produced by post-menopausal women (MacDonald weight (Rizkallah et al. 1975; MacDonald et al. possible relationships among the climacteric symp

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1 Climacteric symptoms, fat mass, and plasma concentrations of LH, FSH, Prl, oestradiol-17\gb\ and androstenedione in the early post-menopausal period C. Hagen, C. Christiansen, M. S. Christensen and I. Transb\lo/\l Department ofendocrinology, Hvidovre Hospital, University ofcopenhagen, DK-2650 Hvidovre, and Department ofclinical Chemistry, Glostrup Hospital, University ofcopenhagen, DK-2600 Glostrup, Denmark. Abstract. The relations between climacteric symptoms, fat mass, time after the menopause, and plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (Prl), oestradiol-17\gb\,and androstenedione were studied in 313 normal females in their early post-menopausal period. The mean age of the women was 50 years (45\pn-\54years, range) and the time elapsed since the last menstrual bleeding was 19.8 months (4\pn-\46months). Most women had mild to moderate climacteric complaints. The participants examined and filled in a questionnaire were containing the 11 symptoms of Kupperman index. A total of 61% of the women complained of hot flushes and from 9% to 44% complained of the remaining 10 Kupperman symptoms. Women with hot flushes (n 196) had a higher mean score (P<0.01) of the remaining symptoms than women without (n 117). Plasma concentrations of LH and FSH were higher significantly and levels of oestradiol-17\gb\and androstenedione were significantly lower in women complaining of hot flushes than in women without. Plasma levels of FSH was significantly (P < 0.05) higher and levels of oestradiol- 17\gb\ was signficantly (P<0.01) lower in women with insomnia than in women not complaining of this symptom and women with depression had significantly (P< 0.01) higher Prl levels than women without. The months since the menopause were related to plasma levels of FSH (r , P <0.01) and oestradiol-17\gb\ levels (r \m-\0.306,p< 0.001) but not to plasma concentration of LH, Prl and androstenedione. Fat mass was related to plasma FSH and androstenedione concentrations and correlation was found between oestradiol-17\gb\ and androstenedione (r , P< 0.001). Surprisingly, no correlation between hot flushes and fat mass was found. Of the 11 climacteric symptoms included in the Kupperman index (Kupperman et al. 1959) only hot flushes and insomnia respond significantly to treatment with oestrogen (Utian 1972; Campbell & Whitehead 1977; Hagen etal. 1982). However, the relationship between hot flushes and the basal plasma concentrations of pituitary-gonadal hor mones in post-menopausal women is controversial (Abe et al. 1977; Hutton et al. 1978; Badawy et al. 1979). Factors such as wide range of post-meno pausal age and small number of subjects could be responsible for these findings. Extraglandular aromatization of androstenedione to oestrone accounts for most of the endogenous oestrogen produced by post-menopausal women (MacDonald et al. 1967; Longcope et al. 1969; Grodin et al. 1973). Furthermore, the rate of conversion of these steroids appears to correlate with body weight (Rizkallah et al. 1975; MacDonald et al. 1978; Vermeulen & Verdonck 1978). Accordingly, fat mass may be related to the development of climacteric symptoms. The present study was undertaken to examine possible relationships among the climacteric symp toms, fat mass, time after the menopause, and plasma levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (Prl), oestra diol-17ß (E2) and androstenedione (A) in normal females in their early post-menopausal period.

