British Mahcal BidUtui (1992) Vol. 48, No. 2, pp 249-261 © The Bririjh Council 1992
Epidemiology of the menopause KTKhaw University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
Profound changes in birth and mortality rates in this century are resulting in the ageing of the population of Britain and other developed countries. The enormous decline in maternal mortality, in particular, has meant that increasing proportions of women are surviving to the menopause and years of active life beyond it. Women aged 55 years and over now comprise 15% of the population of Britain. The average life expectancy for women in developed countries is around 75 years; approximately 90% of women reach the age of 65 years, and 30% reach 80 years. If the average age of menopause is 50 years, most women will spend approximately one third of their lifetime in postmenopausal life; one in every two women will experience about 30 years of postmenopausal life.
All women living beyond the age of 55 years or so will experience the menopause, that is, the transition from the reproductive to the non-reproductive stage of life, characterised by the cessation of menstruation. However, the menopause has come to signify much more than simply the loss of reproductive capacity, and has been associated with numerous acute and chronic conditions. Some have even argued that the menopausal syndrome is a distinct entity of somatic and psychological symptoms and illness. Whether this is so, and if so, how much might be due to changing hormonal status, how much to increasing biological age and how much to the social and cultural significance of the menopause is still debatable. On one hand, it has been argued that a large proportion of the conditions associated with the peri- and postmenopausal period can be largely attributed to oestrogen deficiency associated with the menopause, and hence, potentially remediable by hormone
250
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replacement therapy. 12 These conditions include acute symptoms—such as hot flushes, night sweats and depression—as well as chronic disease—such as cardiovascular disease and osteoporosis—which increase after the menopause. On the other hand, the increasing incidence of many diseases associated with the menopause may largely reflect the biological ageing that would occur in any case. It has been suggested that many of the symptoms associated with the menopause, such as depression, are related to the social and cultural context in which the menopause occurs.3"5 The implications in terms of optimal strategies for dealing with the symptomatology and other conditions occurring in peri- and postmenopausal women are considerable. DEFINITIONS OF THE MENOPAUSE The term menopause literally signifies the permanent cessation of menstruation. By convention, this is a diagnosis made in retrospect following a period of amenorrhea for 12 months. In clinical practice, the term menopause is often used to indicate the period of time during which spontaneous menstruation normally ceases; it is characterised endocrinologically by evidence of decreasing ovarian activity, biologically by decreasing fertility, and clinically by alterations in menstrual cycle intervals and by a variety of symptoms. Though the diagnosis of menopause is based on clinical signs and symptoms; primarily, amenorrhoea, and confirmed when necessary with assays for steroid hormones or gonadotrophins, the loss of ovarian function is the essential characteristic of menopause. Thus, a surgical menopause should be confined to the procedure of bilateral oophorectomy, with or without hysterectomy but not include cessation of menstruation following a simple hysterectomy. A World Health Organization report on the menopause6 suggested the following definitions: 1. The menopause should be defined as the permanent cessation of menstruation resulting from loss of ovarian follicular activity. 2. The perimenopause (or climacteric) should be used to include the period immediately prior to the menopause with endocrinological, biological and clinical features of approaching menopause, and at least the first year after the menopause. 3. The postmenopause should be defined as dating from the menopause, although it cannot be determined until after a period of 12 months of spontaneous amenorrhea has been observed.
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ENDOCRINOLOGY OF THE MENOPAUSE This is detailed in the next chapter. Briefly, studies have indicated that in menstruating women, with increasing age, the length of the follicular phase gradually declines; towards the menopause oestradiol levels are lower and follicle stimulating hormone (FSH) levels are elevated during the early follicular phase compared to younger women.7'8 After the menopause, levels of FSH increase to 10-15 times the early follicular phase levels in young women, while luteinising hormone (LH) reaches a maximum three times higher about 2 years after the menopause.9 Premenopausally, the ovary is the major source of circulating oestrogens, predominantly oestradiol. After the menopause, the major source of oestrogens is from peripheral conversion in adipose tissue of adrenal androgen precursors, notably androstenedione, to oestrogens, mainly oestrone: the amount of body fat is hence a major determinant of oestrogen levels in postmenopausal women.10"12 Table 1 shows approximate plasma or serum concentrations in pre- and postmenopausal women. Most detailed studies on hormonal changes associated with the menopause have been conducted on Western women. However, while overall the pattern of hormonal changes with the menopause, namely the fall in oestrogen levels, are similar in all women, several studies have indicated that absolute levels of endogenous sex hormones may differ considerably in different communities; for example, Chinese and Japanese women have lower oestrogen levels both pre- and post-menopausally.13 Exogenous factors, in particular diet, have been suggested to play a role in determining sex hormone levels: high fat intakes have been associated with higher endogenous androgens or oestrogen levels,13'14 whereas a vegetarian diet, or high fibre intake is associated with lower oestrogen Table 1 Plasma or serum concentrations of sex hormones in pre-and postmenopausal women (data from Reference 12) Mean plasma or serum concentrations Premenopausal Oestradiol (pmol/1) Oestrone (pmol/1) Androstenedione (pmol/1) Testosterone (pmol/1) Dehydroepiandrosterone (nmol/1) Dehydroepiandrosterone sulphate (nmol/1)
620 440 6300 1000 17000 5400
Postmenpausal 40 110 3100 800 5500 1000
