PRIMER

Menopause
Susan R. Davis1, Irene Lambrinoudaki2, Maryann Lumsden3, Gita D. Mishra4,
Lubna Pal5, Margaret Rees6, Nanette Santoro7 and Tommaso Simoncini8
Abstract | Menopause is an inevitable component of ageing and encompasses the loss of ovarian
reproductive function, either occurring spontaneously or secondary to other conditions. It is not yet
possible to accurately predict the onset of menopause, especially early menopause, to give women
improved control of their fertility. The decline in ovarian oestrogen production at menopause can cause
physical symptoms that may be debilitating, including hot flushes and night sweats, urogenital atrophy,
sexual dysfunction, mood changes, bone loss, and metabolic changes that predispose to cardiovascular
disease and diabetes. The individual experience of the menopause transition varies widely. Important
influential factors include the age at which menopause occurs, personal health and wellbeing, and each
woman’s environment and culture. Management options range from lifestyle assessment and intervention
through to hormonal and non-hormonal pharmacotherapy, each of which has specific benefits and risks.
Decisions about therapy for perimenopausal and postmenopausal women depend on symptomatology,
health status, immediate and long-term health risks, personal life expectations, and the availability and
cost of therapies. More effective and safe therapies for the management of menopausal symptoms need
to be developed, particularly for women who have absolute contraindications to hormone therapy.
For an illustrated summary of this Primer, visit: http://go.nature.com/BjvJVX

Correspondence to S.R.D. 
e‑mail: susan.davis@
monash.edu
School of Public Health and
Preventive Medicine,
Monash University,
99 Commercial Road,
Melbourne, Victoria 3004,
Australia.
Article number: 15004
doi:10.1038/nrdp.2015.4
Published online
23 April 2015
Menopause is the permanent cessation of menstrual
cycles following the loss of ovarian follicular activity
(FIG. 1). This may be spontaneous (natural menopause)
or iatrogenic (secondary menopause). The latter includes
removal of both ovaries (surgical menopause), as well as
ovarian failure resulting from chemotherapy or radio-
therapy. To facilitate research on menopause, investiga-
tors convened in 2001 and reported the first Staging of
Reproductive Aging Workshop (STRAW) recommenda-
tions1. Staging is not only useful for research; it can also
facilitate dialogue between a woman and her clinician,
and between clinicians. A refined STRAW classification
was published in 2012 and includes several data-driven
adjustments to the original publication2–5.
Briefly, the STRAW classification (summarized in
FIG. 2) separates a woman’s life into seven segments,
with segments –2, –1 and 0 including the early meno-
pausal transition, the late menopausal transition and
the final menstrual period, respectively. Age at natural
menopause is used to indicate the timing of menopause
and is confirmed after 1 year of amenorrhoea. The early
transition is defined as a departure from previously
regular menstrual cycle lengths of ≥7 days, or a skipped
menstrual period. During this stage, oestrogen levels
are fluctuating but are sufficient overall, and cycles
are usually ovulatory. If oestrogen levels drop, they are
not maintained at a very low level for long, but will
fluctuate until after menopause. Thus, symptoms are
generally mild at this stage of the transition and most
women will notice them but not require treatment.
Clearly, the STRAW staging primarily applies to
women experiencing spontaneous menopause and not
those with secondary menopause. It is also less useful
for women who are unable to observe a change in their
menstrual bleeding patterns, owing to hysterectomy,
endometrial ablation, hormonal contraception with
suppressed ovarian cycles or a progestin intrauterine
device, for example. For such women, the occurrence of
menopausal symptoms, due to the fall in ovarian oestro-
gen production, may provide the first indication of the
menopause6. Although not all women experience sig-
nificant symptoms, the fall in oestrogen at menopause
results in changes throughout the body including bone
loss, a tendency to increased abdominal fat and a more
adverse cardiovascular risk profile. In this Primer article,
we summarize the current understanding of the physiol-
ogy and clinical consequences of menopause, as well as
the available treatment options.
Epidemiology
The first reliable epidemiological estimates for the tim-
ing of menopause give a median age at natural meno-
pause of 48–52  years among women in developed
nations7. In a more recent and broader meta-analysis8 of
36 studies spanning 35 countries, the overall mean age
was 48.8 years (95% CI 48.3–49.2), with considerable

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 PRIMER

Author addresses
variation by geographical region (TABLE 1). Although
studies in the United States and Asia tend to show results
1
School of Public Health and Preventive Medicine, Monash University, 99 Commercial close to this mean figure, age at menopause is gener-
Road, Melbourne, Victoria 3004, Australia. ally lower in Africa, Latin America and Middle-Eastern
2
Medical School, University of Athens, and Aretaieio University Hospital, Athens, countries (regional means: 47.2–48.4 years), and higher
Greece.
in Europe and Australia (50.5–51.2 years)8. The reasons
3
Reproductive & Maternal Medicine, Glasgow Royal Infirmary, Glasgow, UK.
4
School of Population Health, Faculty of Medicine and Biomedical Sciences, University
for such regional differences remain far from clear;
of Queensland, Australia. however, previous studies suggest a modest rise of the
5
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University menopausal age for women in wealthy nations during
School of Medicine, New Haven, Connecticut, USA. the twentieth century 9–13. The biological and environ-
6
Women’s Centre, John Radcliffe Hospital, Oxford, UK. mental factors — and interactions between them — that
7
University of Colorado School of Medicine, Aurora, Colorado, USA. account for regional differences and historical trends in
8
University of Pisa, Pisa, Italy. the timing of menopause remain unclear.
Distinguishing the effects of menopausal transi-
tion on a woman’s health and quality of life (QoL) from
a Reproductive phase the effects of ageing is a major challenge for cross-­
GnRH
sectional, observational studies. Moreover, other major
life events can occur during midlife, such as needing
FSH to care for elderly parents and children leaving home
LH permanently. Findings from a study in the United
Oestradiol States indicate that the perimenopausal stage lasts on
Inhibin B average for almost 4 years, although for some women
Hormone levels

it can last much longer, with a longer perimenopause

being associated with a higher rate of medical consulta-
tions14. Vasomotor symptoms (hot flushes and cold or
night sweats) and vaginal dryness are well-established
symptoms during and after perimenopause15. Indeed,
75% of postmenopausal women <55 years of age report
vasomotor symptoms, and 28.5% of them have moder-
ate to severe symptoms16. Longitudinal analysis of data
0 14 28 from women in the Medical Research Council 1946
Time within cycle (days) British birth cohort has unravelled other effects on
b Menopause QoL. After adjusting for age, life events and a range of
other socio­economic and lifestyle factors, two aspects of
QoL declined with the menopausal transition: namely,
perceived physical health (including energy levels) and
Average hormone levels

psychosomatic status (such as nervous emotional state

and ability to concentrate). These changes were associ-
ated with a longer duration of perimenopause17, which
is consistent with an earlier study from the United States
that found longer perimenopause was associated with
higher rates of medical consultations14.
Vasomotor symptoms are among the most frequently
reported physiological symptoms during and after
meno­pause18,19, but their prevalence among women
in developed nations ranges from 30% to 75%16,20,21.
–5 0 +5 A systematic review of the prevalence of menopausal
Time from last period (years) symptoms in Asian countries found a predominance of
Figure 1 | Regulation of menstrual cycles.  a | In theNature
premenopausal
Reviews |years,
Diseasepulsatile
Primers other physical symptoms over vasomotor and psycho-
release of gonadotropin-releasing hormone (GnRH; indicated by arrows) stimulates the logical symptoms. Furthermore, vasomotor symptoms
synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) occurred in premenopausal, perimenopausal and post-
from the anterior pituitary gland. FSH, in particular, stimulates oestradiol and inhibin B menopausal women22. However, most studies that were
production by ovarian follicles. Oestradiol and inhibin B exert feedback on the pituitary considered for this systematic review showed low exter-
gland and hypothalamus that, in turn, modifies the production of GnRH, LH and FSH. nal and internal validity when evaluated by a risk of bias
Co‑ordinated and timed production and release of pituitary FSH and LH result in the tool. Thus, further studies of representative samples and
development of ovarian follicles, ovulation and menstruation. Inhibin B is produced by
using validated questionnaires are needed to clarify the
the ovarian granulosa cells and inhibits FSH synthesis and secretion. b | After menopause,
the ovaries are depleted of follicles, oestradiol and inhibin B production falls, and prevalence of menopausal symptoms in Asian women.
ovulation and menstruation no longer occur. The loss of ovarian responsiveness to FSH Epidemiological studies have provided a detailed
and LH, and the loss of negative feedback of oestradiol and inhibin B on the picture of symptom trajectories experienced through
hypothalamic–pituitary unit, result in increased production and release of GnRH, FSH the menopausal transition and into postmenopause.
and LH. Increased FSH is particularly characteristic of postmenopause. For instance, findings from two studies15,23 have shown

