50 Nick Panay1,2 1 Queen Charlotte’s & Chelsea and Westminster Hospitals, West London Menopause and PMS Centre, London, UK 2 Imperial College London, London, UK Menopause, from the Greek menos (month) and pausis (cessation), is defined as the last menstrual period after a minimum of one year’s amenorrhoea. The average age of the female menopause (51 years) has remained unchanged since ancient Greek and Roman times even though the average lifespan has increased. Thus, an increasing number of women are now spending almost half their lifespan in a hypo‐oestrogenic state. The physiological changes which result in the final menstrual period start many years before the cessation of periods during the perimenopause. This episode of dynamic neuroendocrine change occurs due to a progressive reduction in ovarian reserve and is commonly associated with distressing physical and psychological symptoms in the last decade of a woman’s reproductive lifespan. These endocrine, biomarker and menstrual changes have recently been studied and documented by the Stages of Reproductive Aging Workshop + 10 (STRAW + 10) [1] (Fig. 50.1). Fig. 50.1 The Stages of Reproductive Aging Workshop (STRAW) + 10 staging system for reproductive ageing in women. AMH, anti‐Müllerian hormone; FMP, final menstrual period; FSH, follicle stimulating hormone. Source: adapted from Harlow et al. [1]. Recent publication of the UK National Institute for Health and Care Excellence (NICE) menopause guidelines [2] has provided a much‐needed rigorous analysis of the data on the diagnosis and management of the menopause. It is now vitally important that this information is efficiently disseminated to healthcare professionals, especially in primary care and gynaecology. This chapter uses the analyses of the NICE guidelines and the recently published guidelines from the various menopause societies as core information, which will be conveyed to the reader in a practical manner with signposts to key sources of information. It is generally accepted that oestrogen plays an integral role in the genesis of vasomotor symptoms but the precise aetiology remains unknown. The hypothesis proposed by Robert Freeman still seems the most plausible [3,4]. In the asymptomatic woman there is a thermoneutral zone (about 0.4 °C) within which fluctuations of core body temperature do not trigger compensatory autonomic mechanisms such as flushing or sweating. In the symptomatic woman the thermoneutral zone is considerably reduced, so that even minor fluctuations in core body temperature reach the limits of the zone and initiate a thermoregulatory response. The narrowing of the zone may be due to elevated central noradrenergic activation and probably precipitated by changes in oestrogen. Recent data suggest that vasomotor symptoms such as flushes and sweats may be associated with an increased risk of cardiovascular disease [5,6]. Other typical immediate menopausal symptoms include insomnia, anxiety, irritability, memory loss, tiredness, poor concentration and musculoskeletal aches and pains. Falling oestrogen levels are thought to lead to similar falls in neurotransmitter levels, such as serotonin, which trigger mood symptoms. Women who have suffered from postnatal depression and premenstrual syndrome appear to be particularly predisposed to depression in the perimenopause [7]. The menopause transition is often associated with a significant reduction in sexuality and libido that is multifactorial but at least partly related to falling androgen levels [8]. Oestrogen deficiency leads to the rapid loss of collagen, which contributes to the generalized atrophy that occurs after the menopause. In the genital tract this is manifested by dyspareunia and vaginal bleeding due to vulvovaginal atrophy (VVA). In the lower urinary tract, atrophy of the urethral epithelium occurs with decreased sensitivity of urethral smooth muscle and decreased amount of periurethral collagen. All this results in dysuria, urgency and frequency, commonly termed the urethral syndrome. The position statement from the International Menopause Society emphasizes the importance of enquiring about urogenital symptoms, the history of which might not be readily volunteered by the menopausal patient [9]. Recent studies have shown that the incidence of VVA is higher than originally thought due to under‐reporting and that these symptoms often have a devastating effect on relationships [10]. A new classification system which encompasses VVA and urinary tract problems has recently been proposed in North America called the genitourinary syndrome of menopause (GSM) and could be adopted universally in due course [11]. Osteoporosis is a systemic skeletal disorder of the bone matrix resulting in a reduction of bone strength, to the extent that there is a significantly increased risk of fracture when a woman suffers a fall from her own body height. Bone strength is determined by bone density and microarchitectural integrity. Osteoporosis is predominantly a disease of