Each ovary receives a finite endowment of oocytes, the numbers of which are maximal at 20–28 weeks of intrauterine life. From mid-gestation onwards, a logarithmic reduction in these germ cells occurs until, approximately 50 years later, the stock of oocytes is depleted (Burger et al 2008). The main steroid hormones produced by the ovary are oestradiol, progesterone and testosterone. Premenopausally, ovarian function is controlled by the two pituitary gonadotrophins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH is controlled primarily by the pulsatile secretion of hypothalamic GnRH, and is modulated by the negative feedback of oestradiol and progesterone and the ovarian peptide inhibin B. The peptide is a major regulator of FSH secretion and a product of small antral follicles. Its levels respond to the early-follicular-phase increase and decrease in FSH. The age-related decrease in ovarian primordial follicle numbers, which is reflected in a decrease in the number of small antral follicles, leads to a decrease in inhibin B, which in turn leads to an increase in FSH. LH is principally controlled by GnRH, with negative feedback control from oestradiol and progesterone for most of the cycle; positive oestradiol feedback generates the mid-cycle surge in levels of LH that triggers ovulation.

The ovary gradually becomes less responsive to gonadotrophins several years before menstruation stops, oestrogen levels fall and gondatrophin levels rise. These changes in circulating levels of hormones frequently occur with ovulatory cycles. As ovarian unresponsiveness becomes more marked, cycles tend to become anovulatory, and complete failure of follicular development eventually occurs. Production of oestradiol is no longer sufficient to stimulate the endometrium, leading to amenorrhoea, with levels of FSH and LH now persistently elevated. Levels of FSH above 30 IU/l are generally considered to be in the postmenopausal range.

The ovaries are also an important source of testosterone, which is hydroxylated to dihydrotestosterone. Testosterone can also be aromatized to oestradiol. Precursor hormones, such as androstenedione and dehydroepiandrosterone (DHEA), are produced in the ovaries and the adrenals, and both possess a less potent androgenic effect than testosterone. By the time women reach their mid-40s, mean circulating levels of testosterone, androstenedione, DHEA and DHEA sulphate are approximately half those of women in their 20s. However, menopausal status does not affect levels of androgens in women aged 45–54 years, and the postmenopausal ovary seems to be an ongoing site of testosterone production.

Stages of reproductive ageing

A staging system that uses the final menstrual period as the anchor to describe reproductive ageing was proposed by the Stages of Reproductive Aging Workshop (STRAW) (Soules et al 2001) (Figure 28.1). This incorporates both menstrual cycle and hormonal parameters. Progression through the STRAW stages is associated with elevations in serum FSH, LH and oestradiol, and decreases in luteal-phase progesterone.

Figure 28.1 The STRAW reproductive staging system. FSH, follicle-stimulating hormone.

Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Fertil Steril 2001;76:874–8.

Menopause symptoms

Menopause symptoms include hot flushes and night sweats, depression, tiredness and sexual problems. Symptom reporting varies between cultures (Melby et al 2005). Approximately 70% of women in Western cultures will experience vasomotor symptoms, such as hot flushes and night sweats. However, Japanese women have fewer menopausal complaints than their North American counterparts. Furthermore, rural Mayan women living in the Yucatan, Mexico do not report either hot flushes or night sweats.

Classification	Definition
I Sexual desire disorders
A Hypoactive sexual desire disorder	The persistent or recurrent deficiency (or absence) of sexual fantasies/thoughts and/or desire for, or receptivity to, sexual activity, which causes personal distress
B Sexual aversion disorder	The persistent or recurrent phobic aversion and avoidance of sexual contact with a sexual partner, which causes personal distress
II Sexual arousal disorders	The persistent or recurrent inability to attain or maintain sufficient sexual excitement, causing personal distress, which may be expressed as a lack of subjective excitement, or genital (lubrication/swelling) or other somatic responses
III Orgasmic disorder	The persistent or recurrent difficulty, delay in or absence of attaining orgasm after sufficient sexual stimulation and arousal, which causes personal distress
IV Sexual pain disorders
A Dyspareunia	The recurrent or persistent genital pain associated with sexual intercourse
B Vaginismus	The recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina, which interferes with vaginal penetration and causes personal distress
C Non-coital sexual pain disorders	Recurrent or persistent genital pain induced by non-coital sexual stimulation

Each of the categories above is subtyped on the basis of the medical history, physical examination and laboratory tests as: (A) lifelong vs acquired; (B) generalized vs situational; or (C) aetiology (organic, psychogenic, mixed or unknown).

Adapted from Basson R, Berman J, Burnett A, et al. Report of the international consensus development conference on female sexual dysfunction: definitions and classifications. J Urol 2000;163:888-93.

Chronic Conditions Affecting Postmenopausal Health

These include cardiovascular disease (CVD), osteoporosis, dementia and urinary incontinence.

Cardiovascular disease

Worldwide, CVD is the leading cause of death and disability in both sexes. It is the major cause of death in women, accounting for one-third of all deaths. As CVD increases in prevalence with age, and as women live longer than men, more women than men die from CVD each year in many countries. Coronary heart disease (CHD) and stroke are the primary clinical endpoints of CVD. In the UK, approximately half (48%) of all deaths from CVD are from CHD and more than one-quarter (28%) are from stroke. Approximately one in six women die from CHD.

Osteoporosis

Osteoporosis affects one in three women. Osteoporosis is defined in a National Institute of Health Consensus Statement as ‘a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture’. Bone strength reflects the integration of two main features: bone density and bone quality. Bone density is expressed as grams of mineral per area or volume. Bone quality refers to architecture, turnover, damage accumulation (e.g. microfractures) and mineralization. The main clinical manifestations of osteoporosis are fractures of the hip, vertebrae and wrist (Colles’ fractures). They have an enormous impact on quality of life, result in significant economic burden and, particularly in the case of hip fractures, are associated with considerable excess mortality. In the year after a hip fracture, mortality is approximately 30%. Approximately 50% of patients who survive a hip fracture have permanent disability and fail to regain their previous level of independence. The number of hip fractures worldwide due to osteoporosis is expected to rise three-fold by the middle of the next century, from 1.7 million in 1990 to 6.3 million by 2050.

Definitions of osteoporosis according to the World Health Organization

The World Health Organization’s definitions are based on measurement of bone mineral density (BMD) (Table 28.2). Severe osteoporosis is defined as the presence of a fragility or minimal trauma fracture and low BMD (T-score less than −2.5). The T-score is the number of standard deviations by which the bone in question differs from the young normal mean. Although BMD is a major contributor to risk, other factors, including age, BMI and falls, play a part in determining whether a person will get a fracture. The FRAX tool has been developed by the World Health Organization to evaluate fracture risk (Kanis et al 2008). It is based on individual patient models that integrate the risks associated with clinical risk factors as well as femoral neck BMD. The clinical risk factors comprise BMI (as a continuous variable), a prior history of fracture, a parental history of hip fracture, use of oral glucocorticoids, rheumatoid arthritis and other secondary causes of osteoporosis, current smoking and alcohol intake of 3 or more units/day. The FRAX algorithms give the 10-year probability of hip and other major osteoporotic fractures.

Table 28.2 Definitions of osteoporosis according to the World Health Organization

Description	Definition
Normal	BMD value between −1 SD and +1 SD of the young adult mean (T-score −1 to +1)
Osteopenia	BMD reduced between −1 and −2.5 SD from the young adult mean (T-score −1 to −2.5)
Osteoporosis	BMD reduced by equal to or more than −2.5 SD from the young adult mean (T score −2.5 or lower)

BMD, bone mineral density; SD, standard deviation.