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 PRIMER

Regular menstrual cycle Subtle changes Menstrual cycle of Interval of amenorrhoea • Variable but • FSH stabilizes
in flow/length variable length, ≥60 days elevated FSH • Very low AMH
• Low FSH of menstrual persistent ≥7-day • Low AMH • Very low inhibin B
• Low AMH cycle difference in length • Elevated >25 IU/l FSH** • Low inhibin B • Very low antral
• Low antral follicle count of consecutive • Low AMH • Very low antral follicle count
• Variable FSH cycles • Low inhibin B follicle count
• Low AMH • Low antral follicle count
Regular menstrual cycle Increasing
• Low inhibin B • Variable but Vasomotor
• Low antral elevated FSH* Vasomotor symptoms likely symptoms most symptoms of
Variable to follicle count • Low AMH likely urogenital atrophy
regular menstrual • Low inhibin B
cycle • Low antral follicle
count
Stage
–5 –4 –3b –3a –2 –1 0 +1a +1b +1c +2

Early Peak Late Early Late Early Late

Reproductive Menopausal transition Postmenopause
Variable duration FMP (0)
Menarche Perimenopause
Principal criteria
Supportive criteria Variable Remaining
Descriptive characteristics duration 1–3 years 2 years (1+1) 3–4 years lifespan

Figure 2 | The stages of reproductive ageing in women.  The Stages of Reproductive Aging NatureWorkshop Disease defined
Reviews |(STRAW) Primers
seven stages ranging from the onset of menstrual cycles at menarche and the reproductive age to the perimenopausal
and postmenopausal phases. Principal (menstrual cycle), supportive (biochemical and imaging) and descriptive criteria
(symptoms) are used to characterize the phases. AMH, anti-Müllerian hormone; FMP, final menstrual period; FSH, follicle-
stimulating hormone. *Blood drawn on cycle days 2–5. **Approximate expected level based on assays using current
international pituitary standard. Figure reproduced from Climacteric (REF. 4) with permission from Informa Healthcare
(www.informahealthcare.com). Figure reprinted by permission from the American Society for Reproductive Medicine
(Fertility and Sterility, 2012, 97, 843–851). Figure republished with permission of Endocrine Press, from the Journal of
Clinical Endocrinology and Metabolism, Harlow, S. D. et al., 97, 1159–1168, 2012; permission conveyed through Copyright
Clearance Center, Inc. Figure reproduced from Harlow, S. D. et al. Executive summary of the Stages of Reproductive Aging
Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause 19 (4), 387–395 (2012).

that women who experienced strong vasomotor underlying biological mechanisms often remain unclear.
symptom peaks either before or after menopause had For instance, primary ovarian insufficiency (menopause
a quick decline in postmenopause. Such trajectories before the age of 40 years) is associated with reduced
for the severity of these symptoms were not evident risk of breast and ovarian cancers, but higher risk of
when analysed according to chronological age, but only cardiovascular disease and osteoporosis24–26. This does
when their timing was examined with respect to age at not necessarily imply any causal relationships, but could
menopause. Such results may help to guide the optimal result from common risk factors. This may be the case
treatment and management of symptoms. for cardio­vascular disease, for which recent findings
Age at menopause is also increasingly recognized suggest that pre-existing risk factors, such as raised total
as an indicator for health outcomes in later life, espe- serum cholesterol and blood pressure, are also associ-
cially those related to oestrogen exposure, although the ated with earlier menopause27. Overall, however, each
additional year of later menopause is linked with a 2%
reduction in all-cause mortality 28,29.
Table 1 | Geographical variation in age at menopause*
Region or n Number Mean age at Heterogeneity Mechanisms/pathophysiology
country of studies menopause (I‑squared; %) Factors influencing menopause
(95% CI) The functional lifespan of human ovaries is determined
Africa 1,175 3 48.4 (48.1–48.6) 0.0 by a complex and yet largely unidentified set of genetic,
Asia 39,158 8 48.8 (48.1–49.4) 98.9 hormonal and environmental factors (FIG. 3). Women
undergo menopause when follicles in their ovaries are
Australia 9,268 2 51.3 (49.8–52.8) 99.1
exhausted. However, the clinical manifestations of meno­
Europe 18,692 6 50.5 (50.0–51.1) 96.6 pause result from dynamic interactions between neuro­
Latin America 18,073 3 47.2 (45.9–48.6) 99.1 endocrine changes and alterations in the reproductive
Middle East 7,733 8 47.4 (46.9–47.8) 97.2 endocrine axis that governs the function of the ovaries.
It is unclear why ovaries start their function at
United States 15,690 6 49.1 (48.8–49.4) 94.6
puberty and stop it at menopause, and understanding
Total 109,789 36 48.8 (48.3–49.2) 99.6 this phenomenon would have far-reaching implications
*Data from REF. 8. for reproductive and health issues.

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PRIMER

• Genetic factors Hypothalamus Hypothalamic ageing identified a region on chromosome 8 that is associated
• Environment with age at menopause39. Interestingly, the gene encod-
• Lifestyle Desynchronized
GnRH GnRH secretion ing the gonadotropin-releasing hormone (GnRH) is
• Systemic diseases
near this region.
Brain Studies looking at associations between genes
Impaired timing
LH of LH surge encoding factors that are involved in reproductive
FSH pathophysiology and menopause have been disap-
FSH increase pointing. Most studies have failed to identify asso-
ciations or the results could not be replicated. Among
Pituitary gland the genes investigated, those encoding the oestrogen
receptor-α (ESR1), 17β-hydroxysteroid dehydrogenase
type 1 (HSD17B1), anti-Müllerian hormone (AMH)
Ovary
and AMH receptor type 2 (AMHR2) have been the
most promising 37. Women who are carriers of genetic
Uterus Follicle
loss Active mutations in early onset breast cancer 1 (BRCA1) or
follicles Functional
ovarian ageing BRCA2 are on average 3 years younger at menopause
than matched controls (50 years versus 53 years)40. A
AMH Decline in
inhibin B number of known genetic disorders result in earlier
Inhibin B
Oestradiol
menopause, including mutation of the gene encoding
Decline in AMH
forkhead box protein L2 (FOXL2), which also causes
Decrease in Oestradiol the blepharophimosis, ptosis and epicanthus inversus
ovarian follicle fluctuation (BPES) syndrome41. Mutations of the genes encoding
mass and function and decline
bone morphogenetic protein 15 (BMP15) and growth
and differentiation factor 9 (GDF9) result in premature
Anovulatory cycles and finally menopause42,43. Galactosaemia has been associated with
loss of menstrual cycles
menopause prior to the age of 40 years in one study 44,
Figure 3 | Menopausal loss of ovarian function.  Several processes
Nature Reviewscontribute
| DiseasetoPrimers
but no relationship was observed in a follow‑up study
declining ovarian function and the development of menopause including: hypothalamic of a similarly sized cohort 45. Variants of other genes that
and functional ovarian ageing; environmental, genetic and lifestyle factors; and systemic are involved in ovarian function, such as those encoding
diseases. Hypothalamic ageing leads to desynchronized gonadotropin-releasing follicle-stimulating hormone (FSH) and inhibin recep-
hormone (GnRH) production and an impaired surge of luteinizing hormone (LH) release tors, have been shown to be associated with early and
from the pituitary gland. These central nervous system changes, together with ovarian premature menopause43. Women who are carriers for
ageing, impair ovarian follicle maturation, hormone production (inhibin B, anti-Müllerian the fragile X mutation and have an intermediate num-
hormone (AMH) and oestradiol) and ovulation. This leads to cycle irregularities and ber of CGG repeats in the fragile X mental retardation 1
follicle-­stimulating hormone (FSH) upregulation.
(FMR1) gene have been observed to undergo early and
premature menopause46.
Recently, genome-wide association studies have
Genetic factors. The timing of menopause reflects found new genes that might influence ovarian ageing
a complex interplay of genetic, epigenetic, socio­ and menopause47–50. The most relevant are the BR serine/­
economic and lifestyle factors. Estimates of the herit- threonine kinase 1 gene (BRSK1), which encodes an
ability in meno­pausal age range from 30% to 85%30,31. AMP-activated protein kinase (AMPK)-related kinase,
Approximately 50% of the interindividual variability and the gene encoding the minichromosomal mainte-
in age at menopause is related to genetic effects 32. nance complex component 8 (MCM8), which is essential
Women whose mothers or other first-degree relatives for genome replication.
were known to have early menopause have been found
to be 6–12‑fold more likely to undergo early meno- Ovarian lifespan and follicle loss. The ovaries and the
pause themselves33,34. Furthermore, cross-sectional follicles are central to determining menopause timing 51.
and cohort studies have shown that a woman’s age at The number of follicular cells is determined before birth,
menopause is strongly associated with her mother’s age when oocytes expand to a maximum of 6–7 million at
at menopause30–36. However, genetic studies have so far mid-gestation. Afterwards, oocytes are rapidly lost due
failed to clearly identify the genetic traits that underlie to apoptosis, leading to a population of 700,000 at birth
this heritability 37. and 300,000 at puberty. Continuing apoptosis, along
Linkage analysis studies pinpoint areas on chromo- with the loss of oocytes during the 400–500 cycles of fol-
some X (region Xp21.3) that are associated with early licular recruitment in a normal reproductive life (some-
(<45 years) or premature (<40 years) menopause38. times involving multiple follicles per cycle), leads to
A region on chromosome 9 (9q21.3) is also associated final exhaustion of these cells at midlife and menopause
with age at menopause. This region contains multiple between 45 and 55 years of age51. These numbers high-
genes, including one that encodes a protein of the B cell light that the duration of ovarian functionality depends
lymphoma 2 (BCL‑2) family 38. BCL‑2 is involved in only little on ovulation and is mostly determined by the
apoptosis, and may thus influence menopause through extent and rapidity of oocyte apoptosis — what governs
follicular depletion. Other linkage analysis studies have this process is unknown.

