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
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 radiotherapy. To facilitate research on menopause, investigators convened in 2001 and reported the first Staging of Reproductive Aging Workshop (STRAW) recommendations1. 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,
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 menopausal 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 oestrogen production, may provide the first indication of the menopause6. Although not all women experience significant 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 physiology and clinical consequences of menopause, as well as the available treatment options.
The first reliable epidemiological estimates for the timing of menopause give a median age at natural menopause 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 variation by geographical region (Table 1). Although studies in the United States and Asia tend to show results close to this mean figure, age at menopause is generally lower in Africa, Latin America and Middle-Eastern countries (regional means: 47.2–48.4 years), and higher in Europe and Australia (50.5–51.2 years)8. The reasons for such regional differences remain far from clear; however, previous studies suggest a modest rise of the menopausal age for women in wealthy nations during the twentieth century9,
Distinguishing the effects of menopausal transition on a woman's health and quality of life (QoL) from the effects of ageing is a major challenge for cross-sectional, observational studies. Moreover, other major life events can occur during midlife, such as needing to care for elderly parents and children leaving home permanently. Findings from a study in the United States indicate that the perimenopausal stage lasts on average for almost 4 years, although for some women it can last much longer, with a longer perimenopause being associated with a higher rate of medical consultations14. 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 moderate to severe symptoms16. Longitudinal analysis of data from women in the Medical Research Council 1946 British birth cohort has unravelled other effects on 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 psychosomatic status (such as nervous emotional state and ability to concentrate). These changes were associated 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. A systematic review of the prevalence of menopausal symptoms in Asian countries found a predominance of other physical symptoms over vasomotor and psychological symptoms. Furthermore, vasomotor symptoms occurred in premenopausal, perimenopausal and postmenopausal women22. However, most studies that were considered for this systematic review showed low external and internal validity when evaluated by a risk of bias tool. Thus, further studies of representative samples and using validated questionnaires are needed to clarify the prevalence of menopausal symptoms in Asian women.
Epidemiological studies have provided a detailed picture of symptom trajectories experienced through the menopausal transition and into postmenopause. For instance, findings from two studies15,23 have shown that women who experienced strong vasomotor symptom peaks either before or after menopause had a quick decline in postmenopause. Such trajectories for the severity of these symptoms were not evident when analysed according to chronological age, but only when their timing was examined with respect to age at menopause. Such results may help to guide the optimal treatment and management of symptoms.
Age at menopause is also increasingly recognized as an indicator for health outcomes in later life, especially those related to oestrogen exposure, although the underlying biological mechanisms often remain unclear. For instance, primary ovarian insufficiency (menopause before the age of 40 years) is associated with reduced risk of breast and ovarian cancers, but higher risk of cardiovascular disease and osteoporosis24,
Factors influencing menopause
The functional lifespan of human ovaries is determined by a complex and yet largely unidentified set of genetic, hormonal and environmental factors (Fig. 3). Women undergo menopause when follicles in their ovaries are exhausted. However, the clinical manifestations of menopause result from dynamic interactions between neuroendocrine changes and alterations in the reproductive endocrine axis that governs the function of the ovaries.
It is unclear why ovaries start their function at puberty and stop it at menopause, and understanding this phenomenon would have far-reaching implications for reproductive and health issues.
Genetic factors. The timing of menopause reflects a complex interplay of genetic, epigenetic, socioeconomic and lifestyle factors. Estimates of the heritability in menopausal age range from 30% to 85%30,31. Approximately 50% of the interindividual variability in age at menopause is related to genetic effects32. Women whose mothers or other first-degree relatives were known to have early menopause have been found to be 6–12-fold more likely to undergo early menopause themselves33,34. Furthermore, cross-sectional and cohort studies have shown that a woman's age at menopause is strongly associated with her mother's age at menopause30,
Linkage analysis studies pinpoint areas on chromosome X (region Xp21.3) that are associated with early (<45 years) or premature (<40 years) menopause38. A region on chromosome 9 (9q21.3) is also associated with age at menopause. This region contains multiple genes, including one that encodes a protein of the B cell lymphoma 2 (BCL-2) family38. BCL-2 is involved in apoptosis, and may thus influence menopause through follicular depletion. Other linkage analysis studies have identified a region on chromosome 8 that is associated with age at menopause39. Interestingly, the gene encoding the gonadotropin-releasing hormone (GnRH) is near this region.