Dementia and cognitive decline

Worldwide, approximately 25 million people have dementia, with 4.6 million new cases of dementia every year (one new case every 7 seconds). It has been estimated that the number of people affected will double every 20 years to 81.1 million by 2040. Dementia is a clinical term used to describe a condition in which there is impairment of cognitive faculties, including loss of memory, language, thinking and judgement, which cause significant difficulties in functioning. A wide variety of disorders can cause dementia; the most common are Alzheimer’s disease, vascular dementia and dementia with Lewy bodies.

Dementia causes significant distress to patients, their carers and families, and has an enormous impact on society. While most people with dementia live in the community, they are likely to require residential or nursing home care in the long term.

Urogenital atrophy and urinary incontinence

The lower urinary and genital tracts have a common embryological origin and are approximated closely in adult women. Oestrogen and progesterone receptors are present in the vagina, urethra, bladder and pelvic floor musculature. Urogenital atrophy is common, affecting approximately 25% of women even if they are taking systemic oestrogen replacement. A lack of oestrogen results in the vaginal epithelium becoming thinner, losing its rugae, and becoming pale or erythematous with fine petechial haemorrhages. Vaginal and cervical secretions also decrease, leading to reduced lubrication. The resulting symptoms include dyspareunia, itching, burning and dryness which can coexist with urinary symptoms.

Urinary incontinence affects millions of women throughout the world. It affects the quality of life of women of all ages and poses a large financial burden on society. The population-based prevalence of urinary incontinence in the USA has been estimated to be 45% (Melville et al 2005). Prevalence increased with age, from 28% for women aged 30–39 years to 55% for women aged 80–90 years. Eighteen percent of respondents reported severe urinary incontinence. The prevalence of severe urinary incontinence also increased notably with age, from 8% for women aged 30–39 years to 33% for women aged 80–90 years. Other surveys have reported similar findings.

Therapeutic Options

Oestrogen-based hormone replacement therapy

A wide variety of oestrogen-based preparations are available worldwide, which feature different strengths, combinations and routes of administration (Clinical Knowledge Summaries 2009). Various designations are used: hormone replacement therapy (HRT), hormone therapy, oestrogen therapy, and oestrogen and progestogen therapy for combined preparations (sequential or continuous combined).

HRT consists of an oestrogen, and a progestogen is added in non-hysterectomized women. Progestogens are given cyclically or continuously with the oestrogen.

Oestrogens

Two types of oestrogen are available: natural and synthetic. Natural oestrogens include oestradiol, oestrone and oestriol. Conjugated equine oestrogens contain approximately 50–65% oestrone sulphate, and the remainder consists of equine oestrogens, mainly equilin sulphate. These are also classified as ‘natural’. The generally accepted minimum bone-sparing doses of oestrogen are listed in Table 28.3, although increasing evidence shows that even lower doses may be effective. Synthetic oestrogens, such as ethinyl oestradiol used in the combined oral contraceptive pill, are generally considered to be unsuitable for HRT because of their greater metabolic impact, apart for treating young women with premature ovarian failure (POF).

Table 28.3 Minimum bone-sparing doses of oestrogen

Oestrogen	Dose
Oestradiol oral	1–2 mg
Oestradiol patch	25–50 µg
Oestradiol gel	1–5 g*
Oestradiol implant	50 mg every 6 months
Conjugated equine oestrogens	0.3–0.625 mg daily

* Depends on preparation.

Different routes of administration are employed: oral, transdermal (patches and gels), subcutaneous (implants) and vaginal. The vaginal route is used to treat urogenital symptoms. Vaginal therapies include oestradiol by tablet or ring, or oestriol by cream or pessary. Conjugated equine oestrogen cream is also available but this is well absorbed from the vagina and can cause endometrial stimulation. Systemic absorption with oestradiol vaginal tablets or ring is low, and hormone levels remain within the postmenopausal range. Thus, if the recommended topical oestradiol and oestriol preparations are used, there is no need to add a progestogen for endometrial protection. However, if conjugated equine oestrogens are used on a long-term basis, a progestogen should also be given. Vaginal oestrogens can also be used with systemic oestrogens.

Progestogens

The progestogens used in HRT are almost all synthetic, are structurally different to progesterone and are derived from plant sources. Currently, most are given orally, although norethisterone and levonorgestrel are available in transdermal patches combined with oestradiol, and levonorgestrel can be delivered directly to the uterus. Progesterone itself is available either orally or as a vaginal gel, but availability varies worldwide.

Androgens

Testosterone may be given as patches or as subcutaneous implants to improve libido, but this is not successful in all women, as other factors, such as marital problems, may be involved. Testosterone patches have the advantage of an easily reversible delivery system, as implants cannot be removed easily.

Bioidentical hormones

In some countries, ‘natural’ or ‘ bioidentical’ hormones are used as an alternative approach. In the USA, the Food and Drug Administration is concerned with the claims for safety, effectiveness and superiority of preparations that are made in compounding pharmacies.

Tibolone

Tibolone is classified as HRT in the UK British National Formulary. Tibolone is a synthetic steroid compound that is itself inert, but, on absorption, is converted in vivo to metabolites with oestrogenic, progestogenic and androgenic actions. Tibolone is used in postmenopausal women who wish to have amenorrhoea. It is used to treat vasomotor, psychological and libido problems, and the daily dose is 2.5 mg. Tibolone conserves bone mass and reduces the risk of vertebral and non-vertebral fracture.

Hysterectomized women

In general, hysterectomized women should be given oestrogen alone and have no need for a progestogen. However, in women who have had a subtotal hysterectomy, there may be concern about a remnant of endometrium in the cervical stump. If this is suspected to be the case, the presence or absence of bleeding induced by monthly sequential HRT may be a useful diagnostic test before giving oestrogen alone.

Non-hysterectomized women

Progestogens are added to oestrogens to reduce the increased risk of endometrial hyperplasia and carcinoma that is associated with unopposed oestrogen. Progestogen can be given ‘sequentially’ for 10–14 days every 4 weeks, for 14 days every 13 weeks, or every day. The first schedule leads to monthly bleeds, the second leads to bleeds every 3 months, and the last aims to achieve amenorrhoea. Progestogen must be given to women who have undergone endometrial ablative techniques or radiotherapy for gynaecological cancer, as it cannot be assumed that all of the endometrium has been destroyed.

Women’s Health Initiative and Million Women Study

Publication of the results of the US Women’s Health Initiative (WHI) and UK Million Women Study (MWS) since 2002 has led to considerable uncertainties regarding the use of oestrogen-based HRT (Writing Group for the Women’s Health Initiative Investigators 2002, Million Women Study Collaborators 2003, Women’s Health Initiative Steering Committee 2004). Several publications have questioned the design, analysis and conclusions of both these studies (Shapiro 2007). For example, in the WHI, women in their 70s were given HRT for the first time, which does not reflect usual clinical practice. In the MWS, it was not easy to control for differences between attendees and non-attendees of the National Health Service Breast Screening Programme and between attendees who agreed or declined to participate in the study. Both studies were undertaken in women aged 50 years and over, and their findings cannot be extrapolated to younger women such as those with premature menopause in their 20s and 30s.

The design of the studies will be described, together with the benefits, risks and uncertainties about oestrogen use in clinical practice.

