Taken at face value, the menopause should be viewed as a normal life event. The last menses simply signifies the beginning of a new era in the woman’s life cycle: the postmenopausal phase. Since all women will undergo the menopause (or die beforehand), it cannot be regarded per se as abnormal. The menopause marks the cessation of the female reproductive potential and is characterized by markedly decreased estrogen levels and very low progesterone levels. The roles of these hormones are quite varied. The physiologic function of progesterone appears to be confined mainly to pregnancy, but that of estrogen reaches far beyond with effects on various organs and systems; and this, coupled with the confirmed relationship between the decline in estrogen and hot flashes and sweats, has undoubtedly contributed to the definition of the menopause as an estrogen deficiency state. The menopause coincides with an age-related increase in incidence of a wide variety of potentially serious medical conditions. It is little wonder that research into the relationship, if any, between the reproductive hormones, especially estrogen, and cardiovascular disease (CVD), osteoporosis and Alzheimer’s disease, for example, has attracted so much attention.

There is a tendency, however, to concentrate on the decline in estrogen levels and to describe the menopause as an ‘estrogen deficiency state’ or ‘ovarian failure’. Although these terms can be used to define the menopause, this approach is simplistic and creates an impression of pathology. The association of the menopause with, for example, CVD, osteoporosis and urinary incontinence gives an impression of causality, which may or may not exist. It can be argued that the menopause is only one of many factors which — together with life-style, diet, genetic predisposition and the process of aging — can be blamed for various diseases that occur with higher frequencies during the postmenopausal phase of the woman’s life. Inevitably, low estrogen levels, hormonal changes and hormonal replacement figure prominently in discussions of the menopause, partly because of the causality theory and partly because there are numerous data and research studies to draw from. However, we believe in a balanced, wider, holistic approach to the menopause. We hope that in future non-hormonal strategies will figure in chapters on the menopause more prominently.

Life expectancy in the developed world has increased steadily during the twentieth century, and women commonly live more than one-third of their life in a postmenopausal state (see Life expectancy in the UK for people of various ages). In the UK, 18% of the entire population comprises women over 50 years of age. There are over 10 million women in the UK in a low estrogen state.

Table Life expectancy in the UK for people of various ages

Men

Women

Age (years)

1911

1971

1991

2011

1911

1971

1991

2011

0

50.4

68.8

73.2

77.4

53.9

75.0

78.8

81.6

20

44.0

50.9

54.2

58.0

46.4

56.7

59.6

62.0

40

27.5

31.8

35.2

39.0

29.8

37.3

40.0

42.5

60

13.7

15.3

17.7

21.0

15.3

19.8

21.9

24.1

80

4.9

5.5

6.4

77.0

5.6

6.9

8.4

9.1

The impact of these statistics upon health resources has recently begun to be understood more fully because of the greater knowledge of the effects of estrogen deficiency on the various organ systems. As discussed below, estrogen deficiency has been linked to osteoporosis and coronary heart disease (CHD). The financial impact of osteoporosis alone has been estimated to amount to £1.7 billion in the UK with some 70 000 hip fractures each year, leading to 40 premature deaths every day. CHD is the leading cause of death in women in the UK and USA: it accounts for the death of 17% of all women and 27% of women under the age of 75 years in the UK. CHD presents an enormous financial burden to the economies of the developed world, currently estimated at £10 billion per year in the UK alone (total including both direct and indirect costs to the economy). It is thus important to define precisely the link between the effects of estrogen deficiency and CHD, and preventive strategies need to be developed, if possible. This chapter presents an overview of the current understanding of hormonal and especially estrogen deficiency on various target organs, outlines the principles of hormone replacement therapy (hormone replacement therapy) and describes non-hormonal interventions which may improve the health of postmenopausal women.

Estrogens

Estrogen describes a group of steroid hormones produced primarily in the ovaries during reproductive life, but additionally in extra-gonadal sites such as adipose tissue. Estradiol is the primary estrogen during reproductive life, and is secreted by the granulosa cells of the developing follicle in response to follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion from the anterior pituitary gland. The estradiol concentration varies throughout the menstrual cycle, with low levels in the early follicular phase (150-200 pmol/1), a peak at mid-cycle (1200-1500 pmol/1) and intermediate levels (500 pmol/1) in the luteal phase. A small amount of estrone is also produced, derived mainly by peripheral conversion of androstenedione in adipose tissue, and the ratio of estradiol:estrone in the premenopausal woman remains at around 3:1. The daily production of estradiol during the reproductive years is 0.07-0.8 mg, dependent upon the phase of the cycle. In the serum, 38% of estradiol binds to sex hormone binding globulin, a (3-globulin. About 60% of estradiol binds with lower affinity to albumin. A small fraction (2-3%) remains unbound. Following the menopause, estradiol levels are commonly below 110 pmol/1, but the peripheral conversion of androstenedione to estrone increases. In the postmenopause, estradiol levels decrease more relative to estrone levels, leading to a reversal of the estradiol:estrone ratio to 1:3. Estrone becomes the primary postmenopausal estrogen, but its potency is only 1-30% compared with estradiol. Potency is measured in vivo and in vitro using a variety of assays (thus explaining the breadth of the potency range above), e.g., inducing estrus in animals, cornification (maturation) of vaginal epithelial cells, uterine weight in rodents and studying effects on cell cultures. Consequently the classic symptoms of estrogen deficiency develop, as discussed below. Endogenous estrogens are primarily metabolized in the liver where they are conjugated with glucoronide (and sulfate) to form water-soluble products, and then excreted in the bile and urine in an inactive form. In the bowel, bacteria are able to remove the glucoronide and the sulfate groups. This frees some estrogen for reabsorption which then re-enters the liver through the portal vein. This process is known as the enterohepatic cycle.