women, who achieve a lower peak bone mass than men and are then subjected to an accelerated loss of bone density following the menopause due to loss of oestrogen. Women lose 50% of their skeleton by the age of 70 years, but men only lose 25% by the age of 90 years. The loss of height occurs not only due to vertebral fractures but also loss of the intervertebral disc space as a result of deterioration and loss of collagen [12]. Osteoporosis‐related fractures cause considerable morbidity in the elderly, requiring prolonged hospital care and difficulties in remobilization. There is increasing awareness that avoiding sarcopenia (muscle loss and weakness) through regular exercise will maintain strength and posture and reduce the risk of injuries including osteoporosis‐related fractures. Hormone therapy may help muscle as well as bone strength but this requires confirmation [13]. Cardiovascular disease is the principal cause of morbidity and mortality in women. Women are protected against cardiovascular disease before the menopause, after which the incidence rapidly increases, reaching a similar frequency to men by the age of 70 years. The protective effect of oestrogen in premenopausal women is also thought to be mediated by a favourable effect on the ratio of high‐density lipoprotein (HDL) to low‐density lipoprotein (LDL), by nitric oxide‐mediated vasodilatation leading to increased myocardial blood flow, by an antioxidant effect on endothelial cells and by a direct effect on the aorta decreasing atheroma. Cross‐sectional and prospective observational studies have shown that women going through the menopause transition have elevation of cholesterol, triglyceride and LDL levels, a reduction in HDL2 levels and a rise in insulin resistance. As oestrogen levels begin to fall, the somatotrophic axis becomes less active leading to insulin resistance and a rise in central adiposity. This in turn leads to the change in body shape from the female gynaecoid shape to the male android shape, itself an independent risk factor for coronary heart disease (CHD) [14]. A number of factors are involved in perimenopausal weight gain including genetic predisposition, socioeconomic influences, reduction in caloric need and expenditure, reduced lean body mass and a reduction in resting basal metabolic rate. Major primary prevention measures include smoking cessation, weight loss, blood pressure reduction, regular aerobic exercise and diabetes and lipid control. During the menopause transition, poor concentration and other cognitive problems are common [15]. Although these symptoms do not usually persist long term, the incidence of Alzheimer’s dementia is significantly higher in women compared with men. Studies have demonstrated that oestrogen may improve cerebral perfusion and cognition in women below 60 years. Oestrogen appears to have a direct effect on the vasculature of the central nervous system and promotes neuronal growth and neurotransmission. In the long term, exogenous oestrogen may prevent diseases with a vascular aetiology such as vascular dementia and Alzheimer’s, but long‐term randomized data are required to confirm this. The failure of oestrogen to show benefit for dementia in women commencing treatment above 60 years, and possibly an increased risk in some studies, may reflect the predominance of the prothrombotic effect of oestrogen in women of this age group. The prediction of menopause has progressed significantly over the last 5 years. These are not tests that are widely performed but can be useful where premature ovarian insufficiency (POI) is suspected or where there is a family history of POI. Follicle stimulating hormone (FSH) levels can be misleading even when the test is timed to the early follicular phase of the cycle and levels often vary from cycle to cycle depending on ovarian activity. The most accurate predictors of ovarian reserve currently available appear to be measurement of anti‐Müllerian hormone (AMH) production by the primordial and pre‐antral follicles and estimation of antral follicle count by ultrasonographic estimation. AMH is independent of the day of cycle and its predictive value of ovarian reserve is claimed to last for up to 2 years from when the sample is taken. A systematic review [16] was recently carried out to appraise data on prediction of age at natural menopause (ANM) based on AMH, antral follicle count and mother’s ANM to evaluate clinical usefulness and to identify directions for further research. It found that AMH was currently the most promising marker for prediction of ANM. However, prediction models do not predict the extremes of menopause age very well and have wide prediction intervals. Markers need improvement before they can be used for individual prediction of menopause in the clinical setting. The diagnosis of natural menopause can usually be made from the characteristic history of the vasomotor symptoms of hot flushes and night sweats and/or amenorrhoea. Measurement of the concentrations of plasma