Menopause - Nature article

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<p>Menopause is the permanent cessation of menstrual</p><p>cycles following the loss of ovarian follicular activity</p><p>(FIG. 1). This may be spontaneous (natural menopause)</p><p>or iatrogenic (secondary menopause). The latter includes</p><p>removal of both ovaries (surgical menopause), as well as</p><p>ovarian failure resulting from chemotherapy or radio-</p><p>therapy. To facilitate research on menopause, investiga-</p><p>tors convened in 2001 and reported the first Staging of</p><p>Reproductive Aging Workshop (STRAW) recommenda-</p><p>tions1. Staging is not only useful for research; it can also</p><p>facilitate dialogue between a woman and her clinician,</p><p>and between clinicians. A refined STRAW classification</p><p>was published in 2012 and includes several data-driven</p><p>adjustments to the original publication2–5.</p><p>Briefly, the STRAW classification (summarized in</p><p>FIG. 2) separates a woman’s life into seven segments,</p><p>with segments –2, –1 and 0 including the early meno-</p><p>pausal transition, the late menopausal transition and</p><p>the final menstrual period, respectively. Age at natural</p><p>menopause is used to indicate the timing of menopause</p><p>and is confirmed after 1 year of amenorrhoea. The early</p><p>transition is defined as a departure from previously</p><p>regular menstrual cycle lengths of ≥7 days, or a skipped</p><p>menstrual period. During this stage, oestrogen levels</p><p>are fluctuating but are sufficient overall, and cycles</p><p>are usually ovulatory. If oestrogen levels drop, they are</p><p>not maintained at a very low level for long, but will</p><p>fluctuate until after menopause. Thus, symptoms are</p><p>generally mild at this stage of the transition and most</p><p>women will notice them but not require treatment.</p><p>Clearly, the STRAW staging primarily applies to</p><p>women experiencing spontaneous menopause and not</p><p>those with secondary menopause. It is also less useful</p><p>for women who are unable to observe a change in their</p><p>menstrual bleeding patterns, owing to hysterectomy,</p><p>endometrial ablation, hormonal contraception with</p><p>suppressed ovarian cycles or a progestin intrauterine</p><p>device, for example. For such women, the occurrence of</p><p>menopausal symptoms, due to the fall in ovarian oestro-</p><p>gen production, may provide the first indication of the</p><p>menopause6. Although not all women experience sig-</p><p>nificant symptoms, the fall in oestrogen at menopause</p><p>results in changes throughout the body including bone</p><p>loss, a tendency to increased abdominal fat and a more</p><p>adverse cardiovascular risk profile. In this Primer article,</p><p>we summarize the current understanding of the physiol-</p><p>ogy and clinical consequences of menopause, as well as</p><p>the available treatment options.</p><p>Epidemiology</p><p>The first reliable epidemiological estimates for the tim-</p><p>ing of menopause give a median age at natural meno-</p><p>pause of 48–52 years among women in developed</p><p>nations7. In a more recent and broader meta-analysis8 of</p><p>36 studies spanning 35 countries, the overall mean age</p><p>was 48.8 years (95% CI 48.3–49.2), with considerable</p><p>Correspondence to S.R.D.</p><p>e‑mail: susan.davis@</p><p>monash.edu</p><p>School of Public Health and</p><p>Preventive Medicine,</p><p>Monash University,</p><p>99 Commercial Road,</p><p>Melbourne, Victoria 3004,</p><p>Australia.</p><p>Article number: 15004</p><p>doi:10.1038/nrdp.2015.4</p><p>Published online</p><p>23 April 2015</p><p>Menopause</p><p>Susan R. Davis1, Irene Lambrinoudaki2, Maryann Lumsden3, Gita D. Mishra4,</p><p>Lubna Pal5, Margaret Rees6, Nanette Santoro7 and Tommaso Simoncini8</p><p>Abstract | Menopause is an inevitable component of ageing and encompasses the loss of ovarian</p><p>reproductive function, either occurring spontaneously or secondary to other conditions. It is not yet</p><p>possible to accurately predict the onset of menopause, especially early menopause, to give women</p><p>improved control of their fertility. The decline in ovarian oestrogen production at menopause can cause</p><p>physical symptoms that may be debilitating, including hot flushes and night sweats, urogenital atrophy,</p><p>sexual dysfunction, mood changes, bone loss, and metabolic changes that predispose to cardiovascular</p><p>disease and diabetes. The individual experience of the menopause transition varies widely. Important</p><p>influential factors include the age at which menopause occurs, personal health and wellbeing, and each</p><p>woman’s environment and culture. Management options range from lifestyle assessment and intervention</p><p>through to hormonal and non-hormonal pharmacotherapy, each of which has specific benefits and risks.</p><p>Decisions about therapy for perimenopausal and postmenopausal women depend on symptomatology,</p><p>health status, immediate and long-term health risks, personal life expectations, and the availability and</p><p>cost of therapies. More effective and safe therapies for the management of menopausal symptoms need</p><p>to be developed, particularly for women who have absolute contraindications to hormone therapy.</p><p>For an illustrated summary of this Primer, visit: http://go.nature.com/BjvJVX</p><p>PRIMER</p><p>NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 1</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>mailto:susan.davis@ monash.edu</p><p>mailto:susan.davis@ monash.edu</p><p>http://go.nature.com/BjvJVX</p><p>variation by geographical region (TABLE 1). Although</p><p>studies in the United States and Asia tend to show results</p><p>close to this mean figure, age at menopause is gener-</p><p>ally lower in Africa, Latin America and Middle-Eastern</p><p>countries (regional means: 47.2–48.4 years), and higher</p><p>in Europe and Australia (50.5–51.2 years)8. The reasons</p><p>for such regional differences remain far from clear;</p><p>however, previous studies suggest a modest rise of the</p><p>menopausal age for women in wealthy nations during</p><p>the twentieth century9–13. The biological and environ-</p><p>mental factors — and interactions between them — that</p><p>account for regional differences and historical trends in</p><p>the timing of menopause remain unclear.</p><p>Distinguishing the effects of menopausal transi-</p><p>tion on a woman’s health and quality of life (QoL) from</p><p>the effects of ageing is a major challenge for cross-</p><p>sectional, observational studies. Moreover, other major</p><p>life events can occur during midlife, such as needing</p><p>to care for elderly parents and children leaving home</p><p>permanently. Findings from a study in the United</p><p>States indicate that the perimenopausal stage lasts on</p><p>average for almost 4 years, although for some women</p><p>it can last much longer, with a longer perimenopause</p><p>being associated with a higher rate of medical consulta-</p><p>tions14. Vasomotor symptoms (hot flushes and cold or</p><p>night sweats) and vaginal dryness are well-established</p><p>symptoms during and after perimenopause15. Indeed,</p><p>75% of postmenopausal women</p><p>during intercourse, but</p><p>they do not treat the underlying problem.</p><p>Physical activity, diet and lifestyle</p><p>All women at midlife should be encouraged to maintain</p><p>or achieve a normal body weight, be physically active,</p><p>adopt a healthy diet, limit alcohol consumption and not</p><p>smoke. Anecdotally, some women find that avoidance</p><p>of spicy food, hot drinks and alcohol lessens their vaso-</p><p>motor symptoms. Obesity is associated with a greater</p><p>likelihood of vasomotor symptoms, although women</p><p>who are overweight (BMI from 25 to</p><p>More research</p><p>into the central thermal control mechanisms influ-</p><p>enced by oestrogen is needed, and our understanding</p><p>of the effects of oestrogen deficiency on this remains</p><p>in its infancy. We also need to better understand the</p><p>mechanisms by which oestrogen deficiency results in</p><p>sleep disturbance, as this has extensive adverse effects</p><p>on women that persist for years. For other symptoms</p><p>of oestrogen deficiency, the underlying mechanisms</p><p>remain elusive, including arthralgia and mood changes,</p><p>particularly anxiety. A greater understanding of the bio-</p><p>chemical pathways by which oestrogen deficiency con-</p><p>tributes to central fat accumulation could lead to novel</p><p>targeted approaches for preventing central weight gain</p><p>in women, and possibly in men.</p><p>Box 1 | Assessing quality of life and menopausal symptoms</p><p>Several instruments can be used to measure quality of life (QoL) during menopause;</p><p>the domains covered by each instrument are shown in brackets.