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© 2015 Macmillan Publishers Limited. All rights reserved


Although oocyte loss is fundamental for menopause,
the specialized granulosa and theca steroid-secreting
cells, and not the oocytes, determine the coordinated
processes that drive the menstrual cycle. Follicular
cells are regulated by pituitary gonadotropins, as well
as by locally produced hormones. Loss of sensitivity to
stimulating factors by follicular cells is thought to have a
key role in the decline of ovarian function52. Consistent
with this view, the most replicable and linear endocrine
change throughout the menopausal transition is the pro-
gressive decline in inhibin B and AMH, which marks
the decrease in follicular mass and/or functionality and
explains why fertility is impaired in women well before
any disruption of menstrual cyclicity 53.
Neuroendocrine events. The hypothalamic–pituitary
reproductive axis undergoes considerable changes dur-
ing the menopausal transition. These modifications are
in part secondary to declining ovarian function, but
several lines of evidence suggest that the brain under-
goes independent functional modifications that are
important for reproductive ageing 54. According to this
hypothesis, menopause may mirror puberty, a time at
which a set of hypothalamic processes also influences
the reproductive axis.
Increases in pituitary-derived FSH can be identified
in middle-aged women well before oestrogen declines
or cycle irregularities are noticed. Similarly, changes in
luteinizing hormone (LH) secretion patterns are found
at this stage, with broader and less frequent pulses.
Experimental work in rodents55 suggests that an age-
related desynchronization of the neurochemical signals
involved in activating GnRH neurons takes place before
changes in oestrous cyclicity. Several hypothalamic
neuro­peptides and neurochemical agents (for example,
glutamate, noradrenaline and vasoactive intestinal pep-
tide) that drive the oestrogen-mediated surge of GnRH
and LH seem to dampen with age or lack the precise
temporal coordination that is required for a specific
pattern of GnRH secretion55. Disruption of this hypo-
thalamic biological clock would lead to progressive
impairment in the timing of the preovulatory LH surge,
which would add to the poor ovarian responsiveness that
is encountered at this reproductive stage.
Endocrine changes during the transition. As discussed
above, the endocrine changes of the late reproduc-
tive years depend on the combined dysfunction of
the ovaries and the hypothalamus56. A shortened fol-
licular phase and the associated increase in FSH levels
are characteristic of early menopausal transition. This
accounts for the shorter cycle intervals that are expe-
rienced by many women in this period of life. Cohort
studies have demonstrated that shortened follicular
phases are associated with accelerated ovulation, which
occurs at a smaller follicle size57. The prevailing expla-
nation for this phenomenon is the loss of inhibin B
production, which leads to increased FSH release and,
therefore, to an ‘overshoot’ of oestrogen production.
This would facilitate (and accelerate) the achievement
of the LH surge57.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 5
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
With time, the age-related hypothalamic modifica-
tions determine a decrease in oestrogen sensitivity and the
LH surge becomes more erratic. Follicles also become less
sensitive to gonadotropins, which leads to luteal-phase
defects and anovulatory cycles, and accordingly, to the
first menstrual irregularities. Hypothalamic insensitivity
to oestrogens also explains why menopausal symptoms —
such as hot flushes and night sweats — commonly occur
at this stage, when women have rather high levels of oes-
trogens, as well as why exogenous oestrogens are effective
in reducing the symptoms.
In summary, natural menopause is the consequence
of lost ovarian function. This is the final step in a long
and irregular cascade of events taking place both in
the brain and in the ovaries. Genetic factors influence
the timing of this process, but the key molecular path-
ways involved are still unknown. Identifying such fac-
tors would be invaluable to inform the development of
new strategies to treat reproductive dysfunction and
menopause-­associated diseases.
Symptoms and consequences
Menopausal symptoms. Most women entering meno-
pause experience vasomotor symptoms. A hot flush
is a sudden episode of vasodilation in the face and
neck, which lasts 1–5 minutes and is accompanied by
profuse sweating. Women experiencing hot flushes
are reported to have a narrower thermoneutral zone,
such that subtle changes of core temperature elicit
thermoregulatory mechanisms such as vasodilation,
sweating or shivering. Declining levels of oestrogens
and inhibin B, as well as increasing FSH levels, explain
only part of the disturbed thermoregulation, which is
associated with changes in brain neurotransmitters
and peripheral vascular reactivity 58.
Hot flushes usually occur in late perimenopause and
the first postmenopausal years. Some women, however,
may continue to experience vasomotor symptoms for
many years after menopause59. Occasionally, hot flushes
occur in the late reproductive years16,60, or several years
after menopause60. The occurrence and intensity of
menopausal symptoms vary widely between women
and depend on genetic, environmental, racial, lifestyle
and anthropometric factors. Black race, smoking and
overweight — in particular central obesity — increase
the prevalence and severity of vasomotor symptoms61,62.
Sleep disturbances are also very common during the
menopausal transition and they are mainly attributed
to frequent arousals due to night sweats and occurring
secondarily to psychological factors63,64. Mood disorders
such as depression and anxiety are not caused by meno-
pause; vulnerable women, however, may have their first
episode or a relapse during the transition65. Muscle and
joint pain is also part of the menopausal symptomatol-
ogy 66 and it is highly correlated with hot flushes and
depressed mood67.
Urogenital atrophy. The anatomy and function of the
female lower genital tract is oestrogen-dependent. Upon
menopausal oestrogen decline, tissues lining the vagina,
vulva, bladder and urethra undergo atrophy, which
PRIMER
Ageing Menopausal oestrogen decline
• Vitamin D deficiency • Reduced Osteoblasts
• Decline in intestinal physical activity
calcium absorption • Sarcopenia
• Impaired renal synthesis
• Increased RANKL
of 1,25(OH)2 vitamin D3
• Decreased OPG
Loss of mechanical stimulation of osteocytes
Decreased bone formation Pre-osteoclasts
Secondary
hyperparathyroidism Osteoclasts
Increased bone resorption
Low bone mass and
loss of bone architecture
Low-trauma fracture
Figure 4 | Pathogenesis of postmenopausal osteoporosis.  Nature | Disease Primers
Reviewsoestrogen
Reduced
production results in increased receptor activator of nuclear factor-κB ligand (RANKL)
levels, which leads to osteoclast activation and increased bone resorption. Furthermore,
production of osteoprotegerin (OPG), an osteoclast inhibitor, by osteoblasts is
decreased. These changes may be compounded by general age-related changes in bone
metabolism and remodelling, including disturbed vitamin D and calcium homeostasis,
secondary hyperparathyroidism and less mechanical stimulation of bone turnover.
causes a cluster of symptoms including vaginal dry-
ness, painful intercourse (dyspareunia), vulvar pruritus,
burning and discomfort, as well as recurrent urogenital
infections68. Vulvovaginal atrophy and urinary tract atro-
phy, due to oestrogen deficiency, are collectively called
the genitourinary syndrome of menopause69. Unlike
hot flushes and night sweats, which improve over time,
symptoms of urogenital atrophy persist throughout
postmenopausal life and may have a serious impact on
sexual health and QoL70. Pain during intercourse, sec-
ondary to vulvovaginal atrophy, leads to diminished
sexual desire, arousal difficulties, relationship problems,
and diminished physical and emotional sexual satisfac-
tion71. Although the majority of women have signs of
uro­genital atrophy upon physical examination, less than
half of the postmenopausal population report bother-
some complaints68. Age, sexual activity, ethnicity and
attitudes towards menopause influence the occurrence
and the severity of urogenital symptoms70.
Osteoporosis. Bone is a dynamic tissue that undergoes
continuous remodelling throughout life. This process
begins with bone resorption, which is carried out by
multinucleated giant cells called osteoclasts. The lacuna
created by osteoclasts is subsequently filled with oste-
oid — new non-mineralized bone synthesized by osteo­
blasts — which is later mineralized to form mature bone
6 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
tissue. Oestrogens regulate the coupling of the bone
resorption and formation processes. Postmenopausal
oestrogen decline leads to the uncoupling of bone
remodelling, which results in excessive resorption.
More specifically, oestrogen deficiency results in exces-
sive production of the cytokine RANKL (receptor
activator of nuclear factor-κB ligand; also known as
TNFSF11) by osteoblasts, which — upon binding to
its receptor RANK (also known as TNFRSF11A) on
the surface of pre-osteoclasts and mature osteoclasts
— promotes osteoclasto­genesis and bone resorption72.
Osteoprotegerin (OPG; also known as TNFRSF11B)
is a cytokine secreted by osteoblasts following oestro-
gen stimulation and is a natural inhibitor of RANKL72.
Oestrogen deficiency is associated with decreased OPG
production, further augmenting RANKL activity73,74.
The age-associated decline in intestinal calcium absorp-
tion, vitamin D deficiency and impaired synthesis of
active 1,25‑dihydroxyvitamin D3 by the kidney lead to
secondary hyperparathyroidism, which further con-
tributes to accelerated bone resorption75. Finally, loss
of skeletal mechanical stimulation due to reduced daily
activity and loss of skeletal muscle mass may interact
with decreased bone formation due to the absence of
oestrogen-mediated downregulation of sclerostin pro-
duction by osteocytes76. Both processes — increased
bone resorption and decreased bone formation — lead
to diminished bone strength and to fractures upon min-
imal skeletal load. The earlier the age at menopause, the
higher is the risk of osteoporosis later in life77 (FIG. 4).
Metabolic consequences. The prevalence of obesity is
higher in postmenopausal women than in premenopau-
sal women78. This is a consequence of a multifactorial
process that involves reduced energy expenditure due
to physical inactivity, which is sometimes compounded
by depression, as well as due to muscle atrophy and
a lower basal metabolic rate78. Whereas menopause
per se is not associated with weight gain, it leads to an
increase of total body fat and a redistribution of body
fat from the periphery to the trunk, which results in
visceral adiposity78,79. Abdominal obesity and meno-
pausal oestrogen decline are associated with adverse
metabolic changes such as insulin resistance, a pro-
pensity to develop type 2 diabetes mellitus and dys-
lipidaemia characterized by high triglyceride levels,
low high-density lipoprotein (HDL) cholesterol levels
and an increased frequency of small, dense low-­density
lipoprotein (LDL) particles 79,80. Altered adipokine
secretion, which leads to chronic inflammation, is a
possible mechanism that links abdominal obesity to
its metabolic consequences79,81,82 (FIG. 5).
Cardiovascular disease. Beyond the beneficial effects
on metabolic and immune parameters, oestrogens are
potent vasoactive hormones that promote vascular
remodelling and elasticity, and regulate reactive dila-
tion and local inflammatory activity83. Oestrogen defi-
ciency after menopause leads to the activation of the
renin–angiotensin system, the upregulation of the potent
vasoconstrictor endothelin and the impairment of nitric