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and increased sex hormone binding globulin levels.14'15 Animal studies have indicated one possible mechanism to be plant phytooestrogens which have a very weak competitive oestrogenic effect, possibly suppressing pituitary FSH and LH secretion.16 Cauley reported that physical activity was inversely related to oestrone levels in postmenopausal women,17 and yet other studies have indicated that cigarette smoking is associated with decreased oestrogenic activity and higher adrenal androgen levels in postmenopausal women.18"20 We still have an incomplete understanding of the hormonal changes occurring at the menopause, how they may vary in different populations, and how they may be influenced by exogenous factors, such as diet. Hormone replacement therapy not only, as expected, increases levels of circulating oestrogens but also has considerable other effects including a decrease in endogenous androgens and increase in sex hormone binding globulin and cortisol levels;21 it is possible that some of the benefits and risks of replacement oestrogens are secondary to these other endocrine changes. Adequate endocrinological characterisation of perimenopausal women, and the clarification of the relationship of sex hormone profiles to postmenopausal disorders, which may vary widely in different women, may help give indications as to the causes of these disorders and hence, clues to prevention. AGE DISTRIBUTION OF THE MENOPAUSE Because the diagnosis of menopause can only be made in retrospect, most studies, both retrospective and prospective have considerable limitations as they have to rely on accurate knowledge and unbiased reporting of age. Comparison between studies is also difficult as definitions of menopause are not identical. Within these limitations, the median age at menopause in most Western industrialised societies, where studied, has been shown to be remarkably constant, around 50 years, though there is a wide range between 35 to 59 years or so around a slightly skewed normal distribution. Premature ovarian failure is well documented in women below the age of 40; at the other end, pregnancies have been documented in women aged 55 years or so: the oldest verifiable mother was reported from California as aged 57 years 129 days.22 The mean age of menarche has been falling, and it has been proposed that the age of menopause has increased over the last 100 years, but no strong evidence supports this; a review by Gins-
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burg23 cited reports from Aristotle, Hippocrates and Roman authors indicating that 2000 years ago, most women entered the menopause in their early 40s; however, medieval authors gave the 50s as the age when menses ceased.24 Gray has reviewed studies showing estimated age at menopause;24 estimates from selected studies25"39 are listed in the Table 2. There is a paucity of data from non-Westernised populations, but some studies have indicated lower menopausal age in communities where malnutrition is common. FACTORS AFFECTING MENOPAUSAL AGE Nutritional status Age at menarche appears to be profoundly related to nutritional status; women with malnutrition in Papua New Guinea had approximately 4 years earlier menopause compared with women who were not malnourished; the malnourished women had both lower heights and weights.36 Other studies have indicated that both height40 and weight28 may influence menopausal age. Cigarette smoking Of all the known possible risk factors, cigarette smoking is perhaps the most well documented. Women who smoke have a menopause on average one to two years earlier than non-smokers.20>41~51 The mechanism for this is not well understood. One possibility is an anti-oestrogenic effect of cigarette smoking: Michnovicz et al.18 reported that women smokers appeared to metabolise exogenous oestrogen more rapidly than non-smokers and other studies have reported lower levels of oestrogens in smokers. Alternatively, components of cigarette smoke, such as aromatic hydrocarbons, might accelerate oocyte ageing.49 Other risk factors No other factors have been consistently related to menopausal age. Reproductive history, including early menarche, parity, upper socio-economic class, higher educational status, and oral contraceptive use have been suggested to be associated with later menopause, but associations have not been consistent, and the confounding effect of cigarette smoking for all these is possible.39'47'50'51
to
Table 2 Estimated age at menopause (data from References 24-37) Country and year of study
Race
England 1951-61 England 1965
Caucasian Caucasian
Scotland 1970 USA 1934-74
Caucasian Caucasian
USA 1966
Caucasian Black Caucasian Caucasian
Australia 1978 Sweden 1968-69; 1974-75 Germany 1972 Finland 1961 Switzerland 1961 Israel 1963 New Zealand 1967 Papua New Guinea 1973
India (Punjab) 1966
Caucasian Caucasian Caucasian Caucasian Caucasian Melanesian
Asian
Mean or median 49.8 median 50.8 median 47.5 mean 50.1 median 49.8 median 49.5 mean 50.0 median 49.3 median 50.4 median 49.6 median 50.4 49.1 mean 49.8 mean 49.8 mean 49.5 mean 50.7 median 47.3 median (not malnourished) 43.6 median (malnourished) 44.0 median
o Study design cross-sectional cross-sectional cross-sectional cohort cross-sectional cross-sectional retrospective and cross-sectional retrospective retrospective retrospective retrospective cross-sectional cross-sectional
cohort and cross-sectional
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255
Most factors that influence age at menopause appear to hasten, not retard menopause. Oral contraceptives in particular are of interest since the menopause occurs when oocyte number falls below the threshold required for ovarian function. Since oral contraceptives inhibit ovulation, it might be hypothesised that prolonged use of oral contraception would postpone the menopause.51 It is not clear what factors determine ovarian failure. However, oral contraceptive use has not been consistently associated with a delayed menopause; Thomford suggested that, based on animal studies, and modelling on observed human data, ovarian failure is only weakly dependent on oocyte number; factors that decrease age at menopause appear to result primarily from an increase in the rate of oocyte atresia.52
SYMPTOMS ASSOCIATED WITH THE MENOPAUSE A large number of vasomotor, psychological, and gynaecological symptoms have been associated with the menopause. Studies reporting frequencies of these complaints based on women attending clinics suffer from obvious selection biases, and population based surveys are needed to document the true incidence and prevalence of such symptoms. Unfortunately, comparability between such population surveys are limited by differing methodologies and definitions. Nevertheless, some researchers have attempted to use standardised ascertainment and criteria enabling cross-cultural comparisons. Consistent symptoms that have emerged include:
Vasomotor symptoms There is clear agreement that the most characteristic symptoms of the perimenopausal period are hot flushes, night sweats, palpitations and headaches, attributed to vasomotor instability; it has been suggested that 75% of women are affected.27'53'54 Jaszmann,55 in a study in the Netherlands, reported 65% of the perimenopausal women experience hot flushes during the menopause, 40% sweats, and 25% palpitations. A Canadian study4 also indicated a frequency of 65% of perimenopausal women reporting hot flushes at some time in the past. However, using identical methodology to the Canadian study, only 19.6% of the women in a Japanese survey5 reported hot flushes.
