Reproductive hormone function: The perimenopausal period and beyond

8 Reproductive Hormone Function: The Perimenopausal Period and Beyond S T A N L E Y G. K O R E N M A N B A R R Y M. S H E R M A N J U L I E C. K O R E N M A N

Women born today in technically advanced cultures have a life expectancy of greater than 75 years at birth. A large and ever-growing population of women enters the menopause and lives many years beyond. In this chapter, we will consider the alterations in reproductive physiology characterizing the perimenopausal and postmenopausal years. We will deal briefly with the current clinical problems relating to the menopause and the data available regarding hormonal management. We will conclude with a suggestion for assessing the need for hormonal therapy. THE P E R I M E N O P A U S A L STATE

Prospective studies of menstrual cycle length have shown that during the years just before menopause there is a marked increase in the variability of intermenstrual intervals (Treloar et al, 1967; Vollman, 1977). The decades of mature reproductive life that precede this phase of cycle variability are characterized by generally regular menses and a slow, steady decrease in cycle length. Thus in a large population, mean cycle length at age 35 was 28 days, at age 25, 30 days and at age 15, 35 days (Treloar et al, 1967). By analysis of basal body temperature records, Vollman was able to show that the decreased cycle length was due to a shortened interval from menses to the thermal shift (follicular phase) and that luteal phase length was constant in women with regular menses, regardless of age. That observation was confirmed in a small group of women by measurement of serum gonadotrophins, LH and FSH, oestradiol and progesterone throughout the menstrual cycle (Figure 1) (Sherman and Korenman, 1975). By contrast, the long, often irregular cycle intervals that occur commonly in young, postmenarchial women are associated with prolongation of the follicular phase (Sherman and Korenman, 1975). Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - -

Vol. 7, No. 3, November1978.

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STANLEY G. KORENMAN, BARRY M. SHERMAN AND JULIE C. KORENMAN

The daily changes in gonadotrophin and steroid hormones during the human menstrual cycle that reflect follicular maturation, ovulation and corpus luteum function were elucidated in a series of studies in young, college age women (Ross et al, 1970; Vande Wiele et al, 1970). When similar studies were carried out in women with regular menses, age 40 to 41, the pattern of FSH, LH, oestradiol (E2) and progesterone (P) hormone concentrations did not differ from those observed in the younger subjects (Figure 1). Hormonal changes reflecting altered function of the ageing ovary were detected when such pattern analyses were extended to regularly menstruating women over 45 years of age (Figure 2). The mean length of the cycles in this group of older women was significantly shorter than that in the younger women and was attributable in all cases to a shortened interval from menses

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627

THE PERIMENOPAUSAL PERIOD AND BEYOND

to the LH peak (follicular phase). The luteal phase, measured from the LH peak to the onset of menses, was 14 to 17 days, and progesterone levels were not different from those observed in the younger women. In the perimenopausal women, E2 levels during active follicular maturation (day 0 to --5), at the mid-cycle peak and during the luteal phase, were lower than those in the younger women. The mean E2 concentration during the

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Figure 2. The mean and range of serum LH, FSH, E2 and P in regularly menstruating women over 45 years old are compared with the mean _+ 2 SEM in women aged 18 to 30. The data are illustrated as in Figure 1. An asterisk indicates a statistically significant difference between the values in the two groups ( P = < 0 . 0 5 ) .

cycles in the older women ranged from 50 to 120 pg/ml, which was less than the mean concentration of 150 pg/ml in the younger group. Concentrations of FSH were strikingly elevated in the early follicular phase and fell as E2 increased during follicular maturation. The FSH levels at the mid-cycle peak and late in the luteal phase were also consistently higher than those in the younger women and decreased during the mid-luteal phase. LH