Menopause Menopausal oestrogen decline
and ageing
• Physical Indirect effects on Direct effects on the vasculature
inactivity cardiovascular risk factors • Activation of the renin–
• Mood • Visceral adiposity angiotensin system
instability • Dyslipidaemia: • Increased angiotensin II
• Sarcopenia increased LDL-c and • Increased endothelin 1
decreased HDL-c • Decreased NO synthase
• Increased triglycerides
• Insulin resistance
• Increased blood pressure • Oxidative stress
• Chronic inflammation • Vascular cell proliferation
• Vascular wall inflammation
• Arterial stiffness
Obesity Atherosclerosis • Endothelial dysfunction
Ischaemic heart disease
and stroke
Nature Reviews
Figure 5 | Consequences of menopause on the cardiovascular | Disease
system.  Primers
The loss of
oestrogen at menopause is associated with increased visceral fat, a more adverse lipid
profile and activation of the renin–angiotensin pathway, which leads to impaired
endothelial function. These changes, together with ageing-related changes, lead to an
increased risk of hypertension, obesity, type 2 diabetes mellitus, atherosclerosis,
ischaemic heart disease and stroke. HDL‑c, high-density lipoprotein cholesterol; LDL‑c,
low-density lipoprotein cholesterol; NO, nitric oxide.
oxide-mediated vasodilation. Oxidative stress, which is
augmented by endothelin and angiotensin II, may fur-
ther contribute to atherosclerotic processes84. Thus, soon
after menopause, women exhibit increases in blood pres-
sure, as well as subclinical vascular disease, which can be
observed as increased carotid and femoral artery intima-
media thickness, coronary artery calcium score and arte-
rial stiffness, and impaired flow-mediated dilation85–88.
Clinical consequences of cardiovascular disease usually
occur later in women than in men and ischaemic heart
disease usually manifests 10 years later in women than in
men89. The risk of stroke doubles during the first decade
after menopause and ultimately exceeds that of men in
older age90. These vascular events tend, however, to have
a more severe prognosis in women89. Early menopause
and primary ovarian insufficiency have consistently
been associated with increased risk of coronary heart
disease, stroke and mortality91–93 (FIG. 5).
Cognition. Oestrogens act in areas of the central nerv-
ous system that control learning, registering and retriev-
ing information, judgement, evaluation processes and
language skills. These areas mainly involve the prefron-
tal cortex, hippocampus and striatum. Oestrogens act
through both genomic and non-genomic mechanisms.
They increase cellular proteins, thus promoting neuronal
growth and survival, neural transmission and function,
and also synaptogenesis94. Furthermore, oestrogens
limit the inflammatory response in the central nervous
system, which helps to avoid repeated inflammatory
insults that might result in dystrophy and a propensity
to dementia95. Most studies indicate that menopause
affects cognitive function and, more specifically, aspects
related to verbal memory and verbal fluency. The effect
size seems to be small; however, cognitive changes are
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 7
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
often bothersome for the affected women96. Although
menopause seems to be associated with changes in cog-
nition, it cannot be assumed that oestrogen therapy will
prevent cognitive decline. There is a general consensus
that oral oestrogen therapy should not be prescribed to
prevent or treat cognitive decline97,98.
Diagnosis, screening and prevention
Risk factors for earlier menopause
Postnatal nutrition might influence the age at meno-
pause. Women in the 1946 British birth cohort who had
been breastfed experienced later menopause than those
who had not 36,99, and women who had a low weight at
2 years of age had earlier menopause99. Similarly, Dutch
children who experienced severe caloric restriction as
a result of the 1944–1945 famine had an earlier meno-
pause than those who were not exposed to the famine100.
There is mixed evidence for relationships between age at
menarche and age at menopause101.
Emotional stress at a young age may affect repro-
ductive ageing and there is evidence that women who
experience parental divorce early in life tend to have
earlier menopause99,102. Some studies have also found
that women with lower adult socioeconomic position,
which may indicate greater exposure to stress, tend to
experience menopause earlier than women of higher
position, even after adjustment for smoking and par-
ity 103–107. A Latin-American study found that women
living at altitudes above 2000 m were also more likely to
experience early menopause107.
Of the various lifestyle and environmental factors in
adulthood that have been investigated with respect to
the timing of menopause, only cigarette smoking 108–110
and nulliparity 34,111,112 are consistently associated with an
earlier menopause. It is controversial whether cessation
of smoking prior to menopause eliminates this effect,
with some studies implicating only current smoking
as a risk factor for earlier menopause113,114, and others
implicating both past and current smoking 115. The lat-
ter association implies that smoking has an overall toxic
effect on the follicle pool, presumably mediated by the
polycyclic aromatic hydrocarbons in cigarette smoke116.
Current, but not past, smoking has also been associated
with reduced levels of AMH, which is a marker for the
ovarian reserve117. Adverse life events, HIV infection and
street-drug use have also been related to earlier meno-
pause113,118–120, but alcohol and coffee consumption gen-
erally show no association115. Birth control pill use has
been shown to be associated with a slightly later age at
menopause in some but not all studies113,121.
A recent systematic review found a modest asso-
ciation between moderate to high physical activity
and earlier menopause in an unadjusted but not an
adjusted meta-analysis, whereas overweight had a
modest association with later menopause8. Overweight
and obesity have been linked with a later menopause
in several studies122,123. Premenopausal weight gain and
premenopausal episodic weight loss of greater than 5 kg
are each independently associated with a later meno-
pause124. Higher body mass index (BMI) has been asso-
ciated with a greater likelihood of transitioning from
PRIMER
Table 2 | Common menopausal symptoms with timing of onset and duration
Symptom Typical age at onset Peak severity
(years)
Hot flushes 47 Late transition
Poor sleep 40–50 Late transition
Adverse mood 49 Late transition
Vaginal dryness 49 Early to late transition
premenopause to perimenopause but not from peri-
menopause to postmenopause123. Non-obese women
tend to have a more rapid decline in oestradiol as they
transit the menopause125.
Clinical diagnosis
The common symptoms of menopause, with their
approximate onsets and durations126–133, are shown in
TABLE 2. As women progress to the late menopausal
transition (STRAW Stage –2 to –1)2–5, their menstrual
cycle length increases to >60 days, anovulation becomes
more likely and periods of time with little or no oes-
trogen secretion occur. At this time, all of the com-
monly observed menopausal symptoms worsen acutely.
Many symptoms peak in their intensity at this time, and
women may require treatment.
A woman is considered postmenopausal when she
is over the age of 45 and has gone at least 12 months
without a spontaneous menstrual period. No specific
diagnostic testing is required unless the clinical presen-
tation is atypical. Atypical presentations would include
substantial mood changes, new-onset anxiety or fatigue,
and arthralgia without flushes or sweats. Earlier ages of
onset of prolonged amenorrhoea require consideration
of other diagnoses such as polycystic ovary syndrome,
secondary hypogonadotropic hypogonadism, hyper­
prolactinaemia, pituitary tumours or uterine problems
such as Asherman syndrome. A menopausal woman
who has undergone at least 12 months of amenorrhoea
is unlikely to ever have another menstrual period, but it
can occur in about 10% of women134.
Biochemical assessment
Although specific diagnostic testing for menopause
is not recommended, clinical situations may arise in
which it is beneficial to document primary gonadal
failure. Usually, an increased FSH level will suffice to
confirm this. Changes in FSH, oestradiol and inhi-
bin B have been well documented in population-based
samples of women undergoing observational research.
Measurement of oestradiol during the perimenopause
is not clinically useful. Inhibin B is the first hormone
to decline, and its drop precedes a rise in FSH135. The
compensatory rise in FSH causes follicles to continue
to grow and leads to a shortening of the follicular phase
of the menstrual cycle. Eventually, the follicle pool
becomes depleted and folliculogenesis no longer occurs
reliably. This juncture is when the late meno­pausal
transition begins. Follicle failure is intermittent in the
late transition and is eventually superseded by perma-
nent amenorrhoea. After menopause has happened,
8 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
Average duration Refs
(years)
6–10 129–131
Variable 132
2–4 126,127,133
Persists lifelong if untreated 128
oestradiol levels are expected to be consistently low
(<20 pg ml–1); progesterone is no longer produced136.
Of note, there is no acute change in testosterone levels
in relation to the menopause transition135,137.
AMH is a member of the transforming growth
factor‑β (TGFβ) superfamily of proteins, and is found
in ovarian granulosa cells and oocytes138. AMH might be
useful for predicting the time of menopause. Serial AMH
measurements in a cohort study of 50 women indicated
that a drop of AMH below 0.05 ng ml–1 predicted meno-
pause within the subsequent 5 years139. Overall, the sen-
sitivity of AMH measurements in published studies to
date does not enable the clinician to predict a woman’s
final menstrual period beyond simple historical and
clinical criteria, such as age and duration of amenor-
rhoea140. Examination of AMH change over time holds
promise for refining our ability to prospectively deter-
mine when menopause will occur 141. Ultimately, with
the development of a sufficiently sensitive AMH assay,
it should be possible to help forecast the final menstrual
period with better accuracy.
Diagnostic imaging
Other measurements have also been proposed for fore-
casting the timing of permanent ovarian failure, includ-
ing both antral follicle counts (assessed by transvaginal
ultrasonography), recording of all follicles measuring
≤7 mm in diameter (usually done in the early follicu-
lar phase of the cycle), and functional ovarian reserve,
which is ascertained by dynamic testing of the ovary
with a stimulating agent (either clomiphene citrate
or FSH). However, these methods are better predic-
tors of the loss of fertility than they are of menopause
per se142. Transvaginal ultrasonography is a very useful
method for assessing fertility status and can provide
information about ovarian ageing when appropriate.
Measurement of the number of antral follicles can pro-
vide useful information about the likelihood of preg-
nancy in women who are of advanced reproductive age
and wish to conceive. However, antral follicle counts
have not been as useful in predicting menopause143.
Other ovarian measurements such as total ovarian vol-
ume and stromal thickness have also been proposed,
but they currently lack the sensitivity and specificity to
be clinically useful.
Screening for osteoporosis
Operationally, osteoporosis is defined as reduced
bone mineral density measured by dual-energy X‑ray
absorptio­metry (DXA). Although the estimated preva-
lence of osteoporosis in women aged 40–65 years is