</p><p>Generic instruments</p><p>• Short-form 36 health survey (SF-36; physical and social functioning; bodily pain;</p><p>general and mental health; vitality; emotional and physical role)</p><p>• EuroQoL (mobility; self-care; usual activities; pain and discomfort; anxiety or</p><p>depression)</p><p>Menopause-specific instruments</p><p>• Greene climacteric scale (psychological, somatic and vasomotor symptoms)</p><p>• Women’s health questionnaire (WHQ; depressed mood; somatic, vasomotor and</p><p>menstrual symptoms; anxiety; sexual behaviour; sleep problems; memory and</p><p>concentration; attractiveness)</p><p>• Menopause-specific QoL questionnaire (MENQOL; vasomotor, psychosocial, physical</p><p>and sexual domains)</p><p>• Menopause rating scale (MRS; psychological, somato-vegetative and urogenital</p><p>symptoms)</p><p>• Menopause QoL scale (MQOL; physical, vasomotor, psychosocial and sexual domains)</p><p>• Utian menopause QoL scale (QQOL; occupational, health-related, emotional and</p><p>sexual QoL)</p><p>Symptom-specific instruments</p><p>• Kupperman index (menopausal symptoms)</p><p>• Hot flush-related daily interference scale (vasomotor symptoms)</p><p>• Sexual activity log (sexual activity)</p><p>P R I M E R</p><p>NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 15</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>The pendulum has swung from the overt enthusiasm of</p><p>pharmaceutical companies to invest in menopausal thera-</p><p>pies in the 1990s to the removal of several highly effective</p><p>hormone therapies from the market (such as intranasal</p><p>oestradiol and transdermal testosterone patches) and</p><p>minimization of women’s health divisions in large compa-</p><p>nies that were previously world leaders in the provision of</p><p>midlife women’s health products. This damage has been a</p><p>consequence of the fear of breast cancer, venous thrombosis</p><p>and stroke, which was engendered by the very first publica-</p><p>tions of the Women’s Health Initiative215. Thus, menopause,</p><p>a condition that affects every woman, is now underfunded</p><p>and under researched. Furthermore, vast numbers of</p><p>highly symptomatic women are not receiving therapies that</p><p>are proven to be effective and many are resorting to alterna-</p><p>tives that are mostly ineffective and unregulated18,97,163,187,192.</p><p>There needs to be greater recognition that meno-</p><p>pause affects all women, that many of the symptoms</p><p>of oestrogen deficiency are not transient but persist for</p><p>decades, and that oestrogen loss adversely influences</p><p>bone, metabolic and cardiovascular health. Hence,</p><p>investment in the management of menopause trans-</p><p>lates into investing in the health of what will equate to</p><p>half of the life of young women today. 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Efficacy of Cimicifuga</p><p>racemosa, Hypericum perforatum and Agnus castus in</p><p>the treatment of climacteric complaints: a systematic</p><p>review. Gynecol. Endocrinol. 28, 703–709 (2012).</p><p>P R I M E R</p><p>18 | 2015 | VOLUME 1 www.nature.com/nrdp</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>http://dx.doi.org/10.1007/s00198-015-3046-9</p><p>http://dx.doi.org/10.3109/13697137.2014.954996</p><p>190. Walega, D. R., Rubin, L. H., Banuvar, S.,</p><p>Shulman, L. P. & Maki, P. M. Effects of stellate</p><p>ganglion block on vasomotor symptoms: findings from</p><p>a randomized controlled clinical trial in</p><p>postmenopausal women. Menopause 21, 807–814</p><p>(2014).</p><p>191. Sinha, A. & Ewies, A. A. Non-hormonal topical</p><p>treatment of vulvovaginal atrophy: an up-to-date</p><p>overview. Climacteric 16, 305–312 (2013).</p><p>192. Gartoulla, P., Worsley, R., Bell, R. J. & Davis, S. R.</p><p>Moderate-severe vasomotor and sexual symptoms</p><p>remain problematic for 60–65 year old women.</p><p>Menopause http://dx.doi.org/10.1097/</p><p>GME.0000000000000383 (2014).</p><p>193. Elavsky, S., Gonzales, J. U., Proctor, D. N., Williams, N.</p><p>& Henderson, V. W. Effects of physical activity on</p><p>vasomotor symptoms: examination using objective and</p><p>subjective measures. Menopause 19, 1095–1103</p><p>(2012).</p><p>194. Daley, A. et al. The effectiveness of exercise as</p><p>treatment for vasomotor menopausal symptoms:</p><p>randomised controlled trial. BJOG 122, 565–575</p><p>(2015).</p><p>This is a randomized trial in primary care that</p><p>examines the effects of exercise on symptoms of</p><p>menopause. It shows no effect, thus questioning</p><p>the recommendation of exercise by healthcare</p><p>providers as a first-line therapy.</p><p>195. Babatunde, O. O., Forsyth, J. J. & Gidlow, C. J. A</p><p>meta-analysis of brief high-impact exercises for</p><p>enhancing bone health in premenopausal women.</p><p>Osteoporos Int. 23, 109–119 (2012).</p><p>196. Martyn-St James, M. & Carroll, S. A meta-analysis of</p><p>impact exercise on postmenopausal bone loss: the</p><p>case for mixed loading exercise programmes. Br.</p><p>J. Sports Med. 43, 898–908 (2009).</p><p>197. Tucker, L. A., Fosson, E., Bailey, B. W. &</p><p>Lecheminant, J. D. Is the dose response relationship</p><p>between body mass and hip bone mineral density in</p><p>women influenced by diet, physical activity, or</p><p>menopause? Am. J. Health Promot. 28, 325–327</p><p>(2013).</p><p>198. Newton, K. M. et al. Efficacy of yoga for vasomotor</p><p>symptoms: a randomized controlled trial. Menopause</p><p>21, 339–346 (2014).</p><p>199. 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J. Med. 122,</p><p>42–52.e2 (2009).</p><p>This paper reinforces the importance of QoL at a</p><p>community level.</p><p>203. Utian, W. H. & Woods, N. F. Impact of hormone therapy</p><p>on quality of life after menopause. Menopause 20,</p><p>1098–1105 (2013).</p><p>204. Archer, D. F. et al. Long-term safety of drospirenone-</p><p>estradiol for hormone therapy: a randomized, double-</p><p>blind, multicenter trial. Menopause 12, 716–727</p><p>(2005).</p><p>205. Al-Akoum, M. et al. Effects of Hypericum perforatum</p><p>(St. John’s wort) on hot flashes and quality of life in</p><p>perimenopausal women: a randomized pilot trial.</p><p>Menopause 16, 307–314 (2009).</p><p>206. Kalay, A. E., Demir, B., Haberal, A., Kalay, M. &</p><p>Kandemir, O. Efficacy of citalopram on climacteric</p><p>symptoms. Menopause 14, 223–229 (2007).</p><p>207. Somunkiran, A., Erel, C. T., Demirci, F. & Senturk, M. L.</p><p>The effect of tibolone versus 17β-estradiol on</p><p>climacteric symptoms in women with surgical</p><p>menopause: a randomized, cross-over study. Maturitas</p><p>56, 61–68 (2007).</p><p>208. Utian, W. et al. Bazedoxifene/conjugated estrogens</p><p>and quality of life in postmenopausal women.</p><p>Maturitas 63, 329–335 (2009).</p><p>209. Wiklund, I. K., Mattsson, L. A., Lindgren, R. &</p><p>Limoni, C. Effects of a standardized ginseng extract on</p><p>quality of life and physiological parameters in</p><p>symptomatic postmenopausal women: a double-blind,</p><p>placebo-controlled trial. Swedish Alternative Med.</p><p>Group. Int. J. Clin. Pharmacol. Res. 19, 89–99 (1999).</p><p>210. Hays, J. et al. Effects of estrogen plus progestin on</p><p>health-related quality of life. N. Engl. J. Med. 348,</p><p>1839–1854 (2003).</p><p>211. Brunner, R. L. et al. Effects of conjugated equine</p><p>estrogen on health-related quality of life in</p><p>postmenopausal women with hysterectomy: results</p><p>from the Women’s Health Initiative randomized clinical</p><p>trial. Arch. Internal Med. 165, 1976–1986 (2005).</p><p>212. Hlatky, M. A., Boothroyd, D., Vittinghoff, E., Sharp, P.</p><p>& Whooley, M. A. Quality-of-life and depressive</p><p>symptoms in postmenopausal women after receiving</p><p>hormone therapy: results from the Heart and Estrogen/</p><p>Progestin Replacement Study (HERS) trial. JAMA 287,</p><p>591–597 (2002).</p><p>213. Ylikangas, S., Sintonen, H. & Heikkinen, J. Decade-long</p><p>use of continuous combined hormone replacement</p><p>therapy is associated with better health-related quality</p><p>of life in postmenopausal women, as measured by the</p><p>generic 15D instrument. J. Br. Menopause Soc. 11,</p><p>145–151 (2005).</p><p>214. Zeleke, B. M., Davis, S. R., Fradkin, P. & Bell, R. J.</p><p>Vasomotor symptoms and urogenital atrophy in older</p><p>women: a systematic review. Climacteric http://dx.doi.</p><p>org/10.3109/13697137.2014.978754 (2014).</p><p>215. Rossouw, J. et al. Risks and benefits of estrogen plus</p><p>progestin in healthy postmenopausal women: principal</p><p>results from the Women’s Health Initiative Randomised</p><p>Controlled Trial. JAMA 288, 321–333 (2002).</p><p>Author contributions</p><p>Introduction (S.R.D.); Epidemiology (G.D.M.); Mechanisms</p><p>and pathophysiology (T.S. and I.L.); Diagnosis, screening and</p><p>prevention (N.S. and S.R.D.); Management (M.R., L.P. and</p><p>S.R.D.); Quality of life (M.L.); Outlook (S.R.D.); and overview</p><p>of Primer (S.R.D.).</p><p>Competing interests statement</p><p>S.R.D. has received an honorarium from Abbott</p><p>Pharmaceuticals for one presentation and is an investigator</p><p>for Trimel Pharmaceuticals and Lawley Pharmaceuticals; all</p><p>other authors declare no competing interests.</p><p>P R I M E R</p><p>NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 19</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>http://dx.doi.org/10.1097/GME.0000000000000383</p><p>http://dx.doi.org/10.1097/GME.0000000000000383</p><p>http://dx.doi.org/10.3109/13697137.2014.978754</p><p>http://dx.doi.org/10.3109/13697137.2014.978754</p><p>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, espe</p><p>Epidemiology</p><p>Figure 1 | Regulation of menstrual cycles. a | In the premenopausal years, pulsatile release of gonadotropin-releasing hormone (GnRH; indicated by arrows) stimulates the synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (</p><p>Table 1 | Geographical variation in age at menopause*</p><p>Mechanisms/pathophysiology</p><p>Figure 2 | The stages of reproductive ageing in women. The Stages of Reproductive Aging Workshop (STRAW) defined seven stages ranging from the onset of menstrual cycles at menarche and the reproductive age to the perimenopausal and postmenopausal phases.