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HORMONE REPLACEMENT THERAPY
Psychological symptoms Depression, insomnia and tiredness reportedly increase in the perimenopausal period55"58 and was reported to affect 25% of perimenopausal women in the Netherlands survey.54 Again, in contrast, a Japanese survey5 showed lower prevalence of 5-10% for these symptoms. Other effects Vaginal dryness, atrophic vaginitis and dyspareunia are said to be virtually universal menopausal problems.54 Loss of libido affected 5% in a Swedish study, which appeared independent of genital symptoms.59 The symptomatology of the menopausal period and possible mechanisms and treatment are discussed in detail by Barlow elsewhere in this issue. While genital atrophy is generally accepted to be largely related to oestrogen deficiency, the mechanisms for symptoms such as the vasomotor and psychological ones are still not clear; in particular, the role of oestrogen deficiency is still debated. However, it is evident that prevalence of such perimenopausal symptoms vary enormously in different cultures. Such differences provide clues as to possible biological or sociological causes for the symptoms. Lock4 suggests that, 'any effort to divorce the biology of menopause from the meanings, both ideological and individuals, that are attributed to the associated social transition are, in clinical circumstances at least, inherently fraught with danger'. If symptomatology can be related to hormonal status, and hormonal profiles can be influenced by either directly by specific exogenous hormonal therapy, or indirectly by behavioural factors, such as physical activity or diet, this may help direct more effective interventions. CHRONIC DISEASES RELATED TO THE MENOPAUSE The incidence of most chronic diseases increase with age. Osteoporotic bone disease and atherosclerotic cardiovascular disease are two major causes of morbidity in women which have been suggested to be exacerbated by the menopause. Several prospective studies have reported that changing from pre- to postmenopausal status is associated with an unfavourable effect on lipid metabolism, namely decline in serum levels of high-density cholesterol
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257
declined compared to premenopausal controls and increase in low density lipoprotein cholesterol.60"63 Witteman60 has suggested that the increased risk of atherosclerosis in women after the menopause is independent of age. Table 3 shows age specific death rates for women by age group by selected causes of death in England and Wales.64 While all mortality rates undoubtedly increase after the menopause, cause specific rates differ in pattern; reproductive cancer rates tend to rise less steeply than cardiovascular disease and fractures. Table 3 also shows death rates for selected causes where available, for Japanese women.65 While the same increase of death rates with age is evident for Japanese women, the absolute rates are considerably lower. Since Japanese women have generally lower oestrogen levels than Caucasian women,66 the considerably lower cardiovascular disease rates in the Japanese cannot be explained by differences in oestrogen levels. Similarly, some studies have indicated accelerated bone loss following the menopause, reviewed by Compston in this issue. However, the two to threefold secular increase in the last thirty years in osteoporotic hip fractures in Britain67 cannot be attributable to any changes in the menopausal age, or to changes in hormone replacement therapy. The large secular and geographic variations in many of the conditions traditionally associated with the menopause suggest that, while the menopause may be a risk factor, there are other determinants which are likely to have a more profound influence. CONCLUSIONS The menopause is inevitable in all women who live beyond the age of 55 years or so. The most marked physiological change is the reduction in oestrogen levels and increase in FSH levels. The perimenopausal period is associated with considerable symptomatology. However, symptoms vary widely between individuals in the same population; the prevalence of such symptomatology also varies considerably between different populations. The relationship between changes in hormone levels and symptoms is not at all clearcut. The menopause has also been shown to be a risk factor for chronic diseases, namely, cardiovascular disease and osteoporosis which are considerable causes of mortality and morbidity in women. It is still not clear how far these conditions are due to oestrogen deficiency, and can be remedied by hormone replacement therapy. The benefits, as well as the risks of such therapy for other diseases of concern to women such as reproduct-
to
Table 3 Death rates per million, for women in England and Wales 1989 (Ref. 63) and Japan 1988 (Ref. 64) Ages in years
00
Cause
o
ENGLAND & WALES All causes All cancers (ICD 140-239) Breast (ICD 174) Uterus (ICD 179,182) (Excluding cervix) Cardiovascular disease (ICD 390-^59) Ischaemic heart disease (ICD 410-414) Stroke (ICD 430-438) Fracture of femur (ICD 820,821)
25-34
35-44
45-54
55-64
65-74
75 +
446
1123
2978
8783
22611
111332
149 36 1
612 234 8
1705
4221 1012
7677 1345
15138 2593
87
165
341
43
159
599
2723
9969
57486
7 19
54 66
299 165
1711 601
5999 2431
24192 19380
-
-
-
6
41
743
13504 4458 190
66758 9381 212
617 20
All causes All cancers (ICD (140-239) Breast (ICD 174) Cardiovascular disease (ICD 390-^59) Ischaemic heart disease (ICD 410-414) Stroke (ICD 430-438)
432
918
2147
oo bo
JAPAN 426 84
1009 170
4859 2174 217
64
167
507
1346
5219
33893
4 19
12 75
50 272
198 634
961 2292
5019 14411
I
EPIDEMIOLOGY OF THE MENOPAUSE
259
