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.

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.