Women’s Health Initiative

The WHI is a large complex series of studies designed in the early 1990s with follow-up until 2010 of strategies for the primary prevention and control of some of the most common causes of morbidity and mortality among healthy postmenopausal women aged 50–79 years. It consisted of a randomized-controlled trial and an observational study. The randomized trial considered not only HRT but also calcium and vitamin D supplementation and a low-fat diet (Box 28.1). If eligible, women could choose to enrol in one, two or all three components of the randomized trial. The randomized trial involved 68,132 women (mean age 63 years): conjugated equine oestrogens (0.625 mg) alone (n = 10,739 hysterectomized women), conjugated equine oestrogens (0.625 mg) in combination with medroxyprogesterone acetate (2.5 mg) (n = 16,608 non-hysterectomized women), low-fat diet (n = 48,835), and calcium and vitamin D supplementation (n = 36,282). Women screened for the clinical trial who were ineligible or unwilling to participate in the controlled trial (n = 93,676) were recruited into an observational study that assessed new risk indicators and biomarkers for disease.

Box 28.1 Interventions evaluated by the Women’s Health Initiative

• HRT (unopposed and combined): hypothesized to reduce the risk of CHD and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased risk of breast cancer being studied as a possible adverse outcome.

• Low-fat eating pattern: hypothesized to prevent breast cancer and colorectal cancer and, secondarily, to prevent CHD.

• Supplementation with calcium and vitamin D: hypothesized to prevent hip fractures and, secondarily, to prevent other fractures and colorectal cancer.

Million Women Study

The observational MWS examined different HRT regimens, excluding vaginal preparations, in women aged 50–64 years (mean age 57 years) attending the National Health Service Breast Screening Programme in the UK. In total, 1,084,110 women were recruited between 1996 and 2001; approximately half of these women had ever used HRT. The average duration of follow-up was 2.6 years.

Benefits, risks and uncertainties of oestrogen-based hormone replacement therapy

Benefits

Vasomotor symptoms

There is good evidence from randomized placebo-controlled studies, including the WHI, that oestrogen is effective for the treatment of hot flushes, and improvement is usually noted within 4 weeks (Simon and Snabes 2007). It is more effective than non-hormonal preparations such as clonidine and selective serotonin reuptake inhibitors (see below). The most common indication for HRT prescription is relief of vasomotor symptoms, and it is often used for less than 5 years.

Urogenital symptoms and sexuality

Urogenital symptoms respond well to oestrogen administered either topically or systemically. In contrast to vasomotor symptoms, improvement may take several months. Recurrent urinary tract infections may be prevented by vaginal but not oral oestrogen replacement (Perrotta et al 2008). Topical oestrogens may have a weak effect on urinary urge incontinence, but no improvement of stress incontinence. Long-term treatment is often required as symptoms can recur when therapy is stopped. Sexuality may be improved with oestrogen alone, but testosterone may also be required, especially in young oophorectomized women.

Osteoporosis

There is evidence from randomized-controlled trials (including the WHI) that HRT reduces the risk of both spine and hip fractures, as well as other osteoporotic fractures (Writing Group on Osteoporosis for the British Menopause Society Council 2007). Most epidemiological studies suggest that continuous and lifelong use is required for fracture prevention. However, there is now some evidence that a few years of treatment with HRT around the time of the menopause may have a long-term effect on fracture reduction. While alternatives to HRT use are available for the prevention and treatment of osteoporosis in elderly women (see below), oestrogen still remains the best option, particularly in younger (<60 years) and/or symptomatic women. Few data are available on the efficacy of alternatives such as bisphosphonates in women with POF.

Colorectal cancer

Results from the combined arm, but not the oestrogen-alone arm, of the WHI concur with observational studies that HRT reduces the risk of colorectal cancer. However, little is known regarding the risk of colorectal cancer when treatment is stopped. There is no information about HRT in high-risk populations, and current data do not allow prevention as a recommendation.

Risks

Breast cancer

HRT appears to confer a similar degree of risk as that associated with late natural menopause (2.3% compared with 2.8% per year, respectively). There is no increased risk in HRT users with a premature menopause (Ewertz et al 2005).

The WHI found that:

• combined HRT but not oestrogen-alone HRT increased the risk of breast cancer;

• the risk of breast cancer in the oestrogen-alone arm was lower than that in the placebo group. The risk of breast cancer was significantly reduced in women with no previous exposure at study entry; and

• in the combined arm, there was evidence of a duration effect with an increase in risk starting 3 years after randomization, but only in women who had used HRT before entering the study.

The MWS found:

• an increased risk with all HRT regimens (both unopposed oestrogen and combined HRT);

• the greatest degree of risk was with combined HRT and this was not influenced by route of administration; and

• different oestrogens or progestogens did not appear to alter risk, nor did the pattern of progestogen administration (i.e. cyclical or continuous).

The higher risk estimates reported in the MWS compared with the randomized WHI, especially for the oestrogen-alone arm which found a reduced risk, probably reflect the different designs of the studies.

The increased risk of breast cancer with combined HRT compared with oestrogen alone has to be balanced against the reduction in risk of endometrial cancer provided by progestogen addition. The increased risk of breast cancer with long-term use seems to be limited to lean women (BMI <25 kg/m²) in most studies. Also, the increased risk of breast cancer with HRT is low and similar to the risk conferred by obesity, being tall, nulliparity or late age at first full-term pregnancy, and is lower than that conferred by certain inherited genetic mutations or mantle radiotherapy (American Cancer Society 2009).

Also, the risk of breast cancer decreases after stopping HRT, and after 5 years, the risk of breast cancer is no greater than that in women who have never been exposed to HRT. The incidence of breast cancer has been decreasing in the USA and this has been attributed to declining HRT use since publication of the WHI. However, the decrease started in 1998, predating the first WHI publication (Li and Daling 2007).

Endometrial cancer

Unopposed systemic oestrogen replacement therapy increases the risk of endometrial cancer (Weiderpass et al 1999). Sequential progestogen addition, especially when continued for more than 5 years, does not eliminate this risk completely. This has also been found with monthly- and long-cycle HRT. No increased risk of endometrial cancer has been found with continuous combined regimens. Very low doses of systemic oestrogen (0.014 µg/day transdermal oestradiol patch) do not seem to stimulate the endometrium, but studies are limited and require confirmation (Simon and Snabes 2007).

Furthermore, oral treatment, but not vaginal treatment, with low-potency formulations (such as oestriol) increases the relative risk of endometrial neoplasia. The increased risk of endometrial cancer with systemic oestrogen is lower than that found in obese or diabetic women.

Venous thromboembolism

HRT increases the risk of venous thromboembolism (VTE) two-fold, with the highest risk occurring in the first year of use (Canonico et al 2008). However, the absolute risk is small, being 1.7 per 1000 in women over 50 years of age not taking HRT. Advancing age, obesity and an underlying thrombophilia such as factor V Leiden increase the risk of VTE significantly. Randomized trial data strongly suggest that women who have previously suffered a VTE have an increased risk of recurrence in the first year of HRT use. However, transdermal HRT may be associated with a lower risk, even in women with a thrombophilia.

Gallbladder disease

The WHI confirmed the observation of the Heart and Estrogen/Progestin Replacement Study published in 1998 that oral HRT increases the risk of gallbladder disease. However, the MWS found that transdermal therapy confers a lower risk than oral therapy (Liu et al 2008). Gallbladder disease increases with ageing and with obesity, and HRT users may have silent pre-existing disease.