ive cancers remain a focus for debate. Cross cultural comparisons of the differing prevalence and incidence of menopause-related symptoms and diseases, endogenous sex hormone profiles and possible environmental determinants may give indications as to the potential for intervention. REFERENCES 1 Wilson RA, Wilson TA. The fate of the non-treated postmenopausal woman: a plea for maintenance of adequate estrogen from puberty to the grave. J Am Geriatr Soc 1963; 11: 347-362 2 Wilson RA, Wilson TA. The basic philosophy of estrogen maintenance. J Am Geriatr Soc 1972; 20: 521-523 3 Greer G. The Change. Women, ageing and the menopause. London: Hamish Hamilton, 1991 4 Lock M. Contested meanings of the menopause. Lancet 1991; 337: 1270-1272 5 Lock M, Kaufert P, Gilbert P. Cultural construction of the mcnopausal syndrome: the Japanese case. Maruritas 1988; 10: 317-322 6 Report of a WHO Scientific Group. Research on the menopause. WHO Technical report series 670. Geneva: World Health Organization, 1981 7 Sherman BM et al. The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Mctab 1976; 42: 629-636 8 Reyes FI et al. Pituitary-ovarian relationships preceding the menopause. 1. A cross-sectional study of serum follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol and progesterone levels. Am J Obstet Gynecol 1977; 129: 557-564 9 Chakravarti S et al. Hormonal profiles after the menopause. Br Med J 1976; 2: 784-786 10 Siiteri PK, MacDonald PC. Role of extraglandular estrogen in human endocrinology. In: Greep RO, Astwood EB eds. Handbook of Physiology, Vol 2, Part 1. Baltimore: Williams and Wilkins, 1973: pp. 615-629 11 Nordin BEC, Crilly RG, Marshall DH, Barkworth SA. Oestrogens, the menopause and the adrenopause. J Endocrinol 1981; 89: 131P-143P 12 International Agency for Research on Cancer (IARC). Sex hormone (II). Monographs on the Evaluation of carcinogenic risk of chemicals to humans, Vol 21. Lyon: IARC, 1979 13 Goldin BR, Adlercreutz H, Gorbach SL, et al. The relationship between estrogen levels and diets of Caucasian American and Oriental immigrant women. Am J Clin Nutr 1986; 44: 945-953 14 Adlercreutz H, Hamalainen E, Gorbach SL, Goldin BR, Woods MN, Dwyer JT. Diet and plasma androgens in postmenopausal vegetarian and omnivorous women and postmenopausal women with breast cancer. Am J Clin Nutr 1989; 49: 433-442 15 Barbosa JC, Schultz TD, Filley SJ, Nieman DC. The relationship among adiposity, diet, and hormone concentrations in vegetarian and nonvegctarian postmenopausal women. Am J Clin Nutr 1990; 51: 798-803 16 Sctchell KDR, Adlercreutz H. Mammalian lignans and phyto-oestrogens recent studies on their formation, metabolism and biological role in health and disease. In: Rowland IR, ed. Role of the gut flora in toxicity and cancer. New York: Academic Press, 1988: pp. 318-345 17 Cauley JS, Gutai JP, Kuller LH, LeDonne D, Powell JG. The epidemiology of serum sex hormones in postmenopausal women. Am J Epidemiol 1989; 129: 1120-1131
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18 Michnovicz JJ, Herschcopf RJ, Naganuma H, Bradlow HL, Fishman J. Increased 2-hydroxylation of estradiol as a possible mechanism for the antiestrogenic effect of cigarette smoking. N Engl J Med 1986; 315: 1305-1309 19 Khaw KT, Tazuke S, Barrett-Connor E. Cigarette smoking and levels of adrenal androgens in postmenopausal women. N Engl J Med 1988; 318: 17051709 20 Baron J. Smoking and estrogen-related disease. Am J Epidemiol 1984; 119: 9-22 21 Tazuke S, Khaw KT, Barren-Connor E. Exogenous estrogen and endogenous sex hormones. Medicine; 1992 (in press) 22 The Guinness Book of records 1991. McFarlan D, ed. London: Guinness Publishing, 1991 23 Ginsburg J. What determines age at menopause? Br Med J 1991; 302: 1288-9 24 Amundsen DW, Diers CJ. The age of menopause in medieval Europe. Hum Biol 1973; 45: 605-612 25 Gray RH. The menopause—epidemological and demographic considerations. In: Beard RJ, ed. The Menopause. Lancaster: MTP Press, 1976: pp. 25-40 26 McKinlay S, Jefferys M, Thompson B. An investigation of the age at menopause. J Biosoc Sri 1972; 4: 161-173 27 Thompson B, Hart SA, Durno D. Menopausal age and symptomatology in a general practice. J Biosoc Sci 1973; 5: 71-82 28 MacMahon B, Worcester J. Age at menopause: United States 1960-62. US Vital and Health Statistics, Series II, No. 19. Washington DC: 1966 29 Hauser GA, Remen U, Valaer M, Erb H, Mueller T, Obiri J. Menarche and menopause in Israel. Gynaecologia 1963; 38—47 30 Treloar AE. Menarche, menopause and intervening fecundability. Hum Biol 1974; 46521-5: 89-107 31 Wyon JB ct al. Differential age at menopause in the rural Punjab, India. Population Index 1966; 32: 328 32 Frommer DJ. Changing age of menopause. Br Med J 1964; 2: 349-351 33 Burch PRJ, Gunz FW. The distribution of menopausal age in New Zealand. An exploratory study. N Z Med J 1967; 66: 6-10 34 Frere G. Mean Age at menopause and menarche in South Africa. SA J Med Sci 1971; 36: 21-24 35 Abramson JH et al. Age at menopause of urban Zulu women. Science 1960; 132: 356-357 36 Scragg RFR. Menopause and reproductive span in rural Niugini. In: Proceedings of the Annual Symposium of the Papua New Guinea Medical Society, Port Moresby, 1973, pp. 126-144 37 Benjamin F. The age of the menarche and of the menopause in white South African Women and certain factors influencing these times. S Afr Med J 1960; 34: 316-320 38 Walsh J. The age of the menopause of Australian women. Med J Aust 1960; 2: 181-215 39 Bengtsson C et al. Is the menopausal age rapidly changing? Maturitas 1979; 1: 159-164 40 Brand PC, Lehert PH. A new way of looking at environmental variables that may affect the age at menopause. Maturitas 1978; 1: 121-132 41 Lindquist O, Bengtsson C. The effect of smoking on menopausal age. Maturitas 1979; 1: 191-199 42 Jick H, Porter J. Relation between smoking and age of natural menopause. Lancet 1977; ii: 1354-1355 43 Kaufman DW, Slonc D, Rosenberg L, Miettinen O, Shapiro S. Cigarette smoking and age at natural menopause. Am J Public Health 1980; 70: 420-422 44 Andersen FS, Transbol I, Christiansen C. Is cigarette smoking a promoter of the menopause? Acta Med Scand 1982; 212: 137-139