628

STANLEYG. KORENMAN,BARRYM. SHERMANAND JULIEC. KORENMAN

concentrations during these cycles were indistinguishable from those observed in the younger women. These observations of independent modulation of FSH and LH have been confirmed in other studies, including a crosssectional study of older women as well as in the menstrual cycle in the aged rhesus monkey (Hodgen et al, 1977; Reyes, Winter and Faiman, 1977; Van Look et al, 1977). Other studies demonstrated that an elevation of serum FSH could predict the absence of ovarian follicles in patients with primary or secondary amenorrhoea prior to surgery (Goldenberg et al, 1973). Although there are many possible interpretations, the elevated concentration of serum FSH observed in perimenopausal women may be indicative of the reduced number of functional, residual ovarian follicles. It is possible that elevated concentrations of FSH may be responsible for the initiation of follicular maturation at more frequent intervals, and hence for the general decrease in cycle length observed in these older women. Evidence that FSH is more sensitive than LH to the suppressive effects of exogenous oestradiol (Vaitukaitis et al, 1971; Yen and Tsai, 1971) argues against an increase in FSH due only to decreased effective oestrogen concentration. Moreover, during menopause, FSH and LH appear to change proportionally when oestrogen is given. These findings are consistent with the possibility that a decrease in oestrogens may sometimes result in a greater response of FSH than LH due to differential regulation of LH and FSH secretion at the hypothalamic or pituitary level. Alternatively, there may be another ovarian hormone that regulates FSH secretion. Such a factor, analagous to the inhibin postulated to exist in men, would be reduced with age consequent to a reduced number of follicles. A loss of inhibin secretion would explain the elevated follicular phase levels of FSH in older women with relatively normal E2 levels and the marked fluctuations in concentrations of FSH observed in the presence of very modest changes in E2. Inhibin would provide an important mechanism for controlling the number of follicles that mature each cycle for each species and would aid our interpretation of certain disorders of reproductive function. Preliminary studies have identified a non-steroid, inhibin-like material in bovine follicular fluid and bull seminal plasma (Franchimont et al, 1975; De Jong and Sharpe, 1976). The transition from regular cycle intervals characteristic of mature reproductive life to the permanent amenorrhoea of menopause is characterized by a phase of marked menstrual irregularity (Treloar et al, 1967). The duration of this transition varies greatly among women. As shown in Table 1, women who have menopause at an early age have a relatively short duration of cycle variability before amenorrhoea ensues. By contrast, later menopause is accompanied by a steadily lengthening phase of menstrual irregularity characterized by unusually long and short intermenstrual intervals, and an overall increased mean cycle length and variance. The hormonal characteristics of this transitional phase are of special interest and importance, and are illustrated by multiple cycles studied by daily blood drawing in one subject over two years (Figure 3, a and b) (Sherman, West and Korenman, 1976). The initial cycle (I) was normal except for high levels of FSH during the follicular phase. Blood sampling was

629

THE PERIMENOPAUSAL PERIOD AND BEYOND

resumed four months later when she experienced her first unusually long cycle interval. LH and FSH were both clearly in the menopausal range, and vaginal bleeding was preceded by a steady increase in E2 and a sustained increase in P but with levels that did not exceed 10 ng/ml. The subsequent cycle (III) of 51 days showed similar hormonal changes. Late in the luteal phase of that cycle, there was an exaggerated increase of FSH without a similar increase in LH. This occurred when E2 levels were in the range of 100 pg/ml and when P was decreasing from a maximum of 5 ng/ml. Cycles V and VI were of interest because there was no identifiable relationship between the increase in E2 and the LH/FSH peak and vaginal bleeding followed a rise in E2 with no detectable rise in P. Table 1. Mean menstrual cycle length and standard deviation during the lO years before menopause Years before menopause Age at menopause

9--10 Days (SD)

7--8 Days (SD)

5--6 Days (SD)

3--4 Days (SD)

1--2 Days (SD)

~<44 45--49

26.5 (3.8) 26.2 (2.8)

29.4 (12.7) 26.5 (3.4)

27.4 (8.1) 27.6 (6.5)

30.2 (13.8) 35.5 (26.0)

51.6 (39.6) 65.1 (50.8)

50--54 >155

26.8 (2.7) 27.3 (3.3)

26.8 (4.1) 27.3 (3.3)

28.2 (7.2) 31.8 (8.9)

36.0 (23.3) 41.8 (24.9)

69.0 (54.6) 83.3 (72.9)

