743 TABLE V-RESULTS

grossly obtunded patients improved so much that the surgical mortality and morbidity could be reasonably expected to be low. 27-30 We thank Mr J. P. Lanigan, F.R.c.s.t., for allowing us to study tients in his care, and Mrs Lynda Grime for secretarial help. Requests for reprints should be addressed to U. M. C.

’.Mortality of patients who had recurrent hxmorrhage.

of cerebral aneurysm must be assumed to ruptured be sealed by a platelet plug which gradually organises into a blood-clot.’, 17-19 Blood in the subarachnoid space stimulates fibrinolytic activity. This is shown by an increased amount of fibrin-degradation products in the cerebrospinal fluid (c.s.F.) of these patients12,18 and by a raised level of plasmin in plasma and C.S.F. to In some patients this fibrinolytic activity leads to lysis of the protective clot and a recurrent hæmorrhage.2,8,17 Fibrinoly tic activity gradually increases during the 2nd and 3rd weeks after the hxmorrhage, and this accounts for the increased incidence of recurrent haemorrhage during this sac

period.17,20 chiefly by competitive inhibition of the activator that converts inactive plasminogen into active plasmin, a proteolytic enzyme.21,22 E.A.C.A. also inhibits the effect of plasmin23 and reduces the blood-plasminogen level.24 This pharmacological effect of E.A.C.A. helps to prevent lysis of the protective blood-clot and leads to improved clot maturation,8,11,18 thus preventing recurrent haemorrhage. E.A.C.A. acts

Gibbs and O’Gorman2in 1967 found no conclusive E.A.C.A. alters the prognosis in- S.A.H., whereas Mullan and Dalwey in 1968 found that E.A.C.A. sharply reduces the rate of recurrent haemorrhage. Only four studies2,3,7,8 used a control series, and three of these2,3,7 did not reveal significant reduction in recurrent haemorrhage in S.A.H. This prompted us to undertake the present study. Our trial was not strictly randomised, since patients were allocated to the two groups according to the day of admission. Definitive surgical management differed somewhat in the two groups, and hence we have limited our report to consideration of recurrent haemorrhage and to mortality before surgery. We did not encounter an increased incidence of blood coagulability or deep-vein thrombosis. This accords with the results of Nilsson et al.,25 Sengupta et al./ and Nibbelink.12 We did not see any arteriopathic complications in the cerebral vessels as reported by Sonntag and Stein.26 Drug-related nausea and vomiting affected 10% of patients, and 3 patients (4%) temporarily had to be given the drug intravenously to control diarrhoea. Since the immediate-recurrence rate was reduced to 4< with administration of E.A.C.A., it can be said that the drug improves the natural history of S.A.H. We recommend that E.A.C.A. should be used by the primarycare physician as soon as a diagnosis of s.A.H. has been made. This will greatly reduce the rates of recurrent hæmorrhage and mortality that occur between the diagnosis of S.A.H. and the patient’s transfer to a neurosurgical unit. Only 1 of 83 patients receiving E.A.C.A. died from recurrent haemorrhage, and with the passage of time most of the patients showed appreciable clinical improvement. 97% of the patients whose S.A.H. was caused by cerebral-artery aneurysm were operated upon.27 Even

evidence that

pa-

REFERENCES

1. McKissock, W., Walsh, L. Br. med. J. 1956, ii, 559. Gibbs, J. R., O’Gorman, P. Postgrad. med. J. 1967, 43, 779. 3. Profeta, G. J. Neurosurg. Sci. 1975, 19, 77. 4. Shaw, M. D. M., Miller, J. D. Lancet, 1974, ii, 847. 5. Uttley, D., Richardson, A. E. ibid. p. 1080. 6. Post,K. J. Neurosurg. 1977, 46, 290. 7. Girvin, J. P. Trans. Am. neurol. Ass 1973, 98, 150. 8. Sengupta, R. P., So, S. G., Villarejo-Ortega, F. J. J. Neurosurg. 1976, 44, 2.

479. 9. Mullan, S., Dawley, J. F. ibid. 1968, 28, 21. 10. Smith, R. R., Upchurch, J. J. ibid. 1973, 38, 339. 11. Corkill, G. Lancet, 1974, ii, 1319. 12. Nibbelink, D. W. Cerebrovascular Disease; p. 155, New York, 1975. 13. Ransohoff, J. ibid. 1977. 14. Norlen, G., Thulin, C.-A. Neurochirurgia, 1969, 12, 10. 15. Corkill, G. Med. J. Aust. 1974, i, 468. 16. Hunt, W. E., Hess, R. M. J. Neurosurg. 1968, 28, 14. 17. Maurice-Williams, R. S. Br. med. J. 1978, ii, 945. 18. Tovi, D. Acta neurol. scand. 1973, 49, 163. 19. Crompton, M. R. J. Neurol. Neurosurg. Psychiat. 1966, 29, 164. 20. Locksley, H. B. J. Neurosurg. 1966, 25, 321. 21. Alkjaersig, N., Fletcher, A. P., Sherry, S. J. biol. Chem. 1959, 234, 832. 22. Ablondi, F. B., Hagan, J. J., Philips, M., Derenjo, E. C. Archs Biochem.