Table 3 | Differential diagnoses of menopausal symptoms
Type Conditions
Other causes of low • Cyclical perimenstrual flushes
oestrogen • Post-partum changes
• Aromatase inhibitors
• Selective oestrogen receptor modulators
• GnRH agonists and antagonists
Chronic infections Various
Dietary • Alcohol
• Spicy food
• Food additives (for example, monosodium
glutamate and sulphites)
Hormonal • Thyrotoxicosis
• Exogenous thyroid hormone excess
Medications • Some selective serotonin reuptake inhibitors
• Nicotinic acid
• Opiates
• Calcium channel blockers
Hormone-producing Carcinoid tumours leading to carcinoid
tumours syndrome
Phaeochromocytoma
Other • Lymphoma
• Medullary carcinoma of the thyroid
• Pancreatic islet-cell tumours
• Renal cell carcinoma
• Mastocytosis and mast cell disorders
GnRH, gonadotropin-releasing hormone.
low 144, there is a mean vertebral bone loss of 6.4% and
neck of femur loss of 5% during the menopause transi-
tion145. The available data do not support DXA screening
for postmenopausal women of ≤60 years of age who do
not have an identifiable medical condition, do not use
medication that is associated with an increased risk of
osteoporosis or have no past history of a fracture due to
low trauma146. In line with this, the American College of
Preventive Practice has recommended that DXA screen-
ing should be restricted to women aged 50–65 years with
one major risk factor (such as a history of menopause
prior to the age of 45 years or fragility fracture) or two
minor risk factors (such as cigarette smoking or weight
<57 kg)147. However, the debate is ongoing as to which
women aged <65 years should be screened and currently,
no specific recommendations are universally accepted.
A recent study of women aged 40–65 years who under-
went DXA screening has shown that the three strongest
predictors of osteoporosis are being postmenopausal,
not using hormone therapy, and having a low BMI148.
Differential diagnosis of menopause
If a woman is >50 years of age, has stopped menstru-
ating and has classic oestrogen deficiency symptoms, a
diagnosis other than menopause is very unlikely. Other
causes of amenorrhoea should be considered in younger
women and in women aged >50 years who have atypical
symptoms. These causes include thyroid disease, pro-
lactinoma, severe depression or stress, and substantial
weight loss. Each of these may be associated with vaso-
motor symptoms and mood changes. Pregnancy should
always be considered in the setting of amenorrhoea.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 9
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PRIMER
Investigation or laboratory finding
Complete medical history
Body temperature measurement during flush
Careful medical history
Thyroid function tests
Drug history
Increased plasma chromogranin A and
increased urine 5‑hydroxyindoleacetic acid
Increased plasma metanephrines
Medical history, examination and tests as
appropriate
Other causes of vasomotor symptoms should
be excluded if the presentation is atypical (TABLE 3).
Hormonal hot flushes do cause a significant rise in core
temperature. If a woman records an increase in her oral
temperature with flushing or night sweats, infective
causes must be investigated. Thyrotoxicosis can mimic
menopause, with women presenting with agitation and
anxiety, sleep disturbance, overheating, sweating and
palpitations. These symptoms may precede the classic
thyrotoxic symptoms of weight loss and tremor. A care-
ful medical and medication history should identify other
possible causes. Serotonin-producing carcinoid tumours
can present with nocturnal diarrhoea and episodic flush-
ing without sweating. Phaeochromocytomas release the
catecholamines adrenaline and noradrenaline, and are
characterized by persistent hypertension, flushing and
profuse sweating 149.
Some women may present with oligomenorrhoea
and mood changes or depression. Perimenopausal
depression needs to be differentiated from major
depression and simple dysphoria. The diagnosis of
major depression requires at least 2 weeks of depressed
mood, or loss of interest or pleasure in nearly all activi-
ties for most of the day, nearly every day, accompanied
by at least four of the following symptoms: change in
appetite or sleep, fatigue, psychomotor agitation or
retardation, feelings of worthlessness and/or guilt,
diminished concentration or indecisiveness, and sui-
cidal ideation150. By contrast, perimenopausal depres-
sion is usually accompanied by irritability, hostility or
agitation, and anxiety 151. Clinically, it resembles the
mood changes of premenstrual syndrome, with negative
PRIMER
mood, negative self-concept and less effective coping
abilities152. The lability of peri­menopausal depression is
a distinguishing feature, in contrast to the pervasive low
mood that is seen in major depression153.
Factors hindering diagnosis
Although one of the defining features of menopause is
the cessation of the menstrual period, it more broadly
encompasses the permanent cessation of ovarian repro-
ductive function. Thus, the traditional definition is not
useful in the setting of iatrogenic causes of amenorrhoea,
such as hysterectomy, endometrial ablation or progestin
intrauterine devices. Biochemical investigations may
be warranted for women with iatrogenic amenorrhoea
(notably, measurement of FSH and oestradiol) and for
younger women (measurement of AMH). The latter is
less useful in women >50 years of age, as most women
will have low AMH levels by this time. Some women may
report vasomotor symptoms when using combined oral
contraception. In this instance, menopause can only be
effectively diagnosed if the oral contraception is stopped
for several weeks, after which menopausal status can be
assessed both clinically and biochemically.
Screening for menopause
Population screening is not indicated for the diagnosis
of menopause. Nonetheless, women are increasingly
delaying childbearing until their late reproductive years
and many wish to know when their menopause is likely
to occur. Taken together with age, serum AMH levels
provide a good indication. Tehrani et al.154 have reported
that a combination of age and serum AMH levels can be
used to predict menopause using a mathematical equa-
tion. In their analyses, age alone had an 84% adequacy
in predicting age at menopause, and this rose to 92%
when AMH levels were added to their model. The use of
AMH to predict menopause still has several limitations.
For example, AMH assays are not yet standardized155
and are not sufficiently sensitive to predict menopause
with great accuracy. The decline in AMH can be accel-
erated by factors such as cigarette smoking 141, and some
clinical situations — such as hypogonadotropism156 and
obesity 21 — are associated with lower than normal AMH
levels that do not reflect a true functional ovarian reserve
deficit. Thus, the precision of using AMH to estimate
time to the onset of menopause in individuals is yet to
be established.
One group of women that may benefit from AMH
screening for diminished ovarian reserve, and hence
imminent menopause, is carriers of the fragile X gene
(see above). The FMR1 mutation affects approximately
one in 200 women, and approximately 20% of affected
women will experience premature ovarian failure157.
At all ages, carriers of the FMR1 mutation have lower
AMH levels than other women158. Although it has been
suggested that monitoring of ovarian function is appro-
priate for women who carry the FMR1 mutation, the
exact delineation of the onset of ovarian failure remains
challenging. AMH values for carriers of the FMR1 muta-
tion have been published158, but the clinical application
of these is yet to be established.
10 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
Prevention of menopause
That menopause is inevitable is based on the concept
that human females have a fixed ovarian oocyte reserve
at birth and that oocyte numbers decline with age159.
In the later reproductive years, the quality of oocytes
diminishes, such that fertilization and live birth rates fall,
and the risk of birth defects and miscarriage increase.
One group has identified oogonial stem cells in ovarian
cortical tissue of young women160. This gives rise to the
hypothesis that human ovarian germ cells are renewed
during the reproductive years, and even inspires the pos-
sibility that such cells could be used to extend a woman’s
reproductive lifespan, and effectively delay or prevent
menopause. The finding of oogonial stem cells in human
ovaries is controversial161 and is yet to be replicated by
other groups162.
Management
Managing menopausal symptoms need not be complex.
Bothersome vasomotor symptoms, disturbed noctur-
nal sleep and an overall deterioration in QoL are by far
the most common reasons for women to seek medical
attention in midlife. Caregivers and patients can now
choose from an expanding repertoire of pharmacologi-
cal options (both hormonal and non-hormonal)163–165, as
well as some complementary and alternative medications
to treat menopausal symptoms (TABLE 4). Here, we focus
on standard therapies, as the evidence regarding com-
plementary and alternative medications is conflicting 166.
Choosing the right therapy
Oestrogen deficiency is the principal pathophysiologi-
cal mechanism that underlies menopausal symptoms
and various oestrogen formulations are prescribed as
menopausal hormone therapy, which remains the most
effective therapeutic option available (TABLE 5). The addi-
tion of progesterone aims to protect against the con-
sequences of systemic therapy with oestrogen only in
women with intact uteri160: namely, endometrial pathol-
ogies, including hyperplasia and cancer. The risk-benefit
ratios of all treatment options must be considered, tak-
ing into account the nature and severity of symptoms,
and individual treatment-related risks (TABLE 4).
In the systemic circulation, oestradiol and oes-
trone are partly bound to sex hormone-binding glob-
ulin (SHBG), as well as to albumin, as is testosterone.
Increasing or decreasing SHBG levels will affect the
amount of unbound oestrogen and testosterone in the
circulation167. Oral oestrogen therapy increases SHBG
synthesis in the liver through the first-pass effect; by
contrast, standard-dose transdermal oestrogen does
not increase SHBG synthesis168. In some women, oral
oestrogen therapy results in very high SHBG levels, with
a reduction in unbound hormone. This potentially leads
to loss of efficacy of the administered oestrogen and/or
iatrogenic testosterone deficiency.
Upregulation of the hepatic synthesis of pro­
coagulants is another known effect of oral oestrogens.
Transdermal oestradiol does not seem to increase the
risk of venous thromboembolic events 169,170. Thus,
transdermal oestrogen therapy is the preferred mode of