hormones such as estradiol, FSH and luteinizing hormone (LH) in women over the age of 45 years with classical symptoms is not indicated as it is unlikely to change clinical management [2]. However, in the young woman aged below 45 years (and certainly under 40 years) or after hysterectomy with ovarian conservation, where the diagnosis is more difficult and the metabolic implications may be more serious, measurement of FSH levels may be helpful, in which case repeated concentrations of 40 IU/L or above may be regarded as being in the menopause range. Women diagnosed with spontaneous POI should, in addition to hormonal investigations, also have an autoantibody screen (thyroid and adrenal) and should be offered karyotype and fragile X genetic analysis, particularly if they are below 30 years of age. Online programs such as Manage my Menopause can be helpful for both the woman and the healthcare professional in individualizing overall care and specific management [17]. The NICE menopause guidelines recommend that women should be followed up within 3 months of initiation of treatment and annually thereafter. An oestrogen level is only helpful if there has been inadequate response to treatment due to low levels or if side effects suggest that the dose of estradiol is too high. Annual screening should include assessment of body mass index (BMI), blood pressure and a review of medication. A white paper written by cardiologists and menopause experts has highlighted the important role that gynaecologists can play in cardiovascular screening [18]. Fasting lipid profile and estimation of insulin resistance are recommended in women with risk factors (e.g. increased waist circumference or personal/family history of diabetes/cardiovascular disease). Although advice should be given to women about being aware of changes in their breasts and perineum, routine breast palpation and pelvic examination is unnecessary; these need only be performed if clinically indicated. Mammography should be performed as part of the national screening programme every 3 years unless more frequent examinations are clinically indicated. However, if a woman chooses to use hormone replacement therapy (HRT) beyond the current age of breast screening cessation (70 years), mammographic screening should also continue. In women over 45 years of age it is best to arrange screening before starting oestrogen therapy to identify patients with subclinical disease. Ultrasound examination of the pelvis and/or endometrial biopsy are not a necessary prerequisite to treatment with HRT unless there is undiagnosed bleeding. The gold standard measurement of the risk of osteoporosis is still dual‐energy X‐ray absorptiometry (DEXA) measurement of the lumbar spine and hip; some units are now using CT to perform this assessment. Markers of bone formation and breakdown can be useful in that changes occur more rapidly than with bone density, but their use is largely confined to research. The Royal College of Physicians advises that DEXA scans are performed no more frequently than every 2 years because changes in bone mineral density are so small that they often do not exceed the margin of error of the equipment and assessor. The World Health Organization (WHO) has advised that the decision to treat osteoporosis is made by taking into account bone mineral density, age and BMI. The formula for calculating the probability of fracture (FRAX) is available online [19]. Premature ovarian insufficiency remains poorly understood and under‐researched. It describes a syndrome consisting of early cessation of periods, sex steroid deficiency, and elevated levels of the pituitary hormones FSH and LH in women below the age of 40 years. POI can be primary (spontaneous POI) or secondary (induced by radiation, chemotherapy or surgery). Controversy persists over nomenclature, with terms such as ‘premature menopause’, ‘premature ovarian failure/dysfunction’ and ‘primary ovarian insufficiency’ still in use. POI has been estimated to affect about 1% of women younger than 40 years, 0.1% of those under 30 and 0.01% of those under 20. However, as cure rates for cancers in childhood and young women continue to improve it is likely that the incidence of prematurely menopausal women will rise. Data from Imperial College London suggest that the incidence of POI may be significantly higher than originally estimated. Islam and Cartwright [20] studied 4968 participants from a 1958 birth cohort. They found that 370 (7.4%) had either spontaneous or medically induced POI. Smoking and low socioeconomic status were predictive of POI, and poor quality of life (as determined by the SF36 Quality of Life Questionnaire) was twice as common in POI. The incidence of POI also varies according to the population studied. It appears to be significantly higher, greater than 20%, in some Asian populations (personal communications with Indian Menopause Society and Chinese Gynaecological Endocrinology Society). In the past, the focus of medical care has been