Uncertainties

CVD (CHD and stroke)

The role of HRT in both primary and secondary prevention remains uncertain.

CHD primary prevention

Until the late 1990s, oestrogen was thought to protect against CHD (Rees and Stevenson 2008). Many cohort studies showed that HRT was associated with a 40–50% reduction in the incidence of CHD. The effects were the same for both oestrogen alone and combined HRT. However, the WHI did not confirm these observational studies. It has become apparent that there are differences between regimens, and that the timing of HRT initiation may be crucial. The WHI found an early, albeit transient, increase in coronary events in the combined arm but not the oestrogen-alone arm. In the WHI oestrogen-alone arm, there was a non-significant reduction in CHD, which was most marked in younger women (50–59 years). With regard to timing, women in the WHI who started combined HRT within 10 years of the menopause had a lower risk of CHD than women who started later (Rossouw et al 2007). Combining the two HRT arms found that women who initiated hormone therapy closer to the menopause tended to have reduced CHD risk compared with the increase in CHD risk among women who initiated hormone therapy more distant from the menopause. While transdermal oestrogen has less of an effect on coagulation than oral therapy due to avoidance of the first liver pass, it is uncertain whether transdermal delivery is better than oral delivery in terms of CHD risk.

CHD secondary prevention

Although angiographic and cohort studies such as the Nurses’ Health Study suggested a role of oestrogen in the secondary prevention of CHD, this has not been confirmed in randomized-controlled trials with both oral and transdermal therapy (Grodstein et al 2006).

Stroke

Interpretation of observational studies on HRT and stroke is difficult because of differences in design and failure to distinguish between ischaemic and haemorrhagic stroke (Billeci et al 2008). Both arms of the WHI found an increase in ischaemic stroke but not haemorrhagic stroke. However, age or time since menopause did not affect the risk of stroke. In addition, in women who have experienced a previous ischaemic stroke, oestrogen replacement does not reduce mortality or recurrence as evidenced by randomized-controlled trials.

Dementia and cognition

While oestrogen may delay or reduce the risk of Alzheimer’s disease, it does not seem to improve established disease (Barber et al 2005). It is unclear if there is a critical age or duration of treatment for exposure to oestrogen to have an effect on prevention, but there may be a window of opportunity in the early postmenopause when the pathological processes that lead to Alzheimer’s disease are starting and when HRT may have a preventive effect. The WHI found an increased risk of dementia and lower cognitive function in HRT users, but only in women aged over 75 and 65 years, respectively.

Ovarian cancer

Most data pertain to replacement with oestrogen alone with increasing risk in the very long term (>10 years) (Beral et al 2007). However, with continuous combined therapy, this increase does not seem apparent.

Quality of life

While some studies have shown improvement in both symptomatic and asymptomatic women, others have not. This area is difficult to evaluate because of the different questionnaires used, as well as varying levels of menopausal symptomatology.

Tibolone

Tibolone is effective in the treatment of menopausal symptoms. It conserves bone mass and reduces the risk of vertebral and non-vertebral fractures, particularly in patients who have already had a vertebral fracture. It also reduces the risk of invasive breast cancer and colon cancer. However, it does not significantly reduce the risk of hip fracture and it increases the risk of stroke (Cummings et al 2008). The LIFT study also showed that tibolone does not have a deleterious effect on CHD or VTE (Cummings et al 2008). The MWS showed an increased risk of breast cancer and endometrial cancer. However, the increased risk of endometrial cancer has not been confirmed in randomized-controlled trials (Archer et al 2007). The LIBERATE randomized trial of tibolone in breast cancer survivors was discontinued early in 2007 as there was an excess of breast cancer recurrences in the group of women randomized to receive tibolone (Kenemans et al 2009).

Non-Oestrogen-Based Treatments for Menopausal Symptoms

Non-oestrogen-based treatments are used to treat hot flushes and symptoms of urogenital atrophy. These can be either hormonal or non-hormonal (Writing Group for the British Menopause Society Council 2008).

Hormonal

Progestogens

Progestogens such as 5 mg/day norethisterone or 40 mg/day megestrol acetate can reduce hot flushes and night sweats. However, the risk of VTE may be increased with the doses of progestogen used. Also, safety with regard to the breast is uncertain. Availability of megestrol acetate 40 mg tablets varies worldwide.

Non-hormonal

Clonidine

Clonidine is a centrally acting α-adrenoceptor agonist that was originally developed for the treatment of hypertension. While it may be of limited help in women with tamoxifen-induced hot flushes, the evidence for efficacy is conflicting. Side-effects include dry mouth, sedation, dizziness, nausea and nocturnal restlessness. The dose is 50–75 µg twice daily.

Selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors

Fluoxetine, paroxetine, citalopram and venlafaxine have been found to be effective in several studies. However, most are short lasting (only a few weeks). The most convincing data are for venlafaxine [selective serotonin and noradrenaline reuptake inhibitor (SNRI)] at a dose of 37.5 mg twice daily. A randomized trial of a new SNRI, desvenlafaxine, has shown a 64% reduction in hot flushes at 12 weeks. Side-effects include gastrointestinal symptoms (nausea) and sexual dysfunction (delayed or absent orgasm). Some early evidence suggests that selective serotonin reuptake inhibitors may cause bone loss.

Gabapentin

Gabapentin is a γ-aminobutyric acid analogue used to treat epilepsy, neurogenic pain and migraine. It reduces hot flushes at a dose of 900 mg/day by approximately 50%. Side-effects include dry mouth, dizziness and drowsiness, which may improve with continued use.

Vitamin E

Although one study showed that vitamin E reduced hot flushes, the difference between the active and placebo groups was not significant.

Vaginal lubricants and moisturizers

Lubricants usually consist of a combination of protectants and thickening agents in a water-soluble base. They are usually used to relieve vaginal dryness during intercourse. They therefore do not provide a long-term solution. Lubricants must be applied frequently for more continuous relief, and require reapplication before intercourse. Moisturizers may contain a bioadhesive polycarbophil-based polymer, which attaches to mucin and epithelial cells on the vaginal wall and retains water. Moisturizers are promoted as providing long-term relief of vaginal dryness and need to be applied less frequently. Petroleum-based products and baby oil can compromise the integrity of condoms. This is important when condoms are used for contraception and/or to prevent sexually transmitted infections.

Non-Oestrogen-Based Therapy for Osteoporosis

A wide range of pharmacological and non-pharmacological interventions are available (Table 28.4) (Writing Group on Osteoporosis for the British Menopause Society Council 2007). There are very few data regarding long-term efficacy for reducing fractures (i.e. more than 10 years of treatment) and safety of combinations of therapy. Most of these therapies have been studied in elderly women (>60 years) who have osteoporosis or who are at increased risk of the disease. Little is known about their efficacy and safety in women with premature menopause and effects on the developing fetal skeleton. This is of importance because of the long (many years) half-life of bisphosphonates and strontium ranelate.

Table 28.4 Interventions for the prevention and treatment of osteoporosis

	Spine	Hip
1. Bisphosphonates
Etidronate	A	B
Alendronate	A	A
Risedronate	A	A
Ibandronate	A	ND
Zoledronic acid	A	A
2. Calcium and vitamin D	ND	A
3. Calcium	A	B
4. Calcitriol	A	ND
5. Calcitonin	A	B
6. Oestrogen	A	A
7. Raloxifene	A	ND
8. Strontium ranelate	A	A
9. Parathyroid hormone peptides	A	ND

ND, not demonstrated.