Table 4 | Therapeutic options for management of menopausal symptoms
Therapy
Systemic hormone therapy
Oestrogen
Progestogen
Oestrogen and progestogen
Tissue-selective oestrogen receptor
complex (conjugated equine
oestrogen plus BZA (a SERM))
Ospemifene (SERM)
Tibolone
Androgen therapy (testosterone)
Non-hormonal therapies
Selective serotonin reuptake
inhibitors
Selective noradrenaline reuptake
inhibitors
Anticonvulsants (GABAergics)
α2-adrenergic receptor agonists
Sedatives and hypnotics
Complementary or alternative therapies for vasomotor symptoms
Soy or isoflavones
Black cohosh
Vitamin E
Acupuncture
Local vaginal therapy
Oestrogen
Dehydroepiandrosterone
Testosterone
Non-hormonal vaginal moisturizers
Lubricants
Other
Stellate ganglion blockade
Cognitive behavioural therapy
*BZA, bazedoxifene; GABA, γ-aminobutyric acid; NA, not applicable; SERM, selective oestrogen receptor modulator.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 11
PRIMER
Formulations Comments
• Oral, transdermal (patch, gel or spray), vaginal Approved for management of menopausal symptoms
(ring) or implant
• Administered as oestradiol or synthetic
oestrogens
• Oral, vaginal or intrauterine Approved for management of menopausal symptoms
• Administered as progesterone or progestin
(synthetic)
• Combination Approved for management of menopausal symptoms
• Pill or patch
Oral Recently approved in Europe and the United States for
management of menopausal symptoms
Oral Approved for the treatment of women experiencing
moderate to severe dyspareunia (pain during sexual
intercourse)
Oral • Approved for management of menopausal symptoms
in some countries
• Not approved or available in Canada or the United
States
• Oral or vaginal • Prescribed for low desire and low arousal
• Topical, oral or implant • Off-label use of this class of drugs in most countries
Oral Low-dose paroxetine is the first and only non-hormonal
drug to be approved by the FDA in the United States for
menopausal symptom relief
Oral Use for menopausal symptom control represents
off-label use of this class of drugs
Oral Use for menopausal symptom control represents
off-label use of this class of drugs
Oral and transdermal Off-label use for the management of menopausal
vasomotor symptoms
Oral Not recommended
Oral Consistent benefit over placebo effects not
demonstrated
Oral Consistent benefit over placebo effects not
demonstrated
Oral Consistent benefit over placebo effects not
demonstrated
NA Consistent benefit over placebo effects not
demonstrated
Low-dose oestradiol, oestriol and conjugated Approved for the treatment of vaginal atrophy
oestrogen creams, rings and pessaries
Vaginal ovule Undergoing research trials; not approved
Vaginal cream Undergoing research trials; not approved
Vaginal gels and creams Over-the-counter products
Vaginal gels and creams Over-the-counter products
NA Requires specific expertise
NA Requires specific expertise
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER

Table 5 | Prescription therapy options for management of menopausal symptoms

Treatment Benefits Risks Patient-specific considerations
option
Hormone therapy
Systemic • Symptom relief • VTE • Oestrogen-related risk of stroke, VTE and CVD is exaggerated with
oestrogen • Fracture risk • Stroke advancing age and increasing time since onset of menopause
alone* reduction • CVD • Comorbidities such as obesity, hypertension and diabetes all increase the
• Osteoporosis • Breast cancer risk of VTE, CVD and stroke
prevention (not seen in large • Risk reduction against VTE and gallstones achieved by using a transdermal
• Improved QoL clinical trials) route and reduced dose
• Gallstones • For women with natural menopause and bothersome vasomotor
symptoms who are aged <60 years or within 10 years of their
menopause, the benefits of hormone therapy outweigh the potential for
treatment-related harm
• For those with early or premature ovarian insufficiency, benefits outweigh
harm even in the absence of symptoms
Systemic • Symptom relief • VTE • Oestrogen-related risk of stroke, VTE and CVD is exaggerated with
oestrogen and • Fracture risk • Stroke advancing age and increasing time since onset of menopause
progestogen* reduction • CVD • Comorbidities such as obesity, hypertension and diabetes all increase the
• Osteoporosis • Breast cancer risk of VTE, CVD and stroke
prevention • Gallstones • Risk reduction against VTE may be achieved by using a transdermal route
• Improved QoL and reduced oestrogen dose
• Colon cancer risk • Observational data suggest that progesterone may have less impact on
reduction breast cancer risk than MPA in menopausal women, although ideally this
should be tested in an randomized trial
• Endometrial cancer risk is associated with oestrogen dose, as well as the
type, dose and duration of progestin
• Progesterone is less effective than synthetic progestins at negating the
proliferative effects of systemic oestrogen
• For women with natural menopause and bothersome vasomotor
symptoms who are aged <60 years or within 10 years of their
menopause, the benefits of hormone therapy outweigh the potential for
treatment-related harm
• For those with early or premature ovarian insufficiency, benefits outweigh
harm even in the absence of symptoms
Low-dose Effective against Negligible Significant systemic absorption can transiently occur with excessive use of
vaginal genitourinary vaginal oestrogen creams, particularly in the setting of an atrophic vaginal
oestrogen syndrome of epithelium
menopause
Ospemifene Effective against VTE risks are deemed Approved for management of moderate to severe dyspareunia due to
(SERM)* moderate to severe comparable to those of vulvovaginal atrophy in the United States and Europe
dyspareunia due low-dose oestrogen
to vulvovaginal
atrophy
TSEC Symptom relief Similar risk profile to • Approved in the United States and Europe
(combination oestrogen in terms of risk • Indicated for management of menopausal symptoms in women with intact
of conjugated for VTE, stroke, CVD and uteri
equine gallstones • Neutral effects on the uterus and on breast tissue (SERM effect)
oestrogen and • Potential for skeletal benefit as conjugated equine oestrogens and BZA are
BZA (SERM))* effective for fracture risk reduction
Tibolone • Symptom relief • Risk of stroke in women • Neutral effects on the endometrium; no need for concomitant
(synthetic • Fracture risk aged >60 years progestogen therapy
steroid with reduction • Risk of breast cancer may • Not available or approved in North America
oestrogenic, • Osteoporosis be lower than with other
progestogenic prevention therapies
and • Improved QoL
androgenic • Colon cancer risk
activity)* reduction
Options in women for whom hormone therapy is contraindicated
Selective • Relief of vasomotor • Relatively well tolerated • Less efficacious than hormone therapy
serotonin symptoms • Some agents may • Sexual dysfunction may worsen
reuptake • Anxiolytic effects impair chemoprotective
inhibitors efficacy of tamoxifen if
used concomitantly