on improvement of survival rates. Very little attention has been given to the maintenance of quality of life in the short term and to the avoidance of the long‐term sequelae of POI. One of the main reasons for this has been the bias of economic expenditure and medical endeavour to the prolongation of life (e.g. cancer treatments) rather than towards optimizing quality of life in cancer survivors. Should this trend continue we are in danger of creating a population of young women who have been given back the gift of life but left without the zest to live it to its full potential. Causes of spontaneous POI include idiopathic (no known cause), genetic, autoimmune and infective. The typical presentation of spontaneous POI is erratic or complete cessation of periods in a woman younger than 40 years, which may or may not necessarily be accompanied by symptoms. These symptoms may not be typical vasomotor in nature and include mood disturbances, loss of energy and generalized aches and pains. Our data indicate that the next most disturbing aspect of POI after the loss of fertility is the adverse impact on sexual responsiveness and other psychological problems [21]. Thus women with POI require integrated care to address physical, psychosocial and reproductive health as well as preventative strategies to maintain long‐term health. Until recently, there has been an absence of specific evidence‐based guidelines for diagnosis and management of POI, but this has recently been addressed by the European Society for Human Reproduction and Embryology (ESHRE) [22]. POI is a difficult diagnosis for women to accept, and a carefully planned and sensitive approach is required when informing the patient of the diagnosis. A dedicated multidisciplinary clinic separate from the routine menopause clinic will provide ample time and the appropriate professionals to meet the needs of these emotionally traumatized patients. At the West London Menopause Service we have restructured our services and created dedicated clinics for the POI patients. Counselling should include explanation that remission and spontaneous pregnancy can still occur in women with spontaneous or medical POI. Specific areas of management include the provision of counselling and emotional support, diet and nutrition supplement advice, HRT and reproductive healthcare, including contraception and fertility issues. In the UK, the Daisy Network, a voluntary support network for women with POI, provides excellent support and information for POI sufferers. As a minimum, the initial investigation of patients presenting with erratic periods, for which pregnancy should be excluded, includes measurement of serum FSH, estradiol and thyroid hormones. If FSH is in the menopausal range (>40 IU/L), the test should be repeated 4–6 weeks later for confirmation, as levels can fluctuate. Young women with spontaneous POI have pathologically low oestrogen levels compared with their peers who have normal ovarian function. The NICE [2], British Menopause Society [23], International Menopause Society [24] and ESHRE [21] guidelines state that in women with POI, systemic hormone therapy is recommended at least until the average age of the natural menopause (51 years). Hormone treatment with HRT, or the contraceptive pill if pregnancy is not desired, is required not only to control vasomotor and other menopause symptoms, but also minimize risks of cardiovascular disease, osteoporosis and dementia, as well as to maintain sexual function. Three small prospective randomized trials thus far have compared HRT with the combined contraceptive pill in POI. Limited data suggest that both options are effective but HRT appears to be superior in increasing bone mineral density and in its beneficial effects on cardiovascular risk markers. There is an urgent need for large‐scale long‐term randomized prospective studies to determine the optimum routes and regimens of hormone replacement in POI. Outcome measures should include vasomotor, urogenital, quality of life and psychosexual health and the long‐term effect on cardiovascular, cognitive and skeletal health. In the absence of such long‐term trials, a POI registry, funded by Imperial College London, has been developed to collate good‐quality prospective data from healthcare professionals globally [25–27]. There is an unmet need to determine long‐term response to interventions such as the contraceptive pill and HRT and in those not receiving treatment. This is particularly important in women with rare causes and hormone‐sensitive cancers where randomized trials are unlikely to be ever performed. The registry will be used to create a global genetic biobank for genetic studies, with an ultimate goal of defining the specific pathogenic mechanisms involved in the development of POI. The database has the potential to define and characterize the various presentations of POI along the lines of the STRAW + 10 guidelines for natural menopause [1]. It could also be used to further refine the role of