</p><p>Figure 3 | Menopausal loss of ovarian function. Several processes contribute to declining ovarian function and the development of menopause including: hypothalamic and functional ovarian ageing; environmental, genetic and lifestyle factors; and systemic d</p><p>Figure 4 | Pathogenesis of postmenopausal osteoporosis. Reduced oestrogen production results in increased receptor activator of nuclear factor-κB ligand (RANKL) levels, which leads to osteoclast activation and increased bone resorption. Furthermore, produ</p><p>Figure 5 | Consequences of menopause on the cardiovascular system. 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 endothel</p><p>Diagnosis, screening and prevention</p><p>Table 2 | Common menopausal symptoms with timing of onset and duration</p><p>Table 3 | Differential diagnoses of menopausal symptoms</p><p>Management</p><p>Table 4 | Therapeutic options for management of menopausal symptoms</p><p>Table 5 | Prescription therapy options for management of menopausal symptoms</p><p>Table 5 (Cont.) | Prescription therapy options for management of menopausal symptoms</p><p>Quality of life</p><p>Box 1 | Assessing quality of life and menopausal symptoms</p><p>Outlook</p><p>samples and</p><p>using validated questionnaires are needed to clarify the</p><p>prevalence of menopausal symptoms in Asian women.</p><p>Epidemiological studies have provided a detailed</p><p>picture of symptom trajectories experienced through</p><p>the menopausal transition and into postmenopause.</p><p>For instance, findings from two studies15,23 have shown</p><p>0 14</p><p>Time within cycle (days)</p><p>H</p><p>or</p><p>m</p><p>on</p><p>e</p><p>le</p><p>ve</p><p>ls</p><p>28</p><p>Nature Reviews | Disease Primers</p><p>GnRH</p><p>FSH</p><p>LH</p><p>Oestradiol</p><p>Inhibin B</p><p>–5 0</p><p>Time from last period (years)</p><p>A</p><p>ve</p><p>ra</p><p>ge</p><p>h</p><p>or</p><p>m</p><p>on</p><p>e</p><p>le</p><p>ve</p><p>ls</p><p>+5</p><p>a</p><p>b</p><p>Reproductive phase</p><p>Menopause</p><p>Figure 1 | Regulation of menstrual cycles. a | In the premenopausal years, pulsatile</p><p>release of gonadotropin-releasing hormone (GnRH; indicated by arrows) stimulates the</p><p>synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)</p><p>from the anterior pituitary gland. FSH, in particular, stimulates oestradiol and inhibin B</p><p>production by ovarian follicles. Oestradiol and inhibin B exert feedback on the pituitary</p><p>gland and hypothalamus that, in turn, modifies the production of GnRH, LH and FSH.</p><p>Co-ordinated and timed production and release of pituitary FSH and LH result in the</p><p>development of ovarian follicles, ovulation and menstruation. Inhibin B is produced by</p><p>the ovarian granulosa cells and inhibits FSH synthesis and secretion. b | After menopause,</p><p>the ovaries are depleted of follicles, oestradiol and inhibin B production falls, and</p><p>ovulation and menstruation no longer occur. The loss of ovarian responsiveness to FSH</p><p>and LH, and the loss of negative feedback of oestradiol and inhibin B on the</p><p>hypothalamic–pituitary unit, result in increased production and release of GnRH, FSH</p><p>and LH. Increased FSH is particularly characteristic of postmenopause.</p><p>Author addresses</p><p>1School of Public Health and Preventive Medicine, Monash University, 99 Commercial</p><p>Road, Melbourne, Victoria 3004, Australia.</p><p>2Medical School, University of Athens, and Aretaieio University Hospital, Athens,</p><p>Greece.</p><p>3Reproductive & Maternal Medicine, Glasgow Royal Infirmary, Glasgow, UK.</p><p>4School of Population Health, Faculty of Medicine and Biomedical Sciences, University</p><p>of Queensland, Australia.</p><p>5Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University</p><p>School of Medicine, New Haven, Connecticut, USA.</p><p>6Women’s Centre, John Radcliffe Hospital, Oxford, UK.</p><p>7University of Colorado School of Medicine, Aurora, Colorado, USA.</p><p>8University of Pisa, Pisa, Italy.</p><p>P R I M E R</p><p>2 | 2015 | VOLUME 1 www.nature.com/nrdp</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>that women who experienced strong vasomotor</p><p>symptom peaks either before or after menopause had</p><p>a quick decline in postmenopause. Such trajectories</p><p>for the severity of these symptoms were not evident</p><p>when analysed according to chronological age, but only</p><p>when their timing was examined with respect to age at</p><p>menopause. Such results may help to guide the optimal</p><p>treatment and management of symptoms.</p><p>Age at menopause is also increasingly recognized</p><p>as an indicator for health outcomes in later life, espe-</p><p>cially those related to oestrogen exposure, although the</p><p>underlying biological mechanisms often remain unclear.</p><p>For instance, primary ovarian insufficiency (menopause</p><p>before the age of 40 years) is associated with reduced</p><p>risk of breast and ovarian cancers, but higher risk of</p><p>cardiovascular disease and osteoporosis24–26. This does</p><p>not necessarily imply any causal relationships, but could</p><p>result from common risk factors. This may be the case</p><p>for cardio vascular disease, for which recent findings</p><p>suggest that pre-existing risk factors, such as raised total</p><p>serum cholesterol and blood pressure, are also associ-</p><p>ated with earlier menopause27. Overall, however, each</p><p>additional year of later menopause is linked with a 2%</p><p>reduction in all-cause mortality28,29.</p><p>Mechanisms/pathophysiology</p><p>Factors influencing menopause</p><p>The functional lifespan of human ovaries is determined</p><p>by a complex and yet largely unidentified set of genetic,</p><p>hormonal and environmental factors (FIG. 3). Women</p><p>undergo menopause when follicles in their ovaries are</p><p>exhausted. However, the clinical manifestations of meno-</p><p>pause result from dynamic interactions between neuro-</p><p>endocrine changes and alterations in the reproductive</p><p>endocrine axis that governs the function of the ovaries.</p><p>It is unclear why ovaries start their function at</p><p>puberty and stop it at menopause, and understanding</p><p>this phenomenon would have far-reaching implications</p><p>for reproductive and health issues.</p><p>Nature Reviews | Disease Primers</p><p>Principal criteria</p><p>Supportive criteria</p><p>Descriptive characteristics</p><p>+1a–2–4 +2+1b–1–3b +1c0–3a–5</p><p>Stage</p><p>Variable to</p><p>regular menstrual</p><p>cycle</p><p>Reproductive</p><p>Variable duration</p><p>Menopausal transition Postmenopause</p><p>PerimenopauseMenarche</p><p>FMP (0)</p><p>Regular menstrual cycle</p><p>Regular menstrual cycle</p><p>• Low FSH</p><p>• Low AMH</p><p>• Low antral follicle count</p><p>Subtle changes</p><p>in flow/length</p><p>of menstrual</p><p>cycle</p><p>• Variable FSH</p><p>• Low AMH</p><p>• Low inhibin B</p><p>• Low antral</p><p>follicle count</p><p>Menstrual cycle of</p><p>variable length,</p><p>persistent ≥7-day</p><p>difference in length</p><p>of consecutive</p><p>cycles</p><p>• Variable but</p><p>elevated FSH*</p><p>• Low AMH</p><p>• Low inhibin B</p><p>• Low antral follicle</p><p>count</p><p>Interval of amenorrhoea</p><p>≥60 days</p><p>• Elevated >25 IU/l FSH**</p><p>• Low AMH</p><p>• Low inhibin B</p><p>• Low antral follicle count</p><p>Vasomotor</p><p>symptoms most</p><p>likely</p><p>• Variable but</p><p>elevated FSH</p><p>• Low AMH</p><p>• Low inhibin B</p><p>• Very low antral</p><p>follicle count</p><p>Increasing</p><p>symptoms of</p><p>urogenital atrophy</p><p>• FSH stabilizes</p><p>• Very low AMH</p><p>• Very low inhibin B</p><p>• Very low antral</p><p>follicle count</p><p>Vasomotor symptoms likely</p><p>Early Peak Late Early Late Early Late</p><p>Variable</p><p>duration 1–3 years 3–4 years2 years (1+1)</p><p>Remaining</p><p>lifespan</p><p>Figure 2 | The stages of reproductive ageing in women. The Stages of Reproductive Aging Workshop (STRAW) defined</p><p>seven stages ranging from the onset of menstrual cycles at menarche and the reproductive age to the perimenopausal</p><p>and postmenopausal phases. Principal (menstrual cycle), supportive (biochemical and imaging) and descriptive criteria</p><p>(symptoms) are used to characterize the phases. AMH, anti-Müllerian hormone; FMP, final menstrual period; FSH, follicle-</p><p>stimulating hormone. *Blood drawn on cycle days 2–5. **Approximate expected level based on assays using current</p><p>international pituitary standard. Figure reproduced from Climacteric (REF. 4) with permission from Informa Healthcare</p><p>(www.informahealthcare.com). Figure reprinted by permission from the American Society for Reproductive Medicine</p><p>(Fertility and Sterility, 2012, 97, 843–851). Figure republished with permission of Endocrine Press, from the Journal of</p><p>Clinical Endocrinology and Metabolism, Harlow, S. D. et al., 97, 1159–1168, 2012; permission conveyed through Copyright</p><p>Clearance Center, Inc. Figure reproduced from Harlow, S. D. et al. Executive summary of the Stages of Reproductive Aging</p><p>Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause 19 (4), 387–395 (2012).