Studies looking at associations between genes encoding factors that are involved in reproductive pathophysiology and menopause have been disappointing. Most studies have failed to identify associations or the results could not be replicated. Among the genes investigated, those encoding the oestrogen receptor-α (ESR1), 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1), anti-Müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) have been the most promising37. Women who are carriers of genetic mutations in early onset breast cancer 1 (BRCA1) or BRCA2 are on average 3 years younger at menopause than matched controls (50 years versus 53 years)40. A number of known genetic disorders result in earlier menopause, including mutation of the gene encoding forkhead box protein L2 (FOXL2), which also causes the blepharophimosis, ptosis and epicanthus inversus (BPES) syndrome41. Mutations of the genes encoding bone morphogenetic protein 15 (BMP15) and growth and differentiation factor 9 (GDF9) result in premature menopause42,43. Galactosaemia has been associated with menopause prior to the age of 40 years in one study44, but no relationship was observed in a follow-up study of a similarly sized cohort45. Variants of other genes that are involved in ovarian function, such as those encoding follicle-stimulating hormone (FSH) and inhibin receptors, have been shown to be associated with early and premature menopause43. Women who are carriers for the fragile X mutation and have an intermediate number of CGG repeats in the fragile X mental retardation 1 (FMR1) gene have been observed to undergo early and premature menopause46.
Recently, genome-wide association studies have found new genes that might influence ovarian ageing and menopause47,
Ovarian lifespan and follicle loss. The ovaries and the follicles are central to determining menopause timing51. The number of follicular cells is determined before birth, when oocytes expand to a maximum of 6–7 million at mid-gestation. Afterwards, oocytes are rapidly lost due to apoptosis, leading to a population of 700,000 at birth and 300,000 at puberty. Continuing apoptosis, along with the loss of oocytes during the 400–500 cycles of follicular recruitment in a normal reproductive life (sometimes involving multiple follicles per cycle), leads to final exhaustion of these cells at midlife and menopause between 45 and 55 years of age51. These numbers highlight that the duration of ovarian functionality depends only little on ovulation and is mostly determined by the extent and rapidity of oocyte apoptosis — what governs this process is unknown.
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 progressive 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 cyclicity53.
Neuroendocrine events. The hypothalamic–pituitary reproductive axis undergoes considerable changes during the menopausal transition. These modifications are in part secondary to declining ovarian function, but several lines of evidence suggest that the brain undergoes independent functional modifications that are important for reproductive ageing54. 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 peptide) 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 hypothalamic 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 reproductive years depend on the combined dysfunction of the ovaries and the hypothalamus56. A shortened follicular phase and the associated increase in FSH levels are characteristic of early menopausal transition. This accounts for the shorter cycle intervals that are experienced 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 explanation 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.
With time, the age-related hypothalamic modifications 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 oestrogens, 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 pathways involved are still unknown. Identifying such factors 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 menopause 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 reactivity58.
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 menopause; vulnerable women, however, may have their first episode or a relapse during the transition65. Muscle and joint pain is also part of the menopausal symptomatology66 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 causes a cluster of symptoms including vaginal dryness, painful intercourse (dyspareunia), vulvar pruritus, burning and discomfort, as well as recurrent urogenital infections68. Vulvovaginal atrophy and urinary tract atrophy, 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, secondary to vulvovaginal atrophy, leads to diminished sexual desire, arousal difficulties, relationship problems, and diminished physical and emotional sexual satisfaction71. Although the majority of women have signs of urogenital atrophy upon physical examination, less than half of the postmenopausal population report bothersome 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 osteoid — new non-mineralized bone synthesized by osteoblasts — which is later mineralized to form mature bone 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 excessive 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 oestrogen 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 absorption, vitamin D deficiency and impaired synthesis of active 1,25-dihydroxyvitamin D3 by the kidney lead to secondary hyperparathyroidism, which further contributes 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 production by osteocytes76. Both processes — increased bone resorption and decreased bone formation — lead to diminished bone strength and to fractures upon minimal 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 premenopausal 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 menopausal oestrogen decline are associated with adverse metabolic changes such as insulin resistance, a propensity to develop type 2 diabetes mellitus and dyslipidaemia characterized by high triglyceride levels, low high-density lipoprotein (HDL) cholesterol levels and an increased frequency of small, dense low-density lipoprotein (LDL) particles79,80. 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 dilation and local inflammatory activity83. Oestrogen deficiency after menopause leads to the activation of the renin–angiotensin system, the upregulation of the potent vasoconstrictor endothelin and the impairment of nitric oxide-mediated vasodilation. Oxidative stress, which is augmented by endothelin and angiotensin II, may further contribute to atherosclerotic processes84. Thus, soon after menopause, women exhibit increases in blood pressure, as well as subclinical vascular disease, which can be observed as increased carotid and femoral artery intima-media thickness, coronary artery calcium score and arterial stiffness, and impaired flow-mediated dilation85,
Cognition. Oestrogens act in areas of the central nervous system that control learning, registering and retrieving information, judgement, evaluation processes and language skills. These areas mainly involve the prefrontal 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 often bothersome for the affected women96. Although menopause seems to be associated with changes in cognition, 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 menopause. Women in the 1946 British birth cohort who had been breastfed experienced later menopause than those who had not36,99, 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 menopause 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 reproductive 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 parity103,
Of the various lifestyle and environmental factors in adulthood that have been investigated with respect to the timing of menopause, only cigarette smoking108,
A recent systematic review found a modest association 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 menopause124. Higher body mass index (BMI) has been associated with a greater likelihood of transitioning from premenopause to perimenopause but not from perimenopause to postmenopause123. Non-obese women tend to have a more rapid decline in oestradiol as they transit the menopause125.