2 Material and Methods Subjects The participants were selected as follows : of questionnaires sent to all women aged years in certain districts of the Copenhagen area, 9411 were returned. From information about the date of last vagi nal bleeding, earlier gynaecological operations and drug intake, 585 women fulfilled the criteria: 1) menstrual bleeding had stopped spontaneously within the last 54 to 3 years, 2) no treatment with gonadal hormones after the menopause. The 585 were participants invited to an information meeting, at which 463 turned up. Of these 404 gave written consent to participate in the study. At the attendance to our outpatient clinic a detailed history was taken, and a medical and gynaecological examination was performed. Three hundred and fifteen women were free from past or present disease known to influence the hormonal parameters measured, and none received any drugs which could influence the results. Two women with elevated plasma prolactin concentrations (above 60 Hg/1) and presumably a pituitary tumour, were excluded, leaving 313 women as the final study group. The mean age of the 313 women was 50 years (range years) and the mean time elapsed since the last menstrual bleeding was 19.8 months (6 46 months). The mean weight and height of the women were 64 kg ( kg) and 163 cm ( cm), respectively. Climacteric symptoms The participants filled in a questionnaire containing the 11 symptoms of the Kupperman index (Kupperman et al. 1959) (Table 1). For each symptom a score was given from 0 to 3 for no, slight, moderate and severe com plaints, respectively. Fat mass Fat mass was calculated as body weight minus lean body mass, where lean body mass (kg) was calculated according to the formula of Boddy et al. (1972): lean body mas (kg) x 10"2 (14.76 x weight/kg x height/cm 9.05 age/years 1669) - Plasma samples Blood samples all the women in the fasting separated and stored at -20 C until assayed. were drawn between 8 a.m. and 11 a.m. in state. Plasma was then Radioimmunoassays Plasma concentrations of FSH, LH and Prl were measu red by radioimmunoassays. E2 was measured by a direct radioimmunoassay after extraction with diethyl-ether using antiserum and 3H-labelled E2 from CIS Interna tional, France. The intra- and inter-assay coefficient of variations were 9% and 15%, respectively, for values in the observed range. The percentage (w/w) of cross-reac tions between oestradiol-17ß and other steroids were: Table 1. The number (n) and percentage (%) of the 11 Kupper man symptoms in 313 normal women in their early post-menopausal period. Symptoms Women with hot flushes (n 196) Women without hot flushes (n 117) Hot flushes Paraesthesia Insomnia Nervousness Depression Vertigo Fatigue Arthralgia/Myalgia Headache Palpitation Formication oestrone 1.6%, oestriol 0.5%, progesterone < 0.002%, cortisol < 0.002%, androstenedione %. A was extracted from serum with isooctan and measured by radioimmunoassay. Antiserum was from Wien Laborato ries Inc., New Jersey, and 3H-labelled androstenedione was supplied by New England Nuclear, Mass. The sepa ration of the antibody bound fraction was carried out by means of a gel-centrifugation procedure. Intra- and inter-assay coefficient of variations were 8% and 11%, respectively. Statistical evaluation Data were analyzed with unpaired Student's -test and linear regression analysis with the method of least squares. Results Sixty-three per cent of the women complained of hot flushes and 8% to 43% complained of the remaining 10 symptoms. Only 11% (n 36) of the women were without symptoms. The women were divided into two groups according to presence (n 196) or absence (n 117) of hot flushes (Table 1). Women with hot flushes had a signifi cantly higher mean score for the remaining 10 symptoms (0.44 ± 0.05, mean ± SEM, P < 0.01) compared to women without hot flushes (0.18 ±0.03). Insomnia, nervousness, fatique,

3 Table 2. The significance of difference in plasma concentrations of LH, FSH, Prl, oestradiol-17ß (E2), and androstenedione (A) in 313 post-menopausal women with and without climacteric symptoms. Symptoms Number of women with symptoms LH FSH Prl Hot flushes Insomnia Depression Fatigue Headache P<0.01* P<0.00U P< 0.001* P < 0.05* P < 0.05* P<0.02* P<0.01* P< 0.001** P<0.01** P < 0.01** Not significant. * Higher levels in women complaining of symptoms. ** Lower levels in women complaining of symptoms. arthralgia + myalgia and headaches were the most common complaints among women with vaso motor disturbancies, whereas fatigue, arthralgia + myalgia, headaches and paraesthesia were the most common in women without hot flushes. Table 2 shows the significance of difference in plasma hormone concentration in women with and without 5 of the 11 climacteric symptoms. Plasma levels of LH were significantly higher in women with hot flushes (27 ± 0.7 IU/I vs 24 ± 0.8 IU/1, mean ± SEM), and headaches (28 ± 1.0 IU/1 vs 25 ± 0.6 IU/1), whereas FSH levels were higher in women with hot flushes (73 ± 1.8 IU/1 vs 61 ± 2.6 IU/1), insomnia (83 ± 3.3 IU/1 vs 67 ± 1.7 