The Journal of Obstetrics and Gynaecology of fhe British Commonwealflz Feb. 1974. Vol. 81. pp. 150-154.

THE RELATIONSHIP BETWEEN MENOPAUSAL VASOMOTOR SYMPTOMS AND GONADOTROPHIN EXCRETION IN URINE

AFTER OOPHORECTOMY

BY

J. M. AITKEN* A. DAVIDSON

Departments oj‘ Medicine and Gynaecology, Western Infirmary, Glasgow GI 1 6 NT P. ENGLAND

A. D. T. GOVAN Gonadotrophin Laboratory, Royal Maternity Hospital, Glasgow G4 ONA

D. M. HART Department of Gynaecology, Stobhill General Hospital, Glasgow G21 3U W

ANNE KELLY Gonadotrophin Laboratory, Royal Maternity Hospital, Glasgow G4 ONA

R. LINDSAY Department of’ Medicine, Western Infirmary, Glasgow GI1 6NT

ANN MOFFATT Gonadotrophin Laboratory, Royal Maternity Hospital, Glasgow G4 ONA

AND

Summary The prevalence of menopausal vasomotor symptoms was assessed in 190 women seen for the first time at various intervals after oophorectomy. Urinary gonado- trophin excretion was measured and the vasomotor symptoms were assessed in 119 patients who were seen again at least one year after being given prescriptions for two tablets daily of either 20 pg. of mestranol or placebo. The prevalence of symptoms decreased with the elapse of time after oophorectomy and showed a significant inverse correlation with urinary gonadotrophin excretion. Mestranol therapy caused a significant reduction in both the prevalence of symptoms and urinary gonadotrophin excretion. Therapeutic failures were usually the result of inadequate medication. It is suggested that menopausal vasomotor symptoms and gonadotrophin excess both reflect hypothalamic-pituitary dysfunction and are not otherwise causally related.

AT the time of the menopause most women gen output is low and pituitary gonadotrophin experience vasomotor symptoms characterized production is high, and in consequence either by excessive flushing and sweating. These one or both of these changes have been impli- symptoms appear at a time when ovarian oestro- cated in the aetiology of these vasomotor - - _ _

phenomena (Jeffcoate:- 1967). Ferriman and Purdie (1965) reported that hot

Bartholomew’s Hospital, London, EClA 7BE. flushes were relieved by dithiocarbamoyl- * Present address: Medical Professorial Unit, St.

150

VASOMOTOR SYMPTOMS AFTER OOPHORECTOMY 15 1

hydrazine, which is reputed to inhibit gonado- trophin secretion. They postulated that gonado- trophin excess and not oestrogen deficiency was the primary factor in the aetiology of menopausal vasomotor symptoms. This hypothesis would suggest that postmenopausal women with such symptoms should excrete excessive quantities of gonadotrophin in the urine.

In order to test this hypothesis, we made an assessment of vasomotor symptoms in women after oophorectomy, and examined the relation- ship of these symptoms to urinary gonadotrophin excretion and the effect of long-term low dosage oestrogen therapy.

PATIENTS AND METHODS A total of 190 women aged 31 to 58 years

were reviewed for the first time at two months, three years or six years after hysterectomy and bilateral salpingo-oophorectomy, which had been performed for non-malignant disease when they were still menstruating. Of these women, 119 were reassessed after a further interval of one to three years, by which time 57 had been taking up to two 20 pg. mestranol tablets daily whereas the remainder had been taking up to two placebo tablets daily. The women formed part of a double-blind controlled trial of oestro- gen therapy for the prevention of post-meno- pausal osteoporosis (Aitken e f al., 1973) and for which they had freely volunteered. No suggestion was offered to these subjects that the tablets might affect menopausal vasomotor symptoms. The medication was dispensed in boxes containing 120 tablets each, new supplies being obtained by returning a specially coded postcard to the hospital pharmacy. It was possible by this means to make a rough estimate of the number of tablets taken by each woman.

Each subject was asked if she had suffered from excessive flushing and/or sweating over the previous year. The symptoms were scored as follows: no symptoms-Grade 0; occasional symptoms-Grade I ; frequent and persistent symptoms-Grade 11. When these women were reassessed after an interval of at least one year a 24-hour urine collection was made using plastie cans containing 1 g. of streptomycin sulphate. Urine volumes were made up to two litres with distilled water in order to facilitate the calculation of results.