biomarkers such as AMH to precisely predict the course and timing of natural and early ovarian insufficiency. The modern approach to optimizing health in the menopause should start from public education in school and the workplace. Common‐sense lifestyle and dietary approaches instituted well in advance of the menopause will maximize that chances of good health through midlife and beyond. As recommended by the British Menopause Society position statement [28], every woman should be encouraged to take plenty of regular exercise in addition to having a well‐balanced diet, avoiding smoking and minimizing alcohol consumption. Data suggest that women who are more active tend to suffer less from the symptoms of the menopause and have higher bone mineral densities compared with sedentary controls. There is also evidence for reduction in bone loss by ensuring adequate calcium (1000 mg) and vitamin D3 (800–1000 IU) in the diet. However, excessive calcium intake can increase the risk of adverse events such as myocardial infarction [29]. Routine supplementation with calcium is not now recommended unless deficiency has been detected. Ensuring adequate vitamin D3 levels will not only improve calcium absorption but may also have a beneficial effect on general well‐being and musculoskeletal symptoms. A reduction in alcohol and caffeine intake can also reduce the severity and frequency of vasomotor symptoms. There is a general consensus that the minimum effective dose of estradiol should be prescribed and the dose increased if required to alleviate symptoms. However, it is important that the dose is high enough to fully alleviate symptoms. Although there is little evidence that higher doses of exogenous oestrogen are associated with increased risk of breast cancer, there are dose–response effects with venous thromboembolism and stroke. Lower doses of oestrogen are less likely to cause breast tenderness and bleeding problems (due to less endometrial stimulation), which will encourage continuation of therapy. The recommended starting doses of currently available systemic oestrogen are as follows: Data suggest that in many women the benefits of estradiol for symptom relief and bone protection can be achieved with a 0.5‐mg dose when combined with progestogen [30]. Side effects such as bleeding problems are minimized by this dosage and a neutral effect on breast symptoms and mammographic density is possible [31]. Women who suffer POI or early menopause need higher doses of oestrogen to reproduce the physiological hormone levels which would have been present if the ovaries had not failed early. Prior to the menopause the physiological state consists of an estradiol/estrone ratio of 2 : 1. This can only be achieved if estradiol is delivered transdermally, thus avoiding first‐pass hepatic metabolism. Oral estradiol preparations are partially metabolized to estrone by hepatic first‐pass metabolism and therefore do not fully restore this ratio. There are now observational and case–control data showing that the thromboembolic risk is neutralized by avoidance of first‐pass stimulation of coagulation factors, even in women who are obese and thrombophilic [32]. This is particularly important in women who are obese or smokers and are therefore at increased risk of venous thromboembolic disease. There are twice‐weekly or once‐weekly transdermal systems containing both oestrogen and progestogen that can be used either sequentially or as continuous combined HRT. The hormone is adsorbed onto the adhesive matrix and this avoids the skin reactions caused by the old alcohol reservoir patches. Dot matrix patches are the smallest and best‐tolerated patches, with a very low incidence of skin irritation. Estradiol gel is also available either dispensed from a pump or as a low‐volume daily sachet. It is hoped that non‐oral estradiol development will resume to produce commercially available nasal and sublingual tab/wafer products that also avoid first‐pass hepatic metabolism. An expanded product armamentarium facilitates individualized hormone replacement. The most effective treatment for VVA is local application of oestrogen. This can be achieved through the use of creams, tablets and rings delivering estriol and estradiol. There is no significant systemic absorption of oestrogen from these products and therefore do not lead to endometrial hyperplasia or bleeding problems. Long‐term endometrial biopsy data are limited but 1‐year data are consistently reassuring. Endometrial protection with progestogens is not required. The British and International Menopause Societies recommendations [23,24] and recent NICE guidelines [2] highlight the importance of identifying VVA symptoms, which can be very distressing and are easily and safely alleviated with vaginal oestrogen. The regulatory authorities in the UK have granted an ‘indefinite use’ licence to 10‐µg estradiol vaginal tablets. These were developed with the aim of providing the minimum effective dose for relief of urogenital symptoms; a