Thus, the irregular episodes of vaginal bleeding in the perimenopausal women represent the irregular maturation of ovarian follicles with or without hormonal evidence of ovulation. The potential for hormone secretion by these remaining follicles was diminished and variable. Menses were sometimes preceded by maturation of a follicle with limited secretion of both E2 and P. Vaginal bleeding also occurred after a rise and fall in E2 without a measurable increase in P, compatible with anovulatory menses. In view of the spectrum of hormonal changes observed during this transitional period, it can be postulated that residual follicles were responsible for the limited E2 secretion that preceded episodes of anovulatory bleeding and that they differed only in degree from those that demonstrated limited secretion of both hormones. We do not know whether ovulation actually occurred during any of these cycles. Nevertheless, one can see how the potential for conception could exist even during this transitional phase of reproductive life. Figure 3b illustrates three subsequent episodes of follicular maturation in the same women each accompanied by corpus luteum P secretion (VII-IX). The mean E2 concentration during those cycles was 43 pg/ml with maximum levels of 75 pg/ml. Another example of divergent LH and FSH levels was observed late in the luteal phase of cycle VII when an increase in FSH occurred at the time of decreasing concentrations of E2 and P, with no alteration in LH. The subsequent episode of follicular maturation and corpus luteum secretion (IX) was unique in that the luteal phase decrease in concentrations of E2 and P was not followed by vaginal bleeding.

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As in older women with regular cycles, these cycles showed that FSH levels were elevated under conditions when LH was in the normal range and E2 levels were between 50 and 100 pg/ml. Divergent FSH and LH levels were particularly noted in the late luteal phase o f several transitional cycles, a finding that appears to be an exaggeration of the late luteal phase increase of FSH described during menstrual cycles in younger women and postulated to initiate the maturation of one or more follicles during each succeeding cycle. From these findings it is clear that the transitional phase of menstrual irregularity is not one of marked oestrogen deficiency. The very low menopausal plasma oestradiol levels (<20 pg/ml) may not occur until six months or more after the onset of amenorrhoea (Figure 4). During the menopausal transition, high levels of pituitary FSH appear to stimulate residual follicles to secrete bursts of E2 with serum levels often reaching 100 to 250 pg/ml (Van Look et al, 1977). This may be followed by corpus luteum formation, often with limited secretion of progesterone. Because the episodes of follicular maturation and vaginal bleeding are wide-spaced, perimenopausal women may be exposed to persistent oestrogen stimulation in the absence of regular cyclic progesterone secretion which is thought to be related to the dysfunctional uterine bleeding common at this time.

HORMONE METABOLISM AFTER THE MENOPAUSE

The menopausal state has been variously defined, with most authors focusing on a duration of amenorrhoea in women of menopausal age such as one year (Treloar et al, 1967). This definition would include the population of obese, euoestrogenic amenorrhoeic women as well as instances in which there is an extremely delayed follicular maturation (Maroulis and Abraham, 1976). The ultimate requirement for menopause is the absence of a maturable follicle which is associated with a serum E2 of under 20 pg/ml. As we have shown, the serum gonadotrophins, and particularly FSH, are elevated for much of the perimenopausal period (Figure 3a), and therefore cannot be used alone to assess menopausal status. Postmenopausally or after castration, both gonadotrophins become elevated quite rapidly to mean values three to four times mean follicular phase values. There is great variability, however, based in part on pulsatile gonadotrophin secretion (Yen et al, 1972), and presumptively in part on variable individual oestrogen status although there has been no study correlating gonadotrophin and oestrogen levels in postmenopausal women. From the point of view of clinical endocrinology, the definition of menopause requires a very low serum E2 and elevations of both gonadotrophins. The ovarian contribution to the postmenopausal steroid hormone milieu has been studied in relatively few women, usually in their first postmenopausal decade and often presenting to the physician with pelvic pathology. While serum E2 falls to very low levels postmenopausally, oestrone (E~) remained near the follicular phase concentration, no matter whether the menopause was natural or induced by surgery or radiation (Korenman,