The levels of evidence for the various agents are:

A = meta-analysis of randomized-controlled trials (RCTs) or from at least one RCT/from at least one well-designed controlled study without randomization;

B = from at least one other type of well-designed quasi-experimental study or from well-designed non-experimental descriptive studies, e.g. comparative studies, correlation studies, case–control studies.

Pharmacological interventions

All pharmacological interventions except for parathyroid hormone and strontium ranelate act mainly by inhibiting bone resorption.

Bisphosphonates

Bisphosphonates are chemical analogues of naturally occurring pyrophosphates and are classified into two groups: non-nitrogen-containing bisphosphonates, such as etidronate; and nitrogen-containing bisphosphonates, such as alendronate, risedronate, ibandronate and zoledronic acid.

All bisphosphonates are absorbed poorly from the gastrointestinal tract and must be given on an empty stomach. Food or calcium-containing drinks inhibit absorption, which at best is only 5–10% of the administered dose. The principal side-effect of all bisphosphonates is irritation of the upper gastrointestinal tract. Symptoms resolve quickly after drug withdrawal and are reduced by using weekly or monthly dosing rather than daily dosing.

Alendronate, risedronate, etidronate and ibandronate are used in the prevention and treatment of osteoporosis. The indication for zoledronic acid is the treatment of osteoporosis in postmenopausal women at increased risk of fracture. Alendronate, risedronate and etidronate are also used in corticosteroid-induced osteoporosis.

The question of how long to prescribe a bisphosphonate has not been fully clarified because of concerns about ‘frozen bone’, with complete turning off of bone remodelling with long-term use and also development of osteonecrosis in the jaw. Of note, most reports about ostenecrosis refer to high-dose intravenous bisphosphonates used in the oncological setting rather than oral bisphosphonates for osteoporosis. There have been concerns regarding atrial fibrillation with bisphosphonates, but mainly with intravenous regimes, and the mechanism is uncertain.

Five years of treatment with a 2-year ‘holiday’ have been proposed for alendronate, but differences may exist with individual bisphosphonates. This may not be applicable to glucocorticoid-induced osteoporosis.

Alendronate reduces vertebral and non-vertebral fractures by 50% in randomized-controlled trials. The dose for prevention of osteoporosis is 5 mg/day or 35 mg once weekly, and the dose for treatment of established disease is 10 mg/day or 70 mg once weekly.

Risedronate reduces vertebral and non-vertebral fractures in randomized-controlled trials. The dose for treatment of established disease is 5 mg/day or 35 mg once weekly.

Ibandronate reduces vertebral but not non-vertebral fractures by 50% in randomized-controlled trials undertaken in postmenopausal women. The dose is 2.5 mg/day or 150 mg once monthly orally or 3 mg intravenously every 3 months.

Etidronate reduces the risk of vertebral but not non-vertebral fractures. It is given intermittently (400 mg on 14 out of every 90 days) with 1250 mg calcium carbonate (which, when dissolved in water, provides 500 mg calcium as calcium citrate) during the remaining 76 days.

Zoledronic acid significantly reduces the risk of vertebral, hip and other fractures. It is administered intravenously (5 mg annually) and has been evaluated in the treatment of postmenopausal osteoporosis.

Strontium ranelate

Strontium is an alkaline earth element like calcium and is thus incorporated into the skeleton. It reduces the risk of vertebral and hip fractures. The dose is a 2 g sachet/day. It can cause diarrhoea but this resolves on stopping treatment. There appears to be a small increased risk (<1%) of VTE and nervous system disorders (headaches, seizures, memory loss and disturbance in consciousness), but data are limited. Strontium ranelate causes a clinically significant overestimation of BMD because of the high attenuation of X-rays by strontium atoms in bone as it has a higher atomic number than calcium.

Raloxifene

Raloxifene is a selective oestrogen receptor modulator (SERM). These compounds possess oestrogenic actions in certain tissues and antioestrogenic actions in others (Palacios 2007). Other SERMs such as bazedoxifene, arzoxifene, lasofoxifene and ospemifene are currently being evaluated.

Raloxifene reduces vertebral, but not non-vertebral, fractures by 30–50%, depending on the dose. The dose is 60 mg/day. It also reduces the risk of breast cancer to the same extent as tamoxifen. Side-effects include hot flushes and calf cramps. It was thought that it could be cardioprotective from its effects on surrogate markers such as lipids; however, the Raloxifene Use for the Heart study found that it did not reduce the risk of CHD and it increased the risk of fatal stroke and VTE.

Parathyroid hormone peptides

Recombinant 1–34 parathyroid hormone, given as a subcutaneous daily injection of 20 µg, reduces vertebral and non-vertebral fractures in postmenopausal women with osteoporosis. The full 1–84 parathyroid hormone peptide is given in the same way in a daily dose of 100 µg. They both reduce the risk of vertebral fractures but not hip fractures.

Calcitonin

Calcitonin can be given by subcutaneous or intramuscular injection or by nasal spray. An oral preparation is in development. Nasal calcitonin has also been shown to reduce new vertebral fractures in women with established osteoporosis. It may help with pain in the context of an acute vertebral fracture. It may also be helpful as adjunctive treatment after surgery for hip fracture.

Calcitriol

This is the active metabolite of vitamin D and facilitates the intestinal absorption of calcium. The potential dangers of hypercalcaemia and hypercalciuria mean that levels of calcium in serum and urine should be monitored closely. Studies of the effects of calcitriol on bone loss and fractures have produced conflicting results. As such, its use is limited.

Future developments

New treatments are focusing on inhibition of bone turnover (McClung 2007). Receptor activator of nuclear factor-κB ligand (RANKL) is a pivotal regulator of osteoclast activity that provides a new therapeutic target. Denosumab, a highly specific anti-RANKL antibody, reduces bone resorption. Pharmacokinetics of the antibody allow dosing by subcutaneous injection every 3 or 6 months.

Non-pharmacological interventions

Calcium and vitamin D

Provision of adequate dietary or supplemental calcium and vitamin D is an essential part of osteoporosis management, and is the placebo component of clinical trials of agents such as bisphosphonates. Most studies show that approximately 1.5 g elemental calcium is necessary to preserve bone health in women who are not taking HRT. However, the effects of calcium and vitamin D supplements, alone or in combination, on fracture are contradictory and may depend on the study population and compliance with therapy (Tang et al 2007, Lin and Lane 2008). For example, people in sheltered accommodation or residential care may be more frail, have lower dietary intakes of calcium and vitamin D, and are at higher risk of fracture than those living in the community.

Caution has been expressed about the use of supplements in women whose diet is already adequate. Increased risk of kidney stones and CVD has been reported.

Hip protectors

Hip protectors are used to reduce the impact of falling directly on the hip, but evidence of efficacy is conflicting in both community and institutional studies. A systematic review found no evidence of the effectiveness of hip protectors from studies in which randomization was by individual patient within an institution or those living in their own homes (Parker et al 2006).

Diet and exercise

Maintaining a good diet and regular exercise are essential for healthy ageing and reducing the risk of CVD, osteoporosis, urinary incontinence and dementia (Salerno-Kennedy and Rees 2007).

Dietary components

Diet consists of macronutrients and micronutrients. Macronutrients encompass carbohydrate, protein and fat. The World Health Organization recommends that 55–75% of energy input should come from carbohydrate, with less than 10% from free sugars. Emphasis should be placed on carbohydrate-rich foods (e.g. wholegrain breakfast cereals, grains, and breads and bakery products), which also provide fibre and a number of B vitamins.