The common symptoms of menopause, with their approximate onsets and durations126,
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 presentation 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, hyperprolactinaemia, 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.
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 inhibin 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 permanent amenorrhoea. After menopause has happened, 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 menopause within the subsequent 5 years139. Overall, the sensitivity 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 amenorrhoea140. Examination of AMH change over time holds promise for refining our ability to prospectively determine when menopause will occur141. Ultimately, with the development of a sufficiently sensitive AMH assay, it should be possible to help forecast the final menstrual period with better accuracy.
Other measurements have also been proposed for forecasting the timing of permanent ovarian failure, including both antral follicle counts (assessed by transvaginal ultrasonography), recording of all follicles measuring ≤7 mm in diameter (usually done in the early follicular 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 predictors 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 provide useful information about the likelihood of pregnancy 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 volume 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 prevalence of osteoporosis in women aged 40–65 years is low144, there is a mean vertebral bone loss of 6.4% and neck of femur loss of 5% during the menopause transition145. 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 screening 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 underwent 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 menstruating 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, prolactinoma, severe depression or stress, and substantial weight loss. Each of these may be associated with vasomotor symptoms and mood changes. Pregnancy should always be considered in the setting of amenorrhoea.
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 careful medical and medication history should identify other possible causes. Serotonin-producing carcinoid tumours can present with nocturnal diarrhoea and episodic flushing without sweating. Phaeochromocytomas release the catecholamines adrenaline and noradrenaline, and are characterized by persistent hypertension, flushing and profuse sweating149.
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 activities 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 suicidal ideation150. By contrast, perimenopausal depression is usually accompanied by irritability, hostility or agitation, and anxiety151. Clinically, it resembles the mood changes of premenstrual syndrome, with negative 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.
Although one of the defining features of menopause is the cessation of the menstrual period, it more broadly encompasses the permanent cessation of ovarian reproductive 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 equation. 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 accelerated by factors such as cigarette smoking141, and some clinical situations — such as hypogonadotropism156 and obesity21 — 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 appropriate 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 mutation have been published158, but the clinical application of these is yet to be established.
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 possibility 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.
Managing menopausal symptoms need not be complex. Bothersome vasomotor symptoms, disturbed nocturnal 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 pharmacological options (both hormonal and non-hormonal)163,
Choosing the right therapy
Oestrogen deficiency is the principal pathophysiological 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 addition of progesterone aims to protect against the consequences of systemic therapy with oestrogen only in women with intact uteri160: namely, endometrial pathologies, including hyperplasia and cancer. The risk-benefit ratios of all treatment options must be considered, taking into account the nature and severity of symptoms, and individual treatment-related risks (Table 4).
In the systemic circulation, oestradiol and oestrone are partly bound to sex hormone-binding globulin (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 procoagulants is another known effect of oral oestrogens. Transdermal oestradiol does not seem to increase the risk of venous thromboembolic events169,170. Thus, transdermal oestrogen therapy is the preferred mode of 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 preparations 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 atrophy172,173, and a tissue-specific SERM–oestrogen complex (a combination of oral conjugated 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 concurrent 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 oestrogen are preserved. The role of testosterone for the treatment of postmenopausal desire or arousal disorders 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 persistent sexual symptoms despite optimization of menopausal hormone therapies175,176. Urogenital symptoms are effectively treated with either local (vaginal) or systemic oestrogen therapy177. 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 documented 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 thromboembolic risks of systemic oestrogen); administration route179 (thromboembolic risk is suggested to be lower for the use of transdermal oestrogens than oral oestrogens) and theoretically, systemic exposure can be diminished by intrauterine treatment with levonorgestrel 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 dosing seems to reduce the risk of metabolic perturbations and breast cancer compared with continuous combined oestrogen–progesterone regimens)6,180,
Initiation of hormone therapy is usually contraindicated 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 cardiovascular 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 systemic hormone therapy need to be individualized and depend on the end points of treatment. For women with premature ovarian failure or primary ovarian insufficiency, or those with early menopause (before the age of 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 menopausal 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.