</p><p>Table 1 | Geographical variation in age at menopause*</p><p>Region or</p><p>country</p><p>n Number</p><p>of studies</p><p>Mean age at</p><p>menopause</p><p>(95% CI)</p><p>Heterogeneity</p><p>(I‑squared; %)</p><p>Africa 1,175 3 48.4 (48.1–48.6) 0.0</p><p>Asia 39,158 8 48.8 (48.1–49.4) 98.9</p><p>Australia 9,268 2 51.3 (49.8–52.8) 99.1</p><p>Europe 18,692 6 50.5 (50.0–51.1) 96.6</p><p>Latin America 18,073 3 47.2 (45.9–48.6) 99.1</p><p>Middle East 7,733 8 47.4 (46.9–47.8) 97.2</p><p>United States 15,690 6 49.1 (48.8–49.4) 94.6</p><p>Total 109,789 36 48.8 (48.3–49.2) 99.6</p><p>*Data from REF. 8.</p><p>P R I M E R</p><p>NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 3</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>www.informahealthcare.com</p><p>Genetic factors. The timing of menopause reflects</p><p>a complex interplay of genetic, epigenetic, socio-</p><p>economic and lifestyle factors. Estimates of the herit-</p><p>ability in meno pausal age range from 30% to 85%30,31.</p><p>Approximately 50% of the interindividual variability</p><p>in age at</p><p>menopause is related to genetic effects32.</p><p>Women whose mothers or other first-degree relatives</p><p>were known to have early menopause have been found</p><p>to be 6–12-fold more likely to undergo early meno-</p><p>pause themselves33,34. Furthermore, cross-sectional</p><p>and cohort studies have shown that a woman’s age at</p><p>menopause is strongly associated with her mother’s age</p><p>at menopause30–36. However, genetic studies have so far</p><p>failed to clearly identify the genetic traits that underlie</p><p>this heritability37.</p><p>Linkage analysis studies pinpoint areas on chromo-</p><p>some X (region Xp21.3) that are associated with early</p><p>(</p><p>increase in FSH levels</p><p>are characteristic of early menopausal transition. This</p><p>accounts for the shorter cycle intervals that are expe-</p><p>rienced by many women in this period of life. Cohort</p><p>studies have demonstrated that shortened follicular</p><p>phases are associated with accelerated ovulation, which</p><p>occurs at a smaller follicle size57. The prevailing expla-</p><p>nation for this phenomenon is the loss of inhibin B</p><p>production, which leads to increased FSH release and,</p><p>therefore, to an ‘overshoot’ of oestrogen production.</p><p>This would facilitate (and accelerate) the achievement</p><p>of the LH surge57.</p><p>With time, the age-related hypothalamic modifica-</p><p>tions determine a decrease in oestrogen sensitivity and the</p><p>LH surge becomes more erratic. Follicles also become less</p><p>sensitive to gonadotropins, which leads to luteal-phase</p><p>defects and anovulatory cycles, and accordingly, to the</p><p>first menstrual irregularities. Hypothalamic insensitivity</p><p>to oestrogens also explains why menopausal symptoms —</p><p>such as hot flushes and night sweats — commonly occur</p><p>at this stage, when women have rather high levels of oes-</p><p>trogens, as well as why exogenous oestrogens are effective</p><p>in reducing the symptoms.</p><p>In summary, natural menopause is the consequence</p><p>of lost ovarian function. This is the final step in a long</p><p>and irregular cascade of events taking place both in</p><p>the brain and in the ovaries. Genetic factors influence</p><p>the timing of this process, but the key molecular path-</p><p>ways involved are still unknown. Identifying such fac-</p><p>tors would be invaluable to inform the development of</p><p>new strategies to treat reproductive dysfunction and</p><p>menopause- associated diseases.</p><p>Symptoms and consequences</p><p>Menopausal symptoms. Most women entering meno-</p><p>pause experience vasomotor symptoms. A hot flush</p><p>is a sudden episode of vasodilation in the face and</p><p>neck, which lasts 1–5 minutes and is accompanied by</p><p>profuse sweating. Women experiencing hot flushes</p><p>are reported to have a narrower thermoneutral zone,</p><p>such that subtle changes of core temperature elicit</p><p>thermoregulatory mechanisms such as vasodilation,</p><p>sweating or shivering. Declining levels of oestrogens</p><p>and inhibin B, as well as increasing FSH levels, explain</p><p>only part of the disturbed thermoregulation, which is</p><p>associated with changes in brain neurotransmitters</p><p>and peripheral vascular reactivity58.</p><p>Hot flushes usually occur in late perimenopause and</p><p>the first postmenopausal years. Some women, however,</p><p>may continue to experience vasomotor symptoms for</p><p>many years after menopause59. Occasionally, hot flushes</p><p>occur in the late reproductive years16,60, or several years</p><p>after menopause60. The occurrence and intensity of</p><p>menopausal symptoms vary widely between women</p><p>and depend on genetic, environmental, racial, lifestyle</p><p>and anthropometric factors. Black race, smoking and</p><p>overweight — in particular central obesity — increase</p><p>the prevalence and severity of vasomotor symptoms61,62.</p><p>Sleep disturbances are also very common during the</p><p>menopausal transition and they are mainly attributed</p><p>to frequent arousals due to night sweats and occurring</p><p>secondarily to psychological factors63,64. Mood disorders</p><p>such as depression and anxiety are not caused by meno-</p><p>pause; vulnerable women, however, may have their first</p><p>episode or a relapse during the transition65. Muscle and</p><p>joint pain is also part of the menopausal symptomatol-</p><p>ogy66 and it is highly correlated with hot flushes and</p><p>depressed mood67.</p><p>Urogenital atrophy. The anatomy and function of the</p><p>female lower genital tract is oestrogen-dependent. Upon</p><p>menopausal oestrogen decline, tissues lining the vagina,</p><p>vulva, bladder and urethra undergo atrophy, which</p><p>P R I M E R</p><p>NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 5</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>causes a cluster of symptoms including vaginal dry-</p><p>ness, painful intercourse (dyspareunia), vulvar pruritus,</p><p>burning and discomfort, as well as recurrent urogenital</p><p>infections68. Vulvovaginal atrophy and urinary tract atro-</p><p>phy, due to oestrogen deficiency, are collectively called</p><p>the genitourinary syndrome of menopause69. Unlike</p><p>hot flushes and night sweats, which improve over time,</p><p>symptoms of urogenital atrophy persist throughout</p><p>postmenopausal life and may have a serious impact on</p><p>sexual health and QoL70. Pain during intercourse, sec-</p><p>ondary to vulvovaginal atrophy, leads to diminished</p><p>sexual desire, arousal difficulties, relationship problems,</p><p>and diminished physical and emotional sexual satisfac-</p><p>tion71. Although the majority of women have signs of</p><p>uro genital atrophy upon physical examination, less than</p><p>half of the postmenopausal population report bother-</p><p>some complaints68. Age, sexual activity, ethnicity and</p><p>attitudes towards menopause influence the occurrence</p><p>and the severity of urogenital symptoms70.</p><p>Osteoporosis. Bone is a dynamic tissue that undergoes</p><p>continuous remodelling throughout life. This process</p><p>begins with bone resorption, which is carried out by</p><p>multinucleated giant cells called osteoclasts. The lacuna</p><p>created by osteoclasts is subsequently filled with oste-</p><p>oid — new non-mineralized bone synthesized by osteo-</p><p>blasts — which is later mineralized to form mature bone</p><p>tissue. Oestrogens regulate the coupling of the bone</p><p>resorption and formation processes. Postmenopausal</p><p>oestrogen decline leads to the uncoupling of bone</p><p>remodelling, which results in excessive resorption.</p><p>More specifically, oestrogen deficiency results in exces-</p><p>sive production of the cytokine RANKL (receptor</p><p>activator of nuclear factor-κB ligand; also known as</p><p>TNFSF11) by osteoblasts, which — upon binding to</p><p>its receptor RANK (also known as TNFRSF11A) on</p><p>the surface of pre-osteoclasts and mature osteoclasts</p><p>— promotes osteoclasto genesis and bone resorption72.</p><p>Osteoprotegerin (OPG; also known as TNFRSF11B)</p><p>is a cytokine secreted by osteoblasts following oestro-</p><p>gen stimulation and is a natural inhibitor of RANKL72.</p><p>Oestrogen deficiency is associated with decreased OPG</p><p>production, further augmenting RANKL activity73,74.</p><p>The age-associated decline in intestinal calcium absorp-</p><p>tion, vitamin D deficiency and impaired synthesis of</p><p>active 1,25-dihydroxyvitamin D3 by the kidney lead to</p><p>secondary hyperparathyroidism, which further con-</p><p>tributes to accelerated bone resorption75. Finally, loss</p><p>of skeletal mechanical stimulation due to reduced daily</p><p>activity and loss of skeletal muscle mass may interact</p><p>with decreased bone formation due to the absence of</p><p>oestrogen-mediated downregulation of sclerostin pro-</p><p>duction by osteocytes76. Both processes — increased</p><p>bone resorption and decreased bone formation — lead</p><p>to diminished bone strength and to fractures upon min-</p><p>imal skeletal load. The earlier the age at menopause, the</p><p>higher is the risk of osteoporosis later in life77 (FIG. 4).