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Perrin and McCallum, 1969; Tulchinsky and Korenman, 1970). It could be concluded that the ovary contributed relatively little to oestrone production and that it must be derived from the peripheral conversion of adrenal androstenedione. Direct measurement of ovarian and peripheral venous oestrogens and androgens at surgery (Judd et al, 1974) demonstrated substantial ovarian androstenedione and testosterone secretion in some cases but virtually no oestrogen secretion. Interpretation of these data is limited because the women were relatively young, experiencing pelvic pathology and under anaesthesia. A similar study employing women who were undergoing inferior vena cava catheterization demonstrated very little ovarian hormone secretion but some response to hCG (Greenblatt, Colle and Mahesh, 1976). Unfortunately there appears to have been problems with catheter placement. In order for a gland to be a major source of one of these steroids, a step-up of at least 20-fold of the hormonal concentration would be expected between peripheral and glandular venous blood. On that basis, we must conclude that the postmenopausal ovary contributes virtually no oestrogens. There appears to be a significant contribution to the circulating testosterone, particularly in the younger postmenopausal women. More indirect assessments (Abraham and Maroulis, 1975; Vermeulen, 1976) showed substantial reductions of the secretion of pregnenolone, 17hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, corticosterone, DHA, DHA-SO4, androstenedione and E2 in the postmenopausal period. Moderate reductions of testosterone and E~ were also noted. ACTH stimulation produced a remarkable increase of progesterone, 17hydroxyprogesterone, DHA, androstenedione and dihydrotestosterone, while only a slight rise in E, was seen. Intensive suppression with dexamethasone reduced the levels of most of these steroids to a fraction of their initial levels suggesting a predominantly adrenal origin of all of them. However, in a small study, much higher levels of the h53/~ hydroxysteroids pregnenolone, DHA and DHA-SO4 were found in a group of women receiving oestrogen replacement therapy than in a control group, suggesting a regulatory control of oestrogens over adrenal androgen precursor production (Abraham and Maroulis, 1975). The primacy of oestrogen production by the conversion of adrenal androstenedione in peripheral tissues in postmenopausal women was demonstrated and characterized in a series of difficult studies by Siiteri, McDonald and associates (1973) involving the continuous infusion of one or two radioactively labelled hormones and tracing their metabolic fate. They demonstrated unequivocally that in the postmenopausal woman, El is derived almost exclusively from the metabolism of androstenedione by aromatization in peripheral tissues and that most of the circulating E2 came from the conversion of E, (Grodin, Siiteri and McDonald, 1973). Androstenedione production was only 1.75 mg/day, about one-half that determined for premenopausal women. The extent of aromatization of androstenedione to Ex was 2.7 per cent in recently postmenopausal women, in contrast to the 1.3 per cent noted for younger, premenopausal women. As a result, E, production and, as previously noted, plasma concentration, were relatively little changed postmenopausally. Although aromatization of