Protein is an important nutrient for older women and should comprise 10–15% of total energy intake. Total fat intake should account for 15–30% of total energy intake, with saturated fats accounting for less than 10% and polyunsaturated fats for 6–10%. Although, in the past, the main message has been to limit the total amount of fat, particular types such as omega-3 fatty acids, found mainly in oily fish, are important to health.

Micronutrients include vitamins and minerals. Those that may be associated with deficiencies in postmenopausal women include vitamin B12, vitamin A, vitamin C, vitamin D, calcium and other trace minerals. Low intakes of iron, folate and vitamin B12 can cause anaemia as well as other problems such as neuropathies and dementia.

It has been suggested that antioxidant supplements may reduce mortality. However, a systematic review found that vitamin A, beta-carotene, and vitamin E supplements may increase mortality (Bjelakovic et al 2008). No detrimental effects were found with vitamin C or selenium. Of note, most trials in the systematic review investigated the effects of supplements administered at higher doses than those commonly found in a balanced diet, and some of the trials used doses above the recommended daily allowances. These trials should not deter women from consuming fruit and vegetables which contain other substances such as fibre and flavonoids.

Functional foods

A functional food may be defined as a food with health-promoting benefits and/or disease-preventing properties over and above its usual nutritional value (Rudkovska 2008). Functional foods are also known as ‘nutraceuticals’ or ‘designer foods’. They encompass a broad range of products, ranging from foods generated around a particular functional ingredient (e.g. stanol-enriched margarines), through to staple everyday foods fortified with a nutrient that would not normally be present to any great extent (e.g. bread or breakfast cereals fortified with folic acid). Functional foods that show promise in postmenopausal health include probiotics, prebiotics, phytosterols and stanols, omega-3 fatty acids, flavonoids and fibre.

Isoflavones can also be considered as a functional food and are discussed in the section on complementary and alternative therapies. Synbiotics are a food or supplement product containing both probiotics and prebiotics. The name derives from a proposed synergism between probiotics and prebiotics.

Probiotics are live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host. Currently, the best studied probiotics are different species of Lactobacillus or Bifidobacterium, and the yeast Saccharomyces cerevisiae (boulardii). These can be combined in cereals, food bars, yoghurts and drinks. Various health benefits have been proposed. These include: regulation of immune function, prolongation of inflammatory bowel conditions, shortening the duration of infectious diarrhoea in infants, enhanced gastrointestinal tolerance to antibiotic therapy, and control of symptoms associated with lactose intolerance. They may also improve therapeutic outcome for women being treated for bacterial vaginosis, and reduce the severity of symptoms or the incidence of respiratory infections.

Prebiotics are non-digestible food ingredients such as inulin that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon. Thus, prebiotics are food for bacterial species that are considered beneficial for health and well-being.

Phytosterols and stanols reduce low-density-lipoprotein cholesterol by 10% and thus have the potential to reduce the risk of CHD by approximately 25%. Plant sterols and stanols reduce the absorption of cholesterol from the gut, and therefore reduce serum concentrations of cholesterol. They are incorporated into a variety of foods such as spreads, yogurts and drinks. However, studies with the endpoints of cardiovascular events are awaited.

Omega-3 fatty acids include the plant-derived α-linolenic acid (18:3n-3), and the fish-oil-derived eicosapentaenoic acid (20:5n-3) and docoshexaenoic acid (22:6n-3). Consumers of oily fish have a lower risk of CVD. Consumption of a diet rich in omega-3 fatty acids may also protect against dementia and Alzheimer’s disease.

Flavonoids are a large family of polyphenolic compounds synthesized by plants. They are found in a wide variety of fruit and vegetables such as grapes, berries, apples, chocolate, teas, kale and hot peppers. Isoflavones are a subclass of flavonoids with oestrogenic activity. Epidemiological evidence suggests that flavonoids reduce the risk of CVD. This would explain the inverse relationship between the consumption of red wine and CVD mortality (the ‘French paradox’). Animal and in-vitro studies suggest that flavonoids may have a role in preventing cancer and neurodegenerative disease.

Dietary fibre consists of plant substances that resist hydrolysis by digestive enzymes in the small bowel, and is an extremely complex group of substances. Fibre can be classified according to its solubility and fermentability by bacteria: a soluble fibre is readily fermentable by colonic bacteria, and an insoluble fibre is only slowly fermentable. Fibres may act in several ways, including through gel-forming effects in the stomach and small intestine, fermentation by colonic bacteria, a ‘mop and sponge’ effect and concomitant changes in other aspects of the diet. These actions lead to potentially beneficial effects in the gastrointestinal tract and systemically, such as lowering serum cholesterol and improving glycaemic control.

The importance of diet is such that the American Heart Association recommends that ‘Women should consume a diet rich in fruits and vegetables; choose wholegrain, high-fibre foods; consume fish, especially oily fish, at least twice a week; limit intake of saturated fat to <10% of energy, and if possible to <7%, cholesterol to <300 mg/day, alcohol intake to no more than 1 drink per day, and sodium intake to <2.3 g/day (approximately 1 tsp salt). Consumption of trans-fatty acids should be as low as possible (e.g. <1% of energy)’ (Mosca et al 2007).

Exercise

Regular physical activity reduces the risk of CHD, osteoporotic fractures and type 2 diabetes mellitus. Hot flushes, urinary incontinence, insomnia and depression may also be helped. A systematic review found that no conclusions regarding the effectiveness of exercise as a treatment for vasomotor menopausal symptoms could be made due to a lack of trials (Daley et al 2007). With regard to CVD, the Nurses Health Study found that low intensity exercise, such as walking, conferred the same benefit as vigorous exercise, and sedentary women who became active late in life reaped similar benefits as those who remained active throughout their life (Manson et al 2002). Exercise has a key role in the prevention and treatment of osteoporosis. A Cochrane review found that fast walking improved bone density effectively in the spine and the hip, whereas weight-bearing exercises were associated with increases in bone density of the spine but not the hip (Bonaiuti et al 2003).

Exercise regimens can be very helpful in the management of established osteoporosis, and represent a component of falls prevention programmes. Pelvic floor exercises are used commonly for stress incontinence. They are also used in the treatment of women with mixed incontinence, and less commonly for urge incontinence. Systematic reviews support the view that pelvic floor muscle training and bladder training should be included in first-line conservative management programmes for women with stress, urge or mixed urinary incontinence (Shamliyan et al 2008).

Complementary and alternative medicine

Many women use complementary and alternative medicine in the belief that they are safer and ‘more natural’, especially with concerns regarding the safety of oestrogen-based HRT after publication of the WHI and the MWS. However, evidence from randomized trials for complementary and alternative medicine that improves menopausal symptoms or has the same benefits as HRT is poor (Nedrow et al 2006). Very little well-designed research has been undertaken. The range of approaches used includes botanicals, homeopathy, DHEA, transdermal progesterone creams and mechanical methods (e.g. acupuncture, magnetism).

Botanicals

The evidence from clinical trials on the benefit of botanicals on menopausal symptoms is limited and conflicting. Studies may use different products which are not chemically consistent, making comparison difficult. Also, the stability of individual chemicals may vary and may depend on the type of packaging. Herbs may contain many chemical compounds, the individual and combined effects of which are unknown.