</p><p>Metabolic consequences. The prevalence of obesity is</p><p>higher in postmenopausal women than in premenopau-</p><p>sal women78. This is a consequence of a multifactorial</p><p>process that involves reduced energy expenditure due</p><p>to physical inactivity, which is sometimes compounded</p><p>by depression, as well as due to muscle atrophy and</p><p>a lower basal metabolic rate78. Whereas menopause</p><p>per se is not associated with weight gain, it leads to an</p><p>increase of total body fat and a redistribution of body</p><p>fat from the periphery to the trunk, which results in</p><p>visceral adiposity78,79. Abdominal obesity and meno-</p><p>pausal oestrogen decline are associated with adverse</p><p>metabolic changes such as insulin resistance, a pro-</p><p>pensity to develop type 2 diabetes mellitus and dys-</p><p>lipidaemia characterized by high triglyceride levels,</p><p>low high-density lipoprotein (HDL) cholesterol levels</p><p>and an increased frequency of small, dense low- density</p><p>lipoprotein (LDL) particles79,80. Altered adipokine</p><p>secretion, which leads to chronic inflammation, is a</p><p>possible mechanism that links abdominal obesity to</p><p>its metabolic consequences79,81,82 (FIG. 5).</p><p>Cardiovascular disease. Beyond the</p><p>beneficial effects</p><p>on metabolic and immune parameters, oestrogens are</p><p>potent vasoactive hormones that promote vascular</p><p>remodelling and elasticity, and regulate reactive dila-</p><p>tion and local inflammatory activity83. Oestrogen defi-</p><p>ciency after menopause leads to the activation of the</p><p>renin–angiotensin system, the upregulation of the potent</p><p>vasoconstrictor endothelin and the impairment of nitric</p><p>Increased bone resorption</p><p>Nature Reviews | Disease Primers</p><p>Low bone mass and</p><p>loss of bone architecture</p><p>Low-trauma fracture</p><p>Loss of mechanical stimulation of osteocytes</p><p>Osteoblasts</p><p>Menopausal oestrogen decline</p><p>• Vitamin D deficiency</p><p>• Decline in intestinal</p><p>calcium absorption</p><p>• Impaired renal synthesis</p><p>of 1,25(OH)2 vitamin D3</p><p>• Reduced</p><p>physical activity</p><p>• Sarcopenia</p><p>Ageing</p><p>Secondary</p><p>hyperparathyroidism</p><p>Decreased bone formation</p><p>• Increased RANKL</p><p>• Decreased OPG</p><p>Pre-osteoclasts</p><p>Osteoclasts</p><p>Figure 4 | Pathogenesis of postmenopausal osteoporosis. Reduced oestrogen</p><p>production results in increased receptor activator of nuclear factor-κB ligand (RANKL)</p><p>levels, which leads to osteoclast activation and increased bone resorption. Furthermore,</p><p>production of osteoprotegerin (OPG), an osteoclast inhibitor, by osteoblasts is</p><p>decreased. These changes may be compounded by general age-related changes in bone</p><p>metabolism and remodelling, including disturbed vitamin D and calcium homeostasis,</p><p>secondary hyperparathyroidism and less mechanical stimulation of bone turnover.</p><p>P R I M E R</p><p>6 | 2015 | VOLUME 1 www.nature.com/nrdp</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>oxide-mediated vasodilation. Oxidative stress, which is</p><p>augmented by endothelin and angiotensin II, may fur-</p><p>ther contribute to atherosclerotic processes84. Thus, soon</p><p>after menopause, women exhibit increases in blood pres-</p><p>sure, as well as subclinical vascular disease, which can be</p><p>observed as increased carotid and femoral artery intima-</p><p>media thickness, coronary artery calcium score and arte-</p><p>rial stiffness, and impaired flow-mediated dilation85–88.</p><p>Clinical consequences of cardiovascular disease usually</p><p>occur later in women than in men and ischaemic heart</p><p>disease usually manifests 10 years later in women than in</p><p>men89. The risk of stroke doubles during the first decade</p><p>after menopause and ultimately exceeds that of men in</p><p>older age90. These vascular events tend, however, to have</p><p>a more severe prognosis in women89. Early menopause</p><p>and primary ovarian insufficiency have consistently</p><p>been associated with increased risk of coronary heart</p><p>disease, stroke and mortality91–93 (FIG. 5).</p><p>Cognition. Oestrogens act in areas of the central nerv-</p><p>ous system that control learning, registering and retriev-</p><p>ing information, judgement, evaluation processes and</p><p>language skills. These areas mainly involve the prefron-</p><p>tal cortex, hippocampus and striatum. Oestrogens act</p><p>through both genomic and non-genomic mechanisms.</p><p>They increase cellular proteins, thus promoting neuronal</p><p>growth and survival, neural transmission and function,</p><p>and also synaptogenesis94. Furthermore, oestrogens</p><p>limit the inflammatory response in the central nervous</p><p>system, which helps to avoid repeated inflammatory</p><p>insults that might result in dystrophy and a propensity</p><p>to dementia95. Most studies indicate that menopause</p><p>affects cognitive function and, more specifically, aspects</p><p>related to verbal memory and verbal fluency. The effect</p><p>size seems to be small; however, cognitive changes are</p><p>often bothersome for the affected women96. Although</p><p>menopause seems to be associated with changes in cog-</p><p>nition, it cannot be assumed that oestrogen therapy will</p><p>prevent cognitive decline. There is a general consensus</p><p>that oral oestrogen therapy should not be prescribed to</p><p>prevent or treat cognitive decline97,98.</p><p>Diagnosis, screening and prevention</p><p>Risk factors for earlier menopause</p><p>Postnatal nutrition might influence the age at meno-</p><p>pause. Women in the 1946 British birth cohort who had</p><p>been breastfed experienced later menopause than those</p><p>who had not36,99, and women who had a low weight at</p><p>2 years of age had earlier menopause99. Similarly, Dutch</p><p>children who experienced severe caloric restriction as</p><p>a result of the 1944–1945 famine had an earlier meno-</p><p>pause than those who were not exposed to the famine100.</p><p>There is mixed evidence for relationships between age at</p><p>menarche and age at menopause101.</p><p>Emotional stress at a young age may affect repro-</p><p>ductive ageing and there is evidence that women who</p><p>experience parental divorce early in life tend to have</p><p>earlier menopause99,102. Some studies have also found</p><p>that women with lower adult socioeconomic position,</p><p>which may indicate greater exposure to stress, tend to</p><p>experience menopause earlier than women of higher</p><p>position, even after adjustment for smoking and par-</p><p>ity103–107. A Latin-American study found that women</p><p>living at altitudes above 2000 m were also more likely to</p><p>experience early menopause107.</p><p>Of the various lifestyle and environmental factors in</p><p>adulthood that have been investigated with respect to</p><p>the timing of menopause, only cigarette smoking108–110</p><p>and nulliparity34,111,112 are consistently associated with an</p><p>earlier menopause. It is controversial whether cessation</p><p>of smoking prior to menopause eliminates this effect,</p><p>with some studies implicating only current smoking</p><p>as a risk factor for earlier menopause113,114, and others</p><p>implicating both past and current smoking115. The lat-</p><p>ter association implies that smoking has an overall toxic</p><p>effect on the follicle pool, presumably mediated by the</p><p>polycyclic aromatic hydrocarbons in cigarette smoke116.</p><p>Current, but not past, smoking has also been associated</p><p>with reduced levels of AMH, which is a marker for the</p><p>ovarian reserve117. Adverse life events, HIV infection and</p><p>street-drug use have also been related to earlier meno-</p><p>pause113,118–120, but alcohol and coffee consumption gen-</p><p>erally show no association115. Birth control pill use has</p><p>been shown to be associated with a slightly later age at</p><p>menopause in some but not all studies113,121.</p><p>A recent systematic review found a modest asso-</p><p>ciation between moderate to high physical activity</p><p>and earlier menopause in an unadjusted but not an</p><p>adjusted meta-analysis, whereas overweight had a</p><p>modest association with later menopause8. Overweight</p><p>and obesity have been linked with a later menopause</p><p>in several studies122,123. Premenopausal weight gain and</p><p>premenopausal episodic weight loss of greater than 5 kg</p><p>are each independently associated with a later meno-</p><p>pause124. Higher body mass index (BMI) has been asso-</p><p>ciated with a greater likelihood of transitioning from</p><p>Nature Reviews | Disease Primers</p><p>Indirect effects on</p><p>cardiovascular risk factors</p><p>• Visceral adiposity</p><p>• Dyslipidaemia:</p><p>increased LDL-c and</p><p>decreased HDL-c</p><p>• Increased triglycerides</p><p>• Insulin resistance</p><p>• Increased blood pressure</p><p>• Chronic inflammation</p><p>Direct effects on the vasculature</p><p>• Activation of the renin–</p><p>angiotensin system</p><p>• Increased angiotensin II</p><p>• Increased endothelin 1</p><p>• Decreased NO synthase</p><p>• Oxidative stress</p><p>• Vascular cell proliferation</p><p>• Vascular wall inflammation</p><p>• Arterial stiffness</p><p>• Endothelial dysfunctionObesity</p><p>Menopausal oestrogen decline</p><p>• Physical</p><p>inactivity</p><p>• Mood</p><p>instability</p><p>• Sarcopenia</p><p>Menopause</p><p>and ageing</p><p>Atherosclerosis</p><p>Ischaemic heart disease</p><p>and stroke</p><p>Figure 5 | Consequences of menopause on the cardiovascular system. The loss of</p><p>oestrogen at menopause is associated with increased visceral fat, a more adverse lipid</p><p>profile and activation of the renin–angiotensin pathway, which leads to impaired</p><p>endothelial function. These changes, together with ageing-related changes, lead to an</p><p>increased risk of hypertension, obesity, type 2 diabetes mellitus, atherosclerosis,</p><p>ischaemic heart disease and stroke. HDL-c, high-density lipoprotein cholesterol; LDL-c,</p><p>low-density lipoprotein cholesterol; NO, nitric oxide.