Total urinary gonadotrophins were estimated by bioassay using the mouse uterine weight method of Kleinfelter et af. (1943) and employing the kaolin-acetone extraction procedure des- cribed by Loraine and Brown (1959). Urinary luteinizing hormone (LH) was measured by a haemaglutination inhibition technique, using Luteonosticon kits as manufactured by Organon Laboratories. The test involves the agglutination of erythrocytes coated with human chorionic gonadotrophin (HCG) using an HCG antiserum. Urinary LH crossreacts with HCG and thereby inhibits agglutination. This method is semi- quantitative only, detecting 25 to 400 IU of LH per litre as a result of five doubling dilutions of urine.

RESULTS Assessment a t j r s t visit

Some details of the women at their first visit are given in Table 1. Of those women seen within two months of oophorectomy, 93 per cent were experiencing vasomotor symptoms, whereas the prevalence was 89 per cent and 71 per cent at three years and six years respectively. A total of 1 1 per cent of the women seen three or six years after oophorectomy had at some time been prescribed an oestrogen-containing preparation and of these one-third continued hormone therapy until the time they were first seen.

Placebo-treated women Some details of the women seen again after

taking placebo tablets are shown in Table 11. Grade I1 vasomotor symptoms were found in 58 per cent of this group. These women were slightly younger and a significantly shorter period of time had elapsed since oophorectomy than was found in the women with no symptoms (p<0-005), but mean urinary total gonado- trophin and LH excretion tended to be higher in those women without symptoms. Of the 13 symptom-free women, 7 (54 per cent) had urinary total gonadotrophin values of 30 HMG units per 24 hours or more, whereas only 14 out of 36 (39 per cent) of the women with Grade 11 symptoms had values in this range. Conversely 2 out of 13 (15 per cent) of the symptom-free women had urinary total gonadotrophin values of 10 HMG units per 24 hours or less, whereas

152 AITKEN, DAVIDSON, ENGLAND, GOVAN, HART, KELLY, LINDSAY AND MOFFATT

TABLE I Prevalence of menopausal vasomotor symptoms after oophorectomy in I90 women seen at the onset of the study

Number Number Time after Number of Age Number with symptoms given given

oophorectomy women (years) oestrogens oestrogens Grade 0 Grade I Grade I1 intermittently continuously

- - 2 months 30 4 4 . 8 2 0 28 3 years 120 49.4 13 16 91 10 5 6 years 40 52.1 11 9 20 2 1

as many as 12 out of 36 (33 per cent) of the women with Grade I1 symptoms had values in this range. Likewise 50 per cent of the symptom- free women excreted 200 1U of LH or more in 24 hours as opposed to only 31 per cent of the women with Grade I1 symptoms.

The relationship between the prevalence of vasomotor symptoms and gonadotrophin excre- tion in these placebo treated women was examined with special reference to the number of years which had elapsed between oophorectomy and review (see Fig. 1). A significant inverse correlation was found between the mean symptom score and the mean total gonado- trophin excretion (P< 0-05), although this was not strictly dependent upon the time since oophorectomy. Of these women, those who were aged 50 years or less excreted a mean of 25.6f2-6 HMG units of gonadotrophin per 24 hours, whereas the mean was 33-1&4-3 HMG units per 24 hours in the women over the age of 50 years.

Mestranol treated women Some details of the oophorectomized women

who had been prescribed mestranol for at least one year are shown in Table 111. The mean tablet consumption was very significantly lower in the women with persistent symptoms (p< 0 401) than in those who were symptom-free. Although these symptomatic women claimed that they were taking two tablets daily (or about 720 tablets per year), half of them were actually taking less than two tablets per week.

DISCUSSION Urinary gonadotrophin excretion increases

and urinary oestrogen excretion decreases progressively for about fifteen years after the cessation of menstruation in normal women

(Albert, 1956; Lauritzen, 1972). Our results suggest that urinary gonadotrophin excretion also increased progressively over an eight-year period after oophorectomy. Most medical practitioners believe that the prevalence and severity of menopausal vasomotor symptoms are greatest at the time of the cessation of ovarian function. Rhodes (1968) stated that these symptoms usually disappear within a year or two, but the present study showed that over 50 per cent of women were still affected eight years after oophorectomy. During this time interval there was a significant inverse relation- ship between the prevalence of vasomotor symptoms and the mean total gonadotrophin excretion.