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 PRIMER

Table 5 (Cont.) | Prescription therapy options for management of menopausal symptoms

Treatment Benefits Risks Patient-specific considerations
option
Selective Relief of vasomotor • Relatively well tolerated Less efficacious than hormone therapy
noradrenaline symptoms • Slight rise in blood
reuptake pressure may be seen;
inhibitors caution advised in
the setting of known
hypertension
Clonidine (an Relief of vasomotor Postural hypotension Less efficacious than hormone therapy
α2-adrenergic symptoms
receptor
agonist)
GABAergics Relief of vasomotor • Relatively well tolerated • Less efficacious than hormone therapy
symptoms • Somnolence • Improved sleep, particularly in the presence of restless leg syndrome
*Caution advised when considering use in an older postmenopausal woman with existing comorbidities who is remote from onset of menopause. BZA, bazedoxifene;
CVD, cardiovascular disease; GABA, γ-aminobutyric acid; MPA, medroxyprogesterone acetate; QoL, quality of life; SERM, selective oestrogen receptor modulator;
TSEC, tissue-selective oestrogen complex; VTE, venous thromboembolism.

treatment in women with an increased thrombosis risk,
such as obese women and smokers. In addition, unlike
oral oestrogen, transdermal oestradiol does not increase
the risk of gallbladder disease171.
In the past 2 years, two new pharmaceutical prepa-
rations were approved in the United States and Europe
for the treatment of menopausal symptoms. An oral
selective oestrogen receptor modulator (SERM),
ospemifene, has been approved for the treatment of
moderate to severe pain during intercourse associated
with vulvo­vaginal atrophy 172,173, and a tissue-specific
SERM–oestrogen complex (a combination of oral con-
jugated equine oestrogen and bazedoxifene (a SERM))
has been approved for the management of moderate to
severe vasomotor symptoms in women with an intact
uterus174. Tissue selectivity is achieved through the con-
current use of oestrogen and a SERM, which replaces
a progestogen and selectively blocks the undesirable
actions of oestrogen. In the case of conjugated equine
oestrogen–bazedoxifene, the proliferative effects of
oestrogen are blocked in the uterus and possibly also
the breast, whereas the bone-sparing actions of oes-
trogen are preserved. The role of testosterone for the
treatment of postmenopausal desire or arousal dis­
orders and the long-term implications of such a therapy
in postmenopausal women are unclear. This strategy
may benefit a certain subset of women, such as those
with surgically induced menopause, who have persis-
tent sexual symptoms despite optimization of meno-
pausal hormone therapies175,176. Urogenital symptoms
are effectively treated with either local (vaginal) or sys-
temic oestrogen therapy 177. Oestrogen therapy restores
normal vaginal flora, lowers the pH, and thickens
and revascularizes the vaginal lining. The number of
superficial epithelial cells is increased and symptoms
of atrophy are alleviated. Importantly, low-dose vaginal
oestrogen improves vaginal atrophy without causing
proliferation of the endometrium177. Given the docu-
mented efficacy and proven safety, vaginal oestrogen
is the first-line approach to treat symptoms of vaginal
atrophy in the majority of women.
Hormone therapy risk reduction
In addition to an individualized risk-benefit assessment,
mitigating the risk of hormone therapy is important.
Several factors influence the treatment-related risks:
oestrogen dose163,178 (lower doses reduce the thrombo­
embolic risks of systemic oestrogen); administration
route179 (thromboembolic risk is suggested to be lower
for the use of transdermal oestrogens than oral oes-
trogens) and theoretically, systemic exposure can be
diminished by intrauterine treatment with levonorg-
estrel compared with oral formulations; progestogen
type179,180 (risk for postmenopausal breast cancer, as
well as for thrombosis, may be lessened by the use of
pro­gesterone compared with synthetic progestins);
and treatment schedule (infrequent progesterone dos-
ing seems to reduce the risk of metabolic perturbations
and breast cancer compared with continuous combined
oestrogen–progesterone regimens)6,180–183. Infrequent
progestogen dosing schedules are increasingly used,
partly owing to patient preference, as they reduce the
frequency of therapy-related bleeding episodes and, to
some extent, as a strategy to minimize breast exposure to
progestogens. However, data on the endometrial safety
of long-cycle progestogen regimens are not only sparse,
but even suggest a higher likelihood for endometrial
hyperplasia and even cancer 184.
Initiation of hormone therapy is usually contraindi-
cated in women with a personal history of breast cancer
or venous thromboembolism, or those with a high risk
for breast cancer, thrombosis or stroke. Transdermal
oestrogen therapy may be considered and preferred
when highly symptomatic women with type 2 diabetes
mellitus or obesity, or those at high risk of cardiovascu-
lar disease, do not respond to non-hormonal therapies.
In general, commencement of hormone therapy is not
recommended for women who are aged >60 years.
Recommendations regarding the duration of sys-
temic hormone therapy need to be individualized and
depend on the end points of treatment. For women with
premature ovarian failure or primary ovarian insuffi-
ciency, or those with early menopause (before the age of

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 13

© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER
45 years), therapy can be continued until the average age
of the natural menopause (early 50s), at which time the
need for hormone therapy should be reassessed. There
are no arbitrary limits regarding the duration of meno-
pausal hormone therapy; it can be used for as long as
the woman feels the benefits outweigh the risks for her,
but treatment should be re-evaluated frequently. When
hormone therapy is initiated for vasomotor symptoms,
clinicians should strive to control symptoms with the
lowest possible hormone dose, and continued therapy
for >5 years must be individualized on the basis of
symptom severity and the risk for breast cancer and
vascular events, and also with due regard to the patient’s
preference and choice.
Non-hormonal therapies
A number of non-hormonal therapies are efficacious
against menopausal vasomotor symptoms (TABLE 4) and
should be considered for women who do not wish to
take oestrogen or those with contraindications.
For vasomotor symptoms, many drugs have dem-
onstrated efficacy in several studies: paroxetine, fluox-
etine and citalopram (which are selective serotonin
reuptake inhibitors); venlafaxine and desvenlafaxine
(selective noradrenaline reuptake inhibitors); clonidine
(α2-adrenergic receptor agonist); and anticonvulsants
(gabapentin and pregabalin)2,3. Paroxetine and fluoxe-
tine are potent cytochrome P450 2D6 (CYP2D6) inhibi-
tors, and as they decrease the metabolism of tamoxifen
(a SERM used in the treatment of breast cancer) — which
may reduce its anticancer effects — these drugs should
be avoided in tamoxifen users185. However, consistency of
treatment response and efficacy of the various alternative
options remain questionable186–189. Stellate ganglion block
achieved by injecting an anaesthetic such as bupivacaine
under fluoroscopic guidance around the stellate ganglion
— which is the cervicothoracic ganglion of the sympa-
thetic system — has been shown to improve vasomotor
symptoms in a small randomized controlled trial190.
Alternatives to vaginal therapies, such as vaginal
lubricants and moisturizers, are less effective than vagi-
nal oestrogen191. Although vaginal moisturizers lower
the vaginal pH and may normalize vaginal cell compo-
sition, sustained symptom relief has not been seen in all
studies191. Vaginal moisturizers do not reduce urinary
tract symptoms or asymptomatic bacteriuria191. Vaginal
lubricants offer transient relief from vaginal atrophy-
related discomfort when used during intercourse, but
they do not treat the underlying problem.
Physical activity, diet and lifestyle
All women at midlife should be encouraged to maintain
or achieve a normal body weight, be physically active,
adopt a healthy diet, limit alcohol consumption and not
smoke. Anecdotally, some women find that avoidance
of spicy food, hot drinks and alcohol lessens their vaso-
motor symptoms. Obesity is associated with a greater
likelihood of vasomotor symptoms, although women
who are overweight (BMI from 25 to <30 kg m–2), as
opposed to obese (BMI ≥30 kg m–2), are more likely to
have severe symptoms192. For obese women, weight loss
14 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
may lessen vasomotor symptoms, as well as reduce the
risks of cardiovascular disease; diabetes; urinary incon-
tinence; breast, pancreatic and endometrial cancer; and
dementia78. Increasing physical activity has been recom-
mended to alleviate vasomotor symptoms; however, this
may exacerbate symptoms in women with a low level of
fitness193. Furthermore, a recent prospective study has
shown no benefit of exercise in reducing these symp-
toms194. Regular physical activity is to be encouraged to
maintain muscle mass and balance, thereby reducing
the risk of fall and fracture. A fairly high and consist-
ent degree of impact exercise seems to be required to
improve bone density 195,196. It is unlikely that physical
activity alone will improve bone mineral density in
women who are underweight197. Yoga has been shown to
improve sleep, but not to reduce vasomotor symptoms198.
Menopause management in perspective
Hormone therapy remains the most efficacious of the
available strategies for managing menopausal symp-
toms. Safety and efficacy of low-dose topical oestrogen
against local urogenital symptoms69,177 is well established
and now, oral ospemifene, if available, offers added flex-
ibility for women experiencing isolated urogenital symp-
toms199. In the majority of young and otherwise healthy
early menopausal women who are within 10 years of
onset of menopause, the benefits of systemic hormone
therapy will probably outweigh any potential for harm.
By contrast, in older women or women with comor-
bidities that increase the risk for cardiovascular disease
and stroke (such as hypertension, obesity, longstand-
ing smoking history, and/or a strong family history
of stroke and premature atherosclerosis) the potential
harm of systemic hormone therapy outweighs the ben-
efits. For these women, non-hormonal approaches are
the preferred first-line strategy to control menopausal
symptoms. Treatment should always be individualized.
Some women with severe symptoms that are refrac-
tory to non-hormonal therapy may accept a substantial
degree of risk of hormone therapy in order to have an
acceptable QoL. To simplify the risk-benefit assessment
for the various treatment options, the North American
Menopause Society has recently endorsed an easy-to-
follow algorithm182 (available as a mobile phone app).
It helps women’s healthcare providers from across the
globe to identify the optimal treatment strategy (hor-
monal or non-hormonal) on the basis of each patient’s
individualized risk profile.
Quality of life
QoL has been shown to change during menopause,
often in relation to the presence or absence of symp-
toms200. The primary objective of the care of sympto-
matic menopausal women is enhancement of QoL. Like
pain, an individual’s perception of QoL is not easy to
determine and is purely subjective. There is no univer-
sal agreement on a QoL definition or how it should be
measured, although it is becoming increasingly valued
as a therapeutic outcome (BOX 1). General QoL reflects
the individual’s beliefs about functioning and achieve-
ments in various aspects of life, and an overall sense
 PRIMER