</p><p>P R I M E R</p><p>NATURE REVIEWS | DISEASE PRIMERS</p><p>VOLUME 1 | 2015 | 7</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>premenopause to perimenopause but not from peri-</p><p>menopause to postmenopause123. Non-obese women</p><p>tend to have a more rapid decline in oestradiol as they</p><p>transit the menopause125.</p><p>Clinical diagnosis</p><p>The common symptoms of menopause, with their</p><p>approximate onsets and durations126–133, are shown in</p><p>TABLE 2. As women progress to the late menopausal</p><p>transition (STRAW Stage –2 to –1)2–5, their menstrual</p><p>cycle length increases to >60 days, anovulation becomes</p><p>more likely and periods of time with little or no oes-</p><p>trogen secretion occur. At this time, all of the com-</p><p>monly observed menopausal symptoms worsen acutely.</p><p>Many symptoms peak in their intensity at this time, and</p><p>women may require treatment.</p><p>A woman is considered postmenopausal when she</p><p>is over the age of 45 and has gone at least 12 months</p><p>without a spontaneous menstrual period. No specific</p><p>diagnostic testing is required unless the clinical presen-</p><p>tation is atypical. Atypical presentations would include</p><p>substantial mood changes, new-onset anxiety or fatigue,</p><p>and arthralgia without flushes or sweats. Earlier ages of</p><p>onset of prolonged amenorrhoea require consideration</p><p>of other diagnoses such as polycystic ovary syndrome,</p><p>secondary hypogonadotropic hypogonadism, hyper-</p><p>prolactinaemia, pituitary tumours or uterine problems</p><p>such as Asherman syndrome. A menopausal woman</p><p>who has undergone at least 12 months of amenorrhoea</p><p>is unlikely to ever have another menstrual period, but it</p><p>can occur in about 10% of women134.</p><p>Biochemical assessment</p><p>Although specific diagnostic testing for menopause</p><p>is not recommended, clinical situations may arise in</p><p>which it is beneficial to document primary gonadal</p><p>failure. Usually, an increased FSH level will suffice to</p><p>confirm this. Changes in FSH, oestradiol and inhi-</p><p>bin B have been well documented in population-based</p><p>samples of women undergoing observational research.</p><p>Measurement of oestradiol during the perimenopause</p><p>is not clinically useful. Inhibin B is the first hormone</p><p>to decline, and its drop precedes a rise in FSH135. The</p><p>compensatory rise in FSH causes follicles to continue</p><p>to grow and leads to a shortening of the follicular phase</p><p>of the menstrual cycle. Eventually, the follicle pool</p><p>becomes depleted and folliculogenesis no longer occurs</p><p>reliably. This juncture is when the late meno pausal</p><p>transition begins. Follicle failure is intermittent in the</p><p>late transition and is eventually superseded by perma-</p><p>nent amenorrhoea. After menopause has happened,</p><p>oestradiol levels are expected to be consistently low</p><p>(50 years of age, has stopped menstru-</p><p>ating and has classic oestrogen deficiency symptoms, a</p><p>diagnosis other than menopause is very unlikely. Other</p><p>causes of amenorrhoea should be considered in younger</p><p>women and in women aged >50 years who have atypical</p><p>symptoms. These causes include thyroid disease, pro-</p><p>lactinoma, severe depression or stress, and substantial</p><p>weight loss. Each of these may be associated with vaso-</p><p>motor symptoms and mood changes. Pregnancy should</p><p>always be considered in the setting of amenorrhoea.</p><p>Other causes of vasomotor symptoms should</p><p>be excluded if the presentation is atypical (TABLE 3).</p><p>Hormonal hot flushes do cause a significant rise in core</p><p>temperature. If a woman records an increase in her oral</p><p>temperature with flushing or night sweats, infective</p><p>causes must be investigated. Thyrotoxicosis can mimic</p><p>menopause, with women presenting with agitation and</p><p>anxiety, sleep disturbance, overheating, sweating and</p><p>palpitations. These symptoms may precede the classic</p><p>thyrotoxic symptoms of weight loss and tremor. A care-</p><p>ful medical and medication history should identify other</p><p>possible causes. Serotonin-producing carcinoid tumours</p><p>can present with nocturnal diarrhoea and episodic flush-</p><p>ing without sweating. Phaeochromocytomas release the</p><p>catecholamines adrenaline and noradrenaline, and are</p><p>characterized by persistent hypertension, flushing and</p><p>profuse sweating149.</p><p>Some women may present with oligomenorrhoea</p><p>and mood changes or depression. Perimenopausal</p><p>depression needs to be differentiated from major</p><p>depression and simple dysphoria. The diagnosis of</p><p>major depression requires at least 2 weeks of depressed</p><p>mood, or loss of interest or pleasure in nearly all activi-</p><p>ties for most of the day, nearly every day, accompanied</p><p>by at least four of the following symptoms: change in</p><p>appetite or sleep, fatigue, psychomotor agitation or</p><p>retardation, feelings of worthlessness and/or guilt,</p><p>diminished concentration or indecisiveness, and sui-</p><p>cidal ideation150. By contrast, perimenopausal depres-</p><p>sion is usually accompanied by irritability, hostility or</p><p>agitation, and anxiety151. Clinically, it resembles the</p><p>mood changes of premenstrual syndrome, with negative</p><p>Table 3 | Differential diagnoses of menopausal symptoms</p><p>Type Conditions Investigation or laboratory finding</p><p>Other causes of low</p><p>oestrogen</p><p>• Cyclical perimenstrual flushes</p><p>• Post-partum changes</p><p>• Aromatase inhibitors</p><p>• Selective oestrogen receptor modulators</p><p>• GnRH agonists and antagonists</p><p>Complete medical history</p><p>Chronic infections Various Body temperature measurement during flush</p><p>Dietary • Alcohol</p><p>• Spicy food</p><p>• Food additives (for example, monosodium</p><p>glutamate and sulphites)</p><p>Careful medical history</p><p>Hormonal • Thyrotoxicosis</p><p>• Exogenous thyroid hormone excess</p><p>Thyroid function tests</p><p>Medications • Some selective serotonin reuptake inhibitors</p><p>• Nicotinic acid</p><p>• Opiates</p><p>• Calcium channel blockers</p><p>Drug history</p><p>Hormone-producing</p><p>tumours</p><p>Carcinoid tumours leading to carcinoid</p><p>syndrome</p><p>Increased plasma chromogranin A and</p><p>increased urine 5-hydroxyindoleacetic acid</p><p>Phaeochromocytoma Increased plasma metanephrines</p><p>Other • Lymphoma</p><p>• Medullary carcinoma of the thyroid</p><p>• Pancreatic islet-cell tumours</p><p>• Renal cell carcinoma</p><p>• Mastocytosis and mast cell disorders</p><p>Medical history, examination and tests as</p><p>appropriate</p><p>GnRH, gonadotropin-releasing hormone.</p><p>P R I M E R</p><p>NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 9</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>mood, negative self-concept and less effective coping</p><p>abilities152. The lability of peri menopausal depression is</p><p>a distinguishing feature, in contrast to the pervasive low</p><p>mood that is seen in major depression153.</p><p>Factors hindering diagnosis</p><p>Although one of the defining features of menopause is</p><p>the cessation of the menstrual period, it more broadly</p><p>encompasses the permanent cessation of ovarian repro-</p><p>ductive function. Thus, the traditional definition is not</p><p>useful in the setting of iatrogenic causes of amenorrhoea,</p><p>such as hysterectomy, endometrial ablation or progestin</p><p>intrauterine devices. Biochemical investigations may</p><p>be warranted for women with iatrogenic amenorrhoea</p><p>(notably, measurement of FSH and oestradiol) and for</p><p>younger women (measurement of AMH). The latter is</p><p>less useful in women >50 years of age, as most women</p><p>will have low AMH levels by this time. Some women may</p><p>report vasomotor symptoms when using combined oral</p><p>contraception. In this instance, menopause can only be</p><p>effectively diagnosed if the oral contraception is stopped</p><p>for several weeks, after which menopausal status can be</p><p>assessed both clinically and biochemically.</p><p>Screening for menopause</p><p>Population screening is not indicated for the diagnosis</p><p>of menopause. Nonetheless, women are increasingly</p><p>delaying childbearing until their late reproductive years</p><p>and many wish to know when their menopause is likely</p><p>to occur. Taken together with age, serum AMH levels</p><p>provide a good indication. Tehrani et al.154 have reported</p><p>that a combination of age and serum AMH levels can be</p><p>used to predict menopause using a mathematical equa-</p><p>tion. In their analyses, age alone had an 84% adequacy</p><p>in predicting age at menopause, and this rose to 92%</p><p>when AMH levels were added to their model. The use of</p><p>AMH to predict menopause still has several limitations.