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45 Adcna MA, Gallagher HG. Cigarette smoking and the age at menopause. Ann Hum Biol 1982; 9: 121-130 46 McKinlay SM, Bifano NL, McKinlay JB. Smoking and age at menopause in women. Ann Intern Med 1985; 103: 350-356 47 Brambilla DJ, McKinlay SM. A prospective study of factors affecting age at menopause. J Clin Epidemiol 1989; 42: 1031-1039 48 Willett W, Stampfer MJ, Bain C, Lipnick R, Speizer FE, Rosner B, Cramer D, Hennekens CH. Cigarette smoking, relative weight and menopause. Am J Epidemiol 1983; 117: 651-658 49 Mattison DR, Thorgeirsson SS. Smoking and industrial pollution, and their effects on menopause and ovarian cancer. Lancet 1978; i: 187-188 50 Soberon J, Calderon JJ, Goldzieher JW. Relation of parity to age at menopause. Am J Obstet Gynecol 1966; 96: 96-100 51 Stanford JL, Hartge P, Brinton LA, Hoover RN, Brookmeyer R. Factors influencing the age at natural menopause. J Chron Dis 1987; 40: 995-1002 52 Thomford PJ, Jelovsek FR, Mattison DR. Effect of oocyte number and rate of atresia on the age of menopause. Reprod Toxicol 1987; 1: 41-51 53 McKinlay SM, Jefferys M. The menopausal syndrome. Br J Prev Soc Med 1974; 28: 108-115 54 Studd JWW, Watson NR, Henderson A. Symptoms and metabolic sequelae of the menopause. In: Drife JO, Studd JWW, eds. HRT and osteoporosis. London: Springer Verlag, 1990: pp. 23-34 55 Jaszmann LJB. Epidemiology of the climacteric syndrome. In: Campbell S, ed. The management of the menopause and post-menopausal years. Proceedings of the International Symposium, 1975. Baltimore: University Park Press, 1976: pp. 11-24 56 Ballinger CB. Psychiatric morbidity and the menopause; screening of a general population sample. Br Med J 1975; 3: 344-346 57 Bungay GT et al. Study of symptoms in middle life with special reference to the menopause. Br Med J 1980; 281: 181-183 58 Winokur G. Depression in the menopause. Am J Psychiatr 1973; 130: 92-93 59 Hallstrom MT. Sexuality of women in middle age: the Goteborg study. J Biosoc Sci 1979; (Suppl 6): 165-175 60 Witteman JCM, Grobbec DE, Kok FJ, Hofman A, Valkenburg HA. Increased risk of atherosclerosis in women after the menopause. Br Med J 1989; 642-644 61 Lindquist O. Intraindividual changes of blood pressure, serum lipids and body weight in relation to menstrual status: results from a prospective population study of women in Goteborg, Sweden. Prev Med 1982; 11: 162-72 62 Hjortland MC, McNamara PM, Kannel WB. Some atherogenic concomitants of menopause: the Framingham study. Am J Epidemiol 1976; 103: 304—311 63 Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR. Menopause and risk factors for coronary heart disease. N Engl J Med 1989; 321: 641-646 64 Mortality statistics 1989. Office of Population censuses and surveys Series DH2 no. 16. London: HMSO, 1991 65 World Health Statistics, 1989. Geneva: World Health Organization, 1989 66 Godsland IF, Wynn V, Crook D, Miller NE. Sex, plasma lipoproteins and atherosclerosis. Am Heart J 1987; 114: 1467-1503 67 Boyce WJ, Vessey MP. Rising incidence of fracture of the proximal femur. Lancet 1985; i: 150-151
Epidemiology of the menopause KTKhaw University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
Profound changes in birth and mortality rates in this century are resulting in the ageing of the population of Britain and other developed countries. The enormous decline in maternal mortality, in particular, has meant that increasing proportions of women are surviving to the menopause and years of active life beyond it. Women aged 55 years and over now comprise 15% of the population of Britain. The average life expectancy for women in developed countries is around 75 years; approximately 90% of women reach the age of 65 years, and 30% reach 80 years. If the average age of menopause is 50 years, most women will spend approximately one third of their lifetime in postmenopausal life; one in every two women will experience about 30 years of postmenopausal life.
All women living beyond the age of 55 years or so will experience the menopause, that is, the transition from the reproductive to the non-reproductive stage of life, characterised by the cessation of menstruation. However, the menopause has come to signify much more than simply the loss of reproductive capacity, and has been associated with numerous acute and chronic conditions. Some have even argued that the menopausal syndrome is a distinct entity of somatic and psychological symptoms and illness. Whether this is so, and if so, how much might be due to changing hormonal status, how much to increasing biological age and how much to the social and cultural significance of the menopause is still debatable. On one hand, it has been argued that a large proportion of the conditions associated with the peri- and postmenopausal period can be largely attributed to oestrogen deficiency associated with the menopause, and hence, potentially remediable by hormone
250
HORMONE REPLACEMENT THERAPY
replacement therapy. 12 These conditions include acute symptoms—such as hot flushes, night sweats and depression—as well as chronic disease—such as cardiovascular disease and osteoporosis—which increase after the menopause. On the other hand, the increasing incidence of many diseases associated with the menopause may largely reflect the biological ageing that would occur in any case. It has been suggested that many of the symptoms associated with the menopause, such as depression, are related to the social and cultural context in which the menopause occurs.3"5 The implications in terms of optimal strategies for dealing with the symptomatology and other conditions occurring in peri- and postmenopausal women are considerable. DEFINITIONS OF THE MENOPAUSE The term menopause literally signifies the permanent cessation of menstruation. By convention, this is a diagnosis made in retrospect following a period of amenorrhea for 12 months. In clinical practice, the term menopause is often used to indicate the period of time during which spontaneous menstruation normally ceases; it is characterised endocrinologically by evidence of decreasing ovarian activity, biologically by decreasing fertility, and clinically by alterations in menstrual cycle intervals and by a variety of symptoms. Though the diagnosis of menopause is based on clinical signs and symptoms; primarily, amenorrhoea, and confirmed when necessary with assays for steroid hormones or gonadotrophins, the loss of ovarian function is the essential characteristic of menopause. Thus, a surgical menopause should be confined to the procedure of bilateral oophorectomy, with or without hysterectomy but not include cessation of menstruation following a simple hysterectomy. A World Health Organization report on the menopause6 suggested the following definitions: 1. The menopause should be defined as the permanent cessation of menstruation resulting from loss of ovarian follicular activity. 2. The perimenopause (or climacteric) should be used to include the period immediately prior to the menopause with endocrinological, biological and clinical features of approaching menopause, and at least the first year after the menopause. 3. The postmenopause should be defined as dating from the menopause, although it cannot be determined until after a period of 12 months of spontaneous amenorrhea has been observed.