THE PERIMENOPAUSALPERIOD AND BEYOND

635

androstenedione to El can be carried out in many tissues, a positive correlation with body weight, which was immediately apparent, led to the conclusion that adipose tissue made the greatest contribution. It was recently shown by direct measurement in men that adipose tissue and fat are equally efficient in aromatizing both testosterone and androstenedione (Longcope et al, 1978). Total aromatization was strongly correlated with both body weight and age in both sexes so that in a group of women who were more than 10 years menopausal, the conversion rate was 4.5 per cent (Siiteri and McDonald, 1973). Hepatic disease resulted in an even greater rate of aromatization independent of body weight and, in this group of women, the oestrogens produced a high incidence of endometrial hyperplasia and dysfunctional uterine bleeding. There is evidence that obesity may also result in an increased production of androstenedione. This has been demonstrated in polycystic ovarian disease where the overproduction was out of proportion to body weight and conversion rates to oestrone were normal (Siiteri and McDonald, 1973) and in obese men for whom weight loss readily reduced the androstenedione and oestrone production (Stanik et al, 1978). Androstenedione production in obesity may be increased because cortisol clearance is accelerated (Migeon, Green and Eckert, 1963), resulting in a substantial enhancement of the production of glucocorticoids and adrenal androgens (as a side product) in order to sustain glucocorticoid homeostasis. A final possible cause of increased El production in the obese postmenopausal woman is the tantalizing suggestion that oestrogens stimulate adrenal androgen production, providing a positive feedback response of oestrogens on themselves (Abraham and Maroulis, 1975). The clearances of E~ and E2 are reduced by about 25 per cent in the menopause in comparison to younger women (Longcope, 1971), thus contributing to maintenance of the serum E~ level. The clinical importance of circulating E~ is probably considerable. Unlike E2 which is tightly bound to sex hormone binding globulin and circulates principally in the bound state, E~ has only about one per cent the affinity of testosterone for the protein and circulates principally in the free or active state (Anderson, 1976). It is normally cleared about twice as rapidly as E2 because of its greater availability (Longcope, Layne and Tait, 1968; Hembree, Bardin and Lipsett, 1969). Its intrinsic oestrogenic potency was found to be between 15 and 25 per cent that of E2 as measured by binding to the uterine cytoplasmic receptor (Korenman, 1969). Because of its rapid conversion to oestradiol when administered (Riggs, Hermann and Yen, 1978), it is impossible to ascribe a potency to administered E1 or its conjugates in the whole organism. It is possible to conclude that in the postmenopausal state the ovary contributes at most a small amount of testosterone and androstenedione. The principal source of reproductive steroids is the peripheral conversion of adrenal androstenedione whose secretion is regulated by ACTH and whose conversion to E1 is controlled by a number of factors including predominantly obesity and hepatic disease. A corollary is that there is no negative feedback of exogenous oestrogens on endogenous oestrogen production in the postmenopausal state.

636

STANLEYG. KORENMAN,BARRYM. SHERMANAND JULIEC. KORENMAN THE MENOPAUSAL SYNDROME

Although it is believed that the great majority of women experience a distinctive menopausal syndrome, its true incidence is not clear and may be only 25 per cent (Utian, 1972; Goodman, ,Stewart and Gilbert, 1977). The most specific symptoms appear to be hot flushes and atrophy of the genital organs. The vasomotor symptoms appear quite early and are reported within a week of oophorectomy (Askel et al, 1976) while atrophic changes may take many years to develop. In fact, careful quantitative studies (Meisels, 1966; Sedlis, Turkell and Stone, 1969; Chapman et al, 1976) indicate that an atrophic vaginal smear is uncommon in the early postmenopausal years and that highly oestrogenized smears persist in some women into advanced old age. Although the vaginal smear has never been related to body weight, a study of urinary cytology, which is also oestrogen-dependent, indicated a positive correlation between obesity and persistent oestrogen effects (DeWaard et al, 1972). There have been no good studies detailing a relationship between circulating oestrogens, gonadotrophins and vaginal cytology in postmenopausal women. It appears that menopausal symptoms require both hypergonadotrophinism and severe oestrogen deficiency. The symptoms do not occur in hypogonadotrophic hypogonadisrn of any cause. They are rare in euoestrogenic hypergonadotrophic states such as in the perimenopausal period.

CLINICAL IMPLICATIONS Cessation of ovarian function in the presence or absence of clearcut menopausal symptoms has often been considered to be an adequate indication for the use of oestrogens in 'physiological' concentrations. This approach has been challenged by evidence relating oestrogen administration, whether it be in oral contraceptives or menopausal preparations, to a variety of serious complications. It is necessary to assess these adverse effects in relation to the deleterious effects of long-term sex hormone deprivation. In addition to alleviation of disquieting autonomic symptoms, the major rationale for longterm oestrogen therapy has been prevention of osteoporosis. Bone is a cellular tissue which contains 99 per cent of total body calcium whose metabolic activity is concerned with bone formation, resorption, and remodelling. The rates of these processes are regulated by a variety of metabolic and physical factors. Bone remodelling responds to changes in body weight, posture and physical activity. After age 40, a negative calcium balance indicating an excess of resorption over formation characterizes all studied human populations (Garn, Rohrmann and Wagner, 1967; Perzigian, 1973). While the rate of loss averages 0.3 per cent a year in men, women after the menopause (Dequeker, 1971) or after oophorectomy (Meema and Meema, 1968) have an accelerated bone loss averaging about 0.8 per cent per year. There is great individual variation in the rate of bone demineralization (Nordin et al, 1975; Gallagher and Nordin, 1975). Those women developing crush fractures, for whom the term osteoporosisas distinguished from