</p><p>For example, AMH assays are not yet standardized155</p><p>and are not sufficiently sensitive to predict menopause</p><p>with great accuracy. The decline in AMH can be accel-</p><p>erated by factors such as cigarette smoking141, and some</p><p>clinical situations — such as hypogonadotropism156 and</p><p>obesity21 — are associated with lower than normal AMH</p><p>levels that do not reflect a true functional ovarian reserve</p><p>deficit. Thus, the precision of using AMH to estimate</p><p>time to the onset of menopause in individuals is yet to</p><p>be established.</p><p>One group of women that may benefit from AMH</p><p>screening for diminished ovarian reserve, and hence</p><p>imminent menopause, is carriers of the fragile X gene</p><p>(see above). The FMR1 mutation affects approximately</p><p>one in 200 women, and approximately 20% of affected</p><p>women will experience premature ovarian failure157.</p><p>At all ages, carriers of the FMR1 mutation have lower</p><p>AMH levels than other women158. Although it has been</p><p>suggested that monitoring of ovarian function is appro-</p><p>priate for women who carry the FMR1 mutation, the</p><p>exact delineation of the onset of ovarian failure remains</p><p>challenging. AMH values for carriers of the FMR1 muta-</p><p>tion have been published158, but the clinical application</p><p>of these is yet to be established.</p><p>Prevention of menopause</p><p>That menopause is inevitable is based on the concept</p><p>that human females have a fixed ovarian oocyte reserve</p><p>at birth and that oocyte numbers decline with age159.</p><p>In the later reproductive years, the quality of oocytes</p><p>diminishes, such that fertilization and live birth rates fall,</p><p>and the risk of birth defects and miscarriage increase.</p><p>One group has identified oogonial stem cells in ovarian</p><p>cortical tissue of young women160. This gives rise to the</p><p>hypothesis that human ovarian germ cells are renewed</p><p>during the reproductive years, and even inspires the pos-</p><p>sibility that such cells could be used to extend a woman’s</p><p>reproductive lifespan, and effectively delay or prevent</p><p>menopause. The finding of oogonial stem cells in human</p><p>ovaries is controversial161 and is yet to be replicated by</p><p>other groups162.</p><p>Management</p><p>Managing menopausal symptoms need not be complex.</p><p>Bothersome vasomotor symptoms, disturbed noctur-</p><p>nal sleep and an overall deterioration in QoL are by far</p><p>the most common reasons for women to seek medical</p><p>attention in midlife. Caregivers and patients can now</p><p>choose from an expanding repertoire of pharmacologi-</p><p>cal options (both hormonal and non-hormonal)163–165, as</p><p>well as some complementary and alternative medications</p><p>to treat menopausal symptoms (TABLE 4). Here, we focus</p><p>on standard therapies, as the evidence regarding com-</p><p>plementary and alternative medications is conflicting166.</p><p>Choosing the right therapy</p><p>Oestrogen deficiency is the principal pathophysiologi-</p><p>cal mechanism that underlies menopausal symptoms</p><p>and various oestrogen formulations are prescribed as</p><p>menopausal hormone therapy, which remains the most</p><p>effective therapeutic option available (TABLE 5). The addi-</p><p>tion of progesterone aims to protect against the con-</p><p>sequences of systemic therapy with oestrogen only in</p><p>women with intact uteri160: namely, endometrial pathol-</p><p>ogies, including hyperplasia and cancer. The risk-benefit</p><p>ratios of all treatment options must be considered, tak-</p><p>ing into account the nature and severity of symptoms,</p><p>and individual treatment-related risks (TABLE 4).</p><p>In the systemic circulation, oestradiol and oes-</p><p>trone are partly bound to sex hormone-binding glob-</p><p>ulin (SHBG), as well as to albumin, as is testosterone.</p><p>Increasing or decreasing SHBG levels will affect the</p><p>amount of unbound oestrogen and testosterone in the</p><p>circulation167. Oral oestrogen therapy increases SHBG</p><p>synthesis in the liver through the first-pass effect; by</p><p>contrast, standard-dose transdermal oestrogen does</p><p>not increase SHBG synthesis168. In some</p><p>women, oral</p><p>oestrogen therapy results in very high SHBG levels, with</p><p>a reduction in unbound hormone. This potentially leads</p><p>to loss of efficacy of the administered oestrogen and/or</p><p>iatrogenic testosterone deficiency.</p><p>Upregulation of the hepatic synthesis of pro-</p><p>coagulants is another known effect of oral oestrogens.</p><p>Transdermal oestradiol does not seem to increase the</p><p>risk of venous thromboembolic events169,170. Thus,</p><p>transdermal oestrogen therapy is the preferred mode of</p><p>P R I M E R</p><p>10 | 2015 | VOLUME 1 www.nature.com/nrdp</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>Table 4 | Therapeutic options for management of menopausal symptoms</p><p>Therapy Formulations Comments</p><p>Systemic hormone therapy</p><p>Oestrogen • Oral, transdermal (patch, gel or spray), vaginal</p><p>(ring) or implant</p><p>• Administered as oestradiol or synthetic</p><p>oestrogens</p><p>Approved for management of menopausal symptoms</p><p>Progestogen • Oral, vaginal or intrauterine</p><p>• Administered as progesterone or progestin</p><p>(synthetic)</p><p>Approved for management of menopausal symptoms</p><p>Oestrogen and progestogen • Combination</p><p>• Pill or patch</p><p>Approved for management of menopausal symptoms</p><p>Tissue-selective oestrogen receptor</p><p>complex (conjugated equine</p><p>oestrogen plus BZA (a SERM))</p><p>Oral Recently approved in Europe and the United States for</p><p>management of menopausal symptoms</p><p>Ospemifene (SERM) Oral Approved for the treatment of women experiencing</p><p>moderate to severe dyspareunia (pain during sexual</p><p>intercourse)</p><p>Tibolone Oral • Approved for management of menopausal symptoms</p><p>in some countries</p><p>• Not approved or available in Canada or the United</p><p>States</p><p>Androgen therapy (testosterone) • Oral or vaginal</p><p>• Topical, oral or implant</p><p>• Prescribed for low desire and low arousal</p><p>• Off-label use of this class of drugs in most countries</p><p>Non-hormonal therapies</p><p>Selective serotonin reuptake</p><p>inhibitors</p><p>Oral Low-dose paroxetine is the first and only non-hormonal</p><p>drug to be approved by the FDA in the United States for</p><p>menopausal symptom relief</p><p>Selective noradrenaline reuptake</p><p>inhibitors</p><p>Oral Use for menopausal symptom control represents</p><p>off-label use of this class of drugs</p><p>Anticonvulsants (GABAergics) Oral Use for menopausal symptom control represents</p><p>off-label use of this class of drugs</p><p>α</p><p>2</p><p>-adrenergic receptor agonists Oral and transdermal Off-label use for the management of menopausal</p><p>vasomotor symptoms</p><p>Sedatives and hypnotics Oral Not recommended</p><p>Complementary or alternative therapies for vasomotor symptoms</p><p>Soy or isoflavones Oral Consistent benefit over placebo effects not</p><p>demonstrated</p><p>Black cohosh Oral Consistent benefit over placebo effects not</p><p>demonstrated</p><p>Vitamin E Oral Consistent benefit over placebo effects not</p><p>demonstrated</p><p>Acupuncture NA Consistent benefit over placebo effects not</p><p>demonstrated</p><p>Local vaginal therapy</p><p>Oestrogen Low-dose oestradiol, oestriol and conjugated</p><p>oestrogen creams, rings and pessaries</p><p>Approved for the treatment of vaginal atrophy</p><p>Dehydroepiandrosterone Vaginal ovule Undergoing research trials; not approved</p><p>Testosterone Vaginal cream Undergoing research trials; not approved</p><p>Non-hormonal vaginal moisturizers Vaginal gels and creams Over-the-counter products</p><p>Lubricants Vaginal gels and creams Over-the-counter products</p><p>Other</p><p>Stellate ganglion blockade NA Requires specific expertise</p><p>Cognitive behavioural therapy NA Requires specific expertise</p><p>*BZA, bazedoxifene; GABA, γ-aminobutyric acid; NA, not applicable; SERM, selective oestrogen receptor modulator.</p><p>P R I M E R</p><p>NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 11</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>Table 5 | Prescription therapy options for management of menopausal symptoms</p><p>Treatment</p><p>option</p><p>Benefits Risks Patient-specific considerations</p><p>Hormone therapy</p><p>Systemic</p><p>oestrogen</p><p>alone*</p><p>• Symptom relief</p><p>• Fracture risk</p><p>reduction</p><p>• Osteoporosis</p><p>prevention</p><p>• Improved QoL</p><p>• VTE</p><p>• Stroke</p><p>• CVD</p><p>• Breast cancer</p><p>(not seen in large</p><p>clinical trials)</p><p>• Gallstones</p><p>• Oestrogen-related risk of stroke, VTE and CVD is exaggerated with</p><p>advancing age and increasing time since onset of menopause</p><p>• Comorbidities such as obesity, hypertension and diabetes all increase the</p><p>risk of VTE, CVD and stroke</p><p>• Risk reduction against VTE and gallstones achieved by using a transdermal</p><p>route and reduced dose</p><p>• For women with natural menopause and bothersome vasomotor</p><p>symptoms who are aged 60 years</p><p>• Risk of breast cancer may</p><p>be lower than with other</p><p>therapies</p><p>• Neutral effects on the endometrium; no need for concomitant</p><p>progestogen therapy</p><p>• Not available or approved in North America</p><p>Options in women for whom hormone therapy is contraindicated</p><p>Selective</p><p>serotonin</p><p>reuptake</p><p>inhibitors</p><p>• Relief of vasomotor</p><p>symptoms</p><p>• Anxiolytic effects</p><p>• Relatively well tolerated</p><p>• Some agents may</p><p>impair chemoprotective</p><p>efficacy of tamoxifen if</p><p>used concomitantly</p><p>• Less efficacious than hormone therapy</p><p>• Sexual dysfunction may worsen</p><p>P R I M E R</p><p>12 | 2015 | VOLUME 1 www.nature.com/nrdp</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>treatment in women with an increased thrombosis risk,</p><p>such as obese women and</p><p>smokers. In addition, unlike</p><p>oral oestrogen, transdermal oestradiol does not increase</p><p>the risk of gallbladder disease171.