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ENDOCRINOLOGY OF THE MENOPAUSE This is detailed in the next chapter. Briefly, studies have indicated that in menstruating women, with increasing age, the length of the follicular phase gradually declines; towards the menopause oestradiol levels are lower and follicle stimulating hormone (FSH) levels are elevated during the early follicular phase compared to younger women.7'8 After the menopause, levels of FSH increase to 10-15 times the early follicular phase levels in young women, while luteinising hormone (LH) reaches a maximum three times higher about 2 years after the menopause.9 Premenopausally, the ovary is the major source of circulating oestrogens, predominantly oestradiol. After the menopause, the major source of oestrogens is from peripheral conversion in adipose tissue of adrenal androgen precursors, notably androstenedione, to oestrogens, mainly oestrone: the amount of body fat is hence a major determinant of oestrogen levels in postmenopausal women.10"12 Table 1 shows approximate plasma or serum concentrations in pre- and postmenopausal women. Most detailed studies on hormonal changes associated with the menopause have been conducted on Western women. However, while overall the pattern of hormonal changes with the menopause, namely the fall in oestrogen levels, are similar in all women, several studies have indicated that absolute levels of endogenous sex hormones may differ considerably in different communities; for example, Chinese and Japanese women have lower oestrogen levels both pre- and post-menopausally.13 Exogenous factors, in particular diet, have been suggested to play a role in determining sex hormone levels: high fat intakes have been associated with higher endogenous androgens or oestrogen levels,13'14 whereas a vegetarian diet, or high fibre intake is associated with lower oestrogen Table 1 Plasma or serum concentrations of sex hormones in pre-and postmenopausal women (data from Reference 12) Mean plasma or serum concentrations Premenopausal Oestradiol (pmol/1) Oestrone (pmol/1) Androstenedione (pmol/1) Testosterone (pmol/1) Dehydroepiandrosterone (nmol/1) Dehydroepiandrosterone sulphate (nmol/1)
620 440 6300 1000 17000 5400
Postmenpausal 40 110 3100 800 5500 1000
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HORMONE REPLACEMENT THERAPY
and increased sex hormone binding globulin levels.14'15 Animal studies have indicated one possible mechanism to be plant phytooestrogens which have a very weak competitive oestrogenic effect, possibly suppressing pituitary FSH and LH secretion.16 Cauley reported that physical activity was inversely related to oestrone levels in postmenopausal women,17 and yet other studies have indicated that cigarette smoking is associated with decreased oestrogenic activity and higher adrenal androgen levels in postmenopausal women.18"20 We still have an incomplete understanding of the hormonal changes occurring at the menopause, how they may vary in different populations, and how they may be influenced by exogenous factors, such as diet. Hormone replacement therapy not only, as expected, increases levels of circulating oestrogens but also has considerable other effects including a decrease in endogenous androgens and increase in sex hormone binding globulin and cortisol levels;21 it is possible that some of the benefits and risks of replacement oestrogens are secondary to these other endocrine changes. Adequate endocrinological characterisation of perimenopausal women, and the clarification of the relationship of sex hormone profiles to postmenopausal disorders, which may vary widely in different women, may help give indications as to the causes of these disorders and hence, clues to prevention. AGE DISTRIBUTION OF THE MENOPAUSE Because the diagnosis of menopause can only be made in retrospect, most studies, both retrospective and prospective have considerable limitations as they have to rely on accurate knowledge and unbiased reporting of age. Comparison between studies is also difficult as definitions of menopause are not identical. Within these limitations, the median age at menopause in most Western industrialised societies, where studied, has been shown to be remarkably constant, around 50 years, though there is a wide range between 35 to 59 years or so around a slightly skewed normal distribution. Premature ovarian failure is well documented in women below the age of 40; at the other end, pregnancies have been documented in women aged 55 years or so: the oldest verifiable mother was reported from California as aged 57 years 129 days.22 The mean age of menarche has been falling, and it has been proposed that the age of menopause has increased over the last 100 years, but no strong evidence supports this; a review by Gins-
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burg23 cited reports from Aristotle, Hippocrates and Roman authors indicating that 2000 years ago, most women entered the menopause in their early 40s; however, medieval authors gave the 50s as the age when menses ceased.24 Gray has reviewed studies showing estimated age at menopause;24 estimates from selected studies25"39 are listed in the Table 2. There is a paucity of data from non-Westernised populations, but some studies have indicated lower menopausal age in communities where malnutrition is common. FACTORS AFFECTING MENOPAUSAL AGE Nutritional status Age at menarche appears to be profoundly related to nutritional status; women with malnutrition in Papua New Guinea had approximately 4 years earlier menopause compared with women who were not malnourished; the malnourished women had both lower heights and weights.36 Other studies have indicated that both height40 and weight28 may influence menopausal age. Cigarette smoking Of all the known possible risk factors, cigarette smoking is perhaps the most well documented. Women who smoke have a menopause on average one to two years earlier than non-smokers.20>41~51 The mechanism for this is not well understood. One possibility is an anti-oestrogenic effect of cigarette smoking: Michnovicz et al.18 reported that women smokers appeared to metabolise exogenous oestrogen more rapidly than non-smokers and other studies have reported lower levels of oestrogens in smokers. Alternatively, components of cigarette smoke, such as aromatic hydrocarbons, might accelerate oocyte ageing.49 Other risk factors No other factors have been consistently related to menopausal age. Reproductive history, including early menarche, parity, upper socio-economic class, higher educational status, and oral contraceptive use have been suggested to be associated with later menopause, but associations have not been consistent, and the confounding effect of cigarette smoking for all these is possible.39'47'50'51