THE PERIMENOPAUSALPERIOD AND BEYOND

637

simple osteopenia is reserved, have an above average rate of bone demineralization (Gallagher and Nordin, 1975). Among the factors contributing to age-related bone loss are declining physical activity, including the effects of intercurrent illness, and excessive phosphorus intake, especially carbonated drinks. Inadequate calcium adsorption is also common and includes poor dietary intake because of habit or lactose intolerance and in many cases a degree of malabsorption (Bullamore et al, 1970) which may be related to reduced parathormone concentrations (Riggs et al, 1973). The oestrogenic state of the woman exerts a major regulatory control over bone formation and resorption. Oestrogens reduce both formation and resorption, decrease the serum calcium, morning urinary calcium excretion and urinary hydroxyproline, and prevent demineralization in a dose as low as 25 ~g of ethinyl oestradiol daily (Gallagher and Nordin, 1975). Careful studies of the relationship between vaginal smear (Nordin et al, 1976), the plasma androstenedione and oestrone levels (Marshall, Crilly and Nordin, 1977), and the development of osteoporosis demonstrated a greater degree of oestrogen deficiency in women with osteoporosis than others. An informative epidemiological study linked osteoporosis to slenderness (less than 110 per cent of ideal body weight) and to smoking (Daniell, 1976). These data strongly implicate oestrogen deficiency in the development of osteoporosis. The locus of action of the oestrogen is unknown. Oestrogen receptors have not been demonstrable in bone cells. The administration of oestrogens to postmenopausal women has demonstrated their powerful effect in inhibiting both bone resorption and bone deposition (Riggs et al, 1973), but a net positive effect on bone density after long-term administration has been demonstrated only recently (GaUagher and Nordin, 1975; Meema, Bunker and Meema, 1975; Lindsay et al, 1976; Recker, Saville and Heaney, 1977). While prevention of progressive demineralization for as long as seven years by as little as 25/~g of ethinyl was shown in a few patients (Gallagher and Nordin, 1975), really long-term efficacy and a demonstration of reduced osteoporosis in a treated population have not been reported. On the basis of the available evidence the use of oestrogens would appear to be warranted in women at high risk for osteoporosis because this condition produces serious morbidity and mortality when present. The high risk group would be Caucasian smokers weighing less than 110 per cent of ideal body weight who have strong evidence for severe oestrogen deficiency including severe menopausal symptoms, an atypical vaginal smear and a low serum oestrone as well as oestradiol level. ~[t would also seem prudent to recommend cessation of tobacco use, regular exercise, a daily calcium intake of a gram or more and small doses of vitamin D to most postmenopausal women. The consequences of oestrogen administration in the menopausal setting have been assessed in a number of epidemiological studies. It is important to distinguish these from investigations of the consequences of oral contraceptives and ensure that there is a matched control population so that the effects of age per se can be distinguished from those of oestrogens. The risk of fatal and non-fatal myocardial infarction is increased after ovariectomy (Oliver and Boyd, 1959; Higano, Robinson and Cohen, 1963) and in the menopause as compared to age-matched controls (Kannel et al,