</p><p>In the past 2 years, two new pharmaceutical prepa-</p><p>rations were approved in the United States and Europe</p><p>for the treatment of menopausal symptoms. An oral</p><p>selective oestrogen receptor modulator (SERM),</p><p>ospemifene, has been approved for the treatment of</p><p>moderate to severe pain during intercourse associated</p><p>with vulvo vaginal atrophy172,173, and a tissue-specific</p><p>SERM–oestrogen complex (a combination of oral con-</p><p>jugated equine oestrogen and bazedoxifene (a SERM))</p><p>has been approved for the management of moderate to</p><p>severe vasomotor symptoms in women with an intact</p><p>uterus174. Tissue selectivity is achieved through the con-</p><p>current use of oestrogen and a SERM, which replaces</p><p>a progestogen and selectively blocks the undesirable</p><p>actions of oestrogen. In the case of conjugated equine</p><p>oestrogen–bazedoxifene, the proliferative effects of</p><p>oestrogen are blocked in the uterus and possibly also</p><p>the breast, whereas the bone-sparing actions of oes-</p><p>trogen are preserved. The role of testosterone for the</p><p>treatment of postmenopausal desire or arousal dis-</p><p>orders and the long-term implications of such a therapy</p><p>in postmenopausal women are unclear. This strategy</p><p>may benefit a certain subset of women, such as those</p><p>with surgically induced menopause, who have persis-</p><p>tent sexual symptoms despite optimization of meno-</p><p>pausal hormone therapies175,176. Urogenital symptoms</p><p>are effectively treated with either local (vaginal) or sys-</p><p>temic oestrogen therapy177. Oestrogen therapy restores</p><p>normal vaginal flora, lowers the pH, and thickens</p><p>and revascularizes the vaginal lining. The number of</p><p>superficial epithelial cells is increased and symptoms</p><p>of atrophy are alleviated. Importantly, low-dose vaginal</p><p>oestrogen improves vaginal atrophy without causing</p><p>proliferation of the endometrium177. Given the docu-</p><p>mented efficacy and proven safety, vaginal oestrogen</p><p>is the first-line approach to treat symptoms of vaginal</p><p>atrophy in the majority of women.</p><p>Hormone therapy risk reduction</p><p>In addition to an individualized risk-benefit assessment,</p><p>mitigating the risk of hormone therapy is important.</p><p>Several factors influence the treatment-related risks:</p><p>oestrogen dose163,178 (lower doses reduce the thrombo-</p><p>embolic risks of systemic oestrogen); administration</p><p>route179 (thromboembolic risk is suggested to be lower</p><p>for the use of transdermal oestrogens than oral oes-</p><p>trogens) and theoretically, systemic exposure can be</p><p>diminished by intrauterine treatment with levonorg-</p><p>estrel compared with oral formulations; progestogen</p><p>type179,180 (risk for postmenopausal breast cancer, as</p><p>well as for thrombosis, may be lessened by the use of</p><p>pro gesterone compared with synthetic progestins);</p><p>and treatment schedule (infrequent progesterone dos-</p><p>ing seems to reduce the risk of metabolic perturbations</p><p>and breast cancer compared with continuous combined</p><p>oestrogen–progesterone regimens)6,180–183. Infrequent</p><p>progestogen dosing schedules are increasingly used,</p><p>partly owing to patient preference, as they reduce the</p><p>frequency of therapy-related bleeding episodes and, to</p><p>some extent, as a strategy to minimize breast exposure to</p><p>progestogens. However, data on the endometrial safety</p><p>of long-cycle progestogen regimens are not only sparse,</p><p>but even suggest a higher likelihood for endometrial</p><p>hyperplasia and even cancer184.</p><p>Initiation of hormone therapy is usually contraindi-</p><p>cated in women with a personal history of breast cancer</p><p>or venous thromboembolism, or those with a high risk</p><p>for breast cancer, thrombosis or stroke. Transdermal</p><p>oestrogen therapy may be considered and preferred</p><p>when highly symptomatic women with type 2 diabetes</p><p>mellitus or obesity, or those at high risk of cardiovascu-</p><p>lar disease, do not respond to non-hormonal therapies.</p><p>In general, commencement of hormone therapy is not</p><p>recommended for women who are aged >60 years.</p><p>Recommendations regarding the duration of sys-</p><p>temic hormone therapy need to be individualized and</p><p>depend on the end points of treatment. For women with</p><p>premature ovarian failure or primary ovarian insuffi-</p><p>ciency, or those with early menopause (before the age of</p><p>Table 5 (Cont.) | Prescription therapy options for management of menopausal symptoms</p><p>Treatment</p><p>option</p><p>Benefits Risks Patient-specific considerations</p><p>Selective</p><p>noradrenaline</p><p>reuptake</p><p>inhibitors</p><p>Relief of vasomotor</p><p>symptoms</p><p>• Relatively well tolerated</p><p>• Slight rise in blood</p><p>pressure may be seen;</p><p>caution advised in</p><p>the setting of known</p><p>hypertension</p><p>Less efficacious than hormone therapy</p><p>Clonidine (an</p><p>α2-adrenergic</p><p>receptor</p><p>agonist)</p><p>Relief of vasomotor</p><p>symptoms</p><p>Postural hypotension Less efficacious than hormone therapy</p><p>GABAergics Relief of vasomotor</p><p>symptoms</p><p>• Relatively well tolerated</p><p>• Somnolence</p><p>• Less efficacious than hormone therapy</p><p>• Improved sleep, particularly in the presence of restless leg syndrome</p><p>*Caution advised when considering use in an older postmenopausal woman with existing comorbidities who is remote from onset of menopause. BZA, bazedoxifene;</p><p>CVD, cardiovascular disease; GABA, γ-aminobutyric acid; MPA, medroxyprogesterone acetate; QoL, quality of life; SERM, selective oestrogen receptor modulator;</p><p>TSEC, tissue-selective oestrogen complex; VTE, venous thromboembolism.</p><p>P R I M E R</p><p>NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 13</p><p>© 2015 Macmillan Publishers Limited. All rights reserved</p><p>45 years), therapy can be continued until the average age</p><p>of the natural menopause (early 50s), at which time the</p><p>need for hormone therapy should be reassessed. There</p><p>are no arbitrary limits regarding the duration of meno-</p><p>pausal hormone therapy; it can be used for as long as</p><p>the woman feels the benefits outweigh the risks for her,</p><p>but treatment should be re-evaluated frequently. When</p><p>hormone therapy is initiated for vasomotor symptoms,</p><p>clinicians should strive to control symptoms with the</p><p>lowest possible hormone dose, and continued therapy</p><p>for >5 years must be individualized on the basis of</p><p>symptom severity and the risk for breast cancer and</p><p>vascular events, and also with due regard to the patient’s</p><p>preference and choice.</p><p>Non-hormonal therapies</p><p>A number of non-hormonal therapies are efficacious</p><p>against menopausal vasomotor symptoms (TABLE 4) and</p><p>should be considered for women who do not wish to</p><p>take oestrogen or those with contraindications.</p><p>For vasomotor symptoms, many drugs have dem-</p><p>onstrated efficacy in several studies: paroxetine, fluox-</p><p>etine and citalopram (which are selective serotonin</p><p>reuptake inhibitors); venlafaxine and desvenlafaxine</p><p>(selective noradrenaline reuptake inhibitors); clonidine</p><p>(α2-adrenergic receptor agonist); and anticonvulsants</p><p>(gabapentin and pregabalin)2,3. Paroxetine and fluoxe-</p><p>tine are potent cytochrome P450 2D6 (CYP2D6) inhibi-</p><p>tors, and as they decrease the metabolism of tamoxifen</p><p>(a SERM used in the treatment of breast cancer) — which</p><p>may reduce its anticancer effects — these drugs should</p><p>be avoided in tamoxifen users185. However, consistency of</p><p>treatment response and efficacy of the various alternative</p><p>options remain questionable186–189. Stellate ganglion block</p><p>achieved by injecting an anaesthetic such as bupivacaine</p><p>under fluoroscopic guidance around the stellate ganglion</p><p>— which is the cervicothoracic ganglion of the sympa-</p><p>thetic system — has been shown to improve vasomotor</p><p>symptoms in a small randomized controlled trial190.</p><p>Alternatives to vaginal therapies, such as vaginal</p><p>lubricants and moisturizers, are less effective than vagi-</p><p>nal oestrogen191. Although vaginal moisturizers lower</p><p>the vaginal pH and may normalize vaginal cell compo-</p><p>sition, sustained symptom relief has not been seen in all</p><p>studies191. Vaginal moisturizers do not reduce urinary</p><p>tract symptoms or asymptomatic bacteriuria191. Vaginal</p><p>lubricants offer transient relief from vaginal atrophy-</p><p>related discomfort when used</p>