and mobility in postmenopausal
women181–183. Finally, sarcopenia in women might also be
related to the ultimate decline in androgen production.
Indeed, a longitudinal study in ageing Japanese women
demonstrated that the decrease in free testosterone levels
can predict the risk of loss of appendicular muscle184.
Arguably the most important change in the musculo­
skeletal system during menopause is the loss in BMD.
After attainment of peak bone mass in early adulthood,
maintenance of normal bone structure is ensured by a
fine equilibrium between osteoblastic bone formation
and osteoclastic bone resorption5. When oestrogen levels
decline after menopause, bone resorption exceeds bone
formation during each bone remodelling cycle, resulting
in a net loss in bone mass185. Indeed, circulating levels
of bone resorption markers — such as N‑telopeptide of
type 1 collagen, C‑terminal telopeptide of type 1 col-
lagen and pyridinoline crosslinks — increase by 90%
after menopause, whereas markers of bone formation
increase by only 45%185 (FIG. 2). Oestrogens are known
to stimulate osteoblast proliferation and differentiation,
therefore promoting deposition and mineralization of
bone matrix, and can also induce apoptosis in osteo-
clasts. Their effect on osteoblasts, osteoclasts and oste-
ocytes occurs through activation of high affinity ERs,
including the ERα and ERβ isoforms186. In bone, oestro-
gen deficiency also leads to immune cell activation and
the resulting pro-inflammatory cytokine milieu further
enhances bone resorption186.
The loss of ovarian function might also be associated
with an increase in joint abnormalities with an increase
in pain. Indeed, ERs are present in joint tissues, and
hypoestrogenism might affect cartilage, periarticular
bone, synovial lining, ligaments and the joint capsule187.
It is established that females are predisposed towards
knee osteoarthritis, which might be in part attribut-
able to sex differences in cartilage health, even before
the onset of clinical knee disease188. Indeed, women at
midlife show a markedly greater annual loss of total
tibial and patellar cartilage than men188. However, more
research is necessary to address joint health, specifically
in menopausal women.
Skin ageing and hair changes
Total collagen content was shown to decline at an aver-
age rate of 2.1% per year in postmenopausal women
over a period of 15 years, with a loss of as much as 30%
within the first 5 years after the FMP86. Consequently,
skin thickness decreases at a rate of 1.13% per year in
postmenopausal women97, whereas skin elasticity seems
to decline at a rate of 1.5% per year in early postmeno-
pausal women189. The levels of melanocytes in skin also
decline at a rate of 10–20% per decade in postmenopausal
women, leading to focal depigmentation and uneven col-
our of the skin98. These skin changes are worsened by the
atrophy of the dermal vascular network that occurs after
menopause, resulting in reduced provision of circulating
nutrients and hormones97. In addition, hair loss might
be due to an altered oestrogen:androgen ratio favouring
increased androgen activity (FIG. 2), resulting in a decrease
in the duration of the anagen phase of the hair follicle190.
Dihydrotestosterone — the peripherally active form of
testosterone produced by metabolism of testosterone via
5 alpha-reductase — is responsible for the gradual invo-
lution of scalp hair follicles in androgenic alopecia191. In
genetically susceptible women, dihydrotestosterone pro-
duces a transformation from terminal to vellus hairs191.
The anagen phase of hair growth is progressively short-
ened, whereas the telogen phase is lengthened, leading,
over successive cycles, to the involution of hair follicles191.
A prevalence of androgenic activity has an opposite effect
on facial hair, as nearly 50% of women report excessive
facial hair growth after menopause192; in this case, andro-
gens are responsible for increasing hair follicle size, hair
shaft diameter and increased duration of the anagen
phase of terminal hairs192.