year of use will expose the user to only 1.4 mg of estradiol in total. However, some women require higher doses to fully alleviate their symptoms. The NICE menopause guidelines [2] recognize this and indicate the possibility of higher doses being used judiciously. Options for local vaginal oestrogen are as follows: Ospemifene is an orally active selective oestrogen receptor modulator that has oestrogen‐type activity in the urogenital tract [33]. It is licensed in a few countries, such as the USA and Italy, for treatment of moderate to severe dyspareunia and has recently been made available in the UK. The avoidance of oestrogen may be of advantage in women with a past history of hormone receptor‐positive malignancy whose menopause symptoms are often compounded by the use of tamoxifen or aromatase inhibitors. CO2 laser and erbium laser technology is being used to rejuvenate atrophic vulval and vaginal tissue by facilitating the regeneration of collagen and elastin through improved blood flow [34]. Although the preliminary data are promising, longer‐term randomized placebo‐controlled studies are required to confirm the benefits and duration of effect. Progestogens or progesterone are required in women using systemic oestrogen to minimize the risk of endometrial hyperplasia and carcinoma. If the last menstrual period occurred less than 1 year prior to starting HRT, a sequential combined regimen is recommended (i.e. continuous oestrogen with progestogen for 12 days per cycle). A progestogen challenge should be considered after 3 months of oestrogen alone in women who have had a subtotal hysterectomy to test for residual endometrium. An ultrasound scan could also be performed to check for residual endometrium. Low‐dose continuous progestogen should also be used after endometrial ablation and pelvic radiotherapy and should also be considered in women following hysterectomy for severe endometriosis. The typical dosages of the more commonly used progestogens are shown in Table 50.1. Table 50.1 Minimum doses of progestogen given orally in HRT as endometrial protection. * Not available in the UK at these dosages. If bleeding is heavy or erratic, the dose of progestogen can be doubled or duration increased to 21 days. Persistent bleeding problems beyond 6 months warrant investigation with an ultrasound scan and/or endometrial biopsy. After 1 year of therapy (2 years in POI) women can switch to a continuous combined regimen that aims to give a bleed‐free HRT regimen, which will also minimize the risk of endometrial hyperplasia. Alternatively, women can be switched to the tissue‐selective agent tibolone. Both these regimens may be associated with some erratic bleeding to begin with but 90% of those that persist with these treatments will eventually be completely bleed‐free. If starting HRT de novo, a bleed‐free regimen can be used from the outset if the last menstrual period was over a year ago. One of the main factors for reduced compliance is that of progestogen intolerance. Progestogens have a variety of effects apart from the one for which their use was intended, that of secretory transformation of the endometrium. Symptoms of fluid retention are produced by the sodium‐retaining effect of the renin–aldosterone system which is triggered by stimulation of the aldosterone receptor. Androgenic side effects such as acne and hirsutism are a problem of the testosterone‐derived progestogen due to stimulation of androgen receptors. Mood swings and premenstrual syndrome‐like side effects result from stimulation of the central nervous system progesterone receptors. The dose can be halved and duration of progestogen can be reduced to 7–10 days. However, this may result in bleeding problems and hyperplasia in a few cases (5–10%) so there should be a low threshold for performing ultrasound scans and endometrial sampling in these women. Natural progesterone has fewer side effects due to progesterone receptor specificity and is now available in an oral micronized form, vaginal pessaries and gel (see Table 50.1). HRT regimens containing natural progesterone can minimize the metabolic impact and reduce the risk of thromboembolism [35]. The levonorgestrel intrauterine system, recommended for endometrial protection for up to 5 years, minimizes systemic progestogenic side effects by releasing the progestogen directly into the endometrium with low systemic absorption. Drospirenone, a spironolactone analogue, has been incorporated with low‐dose oestrogen in a continuous combined formulation. It is not only progesterone receptor specific but also has anti‐androgenic and anti‐aldosterone effects, the former making it useful for hirsutism and the latter for fluid retention. It is also mildly antihypertensive [36]. A new product which may be the ideal solution to the progestogen intolerance problem is a combination of conjugated oestrogens with bazedoxifene (BZA), a member of the tissue selective oestrogen complex [37]. In this product, the progestogen has been replaced by