Ovarian

The approaching menopause is associated with loss of ovarian follicular activity. Human ovaries contain approximately 700,000 follicles at birth, but these cells have a high mortality rate and fewer than 500 of them will be ovulated. This number falls progressively with increasing age so that by the time the woman approaches 50 years of age, the number of follicles has fallen to zero or very few. The rate of follicle loss is highest during the decade between 40 and 50 years of age, possibly due to an increase in the rate of degeneration (atresia) of the earliest follicles. Women over the age of 45 years who are menstruating regularly have been shown to have 10 times as many follicles as those with irregular cycles; those who have not had a period for 12 months have few follicles remaining. Thus, the size of the follicular pool is an important determinant in ovarian function.

Ovarian function includes two major roles: the production of eggs (gametogenesis) and the synthesis and secretion of hormones (hormonogenesis). Both of these functions undergo subtle changes with ageing so that fewer ova are produced and they are less readily fertilised, and the hormone levels become irregular. It is the granulosa cells in the developing follicle that normally secrete estradiol, and lack of this follicular activity results in diminishing oestrogen secretion. The diminution in the number of active follicles is followed by an increase in follicle-stimulating hormone (FSH) secretion from the anterior pituitary gland as the normal feedback mechanisms between ovarian estradiol secretion and the hypothalamus–pituitary axis become disrupted. It may be that there is an age-related decrease in sensitivity to feedback inhibition that exacerbates this increase in FSH levels. In women who are still bleeding, an FSH level exceeding 10–12 iu/L on day 2 or 3 of the bleed is indicative of a diminished ovarian response. A high FSH level (above 30 iu/L) and a low estradiol level (below 100 pmol/L) in the plasma characterise menopause. The low oestrogen level fails to stimulate growth of the uterine endometrium. As endometrial growth has not occurred, there can be no menstruation (shedding of the endometrium) and this signifies that menopause has arrived. Since ova are not being released, the production of progesterone from the ovary also ceases and the levels of luteinising hormone (LH) eventually rise. Thus, peri-menopausal and menopausal women are subjected to an increasing ovarian hormone deficiency, as shown in Table 46.1.

Table 46.1 Ovarian hormone secretion after the onset of the normal menstrual cycle

When the ovaries are conserved after hysterectomy they will usually continue to produce some estradiol, but the levels of this hormone will decline up to the age of the natural menopause. Post-menopausally, in all women, androstenedione (secreted from the adrenal cortex) is converted in adipose tissue and muscle (peripheral conversion) to estrone, which becomes the major circulating oestrogen (but estrone is about 10 times less potent than estradiol). The levels of FSH and LH remain elevated for many years if no HRT is given, but these elevated levels have no effect on the ovary since the follicles are atretic.

The cessation of reproductive function in the woman and the declining oestrogen production from the ovary are not the only physiological events associated with menopause. For many years, oestrogen was considered to be associated only with the genitourinary system, but its effects are more wide ranging and the major tissues affected include blood vessels, bones and the brain.

Urogenital system

With the failure in ovarian oestrogen production, the number of uterine endometrial oestrogen receptors occupied falls and endometrial growth is not sustained. Thus, in the post-menopausal woman, the endometrium becomes thin and atrophic. Likewise, in the other target tissues containing oestrogen receptors, the basal layers of the vaginal epithelium are no longer stimulated to maintain the vaginal epithelium and produce natural lubricants from the vaginal glands. The result is vaginal atrophy and a thin, dry vagina may result in dyspareunia. Because the lower urinary tract and the lower genital tract share common embryological origin, deprivation of oestrogen can result in urethral and bladder problems. Often, peri-menopausal and post-menopausal women report an increase in urinary frequency, nocturia and urge incontinence. For some women, these changes may become manifest as long as 10 years after menopause.

Bone

Osteoporosis is defined by WHO as a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk. In 2006, WHO estimated that it affects 200 million women worldwide. In addition, approximately 30% of women over the age of 50 have one or more vertebral fractures compared with one in five men over the age of 50 who will have an osteoporosis-related fracture in their remaining lifetime. The total number of hip fractures in 1950 was 1.66 million, and by 2050, this figure could reach 6.26 million. Twenty percent of people die within 1 year of a hip fracture (Cooper, 1997). Typical morbidities after a vertebral fracture include:

To contextualise risk, the remaining lifetime probability in women at menopause of a fracture at any one of these sites exceeds that of breast cancer (~12%). Also, the likelihood of a fracture at any of these sites is 40% or more in developed countries (Kanis et al., 2000), a figure close to the probability of coronary heart disease. Risk factors for osteoporosis include low body mass index (<19 kg/m²), smoking, early menopause, family history of maternal hip fracture, long-term systemic corticosteroid use and conditions affecting bone metabolism, especially those causing prolonged immobility. Osteoporosis is most common in white women. People with osteoporosis are at risk of fragility fractures, occurring as a result of mechanical forces which would not ordinarily cause fracture. The clinically relevant outcome in evaluating treatments for osteoporosis is the incidence of fragility fracture as otherwise this condition is asymptomatic and therefore undiagnosed. The most common sites for these fractures are the hip, vertebrae and wrist. In the UK, the combined cost of hospital and social care for patients with a hip fracture amounts to more than £1.73 billion per year (Torgerson et al., 2001). This is very similar to the annual £1.75 billion health care system costs of coronary heart disease costs. The cost of treating all osteoporotic fractures in post-menopausal women has been predicted to increase to more than £2.1 billion by 2020 (Burge, 2001).

Cardiovascular system

Young adult women are protected against the development of hypertension and its deleterious consequences in the cardiovascular system. Levels of low-density lipoprotein cholesterol (LDL-C) and very-low-density lipoprotein cholesterol (VLDL-C) are decreased by oestrogen, and the levels of high-density lipoprotein cholesterol (HDL-C) are increased, thereby giving some protection against atherosclerosis. HDL-C is known to promote cholesterol efflux from macrophages in the arterial wall, thereby reducing atheromatous plaque and conferring a protective effect against heart disease. However, after menopause, this protection is lost and the incidence of high blood pressure and associated cardiovascular disease increases to levels similar to those found in age-matched men.

Oestrogen has direct beneficial effects in the control of blood pressure, possibly via regulating endothelium-mediated control of arteriolar tone. In women deprived of oestrogen, endothelium-dependent vasodilation is impaired. This dysfunction is largely associated with a reduction in nitric oxide availability. Oestrogen increases nitric oxide availability by stimulating endothelial nitric oxide synthase (eNOS). Oestrogen also stimulates the production of other endothelium-derived relaxing factors such as prostacyclin (prostaglandin I₂). Research suggests that the oestrogen receptor (ER)α is important in mediating the vascular effects of oestrogen. Studies using selective ERα agonists are being undertaken. However, many pathways are stimulated by oestrogen receptor activation and the relative importance of these different pathways varies from tissue to tissue.

Miscellaneous

Thinning of the skin, brittle nails, hair loss and generalised aches and pains are also associated with reduced oestrogen levels (Hall and Phillips, 2005). The skin is the largest non-reproductive target on which oestrogen acts. Oestrogen receptors, predominantly of the ERβ type, are widely distributed within the skin. Both types of oestrogen receptor (ERα and ERβ) are expressed within the hair follicle and associated structures. Thus, epidermal thinning, declining terminal collagen content, diminished skin moisture, decreased laxity and impaired wound healing (selective ERα ligands are being investigated for their wound-healing properties) have been reported in post-menopausal women.

In addition, women also show increasing body weight associated with ageing. This weight gain tends to increase or begin near menopause. Body fat redistribution to the abdomen also occurs independent of weight gain. This type of centralised abdominal fat distribution is widely recognised as an independent risk factor for cardiovascular disease in women.

Oestrogen therapy

Since the symptoms and long-term effects of menopause are due to oestrogen deprivation, the mainstay of HRT is oestrogen. This may be administered orally or parenterally but, in either case, the oestrogens used are naturally occurring and include:

The use of ‘natural’ oestrogens reduces the risk of the potentially dangerous oestrogenic effects such as raised blood pressure, alteration in coagulation factors and an undesirable lipid profile, which sometimes occur with the more potent synthetic oestrogens used in the oral contraceptive agents. A ‘natural’ oestrogen is defined as one that is normally found in the human female and has a physiological effect. Natural oestrogens are less potent (up to 200 times) than synthetic oestrogens. As they are naturally occurring compounds, the plasma half-life of these oestrogens is similar to that of the ovarian-secreted oestrogens and the duration of action is shorter than the synthetic oestrogens, such as ethinylestradiol, used in many formulations of the contraceptive pill. The plasma ratio of estradiol to estrone is normally about 1:1 to 2:1, and the aim of HRT should be to preserve this ratio.