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Cardiac vagal control
An index of parasympathetic
contribution to cardiac
regulation.
Cardiac index
The volume of blood pumped
by the heart in a minute per
body surface.
Stroke volume index
The volume of blood pumped
by the heart with each beat per
body surface.
Vascular resistance index
An index representing the
degree to which blood vessels
impede the flow of blood.
Predicting future health
Data are emerging from the literature demonstrating
that the presence of some menopausal symptoms might
predict a clinically relevant higher risk of developing
other disorders. An increasing number of studies are
reporting that severe vasomotor symptoms might be
associated with poor cardiovascular health. Indeed,
women who reported frequent hot flashes were found
to have a higher carotid intima–media thickness than
women who did not report hot flashes193. In addition,
a higher incidence of arterial endothelial dysfunction,
indicated by impaired flow-mediated dilation of the
brachial artery, has been reported in women during
the menopausal transition who present with hot
flashes than in women lacking these symptoms194. Data
also indicate that women at midlife have decreased
cardiac vagal control (that is, reduced parasympathetic
cardiac regulation) during vasomotor symptoms195.
Furthermore, it has been reported that vasomotor
symptoms are associated with an unfavourable haemo-
dynamic profile characterized by a lower overall cardiac
index and stroke volume index, a higher overall vascular
resistance index and greater levels of the pro-inflamma-
tory cytokine IL‑6 (REF. 195). Finally, late postmenopau-
sal women with vasomotor symptoms have a higher
prevalence of a previous diagnosis of hypertension than
women without symptoms, indicating that the endothe-
lial dysfunction developed during early postmenopause
might predict the development of hypertension at late
postmenopause196. Vasomotor symptoms are also associ-
ated with a procoagulant haemostatic profile and might
increase the risk of arterial or venous thrombosis197.
When clinical cardiovascular events are considered, it
seems that women with current signs and symptoms
of myocardial ischaemia who present with vasomotor
symptoms beginning early in midlife have a higher mor-
tality due to CVD and reduced endothelial function than
women who have later onset of vasomotor symptoms198.
Sleep disturbances, such as shorter duration and lower
overall quality of sleep, might also be risk factors for
cardio­vascular health as they have been associated with
a greater degree of aortic calcification199 and increased
carotid atherosclerosis among women at midlife 200.
Furthermore, vasomotor symptoms in addition to
poor sleep quality seem to favour the onset of depres-
sive symptoms during the menopausal transition201. In
a study where the GnRH agonist leuprolide was used
to induce oestradiol suppression in premenopausal
women, it was shown that depressive symptoms are asso-
ciated with objectively and subjectively measured sleep
disturbance and the number of night-time, but not day-
time, hot flashes202. In the SWAN cohort, women with
more mood-related symptoms and moderate to severe
vasomotor symptoms displayed worse cognitive perfor-
mance51,52. Awareness of depressive symptoms at midlife
is also important as there is some indication that they
might be associated with the development of dementia
in later life203. Urinary symptoms, such as nocturia and
stress incontinence, are associated with body fat and vis-
ceral fat accumulation and also with sleep disorders204.
Moreover, the presence of vulvovaginal symptoms
increases the risk of specific pelvic floor disorders, such
as pelvic organ prolapse or faecal incontinence205. Bone
tissue also seems to deteriorate more in menopausal
women with vasomotor symptoms who have low spine
and femoral neck BMD206. Furthermore, menopausal
women with vasomotor symptoms have increased rates
of hip fractures compared with asymptomatic women, as
observed in a prospective study with a mean follow‑up
of 8.2 years206.
Age acceleration effects can be estimated by comparing
DNA methylation age — measured in various tissues such
as blood, saliva and buccal mucosa — with an individual’s
chronological age. A study from 2016 has demonstrated
that menopause accelerates epigenetic ageing in women,
therefore showing that age at menopause is a determinant
of biological ageing 207. The finding is particularly relevant
for women who undergo bilateral oophorectomy before
natural menopause because the premature removal of
the ovaries will accelerate the ageing process; this might
explain the increasing evidence that surgical menopause
raises the risk of premature death, CVD, dementia,
osteoporosis and bone fractures207.
Conclusions
Symptoms of menopause are distressing for most
women. CNS-related symptoms such as hot flashes,
mood and sleep disorders, migraine, and memory and
learning difficulties seem to depend on acyclical fluc-
tuations in oestradiol levels, specifically, sudden oestra-
diol withdrawal, which causes secondary neurochemical
changes. Apart from developing vasomotor symptoms
such as hot flashes and night sweats, women transi-
tioning through menopause might also be vulnerable
to developing anxiety, depression, poor quality of sleep
and migraine. By contrast, physical symptoms such as
urogenital atrophy, ageing of the skin and skeletal frac-
tures due to postmenopausal osteoporosis are secondary
to the decline in oestradiol levels. The accumulation and
central distribution of body fat, hair loss, the develop-
ment of facial hair and sexual dysfunction are seemingly
due to transitional increases in androgen bioavailability.
Data from longitudinal studies have demonstrated
that many factors can contribute to worsening a wom-
an’s experience of menopause. Ethnicity seems to largely
affect how a woman will experience the menopau-
sal transition. Indeed, European and Latin American
women have a higher prevalence of hot flashes, sleepless-
ness, mood changes, irritability and reduced sex drive
than women of other ethnicities, and African-American
women experience particularly persistent vasomotor
symptoms. Climatic factors such as higher temperatures
or lower altitudes are also associated with higher inci-
dence of hot flashes and night sweats. In addition, low
exposure to sunlight, an issue particularly in northern
European countries, increases the risk of osteoporotic
bone fracture. Obesity is another major individual fac-
tor that influences symptom prevalence and, contrary
to past belief, does not protect against hot flashes but
actually increases the risk of severe vasomotor symp-
toms. Moreover, obesity is associated with a higher
incidence of urogenital symptoms (including vaginal

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discharge, itching and irritation) compared with women
with normal weight and increases the risk of urinary
incontinence. Anxiety and chronic illness (such as HIV
positivity) also heighten the risk of vasomotor symp-
toms. Mood, memory and sleep disorders arise more in
women who experienced past abuse or those with a his-
tory of premenstrual syndrome. Lower socio­economic
and educational background, poor general health and
stressful life events also favour the onset of menopausal
symptoms in clusters.
An emerging concept is that some menopausal symp-
toms might be predictive of future health complications.
Indeed, severe vasomotor symptomatology and poor
quality of sleep are associated with an increased risk of
CVD and postmenopausal depression. Furthermore,
depressive symptoms, vasomotor symptoms and sleep
disorders might increase the susceptibility to developing
cognitive dysfunction. Severe hot flashes have also been
associated with an increased risk of osteoporosis and
bone fracture. Finally, as menopause seems to accelerate
the ageing process, it is conceivable that, in addition to
loss of ovarian function, the manifestation of menopausal
symptoms might be in part due to ageing.
The large number of studies performed over the past
decade in women transitioning through menopause
underscore the need to closely monitor health param-
eters at this stage and to promote a healthy lifestyle.
These changes in health-care practice should start before
the menopausal transition to counteract the emergent
cardiovascular risk factors and possibly reduce bother-
some symptomatology. It is also important for medical
practitioners to consider a woman’s home and work
environment and also her ethnicity, as these factors will
also profoundly affect her experience through meno-
pause. Although the management of symptoms through
pharmacological or cognitive-behavioural therapy
approaches might improve quality of life in the short
term, future research will be necessary to develop strat-
egies to modify health risks, which are often intensified
by the loss of ovarian function, in the long term.

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Author contributions
P.M., G.M. and A.G. researched data for the article. All
authors made a substantial contribution to discussion of con-
tent, wrote the manuscript and reviewed and/or edited the
manuscript before submission.
Competing interests statement
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

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