A major concern is use without consulting a health professional, leading to interaction with standard pharmacopeia with potentially fatal consequences. Severe adverse reactions, including renal and liver failure and cancer, have been reported. Concern exists regarding the quality control of production. Some have been found to be contaminated or to contain unlabelled ingredients such as conventional medicines (steroids) or banned substances. While a European Union Directive on traditional herbal medicinal products was implemented in October 2005 in the UK, this will not cover preparations bought by women outside Europe.

Herbal remedies need to be used with caution in women with a contraindication to oestrogen, as some botanicals have oestrogenic properties (e.g. soy, red clover, ginseng). Thus, they should not be used by women with a hormone-dependent condition such as breast cancer or endometriosis. They may interact with selective oestrogen receptor modulators (e.g. tamoxifen, raloxifene) or aromatase inhibitors (e.g. anastrozole, letrozole). Other consequences of herb–drug interactions include bleeding when combined with warfarin or aspirin; hypertension, coma and mild serotonin syndrome when combined with serotonin reuptake inhibitors; and reduced efficacy of antiepileptics and oral contraceptives.

Phytoestrogens are plant substances that have effects similar to those of oestrogens. Preparations vary from enriched foods, such as bread or drinks (e.g. soy milk), to tablets containing plant extracts. The most important groups are the isoflavones and lignans. The major isoflavones are genistein and daidzein. The major lignans are enterolactone and enterodiol. The role of phytoestrogens has stimulated considerable interest, as people from populations that consume a diet high in isoflavones, such as the Japanese, seem to have lower rates of menopausal vasomotor symptoms; CVD; osteoporosis; and breast, colon, endometrial and ovarian cancers. PHYTOS, ISOHEART and PHYTOPREVENT are European Union studies examining the role of phytoestrogens in osteoporosis, heart disease and cancer. With regard to menopausal symptoms, the evidence from randomized placebo-controlled trials in Western populations is conflicting for soy and derivatives of red clover (Lethaby et al 2007). Similarly, debate also surrounds the effects on lipoproteins, endothelial function, blood pressure, cognition and the endometrium. Endometrial hyperplasia has been reported in soy users. Further well-designed randomized trials are needed to determine the role and safety of phytoestrogen supplements in perimenopausal and postmenopausal women and those who have survived cancer.

Actaea racemosa (black cohosh) is a herbaceous perennial plant native to North America, used widely to alleviate menopausal symptoms. The results from placebo-controlled trials are conflicting. There is no consensus regarding whether non-oestrogenic or oestrogenic actions are involved in the mechanisms by which it relieves hot flushes. Little is known regarding long-term safety, and liver toxicity has been reported.

Evening primrose oil is rich in γ-linolenic acid. One small placebo-controlled, randomized trial showed it to be ineffective for the treatment of hot flushes.

Angelica sinensis (dong quai) is a perennial plant native to south-west China. It was not found to be superior to placebo in a randomized trial, but may be effective when combined with other herbs. Interaction with warfarin and photosensitization have been reported.

Ginkgo biloba (gingko) is widely used but there is little evidence that it improves menopausal symptoms.

Panax ginseng (ginseng) is a perennial herb native to Korea and China. It does not appear to be effective for hot flushes. Case reports have associated ginseng with postmenopausal bleeding and mastalgia. Interactions have been observed with warfarin, phenelzine and alcohol.

Piper methysticum (kava kava) may be an effective symptomatic treatment for anxiety, but the data about menopausal symptoms are conflicting. Concern about liver damage has led regulatory authorities to suspend or withdraw kava kava.

Wild yam cream, dong quai, St John’s wort, Agnus castus (Chasteberry), liquorice root and Valerian root are also popular, but no good evidence shows that they have any effect on menopausal symptoms. Claims have been made that steroids (e.g. diosgenein) in yams (Dioscorea villosa) can be converted to progesterone in the body, but this is biochemically impossible in humans.

Homeopathy

Samuel Hahnemann (1755–1843), a German physician and scientist, was the first to enunciate the central tenets of homeopathic philosophy. He believed in a ‘vital force’ that animates and regulates the human form and directs growth, healing and repair. He postulated that a homoeopathic remedy acted through the vital force. He then put forward the principle of ‘similars’, which claims that patients with particular signs and symptoms can be cured if given a drug that produces the same signs and symptoms in a healthy individual. He then pursued the concepts of minimum dose and succession (the curative action of certain preparations seemed to be stronger at some of the lower doses, particularly when shaken vigorously). The underlying mechanisms of homeopathy are scientifically unclear. While limited data are encouraging, further research is needed.

Dehydroepiandrosterone

DHEA is a steroid secreted by the adrenal cortex. Blood levels of DHEA decrease dramatically with age. This led to suggestions that the effects of ageing can be counteracted by DHEA ‘replacement therapy’. In the USA, it is classed as a food supplement. No evidence shows that DHEA has any effect on hot flushes (Raven and Hinson 2007). Some studies have shown benefits on the skeleton, cognition, well-being, libido and vagina. The safety of long-term use is, as yet, unknown.

Progesterone transdermal creams

Progesterone is available in gels and creams. One licensed gel is available in Europe; however, it is indicated for local use on the breast but not for systemic therapy. A vaginal gel for endometrial protection has been studied. Progesterone creams have been advocated for the treatment of menopausal symptoms and skeletal protection. However, at present, insufficient published data show that transdermal progesterone has a positive effect on vasomotor symptoms or the skeleton. There is also no consistent evidence that transdermal progesterone creams can prevent mitotic activity or induce secretory change in an oestrogen-primed endometrium. Thus, it should not be used for endometrial protection in women using systemic oestrogen.

Mechanical

These approaches include acupuncture, reflexology, magnetism acupressure, Alexander technique, Ayurveda, osteopathy and Reiki. Data with regard to the menopause are scant, and well-designed adequately powered studies are required.

Premature Ovarian Failure

POF is responsible for 4–18% of cases of secondary amenorrhoea and 10–28% of cases of primary amenorrhoea. It is estimated to affect 1% of women under 40 years of age and 0.1% of those under 30 years of age. Although the terms ‘POF’ and ‘premature menopause’ are often used interchangeably, there is debate regarding which term is best. Some women with POF will have oligomenorrhoea, and have persisting sporadic ovarian activity and can become spontaneously pregnant (Nelson et al 2005). In contrast, menopause implies permanent cessation of ovarian activity and menstruation, and infertility. With regard to an age cut-off, premature menopause should ideally be defined as menopause that occurs at an age more than two standard deviations below the mean estimated for the reference population. In the absence of reliable estimates of age of natural menopause in developing countries, the age of 40 years is often used as an arbitrary limit below which the menopause is said to be premature. In the developed world, however, an age of 45 years should be taken as the cut-off point.

Aetiology

Primary premature ovarian failure

Primary POF can occur at any age, even in teenagers. It can present as primary or secondary amenorrhoea or oligomenorrhoea. In the great majority of cases, no cause is found. Traditionally, ovarian failure has been associated with one of two scenarios:

• a deficient number of primordial follicles from the onset of menarche or accelerated follicle atresia; or

• follicles resistant to stimulation by gonadotrophins.

In the absence of a non-invasive test to differentiate between follicular depletion or dysfunction, the only alternative is ovarian biopsy. The validity of single biopsies has been questioned, with pregnancies occurring despite histological lack of follicles in the biopsy material.

The causes are detailed in Box 28.2.

