Postgrad Med J: first published as 10.1136/pgmj.68.802.615 on 1 August 1992. Downloaded from Postgrad Med J (1992) 68, 615 - 623 ©D The Fellowship of Postgraduate Medicine, 1992 Reviews in Medicine The menopause and hormone replacement therapy Kay-Tee Khaw Clinical Gerontology Unit, University ofCambridge School ofClinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK The menopause: the background Introduction 3. The postmenopause should be defined as dating from the menopause, although it cannot be The menopause is the transition from the reproduc- determined until after a period of 12 months of tive to the non-reproductive stage of life in women spontaneous amenorrhea has been observed. and is characterized clinically by permanent cessa- Though the diagnosis of menopause is based on tion of menstruation and biologically by loss of clinical signs and symptoms, primarily amenor- ovarian function. The menopause occurs around a rhoea, and confirmed when necessary with assays mean age of50 years; virtually all women by the age for steroid hormones or gonadotrophins, the loss of 55 years or so will have experienced the ofovarian function is the essential characteristic of menopause. The changes in birth and mortality menopause. Thus, a surgical menopause occurs by copyright. rates over the last century and, in particular, the after bilateral oophorectomy with or without hys- profound decline in maternal mortality in develop- terectomy, but would not include cessation of ed countries have resulted in an average life menstruation following a simple hysterectomy. expectancy ofwomen ofabout 75 years; thus, most women will be postmenopausal for one third of Age at menopause their lifetime. Such women (9 million in England and Wales) now comprise about 18% of the total The median age at menopause in most Western population. The aim of this review is to highlight industrialized societies has been shown to be re- current issues concerning the menopause and hor- markably constant, around 50 years, though there mone replacement therapy, hence literature cited is is a wide range between 35- 59 years or so around a http://pmj.bmj.com/ not intended to be comprehensive but indicative. slightly skewed normal distribution.>4 Premature This article will briefly describe the epidemiology of ovarian failure is associated with some rare clinical the menopause, summarize the epidemiological conditions such as galactosaemia or can be induced data concerning hormone replacement therapy, the by radiation therapy or cytotoxic chemotherapy. questions these raise and the implications these Some exogenous factors can affect menopausal have concerning health in postmenopausal women. age: notably, women cigarette smokers have a menopause on average 1-2 years earlier than on September 27, 2021 by guest. Protected Definitions ofthe menopause non-smokers; poor nutritional status is another.5'-12 A World Health Organization report on the meno- Endocrine changes pause' suggested the following definitions. 1. The menopause should be defined as the perma- During reproductive years, the preovulatory folli- nent cessation of menstruation resulting from cle and corpus luteum are the major source of sex loss of ovarian follicular activity. steroids: oestradiol predominates, with smaller 2. The perimenopause (or climacteric) should be amounts of oestrone. Androgens, mainly andro- used to include the period immediately prior to stenedione and testosterone, are also produced by the menopause with endocrinological, biolog- stroma and theca. The most marked hormonal ical and clinical features of approaching meno- change following the menopause, with the loss of pause, and at least the first year after the follicular units, is the 10-20-fold reduction in menopause. oestradiol levels. Other hormones, notably oest- rone, androstenedione, testosterone and dehydro- epiandrosterone also decrease markedly."-15 Levels Correspondence: Professor K.-T. Khaw, M.Sc., M.A., of follicle stimulating hormone (FSH) increase to M.R.C.P., D.C.H. 10-15 times the early follicular phase levels in Postgrad Med J: first published as 10.1136/pgmj.68.802.615 on 1 August 1992. Downloaded from 616 K.