to
Table 2 Estimated age at menopause (data from References 24-37) Country and year of study
Race
England 1951-61 England 1965
Caucasian Caucasian
Scotland 1970 USA 1934-74
Caucasian Caucasian
USA 1966
Caucasian Black Caucasian Caucasian
Australia 1978 Sweden 1968-69; 1974-75 Germany 1972 Finland 1961 Switzerland 1961 Israel 1963 New Zealand 1967 Papua New Guinea 1973
India (Punjab) 1966
Caucasian Caucasian Caucasian Caucasian Caucasian Melanesian
Asian
Mean or median 49.8 median 50.8 median 47.5 mean 50.1 median 49.8 median 49.5 mean 50.0 median 49.3 median 50.4 median 49.6 median 50.4 49.1 mean 49.8 mean 49.8 mean 49.5 mean 50.7 median 47.3 median (not malnourished) 43.6 median (malnourished) 44.0 median
o Study design cross-sectional cross-sectional cross-sectional cohort cross-sectional cross-sectional retrospective and cross-sectional retrospective retrospective retrospective retrospective cross-sectional cross-sectional
cohort and cross-sectional
EPIDEMIOLOGY OF THE MENOPAUSE
255
Most factors that influence age at menopause appear to hasten, not retard menopause. Oral contraceptives in particular are of interest since the menopause occurs when oocyte number falls below the threshold required for ovarian function. Since oral contraceptives inhibit ovulation, it might be hypothesised that prolonged use of oral contraception would postpone the menopause.51 It is not clear what factors determine ovarian failure. However, oral contraceptive use has not been consistently associated with a delayed menopause; Thomford suggested that, based on animal studies, and modelling on observed human data, ovarian failure is only weakly dependent on oocyte number; factors that decrease age at menopause appear to result primarily from an increase in the rate of oocyte atresia.52
SYMPTOMS ASSOCIATED WITH THE MENOPAUSE A large number of vasomotor, psychological, and gynaecological symptoms have been associated with the menopause. Studies reporting frequencies of these complaints based on women attending clinics suffer from obvious selection biases, and population based surveys are needed to document the true incidence and prevalence of such symptoms. Unfortunately, comparability between such population surveys are limited by differing methodologies and definitions. Nevertheless, some researchers have attempted to use standardised ascertainment and criteria enabling cross-cultural comparisons. Consistent symptoms that have emerged include:
Vasomotor symptoms There is clear agreement that the most characteristic symptoms of the perimenopausal period are hot flushes, night sweats, palpitations and headaches, attributed to vasomotor instability; it has been suggested that 75% of women are affected.27'53'54 Jaszmann,55 in a study in the Netherlands, reported 65% of the perimenopausal women experience hot flushes during the menopause, 40% sweats, and 25% palpitations. A Canadian study4 also indicated a frequency of 65% of perimenopausal women reporting hot flushes at some time in the past. However, using identical methodology to the Canadian study, only 19.6% of the women in a Japanese survey5 reported hot flushes.
256
HORMONE REPLACEMENT THERAPY
Psychological symptoms Depression, insomnia and tiredness reportedly increase in the perimenopausal period55"58 and was reported to affect 25% of perimenopausal women in the Netherlands survey.54 Again, in contrast, a Japanese survey5 showed lower prevalence of 5-10% for these symptoms. Other effects Vaginal dryness, atrophic vaginitis and dyspareunia are said to be virtually universal menopausal problems.54 Loss of libido affected 5% in a Swedish study, which appeared independent of genital symptoms.59 The symptomatology of the menopausal period and possible mechanisms and treatment are discussed in detail by Barlow elsewhere in this issue. While genital atrophy is generally accepted to be largely related to oestrogen deficiency, the mechanisms for symptoms such as the vasomotor and psychological ones are still not clear; in particular, the role of oestrogen deficiency is still debated. However, it is evident that prevalence of such perimenopausal symptoms vary enormously in different cultures. Such differences provide clues as to possible biological or sociological causes for the symptoms. Lock4 suggests that, 'any effort to divorce the biology of menopause from the meanings, both ideological and individuals, that are attributed to the associated social transition are, in clinical circumstances at least, inherently fraught with danger'. If symptomatology can be related to hormonal status, and hormonal profiles can be influenced by either directly by specific exogenous hormonal therapy, or indirectly by behavioural factors, such as physical activity or diet, this may help direct more effective interventions. CHRONIC DISEASES RELATED TO THE MENOPAUSE The incidence of most chronic diseases increase with age. Osteoporotic bone disease and atherosclerotic cardiovascular disease are two major causes of morbidity in women which have been suggested to be exacerbated by the menopause. Several prospective studies have reported that changing from pre- to postmenopausal status is associated with an unfavourable effect on lipid metabolism, namely decline in serum levels of high-density cholesterol
EPIDEMIOLOGY OF THE MENOPAUSE
257