Box 1 | Assessing quality of life and menopausal symptoms

such as herbal preparations and cognitive behavioural
therapy 205–209. However, when HRQoL is assessed,
Several instruments can be used to measure quality of life (QoL) during menopause; there was no such improvement in the Women’s Health
the domains covered by each instrument are shown in brackets. Initiative study and the Heart and Oestrogen–Progestin-
Generic instruments Replacement Study, neither of which recruited women
• Short-form 36 health survey (SF‑36; physical and social functioning; bodily pain; with severe symptoms, as this would have led to unblind-
general and mental health; vitality; emotional and physical role) ing of the trials210–212. An improvement was observed in
• EuroQoL (mobility; self-care; usual activities; pain and discomfort; anxiety or the 2000 Finnish health survey, in which women had
depression) been prescribed hormone therapy for symptom relief 213.
Menopause-specific instruments This is perhaps not surprising as the purpose of the for-
• Greene climacteric scale (psychological, somatic and vasomotor symptoms) mer studies was to assess chronic disease prevention and
• Women’s health questionnaire (WHQ; depressed mood; somatic, vasomotor and symptom relief was of little importance.
menstrual symptoms; anxiety; sexual behaviour; sleep problems; memory and
concentration; attractiveness) Outlook
• Menopause-specific QoL questionnaire (MENQOL; vasomotor, psychosocial, physical Overall, our understanding from epidemiological stud-
and sexual domains) ies of the effects of menopausal transition on women
• Menopause rating scale (MRS; psychological, somato-vegetative and urogenital and the factors that influence its duration and timing
symptoms) remains unclear and incomplete. Basic questions, such
• Menopause QoL scale (MQOL; physical, vasomotor, psychosocial and sexual domains) as global statistics on the age of menopause and the
• Utian menopause QoL scale (QQOL; occupational, health-related, emotional and variation in the length of the perimenopause, remain
sexual QoL) unanswered. One way forward lies in recent steps that
have been taken to combine individual-level data from
Symptom-specific instruments
numerous international studies of women’s health to
• Kupperman index (menopausal symptoms)
provide a more comprehensive and detailed picture of
• Hot flush-related daily interference scale (vasomotor symptoms) the menopausal transition, its timing and long-term
• Sexual activity log (sexual activity) health implications, not just for women in developed
nations but also for those from developing regions and
from diverse populations.
of satisfaction and wellbeing. When QoL is related to With the increasing lifespan of women in less devel-
health and illness, it is usually known as health-related oped countries, the impact of the menopausal transition
QoL (HRQoL). HRQoL is the patient’s evaluation of the in these countries needs to be better understood22. Data
impact of a health condition and its treatment on life about the persistence of menopausal symptoms beyond
aspects that are most likely to be affected by a change in the age of 65 years and how such symptoms might
health status. This covers physical health and function, adversely affect older women are also sparse214. Studies
emotional function, role limitations and social func- investigating menopause in developing countries and in
tioning. All of these domains are relevant to a woman’s older women are sorely needed.
QoL and measuring their status goes beyond the mere We are getting closer to accurately forecasting the
counting of events. timing of menopause. This is important in the context
Assessment instruments are generic or disease-­ of women delaying childbearing and wanting to have
specific201; the former covering different aspects of daily better control of their fertility. Research to refine the
living. They can also be used in the evaluation of cost use of AMH as a predictor of menopause and studies
effectiveness in health economic analyses202. However, involving the isolation of oogonial stem cells to prevent
assessment of QoL needs to include not only the impact menopause are ongoing. However, we still lack a com-
of symptoms, but also personal and environmen- plete understanding of the basic mechanisms that are
tal factors. This has led to the development of several responsible for vasomotor symptoms, which in turn
menopause-­specific QoL instruments, which can be limits the development of novel non-hormonal treat-
used to assess the benefits of treatment 201. Often more ments for hot flushes and night sweats. More research
than one instrument must be used to cover different into the central thermal control mechanisms influ-
aspects of menopause and treatment in order to assess enced by oestrogen is needed, and our understanding
general QoL and specific symptoms. Also, it is difficult of the effects of oestrogen deficiency on this remains
to incorporate the impact of adverse effects of treatment in its infancy. We also need to better understand the
into the assessment of QoL as the instruments are not mechanisms by which oestrogen deficiency results in
designed to do this. sleep disturbance, as this has extensive adverse effects
The impact of menopausal hormone therapy on QoL on women that persist for years. For other symptoms
depends on whether women are symptomatic or not, as of oestrogen deficiency, the underlying mechanisms
might be expected203. Menopause-specific question- remain elusive, including arthralgia and mood changes,
naires show improvements in vasomotor symptoms, particularly anxiety. A greater understanding of the bio-
sexual functioning and sleep for hormone treatment chemical pathways by which oestrogen deficiency con-
compared with placebo, and this may vary with the tributes to central fat accumulation could lead to novel
type of therapy used204. This is also true of oestrogen– targeted approaches for preventing central weight gain
bazedoxifene, tibolone and alternative treatments, in women, and possibly in men.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 15

© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER

The pendulum has swung from the overt enthusiasm of
pharmaceutical companies to invest in menopausal thera-
pies in the 1990s to the removal of several highly effective
hormone therapies from the market (such as intranasal
oestradiol and transdermal testosterone patches) and
minimization of women’s health divisions in large compa-
nies that were previously world leaders in the provision of
midlife women’s health products. This damage has been a
consequence of the fear of breast cancer, venous thrombosis
and stroke, which was engendered by the very first publica-
tions of the Women’s Health Initiative215. Thus, menopause,
a condition that affects every woman, is now underfunded
and under researched. Furthermore, vast numbers of
highly symptomatic women are not receiving therapies that
are proven to be effective and many are resorting to alterna-
tives that are mostly ineffective and unregulated18,97,163,187,192.
There needs to be greater recognition that meno-
pause affects all women, that many of the symptoms
of oestrogen deficiency are not transient but persist for
decades, and that oestrogen loss adversely influences
bone, metabolic and cardiovascular health. Hence,
investment in the management of menopause trans-
lates into investing in the health of what will equate to
half of the life of young women today. Funding of basic
research is needed to identify novel interventions that
effectively alleviate the symptoms of oestrogen defi-
ciency — notably, vasomotor symptoms, sleep distur-
bance, mood changes and urogenital symptoms — and
abrogate the adverse effects of oestrogen deficiency on
body composition, bone density and the cardiovascular
system, as well as translational research to evaluate the
safety of such new therapies.

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Author contributions
Introduction (S.R.D.); Epidemiology (G.D.M.); Mechanisms
and pathophysiology (T.S. and I.L.); Diagnosis, screening and
prevention (N.S. and S.R.D.); Management (M.R., L.P. and
S.R.D.); Quality of life (M.L.); Outlook (S.R.D.); and overview
of Primer (S.R.D.).
Competing interests statement
S . R . D . h a s re c e i ve d a n h o n o ra r i u m f ro m A b b o t t
Pharmaceuticals for one presentation and is an investigator
for Trimel Pharmaceuticals and Lawley Pharmaceuticals; all
other authors declare no competing interests.