-T. KHAW young women, while luteinizing hormone (LH) While animal and clinical data on the biological reaches a maximum three times higher about 2 effects of oestrogens have long been available, the years after the menopause. After the menopause, large numbers of postmenopausal women taking the major source of oestrogens is from peripheral oestrogens enabled the conduct ofepidemiological conversion in adipose tissue of adrenal androgen studies on the associations between oestrogen use precursors, notably androstenedione, to oestro- and various conditions such as reproductive gens, mainly oestrone: the amount of body fat is cancers, osteoporosis and cardiovascular disease in hence a major determinant of oestrogen levels in women in the general population. These studies, postmenopausal women.'6-18 predominantly from the United States, have been appearing since the mid-1970s to the present, and findings have in turn stimulated more clinical and Hormone replacement experimental studies to identify possible biological therapy mechanisms. The background Hormone replacement therapy andendometrial While the menopause can be viewed simply as part cancer of normal ageing, others have argued that in the past most women did not live until menopausal Of all the effects of oestrogen therapy, perhaps the age. Fertility generally decreases with age in mam- best known is the increased risk of endometrial mals, but the evolutionary significance of the cancer. The first reports from case control studies menopause is unclear. Thus, it has been suggested of increased endometrial cancer associated with that the menopause is an oestrogen-deficient state exogenous use appeared in the mid- 1970s and there which can be remedied by oestrogen replacement is little doubt from both numerous case control and therapy, exemplified by such statements as those by more recently, prospective studies, that oestrogen Wilson below: use increases risk ofendometrial cancer by three to over six fold.24 29 Significantly increased risk by copyright. 'The unpalatable truth must be faced that all appears with a duration ofaround 3 years' use and postmenopausal women are castrates.'"9 its magnitude appears to be related to dose and '... estrogen deficiency is as much a disease as duration of use. However, this risk seems to be thyroid, pancreatic or adrenal deficiency. No more or less abolished by adding progestogen;30-32 attempt will be made here to detail all of the this has led to the widespread use of combined unwholesome effects ofthis deficiency disease; a oestrogen and progestogen preparations. few will suffice, e.g. thinning of bones, dowa- ger's hump, ugly body contours, flaccidity ofthe Hormone replacement therapy and breast cancer breast, and atrophy of the genitalia ... The estrogenic treatment ofolder women will inhibit Oophorectomy has long been recognized to pro- http://pmj.bmj.com/ osteoporosis and thus help to prevent fractures, duce regression of breast cancer in women. How- as long as they continue healthful activities and ever, the evidence for an increased risk of breast appropriate diets. Breasts and genital organs cancer associated with exogenous oestrogen use is will not shrivel. Such women will be much more much more equivocal.33-38 Early case control pleasant to live with and will not become dull studies provided no consistent indication that and unattractive.'20 exogenous oestrogen use increased breast cancer risk though some more recent studies have sug- In contrast, others have argued that many of the gested increased breast cancer risk. Several reviews on September 27, 2021 by guest. Protected conditions associated with the menopause largely have examined this issue.3335 Two possible explan- reflect age-related changes which may be poten- ations have been hypothesized for the inconsistent tially modifiable by behavioural factors.2"22 The findings. Firstly, risk may be related to duration of original indications for oestrogen replacement use and early studies were more likely to have therapy were to treat clinical symptoms associated women who had taken oestrogen for shorter with the menopause such as hot flushes and sweats. periods than later studies. It is likely that short However, with such enthusiastic early proponents duration oestrogen use does not increase risk of of oestrogen replacement therapy as Wilson and breast cancer: recent meta-analyses have indicated others, by the early 1970s in the United States, large relative risks of around 1.00 associated with short- proportions of postmenopausal women (50% of term use.34 However, a meta-analysis which exam- women aged 55-64 and 30% of women aged ined risk by duration of oestrogen use indicated a 65- 74 years in one population study23 ) were using summary relative risk of 1.3 for women using oestrogens, not just for symptomatic relief, but oestrogens for 15 years or more compared to with the idea that oestrogen use promoted main- non-users.35 Secondly, early studies included tenance of youthfulness and health. women who used mainly unopposed conjugated Postgrad Med J: first published as 10.1136/pgmj.68.802.615 on 1 August 1992. Downloaded from THE MENOPAUSE AND HRT 617 oestrogens, but in later studies, women were more more is required before fracture risk is significantly likely to be using a variety ofdifferent formulations decreased. It