BZA, a selective oestrogen receptor modulator, which protects the endometrium against endometrial hyperplasia and carcinoma. Not only is the endometrium protected but there may also be some protection against breast cancer; this requires confirmation from long‐term randomized controlled trials. Bio‐identical hormones are precise duplicates of estradiol, progesterone and testosterone as synthesized by the human ovary. They are manufactured from plant sources in the laboratory and are available as micronized oral tablets, transdermal patches, implants and gels. Regulated bio‐identical products must not be confused with unregulated products from compounding pharmacists. In order to avoid confusion, regulated products should be referred to as body‐identical rather than bio‐identical [38]. The regulatory authorities are attempting to bring the compounding pharmacies under the same regulation as standard hormone therapy products. Compounded bio‐identical hormones are not recommended by the British Menopause Society or by NICE in the recent menopause guideline [2]. The published data thus far suggest that differential effects can be achieved by the use of body‐identical hormones in comparison with synthetic non‐body‐identical HRT. The E3N cohort study, part of the European Prospective Investigation into Cancer and Nutrition (EPIC), showed that oestrogen/progesterone combination HRT was associated with a significantly lower relative risk (neutral for ‘ever use’ of HRT) than for other types of combined HRT (RR 1.7–2.0) [39]. There are also data now indicating that micronized progesterone has a modulating effect on venous thromboembolism (VTE). The risk of VTE appears to be lower with micronized progesterone than it is with more androgenic progestogens when combined with oral oestrogen. The metabolic neutrality of progesterone has been seen as an advantage in avoiding attenuation of the benefits of oestrogen in cardiovascular disease prevention. This is discussed later in the chapter in connection with the new pilot studies which have been performed recently and the need for further major prospective randomized controlled trials will be highlighted. Women with distressing low sexual desire and tiredness should be counselled about the possibility of using androgen supplementation [40]. In the past, 100 mg implanted testosterone pellets were licensed for female testosterone replacement. These are currently only available as unlicensed preparations as the licensed implants were withdrawn for commercial reasons. The 300‐µg testosterone transdermal system was developed to treat hypoactive sexual desire disorder, the American Psychiatric Association’s definition of distressing low sexual desire. A series of randomized controlled trials showed a significant improvement in the number of satisfying sexual episodes in women with surgical menopause and also in women with natural menopause. Benefits were seen in women using concomitant oestrogen and in those using testosterone alone. Similar to the testosterone implants, the licence for the patches was also withdrawn for commercial (profitability) reasons. These developments have restricted the available options for female androgen replacement. Testosterone male gel (Tostran 2% gel) can be used at lower doses off label on an alternate day basis to achieve female physiological levels. Alternatively, 1% testosterone cream (AndroFeme) marketed for female use in Australia, can be accessed internationally, but is only available for private use at time of writing. In my clinical experience, if the free androgen index [(testosterone × 100)/sex hormone‐binding globulin] is kept within the physiological range (<5.0%), there are rarely any side effects such as hirsutism and acne. Scalp hair loss and virilizing effects are rare, and this has been shown in recent meta‐analyses of the data [41,42]. Cardiovascular and breast safety data have been reassuring thus far, although the regulators would like to see further long‐term studies before licensing further female androgen products. A 5‐year study on cardiovascular and breast safety has been completed in the USA but analysis of the data (more than 7000 women‐years of use) has not yet been carried out due to lack of funding. Dehydroepiandrosterone (DHEA) is a weak androgenic steroid produced by the adrenal gland that has androgenic properties. It is mostly produced in a sulfated form (DHEA‐S), which may be converted to DHEA in many tissues. Blood levels of DHEA drop dramatically with age. This had led to suggestions that the effects of ageing can be counteracted by DHEA ‘replacement therapy’. DHEA is being increasingly used in the USA, where it is classed as a food supplement, for its supposed anti‐ageing effects. Some studies have shown benefits on the skeleton, cognition, well‐being, libido and the vagina but these data require confirmation [43]. Concerns about the risks of HRT were raised by the Women’s Health Initiative (WHI) study [44] and the Million Women Study (MWS) [45]. The