Menopause, Hormone Replacement Therapy And Their Effects On The Body

Contraindications And Risks Of Hormone Replacement Therapy

Prescribing Hormone Replacement Therapy

Premature Ovarian Failure

Premature ovarian failure (POF) is the cessation of normal reproductive function before the age of 40 and is seen in about 1% of women. Patients may present clinically with either primary or secondary amenorrhea, or with menstrual irregularity or with hot flashes, sweats, fatigue, irritability or depression. The diagnosis is confirmed by the finding of elevated gonadotropin levels, measured on three separate occasions, one to two months apart. The causes of POF are numerous (Table Causes for premature ovarian failure), but they all converge in a common pathway of accelerated follicular loss. Most cases are idiopathic (about 55-60%), the second in prevalence being Turner’s syndrome (20-25%).

Table Causes for premature ovarian failure

  • Idiopathic
  • Turner’s syndrome
  • Autoimmune
  • Chemotherapy
  • Familial
  • Pelvic surgery
  • Pelvic irradiation
  • Galactosemia
  • 46XY gonadal dysgenesis

Investigations beyond those confirming POF need not be extensive. Chromosomal analysis is necessary for women with primary amenorrhea if there are features suggestive of a chromosomal abnormality. The presence of the Y chromosome increases the risk of a germ cell tumor. The connection between POF and autoimmune disease should be considered and periodic screening for subclinical thyroid disease, adrenal insufficiency, pernicious anemia and antinuclear antibodies is often practiced. Ovarian biopsy does not add information which leads to change of management and is not recommended.

The young woman who is found to have premature ovarian failure requires a great deal of emotional support. Because POF is currently untreatable, it puts the patient at greatly increased risk of CVD and osteoporosis, and the diagnosis has major implication for sexual relationships, sex, sexuality and fertility. It is of paramount importance that patients understand the nature and prognosis of their condition, not least because it helps their acceptance of long-term hormone replacement. hormone replacement therapy will minimize the risk of CVD and osteoporosis, will alleviate menopausal symptoms if present, will bring sexual maturation and development of secondary sexual characteristics in infantile women and will restore and enhance sexuality. Often higher than usual doses of estrogen are necessary in these unfortunate patients. Androgen replacement should be offered to women who, in spite of adequate estrogen replacement, continue of complain of persistent fatigue, loss of determination and general well-being, and low sex drive. Androgen is best administered via subcutaneous implants, 50-100 mg every four to six months. In about a quarter of cases with premature ovarian failure (especially in idiopathic cases or after chemotherapy) there is spontaneous reversal of the condition and patients may start menstruating again or even become pregnant. It may be useful to monitor such patients by stopping hormone replacement therapy every one to two years for three months and measuring their gonadotropins. However, the fertility prognosis is generally poor and those patients desiring a family should be encouraged to think in terms of adoption or egg donation. Provisions for long-term follow-up should be in place to provide continuous support and health surveillance, and to monitor hormone replacement therapy.

Selective Estrogen Receptor Modulators

Non-Hormonal Strategies For Improvement Of Women’s Health In The Menopause

Summary

The physiologic changes in women around and after the menopause are complex and not completely understood. Some of these changes are due to the aging process and some undoubtedly have a hormonal basis. The normal menopause occurs because of aging (not the other way around) and for some time it was widely thought that the clock can be turned back by use of hormone replacement therapy. This belief may have been over-optimistic, but it was not frivolous — there was a mountain of experimental and observational data to support it. Estrogen was thought to prevent coronary heart disease (CHD), improve mood, cognition, sexuality and well-being, delay the onset or change the severity of Alzheimer’s disease and improve stress incontinence. This was on top of the well known effects on the bone, vasomotor symptoms and urogenital atrophy. The pharmaceutical industry responded with developing numerous estrogenic agents, regimens and routes of administration. Hormonal preparations were widely prescribed and poor compliance lamented by doctors and policy makers. With the results of a number of randomized controlled trials being published the current state of affairs is changing. The main conclusions are that: (1) the results are not immediately generalizable to all women and for all hormone replacement therapy preparations; (2) for many women the risks overweight the benefits; (3) women with established coronary heart disease or stroke should not take certain continuous combined hormone replacement therapy preparations; (4) the absolute risks of hormone replacement therapy are small; (5) some suspected benefits are now established, e.g., on incidence of hip fracture and bowel cancer; (6) women should not start hormone replacement therapy with the sole aim of preventing CHD; (7) in normal women with mild or no vasomotor symptoms continuous combined hormone replacement therapy (0.625 mg of CEE and 2.5 mg of MPA per day) does not improve quality of life in terms of sleep, sexual or cognitive function or body pains; (8) hot flashes are not deadly, but can be very disabling and short-term use (2-3 years) of hormone replacement therapy in healthy women is safe and effective treatment to relief this symptom.

Nikolai Manassiev, Fergus Keating and Henry Burger

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