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 demonstrated efficacy in several studies: paroxetine, fluoxetine 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 fluoxetine are potent cytochrome P450 2D6 (CYP2D6) inhibitors, 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,
Alternatives to vaginal therapies, such as vaginal lubricants and moisturizers, are less effective than vaginal oestrogen191. Although vaginal moisturizers lower the vaginal pH and may normalize vaginal cell composition, 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 vasomotor 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 may lessen vasomotor symptoms, as well as reduce the risks of cardiovascular disease; diabetes; urinary incontinence; breast, pancreatic and endometrial cancer; and dementia78. Increasing physical activity has been recommended 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 symptoms194. 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 consistent degree of impact exercise seems to be required to improve bone density195,196. 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 symptoms. Safety and efficacy of low-dose topical oestrogen against local urogenital symptoms69,177 is well established and now, oral ospemifene, if available, offers added flexibility for women experiencing isolated urogenital symptoms199. 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 comorbidities that increase the risk for cardiovascular disease and stroke (such as hypertension, obesity, longstanding smoking history, and/or a strong family history of stroke and premature atherosclerosis) the potential harm of systemic hormone therapy outweighs the benefits. 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 refractory 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 (hormonal 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 symptoms200. The primary objective of the care of symptomatic 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 universal 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 achievements in various aspects of life, and an overall sense of satisfaction and wellbeing. When QoL is related to health and illness, it is usually known as health-related QoL (HRQoL). HRQoL is the patient's evaluation of the impact of a health condition and its treatment on life aspects that are most likely to be affected by a change in health status. This covers physical health and function, emotional function, role limitations and social functioning. All of these domains are relevant to a woman's QoL and measuring their status goes beyond the mere counting of events.
Assessment instruments are generic or disease-specific201; the former covering different aspects of daily living. They can also be used in the evaluation of cost effectiveness in health economic analyses202. However, assessment of QoL needs to include not only the impact of symptoms, but also personal and environmental factors. This has led to the development of several menopause-specific QoL instruments, which can be used to assess the benefits of treatment201. Often more than one instrument must be used to cover different aspects of menopause and treatment in order to assess general QoL and specific symptoms. Also, it is difficult to incorporate the impact of adverse effects of treatment into the assessment of QoL as the instruments are not designed to do this.
The impact of menopausal hormone therapy on QoL depends on whether women are symptomatic or not, as might be expected203. Menopause-specific questionnaires show improvements in vasomotor symptoms, sexual functioning and sleep for hormone treatment compared with placebo, and this may vary with the type of therapy used204. This is also true of oestrogen–bazedoxifene, tibolone and alternative treatments, such as herbal preparations and cognitive behavioural therapy205,
Overall, our understanding from epidemiological studies of the effects of menopausal transition on women and the factors that influence its duration and timing remains unclear and incomplete. Basic questions, such as global statistics on the age of menopause and the variation in the length of the perimenopause, remain unanswered. One way forward lies in recent steps that have been taken to combine individual-level data from numerous international studies of women's health to provide a more comprehensive and detailed picture of the menopausal transition, its timing and long-term health implications, not just for women in developed nations but also for those from developing regions and from diverse populations.
With the increasing lifespan of women in less developed countries, the impact of the menopausal transition in these countries needs to be better understood22. Data about the persistence of menopausal symptoms beyond the age of 65 years and how such symptoms might adversely affect older women are also sparse214. Studies investigating menopause in developing countries and in older women are sorely needed.
We are getting closer to accurately forecasting the timing of menopause. This is important in the context of women delaying childbearing and wanting to have better control of their fertility. Research to refine the use of AMH as a predictor of menopause and studies involving the isolation of oogonial stem cells to prevent menopause are ongoing. However, we still lack a complete understanding of the basic mechanisms that are responsible for vasomotor symptoms, which in turn limits the development of novel non-hormonal treatments for hot flushes and night sweats. More research into the central thermal control mechanisms influenced by oestrogen is needed, and our understanding of the effects of oestrogen deficiency on this remains in its infancy. We also need to better understand the mechanisms by which oestrogen deficiency results in sleep disturbance, as this has extensive adverse effects on women that persist for years. For other symptoms of oestrogen deficiency, the underlying mechanisms remain elusive, including arthralgia and mood changes, particularly anxiety. A greater understanding of the biochemical pathways by which oestrogen deficiency contributes to central fat accumulation could lead to novel targeted approaches for preventing central weight gain in women, and possibly in men.
The pendulum has swung from the overt enthusiasm of pharmaceutical companies to invest in menopausal therapies 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 companies 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 publications 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 alternatives that are mostly ineffective and unregulated18,97,163,187,192.
There needs to be greater recognition that menopause 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 translates 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 deficiency — notably, vasomotor symptoms, sleep disturbance, 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.