There are four main routes of administration for oestrogens in HRT:

The use of oral oestrogen therapy, while convenient for the patient, does mean that the oestrogen will be subjected to conversion to estrone by the liver and the gut, thereby altering the estradiol:estrone ratio in favour of the less active oestrogen, estrone. The oral preparations have different metabolic effects due to first-pass hepatic metabolism. Smoking stimulates metabolism of oestrogens by cytochrome P450 and decreases plasma oestrogen levels by 40–70% in oral oestrogen users. Smoking has no significant effect on plasma oestrogen levels in users of transdermal preparations. Oral delivery compared to transdermal delivery (Table 46.2) also has different effects on lipid levels (Vrablik et al., 2008). In addition, orally administered oestrogens undergo first-pass hepatic metabolism, which may result in some reduction in anti-thrombin III, a potent inhibitor of coagulation. Implants and patches show smaller changes in coagulation, platelet function or fibrinolysis.

Table 46.2 Effect of HRT administration route on lipid profile

More constant levels of oestrogen result from the use of transdermal patches containing estradiol, and these have the added advantage of a more physiological estradiol:estrone ratio (Delmas et al., 1999). However, the adhesive used in these transdermal patches and the alcohol base can cause skin irritation. The patch is applied to the non-hairy skin of the lower body, and care should be taken to ensure that it is placed away from breast tissue. The patch is changed either once or twice a week, thus providing a constant reservoir of estradiol to provide a controlled release into the circulation. Estradiol is also available in a gel formulation, applied daily to the skin over the area of a template (to ensure correct dosage), but this formulation may give erratic absorption. The intranasal preparation, administered as a nasal spray, also avoids hepatic first-pass metabolism.

The oestrogen implant gives a constant level of oestrogen from a few days after insertion for up to 6 months. This formulation maintains the best estradiol:estrone ratio and is a convenient method of administration, requiring repeat implants only every 6 months. However, because the levels of oestrogen are constantly raised, there will be some increase in oestrogen receptor numbers, and this can lead to a recurrence of symptoms of oestrogen deficiency due to the presence of unoccupied oestrogen receptors, even in the presence of normal or even high oestrogen levels. This phenomenon, called tachyphylaxis, results in patients becoming symptomatic and requesting repeat implants earlier and earlier. In such cases, it is unwise to treat with additional oestrogen; the patient should receive counselling and perhaps a change of preparation. The disadvantage of the implant is that, once inserted, it cannot be removed readily and even if it is removed, the oestrogen level will take at least a month to fall. There is also evidence that the uterine endometrium, if present, remains stimulated for some time after removal of the implant.

Both the transdermal and implant preparations avoid the first-pass hepatic effects of oral oestrogens and are less likely to affect liver enzyme systems and clotting factors. Some studies show an increase in the incidence of venous thromboembolism (VTE) in women taking HRT. Therefore, patients who have a history of deep vein thrombosis or pulmonary embolism will need careful guidance, with each woman being considered individually, and the relative risks evaluated. Other risk factors include severe varicose veins, obesity or a family history of deep vein thrombosis (DVT). If HRT is justified in such patients, transdermal preparations are a better alternative than oral preparations.

Vaginal creams containing oestrogen are available but generally fail to produce the reliable plasma levels required to protect against the long-term effects of oestrogen deprivation. They provide short-term relief from menopausal symptoms, in particular, atrophic vaginitis. A vaginal ring which releases estradiol at a controlled rate in physiological levels for up to 3 months is an alternative for women who cannot tolerate transdermal patches.

The dose of oestrogen used in HRT sufficient to preserve bone density is usually higher than that necessary to alleviate vasomotor symptoms. The doses suggested to protect bone density are estradiol 2 mg/day orally, 50 μg/day transdermally and 50 mg every 6 months by implant. If the conjugated equine oestrogens are used, the oral dose should be 0.625 mg/day. The lower doses found in vaginal creams may alleviate the vasomotor symptoms but will not protect against osteoporosis. Current guidelines advise the use of the lowest possible dose of HRT to relieve vasomotor symptoms and recommend alternative treatment to prevent and treat osteoporosis.

Oestrogens should be used alone only in women who have undergone a hysterectomy; if the uterus is present, the endometrium will be stimulated and this increase in endometrial growth may be a precursor to development of a malignant condition. Current practice is to administer progestogens with oestrogen. In the early 1970s, when oestrogen was used alone, HRT received a bad press because in women who had not undergone hysterectomy, there was an increased incidence of endometrial carcinoma. In women who have undergone hysterectomy, oestrogens are usually administered continuously.