638

STANLEYG. KORENMAN,BARRYM. SHERMANAND JULIE C. KORENMAN

1976). Treatment with oestrogens did not influence this risk (Rosenberg, Armstrong and Jick, 1976), although the question is by no means settled and prevention of episodes has been reported (Higano, Robinson and Cohen, 1963). The increase in blood pressure with age is not ameliorated by postmenopausal oestrogen therapy. Mean blood pressure rises primarily because of large increases in a few susceptible individuals (Notelovitz, 1975; Pfeffer and Van den Noort, 1976). The rising incidence of stroke with age does not appear to be influenced by postmenopausal oestrogen therapy (Pfeffer and Van den Noort, 1976). The concentration of clotting factors VII, IX and X and antithrombin III were not affected by the menopause. Significant changes associated with menopausal therapy (Davies et al, 1975; Bonnar et al, 1976) have not appeared to signify an increased risk of thromboembolic events with such therapy. The Boston Collaborative Drug Surveillance (1974) reported that postmenopausal oestrogen therapy resulted in a 2.S-fold increase in the risk of requiring gall bladder surgery. Oestrogen therapy has been shown to lower the serum cholesterol slightly and increase the triglycerides variably (Magnani and Moore, 1976; Notelovitz, 1976; Wallace et al, 1977). These effects are due in substantial part to the direct stimulation of VLDL synthesis (Hazzard et al, 1969; Wynn et al, 1969; Applebaum et al, 1977), and cholesterol synthesis and metabolism resulting in a more highly saturated bile with consequent predisposition to gallstones (Bennion et al, 1976; Bennion, 1977). The effects of oestrogens on many cardiovascular and lipid parameters may well be due to their direct stimulation of selective hepatic protein synthesis. Stimulated proteins include corticosteroid, thyroid and sex hormone binding globulins, caeruloplasmin, clotting factors II, VII, IX and X, al-antitrypsin, angiotensinogen as well as VLDL (Weinberger et al, 1969; Song et al, 1970; Davies et al, 1975). Alteration in clearance rather than increased synthesis has not been ruled out in some cases. The most difficult problem in the menopausal state is the rising incidence of cancer and the relationship to oestrogen therapy. At the time of writing, the evidence seems to be neutral regarding a relationship between either oral contraceptive or postmenopausal oestrogen therapy and breast carcinoma, although evidence of a slightly increased risk has been reported recently (Hoover et al, 1976). By contrast, recent epidemiological reports (Smith et al, 1975; Ziel and Finkle, 1975; Mack et al, 1976; Gray, Christopherson and Hoover, 1977; McDonald et al, 1977) have indicated a substantially increased risk of endometrial carcinoma in postmenopausal women receiving physiological amounts of oestrogens as compared to non-users, as well as an overall increase in the incidence of the disease concomitant in time with the increasing prescription of oestrogens (Weiss et al, 1976). Upon review (Weiss, 1978), it could be shown that the increased risk is ameliorated by earlier diagnosis and a preponderance of lesions confined to the endometrium. Despite the controversy surrounding these studies, the user now carries the burden of proof that oestrogens, particularly long-term oestrogens, constitute an appropriate therapy in the menopause.

THE PERIMENOPAUSAL PERIOD AND BEYOND

639

CONCLUSIONS Even our current incomplete understanding of the dynamics of reproductive hormone production in the perimenopausal and postmenopausal years can be of assistance in arriving at a valid approach toward care. This approach is based on the fact that thin, inactive, Caucasian smokers tend to have the most oestrogen deprivation and develop osteoporosis. It is these women who have the lowest probability of having euoestrogenic amenorrhoea, lowest adrenal androstenedione production, and lowest rate of aromatization. They also have the least likelihood of getting gall bladder disease, or endometrial or breast carcinoma. On the other hand, the obese woman will have more endogenous oestrogen and a much greater likelihood of endometrial carcinoma, gall bladder disease, thromboembolic disease and hypertension. They will also develop euoestrogenic amenorrhoea to a much greater extent than thin women. Oestrogens administered in the postmenopausal state are at least additive to oestrogens produced by the peripheral conversion of adrenal androstenedione because, in the absence of ovarian function, there is no negative feedback regulation over the serum oestrone and oestradiol. Therefore, in many women, a hyperoestrogenic state could follow standard therapy. In the only controlled study, doses of ethinyl oestradiol as low as 5 gg per day could completely normalize gonadotrophins in some post-menopausal subjects (Wise, Gross and Schalch, 1973). Therefore, we would suggest that treatment with oestrogens be reserved for women with specific and major menopausal symptoms, a low serum oestrone and oestradiol level, and an atrophic vaginal smear who are predisposed to osteoporosis. Such therapy should be begun only after the possible consequences of postmenopausal oestrogen therapy are explained and the dose should be adjusted carefully from time to time to the lowest effective level. Supplementation with calcium and small amounts of vitamin D would also be appropriate. Oestrogen therapy should also be strongly considered in women receiving long-term adrenocortical steroid therapy for any reason except for breast cancer.

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