These results and the results of other workers suggest that the increased gonadotrophin excre- tion seen after the menopause reflects a general- ized hypothalamic-pituitary disorder and that menopausal vasomotor symptoms are due to the whole disorder rather than to raised gonado- trophin production and excretion alone. Thus while dithiocarbamoylhydrazine reduces gonado- trophin excretion (Bell et al., 1962; Brown et al., 1963) this drug probably exerts its beneficial effect on menopausal vasomotor symptoms (Ferriman and Purdie, 1965) by its general effect on the hypothalamic-pituitary axis (Tul- loch et al., 1963; Zagni and Benson, 1964). By the same token, oestrogens, which can inhibit or stimulate pituitary gonadotrophin secretion (Smith and Albert, 1955) may well suppress vasomotor symptoms by altering the production of or sensitivity to other hormones (Reifenstein et al., 1946; Frantz and Rabkin, 1965; Jasani et al., 1965; Aitken et al., 1971).

When first seen, only 3 per cent of women were found to be on long-term oestrogen therapy. This probably reflects the over-cautious

VASOMOTOR SYMPTOMS AFTER OOPHORECTOMY 153

TABLE XI Focrors associated with the prevalence of menopousal vasomotor sympfoms in 62 women for whom a placebo had

been prescribed more than one year previously

Time after Total urinary Urinarq Menopausal vasoniotor Number Age oophorectomy gonadotrophins luteinizing

symptoms of (years) (years) (HMG units/ hormone (yearly tablet women 24 hrs). (IU/24 hr.) consumption) Mean&SEM Mean i= SEM MeankSEM Mean1SEM

Grade 0 (*391 k47) 13 50 .610 .8 *5.4 kO.5 *32.2 1 4 . 3 *343 k90 Grade I(380154) 13 4 9 . 8 1 0 . 6 4 . 7 h 0 . 4 3 1 . 1 5 8 . 0 125*28

Grade I1 (*455 +38) 36 49.7h.O. 6 * 3 . 7 1 0 . 2 *28.4+3.4 *224 &42 * t ~ 1.34 * t = 3.42 * t = 0.46 * t = 1.36

NS P<0,005 NS NS

NS = - not Significant.

TOTAL URINARY

iH M G unitr/24hours) GONADOTROPHINS (8)

r I -0.73 T

0.5 I

1.0 I

1.5 I 2.0

MEAN SYMPTOM SCORE

FIG. 1 The relationship between the mean vasomotor symptom score (x) and mean urinary gonadotrophin excretion+SEM ( y ) in 62 placebo treated women one to eight years after oophorectomy (y = 52.0--17*2x) (r -2 0.73;

t = 2.61; p<0.05). The figures in parentheses indicate the number of years between oophorectomy and review. The shaded area is the “normal” premenopausal range for

gonadotrophin excretion.

attitude of British practitioners towards pre- ACKNOWLEDGEMENTS scribing this class of drug for symptoms which This work was supported by grants from the are supposed to be self-limiting. I t was interesting Scottish Hospital Endowments Research Trust. to note that although patients denied it, a the National Fund for Research into Crippling failure to take tablets prescribed by us appeared Diseases, and G. D. Searle & Co. Ltd., who to play a significant role in the persistence of kindly supplied the mestranol and placebo symptoms. tablets. We are also indebted to Professor Tan

154 AITKEN, DAVIDSON, ENGLAND, GOVAN, HART, KELLY, LINDSAY AND MOFFATT

TABLE 111 Fuctors ussociated with the prevalence of menopausal vasomotor symptoms in 57 women given a prescription

more than one year previously for two 20 pg. tablets of mestranol daily ~~~~~~~~~~~~~

Time after Total urinary Menopausal vasomotor Number Age oophorectomy gonadotrophins Urinary LH

symptoms of (years) (years) (HMG units/ (IU/24 hr.) (yearly tablet women 24 hr.) consumption) Mean + SEM MeaniSEM MeaniSEM MeaniSEM

~~ ~~ ~~ ~~~ ~ ~~

Grade 0 (*515-23) 41 * 5 1 . 5 & 0 . 5 *5 .6&0.2 * 1 4 . 8 1 2 . 2 *I11228 Grade 1 (327 t67 ) 7 5 0 . 2 1 1 . 3 5 . 3 1 0 . 7 20.4 &7.7 391&178

Grade I1 (*264150) 9 *47-5 t l . 1 *3.6*0.7 *29.6 *9.4 '378 f 142 * t = 2.34 * t = 3 . 0 3 *t = 4.67 * t = 3.31 * t = 3.27

p- 0.001 Pt0 .005 Pt0 .005 P t O . 0 5 P--CO.Ol

Donald and his staff for permitting us to contact their patients; and to Mr. J. Ferguson for technical assistance.

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