declined compared to premenopausal controls and increase in low density lipoprotein cholesterol.60"63 Witteman60 has suggested that the increased risk of atherosclerosis in women after the menopause is independent of age. Table 3 shows age specific death rates for women by age group by selected causes of death in England and Wales.64 While all mortality rates undoubtedly increase after the menopause, cause specific rates differ in pattern; reproductive cancer rates tend to rise less steeply than cardiovascular disease and fractures. Table 3 also shows death rates for selected causes where available, for Japanese women.65 While the same increase of death rates with age is evident for Japanese women, the absolute rates are considerably lower. Since Japanese women have generally lower oestrogen levels than Caucasian women,66 the considerably lower cardiovascular disease rates in the Japanese cannot be explained by differences in oestrogen levels. Similarly, some studies have indicated accelerated bone loss following the menopause, reviewed by Compston in this issue. However, the two to threefold secular increase in the last thirty years in osteoporotic hip fractures in Britain67 cannot be attributable to any changes in the menopausal age, or to changes in hormone replacement therapy. The large secular and geographic variations in many of the conditions traditionally associated with the menopause suggest that, while the menopause may be a risk factor, there are other determinants which are likely to have a more profound influence. CONCLUSIONS The menopause is inevitable in all women who live beyond the age of 55 years or so. The most marked physiological change is the reduction in oestrogen levels and increase in FSH levels. The perimenopausal period is associated with considerable symptomatology. However, symptoms vary widely between individuals in the same population; the prevalence of such symptomatology also varies considerably between different populations. The relationship between changes in hormone levels and symptoms is not at all clearcut. The menopause has also been shown to be a risk factor for chronic diseases, namely, cardiovascular disease and osteoporosis which are considerable causes of mortality and morbidity in women. It is still not clear how far these conditions are due to oestrogen deficiency, and can be remedied by hormone replacement therapy. The benefits, as well as the risks of such therapy for other diseases of concern to women such as reproduct-
to
Table 3 Death rates per million, for women in England and Wales 1989 (Ref. 63) and Japan 1988 (Ref. 64) Ages in years
00
Cause
o
ENGLAND & WALES All causes All cancers (ICD 140-239) Breast (ICD 174) Uterus (ICD 179,182) (Excluding cervix) Cardiovascular disease (ICD 390-^59) Ischaemic heart disease (ICD 410-414) Stroke (ICD 430-438) Fracture of femur (ICD 820,821)
25-34
35-44
45-54
55-64
65-74
75 +
446
1123
2978
8783
22611
111332
149 36 1
612 234 8
1705
4221 1012
7677 1345
15138 2593
87
165
341
43
159
599
2723
9969
57486
7 19
54 66
299 165
1711 601
5999 2431
24192 19380
-
-
-
6
41
743
13504 4458 190
66758 9381 212
617 20
All causes All cancers (ICD (140-239) Breast (ICD 174) Cardiovascular disease (ICD 390-^59) Ischaemic heart disease (ICD 410-414) Stroke (ICD 430-438)
432
918
2147
oo bo
JAPAN 426 84
1009 170
4859 2174 217
64
167
507
1346
5219
33893
4 19
12 75
50 272
198 634
961 2292
5019 14411
I
EPIDEMIOLOGY OF THE MENOPAUSE
259
ive cancers remain a focus for debate. Cross cultural comparisons of the differing prevalence and incidence of menopause-related symptoms and diseases, endogenous sex hormone profiles and possible environmental determinants may give indications as to the potential for intervention. REFERENCES 1 Wilson RA, Wilson TA. The fate of the non-treated postmenopausal woman: a plea for maintenance of adequate estrogen from puberty to the grave. J Am Geriatr Soc 1963; 11: 347-362 2 Wilson RA, Wilson TA. The basic philosophy of estrogen maintenance. J Am Geriatr Soc 1972; 20: 521-523 3 Greer G. The Change. Women, ageing and the menopause. London: Hamish Hamilton, 1991 4 Lock M. Contested meanings of the menopause. Lancet 1991; 337: 1270-1272 5 Lock M, Kaufert P, Gilbert P. Cultural construction of the mcnopausal syndrome: the Japanese case. Maruritas 1988; 10: 317-322 6 Report of a WHO Scientific Group. Research on the menopause. WHO Technical report series 670. Geneva: World Health Organization, 1981 7 Sherman BM et al. The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Mctab 1976; 42: 629-636 8 Reyes FI et al. Pituitary-ovarian relationships preceding the menopause. 1. A cross-sectional study of serum follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol and progesterone levels. Am J Obstet Gynecol 1977; 129: 557-564 9 Chakravarti S et al. Hormonal profiles after the menopause. Br Med J 1976; 2: 784-786 10 Siiteri PK, MacDonald PC. Role of extraglandular estrogen in human endocrinology. In: Greep RO, Astwood EB eds. Handbook of Physiology, Vol 2, Part 1. Baltimore: Williams and Wilkins, 1973: pp. 615-629 11 Nordin BEC, Crilly RG, Marshall DH, Barkworth SA. Oestrogens, the menopause and the adrenopause. J Endocrinol 1981; 89: 131P-143P 12 International Agency for Research on Cancer (IARC). Sex hormone (II). Monographs on the Evaluation of carcinogenic risk of chemicals to humans, Vol 21. Lyon: IARC, 1979 13 Goldin BR, Adlercreutz H, Gorbach SL, et al. The relationship between estrogen levels and diets of Caucasian American and Oriental immigrant women. Am J Clin Nutr 1986; 44: 945-953 14 Adlercreutz H, Hamalainen E, Gorbach SL, Goldin BR, Woods MN, Dwyer JT. Diet and plasma androgens in postmenopausal vegetarian and omnivorous women and postmenopausal women with breast cancer. Am J Clin Nutr 1989; 49: 433-442 15 Barbosa JC, Schultz TD, Filley SJ, Nieman DC. The relationship among adiposity, diet, and hormone concentrations in vegetarian and nonvegctarian postmenopausal women. Am J Clin Nutr 1990; 51: 798-803 16 Sctchell KDR, Adlercreutz H. Mammalian lignans and phyto-oestrogens recent studies on their formation, metabolism and biological role in health and disease. In: Rowland IR, ed. Role of the gut flora in toxicity and cancer. New York: Academic Press, 1988: pp. 318-345 17 Cauley JS, Gutai JP, Kuller LH, LeDonne D, Powell JG. The epidemiology of serum sex hormones in postmenopausal women. Am J Epidemiol 1989; 129: 1120-1131
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