WHI study claimed that there was an excess risk of cardiovascular disease, stroke and breast cancer in women regardless of age group. However, these studies were heavily criticized due to their design, particularly the WHI study where the average age of recruitment was 63 years and with an excess of obesity, hypertension and pre‐existing cardiovascular disease. There is now strong and consistent evidence that oestrogen therapy may be cardioprotective if started around the time of menopause (referred to as the ‘window of opportunity’ or ’timing’ hypothesis) and may be harmful if started more than 10 years after menopause. In the 13‐year follow‐up of women in the WHI study, the cumulative data in the 50–59‐year‐old age group showed a reduction in CHD (hazard ratio, HR 0.65, 95% CI 0.44–0.96) [46]. The risk of myocardial infarction was also significantly decreased (HR 0.60, 95% CI 0.39–0.91). Women less than 10 years since menopause who received conjugated oestrogens plus medroxyprogesterone acetate showed a non‐significant reduction in CHD (HR 0.90, 95% CI 0.56–1.45), suggesting a potential attenuation of the coronary benefit with this particular regimen using a continuous progestogen. Meta‐analyses of randomized controlled trials, including data from the WHI study, have shown a significant reduction in CHD as well as mortality in women treated with oestrogen under the age of 60. In the WHI study, the cumulative results showed a reduction in all‐cause mortality in the 50–59‐year‐old age group with oestrogen alone and oestrogen–progestogen. When mortality data for conjugated oestrogens and conjugated oestrogens plus medroxyprogesterone acetate from the two WHI trials were combined, the reduction in all‐cause mortality was significantly reduced by 30%. In the most recent Cochrane analysis [47], women within 10 years of menopause had a reduction in all‐cause mortality of 0.70 (95% CI 0.52–0.95) and in cardiovascular mortality of 0.52 (95% CI 0.29–0.96). An observational study from Finland [48] recently reported that estradiol products (oral and transdermal) with and without progestogen decreased coronary and all‐cause mortality significantly (12–54%); of note in this study, while longer duration of use decreased mortality, age of initiation did not make a difference. A number of recent randomized controlled studies (DOPS, KEEPS and ELITE) have shown that cardiovascular risks can be minimized and benefit maximized using HRT in younger populations. The Danish Osteoporosis Prevention Study (DOPS) [49] studied younger women at the onset of menopause who prospectively received standard doses of estradiol and norethisterone in an open‐label fashion or no treatment for 10 years and had 16 years of follow‐up. There were significant reductions in mortality and in hospitalizations for myocardial infarction and congestive heart failure. The Kronos Early Estrogen Prevention Study (KEEPS) [50] showed no difference between conjugated oestrogens 0.45 mg, transdermal estradiol 0.05 mg and placebo for intermediate end‐points: carotid artery intima–media thickness and coronary calcium. These young healthy women had virtually no coronary artery disease and it is possible that there was insufficient progression over 4 years to detect differences between the groups. The Early versus Late Intervention Trial with Estradiol (ELITE) (oral estradiol 1 mg and placebo in two groups of women, <6 years from menopause and the other >10 years) showed a reduction in carotid intima–media thickness over time in the younger women, and no change in the older population, confirming that the timing of oestrogen treatment is important in influencing the progression of coronary disease [51].
Menopause and Postmenopausal Health
Consequences of the menopause
Aetiology of hot flushes and sweats
Other early symptoms
Intermediate symptoms
Long term
Osteoporosis and sarcopenia
Cardiovascular
Central nervous system
Advances in prediction of menopause
Patient assessment and ongoing monitoring
Initial diagnosis
Monitoring
Premature ovarian insufficiency
Interventions
Lifestyle measures
Hormone replacement therapy
Oestrogen
Dose
Route of administration
Vaginal oestrogen
New options for treating VVA
Progestogens/progesterone
Regimens
Progestogen type
Sequential combined daily dosage
Continuous combined daily dosage
Testosterone‐derived progestogens
Norethisterone
5 mg
0.1 mg
Levonorgestrel
75 µg
N/A
Levonorgestrel intrauterine system
N/A
20 µg
Norgestrel
150 µg
50 µg
Progesterone‐derived progestogens
Cyproterone*
2 mg
1 mg
Medroxyprogesterone acetate
5 mg
2.5 mg
Micronized progesterone
200 mg
100 mg
Cyclogest pessaries
400 mg
200 mg
Crinone gel (8%)
Alternate days/12 days per cycle
Twice weekly
Spironolactone‐derived progestogens
Drospirenone
N/A
2 mg
Bleeding problems
Progestogenic side effects
Minimizing progestogen side effects
Bio(body)‐identical HRT
Androgens
Benefit–risk balance of HRT
Coronary heart disease and overall mortality
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