Chromosome abnormalities

Two intact X chromosomes are required for normal follicular development. A critical region on the X-chromosome (POF1), which ranges from Xq13 to Xq26, which relates to normal ovarian function has been identified, as has a second gene of paternal origin (POF2), which is located at Xq13.3–q21.1. Idiopathic POF can be familial or sporadic, and the familial pattern of inheritance is compatible with X-linked with incomplete penetrance or an autosomal-dominant mode of inheritance. Complete absence of one X chromosome (45XO) in Turner’s syndrome results in ovarian dysgenesis and primary ovarian failure. Familial POF has been linked with fragile X permutations. Women with Down’s syndrome (Trisomy 21) also have an early menopause. Blepharophimosis/ptosis/epicanthus (BEPS) syndrome is a rare autosomal-dominant condition that leads to congenital abnormalities of the eye. In BEPS I, eyelid malformation cosegregates with POF and has been mapped to chromosome 3q.17.

FSH receptor gene polymorphism and inhibin B mutation

Gonadotrophin resistance can lead to the clinical features of POF, and this has been shown in a cohort of Finnish families. This is a very rare cause. In addition, a mutation in the inhibin gene has been identified. These patients experienced ovarian failure at an early age, often before the second decade of life.

Enzyme deficiencies

A number of enzyme deficiencies have been found to be associated with an increased risk of POF. The most common is galactosaemia. Other enzyme abnormalities associated with POF include deficiencies of 17α-hydroxylase, 17–20 desmolase and cholesterol desmolase.

Autoimmune disease

POF is frequently associated with autoimmune disorders, particularly hypothyroidism (25%), Addison’s disease (3%) and diabetes mellitus (2.5%). Other coexisting conditions may include Crohn’s disease, vitiligo, pernicious anaemia, systemic lupus erythematosus and rheumatoid arthritis.

Secondary premature ovarian failure

Secondary POF is becoming more important as survival after the treatment of malignancy continues to improve. Techniques to conserve ovarian tissue or oocytes before cancer therapy should help with maintenance of fertility. The causes of secondary POF are detailed below.

Chemotherapy and radiotherapy

The likelihood of ovarian failure after chemotherapy or radiotherapy depends on the agent used, dosage levels, interval between treatments and, particularly, the age of the patient, which probably reflects the age-related progressive natural decline in the oocyte pool. The prepubertal ovary is relatively resistant to the effects of chemotherapeutic alkylating agents. The use of GnRH analogues to suppress ovarian activity in order to mimic prepubertal protection is, as yet, not supported by randomized-controlled trials.

Bilateral oophorectomy or surgical menopause

This results in an immediate menopause which may be intensely symptomatic. The implications of this procedure require detailed discussion with the patient in view of the increased morbidity and mortality in those who cannot, or will not, take oestrogen replacement. This area is of increasing importance in those having prophylactic oophorectomy such as BRCA1 gene carriers.

Hysterectomy without oophorectomy/uterine artery embolization

Both procedures can diminish ovarian reserve and lead to ovarian failure. Diagnosis may be difficult in women where the procedures have made them amenorrhoeic.

Infection

Tuberculosis and mumps are infections that have been implicated most commonly. Malaria, varicella and shigella infections may also cause POF.

Consequences of premature ovarian failure

Women with untreated premature menopause are at increased risk of developing osteoporosis, CVD, cognitive decline, dementia and Parkinsonism, but at lower risk of breast malignancy (Shuster et al 2008). Mean life expectancy in women with menopause before the age of 40 years is 2 years shorter than that in women with menopause after the age of 55 years.

Management

Patients must be provided with adequate information about the condition, its implications on long-term health, use of oestrogen replacement and fertility (Pitkin et al 2007). In those who have not had an oophorectomy, the return of spontaneous ovarian activity and the possibility of spontaneous pregnancy must be explained. While pregnancy may be welcomed by some, this is not true for all women. Women who do not wish to have children need to consider using an effective form of contraception.

Hormone replacement therapy

Oestrogen replacement therapy is the mainstay of treatment for women with POF and is recommended until the average age of natural menopause. This view is endorsed by regulatory bodies. This does not increase the risk of breast cancer to a level greater than that found in normally menstruating women, and women with POF do not need to start mammographic screening early (Ewertz et al 2005). HRT or the combined contraceptive pill may be used. The choice of which to use largely depends on the patient’s age, with the former being more likely to be acceptable to women in their 30s and 40s and the latter being more likely to be acceptable to women in their 20s. There is no evidence to support the efficacy or safety of the use of non-oestrogen-based treatments, such as bisphosphonates, strontium ranelate or raloxifene, in these women. Some patients report reduced libido or sexual function despite apparently adequate doses of oestrogen replacement, especially oophorectomized women, and they may need testosterone addition.

Fertility and contraception

It is important to ascertain whether or not the woman wishes to have children. While women with premature menopause have traditionally been considered to be infertile, the lifetime chance of spontaneous conception in women with karyotypically normal POF has been estimated at 5–15%. A number of ovarian reserve tests (ORTs) have been designed to determine oocyte reserve and quality (Broekmans et al 2006). These include early-follicular-phase blood values of FSH, oestradiol, inhibin B and anti-Müllerian hormone, antral follicle count, ovarian volume, ovarian blood flow, the clomiphene citrate challenge test, the exogenous FSH ORT and the gonadotrophin agonist stimulation test. A systematic review of ORTs has shown that they only have modest-to-poor predictive properties.

Donor oocyte in-vitro fertilization (IVF) is the treatment of choice for women with primary and secondary POF (Lee et al 2006). In women having chemotherapy or radiotherapy, IVF with embryo freezing prior to treatment currently offers the highest likelihood of a future pregnancy should they experience POF as a result of their treatment. Recent advances in oocyte preservation have improved livebirth rates following freezing of mature eggs. It is still less successful than embryo freezing. Ovulation induction risks delaying treatment. Cryopreservation of ovarian tissue is still largely experimental, although pregnancies have been reported. This technique would be an option for prepubertal girls in whom ovulation induction is not possible.

KEY POINTS

1 The menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity, and occurs in the early 50s. Worldwide, the elderly population is increasing, with women forming the majority. Thus, chronic diseases affecting postreproductive health spanning over several decades are major public health issues. The major issues affecting postmenopausal women are vasomotor symptoms, psychological disorders, urogenital atrophy, sexual dysfunction, osteoporosis, CVD, dementia and urinary incontinence.

2 HRT relieves menopausal symptoms and conserves bone mass. Women with POF need HRT until their early 50s. Up to 60 years of age, the benefits of HRT outweigh the risks and mortality is reduced. There are no effective alternatives to oestrogen with long-term safety data for vasomotor symptoms. The role of oestrogen in CVD, dementia and quality of life is currently unclear.

3 With regard to the risks of HRT, the main areas of concern are breast and endometrial cancer and VTE. The increase in risk of breast cancer is approximately equivalent to the increase in relative risk of breast cancer associated with each year the menopause is delayed after 50 years of age. In non-hysterectomized women, progestogen is added to oestrogen to reduce the risk of endometrial cancer. Oral oestrogen, but not transdermal oestrogen, increases the risk of VTE.

4 Non-hormonal treatments for osteoporosis, such as bisphosphonates and strontium ranelate, have mainly been studied in women over 60 years of age at increased risk of the disease. Data for younger women are limited, and these treatments should not be used in women contemplating pregnancy since the effects on the developing fetal skeleton and the long-term consequences are unknown.

5 The evidence that complementary and alternative therapies are effective is poor, and there are concerns about safety and interactions with standard pharmacopoeia.

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