IU/1) fatique (72 ± 2.3 IU/1 vs 66 ± 2.1 IU/1) and head aches (74 ± 2.7 IU/I vs 66 ± 1.9 IU/1). Plasma concentration of oestradiol- 17ß was significantly lower in women with hot flushes (131 ±5 pmol/i vs 164 ± 10 pmol/1) and insomnia (128 ± 8 pmol/1 vs 147 ± 6 pmol/1) whereas plasma androstenedione levels were lower in participants with hot flushes (3.4 ± 0.1 pmol/1 vs 3.7 ± 0.2 pmol/1). Plasma Prl levels were slightly, but significantly higher in women complaining of depression than in women without this symptom (13.3 ±0.7 p.g/1 vs 10.6 ± 0.5 ug/1). Post-menopausal women with paraesthesia, nervousness, vertigo, arthralgia + myalgia, palpitation and formication had the same hormonal levels as those without these symptoms. The relations between plasma hormone concen trations as well as hot flushes and the time after the menopause in the 313 post-menopausal women are summarized in Table 3. A significant correlation was observed between months since the menopause and FSH (r , P < 0.01) as well as oestradiol-17ß (r , P< 0.001) concentrations. No relation between months since the menopause and LH, Prl and androstenedione levels as well as hot flushes was found. However, plasma andro stenedione concentration was significantly (P < 0.05) lower in the group of patients of 13 to 24 months of menopausal age than those of 6 to 12 months. Analysis of possible relationship among LH, FSH, Prl, oestradiol-i7ß, and androstenedione Mean concentrations (: Table 3. 1 SEM) of LH, FSH, Prl, oestradiol-i7ß (E2) and androstenedione (A) in plasma from post-menopausal women. Months after the menopause Number of women LH (IU/1) FSH (IU/1) Prl (Hg/1) E2 (pmol/1) A (nmol/l) Hot flushes (score) > ± 1 27 ± 1 26 ± 1 62 ±3 67 ±2 75 ± ± ± ± ± ±6 4.1 ± ± ± ± ±0.11

4 Table 4. Relationship of fat mass to hot flushes and plasma concentrations of FSH, oestradiol- 17ß (E2) and androstenedione (A) in women > 24 months after the menopause. Values given as mean ± 1 sem. Distribution of fat mass (kg) Number of women Hot flushes (score) FSH (IU/1) E2 (pmol/1) A (nmol/l) Lower 33%, Middle 33%, Upper 33%, 12.1 ± ± ± ± ± ± ±4 77 ±5 69 ±4 115 ±5 128 ± ±6 1.9 ± ± ± 0.2 in the post-menopausal women revealed correla tions between LH and FSH (r , P< 0.001), between FSH and oestradiol-17ß (r , P < 0.001), between LH and oestradiol-17ß (r , P < 0.01), between FSH and androstenedione (r , P<0.01) and between androstenedione and oestradiol-i7ß (r , P< 0.001). The relationship among fat mass, hot flushes, FSH, LH, oestradiol-17ß and androstenedione is shown in Table 4. Only women with a post-meno pausal age of > 24 months, i.e. those with the lowest endogen ovarian oestrogen production were included. When comparing the highest with the lowest quatiles of fat mass the leaner women had the highest plasma FSH concentration (P < 0.05) and the lowest androstenedione levels (P < 0.01). However, plasma oestradiol-17ß concentration and scores of hot flushes were not significantly dif ferent (P > 0.05) between these groups of women. Discussion In recent studies no relation between the Kupper man index (Abe et al. 1977) as well as hot flushes (Stone et al. 1975; Hutton et al. 1978; Badawy et al. 1979) and plasma oestrogen levels have been demonstrated in post-menopausal women. How ever, pre-menopausal women with hot flushes had higher levels of LH and FSH and lower levels of oestradiol than women without hot flushes (Chakravarti et al. 1979). The present study extends these findings to post-menopausal women, and in addition demonstrates that women with hot flushes have lower levels of androstenedione. The reason for these findings may be that the women included are in their early post-menopausal period and have a very wide range in symptomatology as well as in oestradiol-i7ß levels ranging from nor mal pre-menopausal levels to very low levels. In women with hot flushes the frequency of the remaining 10 symptoms were significantly higher than in those without. This support the view (Utian 1972; Chakravarti et al. 1979) that hot flushes is the most important symptom included in the Kupperman index. A weak relation between the climacteric symp tom fatigue and plasma FSH concentration (Table 2) was found. However, fatigue has not previously been directly related to lack of oestrogen or re lieved by the administration of oestrogen or oestrogen/gestagen (Utian 1972; Hagen et al. 1982). Headaches have previously been related to oestro gen withdrawal in the climacteric (Chakravarti et al. 1979; Lauritzen 1973) but was not relieved et al. during oestrogen/gestagen treatment (Hagen 1982). In the present study higher levels of LH and FSH were observed in women with headaches than in women without, but the plasma oestradiol-i7ß concentration did not differ between the two groups. Consequently, changes in the pituitary gonadotrophin secretion might be a more sensitive parameter than the basal oestradiol-17ß levels for the development of headaches in the climacteric. Mean plasma Prl concentration was significantly higher in women complaining of depression than in women without this symptom, whereas no diffe rence was observed between the hormone levels of LH, FSH, oestradiol-i7ß and androstenedione in these groups. Changes in neuronal amine activity in patients with depressive illness have previously been reported (Carroll 1978). Baseline plasma Prl levels were raised in 8 patients with unipolar and 16 patients with bipolar depressive illness (Sachar et al. 1973), whereas Mendlewicz et al. (1980) found elevated Prl levels in unipolars but not in

5 bipolars. Others have reported normal basal and stimulated Prl levels in patients with endogen de pression (Ehrensing et al. 1974; Maeda et al. 1975, 1979; Shaw et al. 1977). Since Prl appears to be primarily under dopaminergic control, the higher Prl levels in the group of patients with depression found in this study may perhaps suggest that these women have a decreased hypothalamic dopaminer gic activity. It has been reported that plasma oestradiol (Chakravarti et al. 1979; Abe et al. 1977; Vermeulen & Verdonck 1978; Badawy et al. 1979) and androstenedione (Chakravarti et al. 1979) decrease to about 20% of their pre-menopausal values within 1 3 years after the menopause. Vermeulen & Verdonck (1978) found no further changes after 4 years of menopausal age whereas others found decreasing oestradiol levels with age until advanced age (Chakravarti et al. 1979; Badawy et al. 1979). In the present study the concentration of andro stenedione and oestradiol showed a fall to about 30% of pre-menopausal values within 1 to 2 years after the menopause, and then no further changes. However, no patient was more than 46 months after the menopausa. In post-menopausal women the major source of circulating oestrogens is the peripheral conversion of androstenedione to oestrone (Grodin et al. 1973; MacDonald et al 1978) which at least in part takes place in fat tissue (Longcope et al. 1978). This conversion has been shown to correlate with body 1975; MacDonald et al. weight (Rizkallah et al. 1978; Vermeulen & Verdonck 1978). Further more, in previous studies in which most women of more than 4 years of post-menopausal age have been included, plasma oestradiol levels were re lated to weight (Vermeulen & Verdonck 1978; Badawy et al. 1979). In the present study fat mass was not related to circulating oestradiol-17ß levels which may suggest that the conversion in fat tissue of androstenedione to oestrone and then to oestra diol and that of testosterone to oestradiol is of little significance in the months period of post menopausal age. In post-menopausal women androstenedione is secreted from the ovary as well as the adrenal an increased (Judd 1976), and in fat subjects adrenal steroid secretion have been reported (Strain et al. 1980). This is in accordance with the present finding of a positive relation between fat mass and androstenedione levels. In addition the negative relation between plasma FSH levels and fat mass indicate an inhibition of pituitary FSH secretion presumably due to the raised levels of androstenedione in these patients leading to en hanced cerebral aromatization of androstenedione to oestrone and then to oestradiol in fat subjects. Secondly, the gonadotrophs may convert andro stenedione to testosterone, a suppressor of FSH secretion. Thirdly, it can not be excluded that small amounts of androgens are aromatized to oestro gens in the periphery because plasma levels of androstenedione were related to oestradiol levels. Our data suggest that only hot flushes and insomnia, included in the 11 symptoms of the Kupperman index, are related to the relative oes trogen deficiency which occurs after the meno pause. In addition, a relation between headaches and raised plasma gonadotrophin levels, and de pression and increased Prl levels were found. Furthermore, the development of hot flushes was not related to fat mass even though oestradiol- 17ß levels were related to androstenedione levels and androstenedione concentrations were re plasma lated to the degree of obesity expressed by fat mass. Acknowledgments We are grateful to Drs. W. R. Butt, A. S. Hartree, H. Friesen and the M.R.C. for reagents used in the radio immunoassays. This study was supported by grants from the Danish Medical Research Council (J.no , , and ); Direktor Jacob Madsen og Hustru Olga Madsens Fond; Danish Hospital Founda tion for Medical Research, Region of Copenhagen, Faroe Islands, and Greenland (J.no. 76/77, 56; 77/78, 52; 78-7; 79-22; 80-18). References Abe T, Furuhashi N, Yamaya Y, Wada Y, Hoshiai A & Suzuki M (1977): Correlation between climacteric symptoms and serum levels of estradiol, progesterone, follicle-stimulating hormone, and luteinizing hor mone. AmJ Obstet Gynecol 129: Badawy S Z A, Elliot L J, Elbadawi A & Marshall L D (1979): Plasma levels of oestrone and oestradiol-17ß in postmenopausal women. Br J Obstet Gynaecol 86: Boddy K, King P C, Hume R & Weyers E (1972): The relation of total body potassium to height, weight, and age in normal adults. J Clin Pathol 25:

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