1959, 82, 153. 23. British Patent specification, 770693. H. M. Stationery Office, 1957. 24. Nibbelink, D. W., Jacobson, C. D. Thromb. Diath. hœmorrh. 1973, 29, 598. 25. Nilsson, I. M., Andersson, L., Bjorkman, S. E. Acta med. scand. 1966, 448,

suppl. p. 5. Sonntag, V. K. H., Stein, B. M. J. Neurosurg. 1974, 40, 48. 27. Chowdhary, U. M., Carey, P. C., Hussein, M. M. Unpublished. 28. Ransohoff, J., Goodgold, A., Vallobenjamin, M. J. Neurosurg. 1972, 36, 525. 29. Drake, C. G. ibid. 1968, 28, 19. 30. Adams, C. B. T., Loach, A. B., O’Laire, S. A. Br. med. J. 1976, ii, 607.

26.

ORAL-CONTRACEPTIVE USE IN RELATION TO MYOCARDIAL INFARCTION SAMUEL SHAPIRO LYNN ROSENBERG

DENNIS SLONE DAVID W. KAUFMAN

Drug Epidemiology Unit, Boston University School of Medicine

PAUL D. STOLLEY

Department of Research Medicine, University of Pennsylvania School of Medicine OLLI S. MIETTINEN Harvard School of Health

Department of Epidemiology,

Public

The effect of oral-contraceptive use on the risk of myocardial infarction and, in particular, the possible accentuation of that effect by cigarette smoking, was investigated in 234 premenopausal women with a first infarction and 1742 hospital controls. The overall rate ratio estimate of acute myocardial infarction for women who had used oral contraceptives in the preceding month was 4· (95% confidence interval, 2·5-6·3). Women who smoked heavily and used oral contraceptives had a point estimate of 39 (lower two-sided 95% confidence limit, 22) compared with those who did neither. This value was appreciably

Summary

744 than could be accounted for by the separate effects of cigarettes and oral contraceptives, and this suggests a considerable accentuation by cigarette smoking of the effect of oral contraceptive use on myocardial infarction.

detailed medical histories (particularly regarding risk indicators for myocardial infarction) were obtained, as were comprehensive histories of drug use. More specifically the women were asked whether thev had ever taken medications for contraception, regulation of periods, menstrual problems, breast conditions, endometriosis, sexual difficulties, or any gynæcological reason. Whenever the patient knew the brand name of the oral contraceptive, it was recorded. Photographs of packets of pills were provided to assist recall, when appropriate. EVIDENCE suggests that oral contraceptives increase The present report is based on data collected between July the risk of venous thromboembolism and stroke.’-’ 1, 1976, and July 31, 1978. Only 2 women below the age of However, early attempts to examine the relation of oral twenty-five had had an infarction, and the analyses presented here are confined to women aged 25-49. diffiuse to infarction proved contraceptive myocardial Cases.-369 women with definite myocardial infarction is rare in the disease because cult, principally young were interviewed. We reviewed the hospital records of the first women. The results of the initial studies were generally 100 cases: 7 did not conform to the World Health Organisation based on small numbers and conflicting findings were diagnostic criteria.22 We therefore judged that the physician’s reported.6-9 diagnosis of definite myocardial infarction was sufficiently acBetween 1970 and 1974, OliverlO-12 reported on a curate for present purposes. We excluded from the analysis the large series of young women with myocardial infarction. 7 women with inadequate diagnostic criteria, 2 with aorticvalve prostheses, 1 with rheumatic mitral-valve disease and Compared with expected usage-rates, as estimated from atrial fibrillation, 1 who had an infarction on the fourteenth general population survey data, there was an excess of hospital day, and 1 whose infarct occurred after multiple infecoral-contraceptive use in his series. He also suggested tions culminating in septicxmia and shock. Of the 359 remainthat risk factors such as diabetes and cigarette smoking ing cases, 32 had sustained a myocardial infarct previously, may enhance the effect of oral contraceptives on the risk and of the remainder, 91 had reached the menopause. The of myocardial infarction. final series of cases consisted of the 234 premenopausal women In 1975 and 1976 British workers reported the results who sustained a first myocardial infarct. The median age was of three case-control studies, twOt3,t6 dealing with fatal 43 years. myocardial infarction and one 14,s,17 with women who Controls.-Of 4241 premenopausal women between the survived their heart-attacks. These studies indicated ages of twenty-five and forty-nine years who were interviewed, that the rate of myocardial infarction is about three to we selected 1786 for further consideration because they had first four fold greater among women using oral contracepdiagnoses that we judged to be unrelated either to oraltives. In addition, in the most detailed study (and the contraceptive use or to cigarette smoking. Thus, for example, women admitted for conditions such as thrombophlebitis or only one giving information on cigarette smoking),14,17 benign breast disease (possibly related to oral-contraceptive the findings suggested that the presence of other risk facuse), or respiratory ailments (possibly related to cigarette tors may enhance the effect of oral contraceptives. Subsmoking) were not eligible as controls. We disqualified 24 of sequently, other workers18,19 re-analysed the original the 1786 women because they gave a history of previous myoBritish findings’a,17 and suggested that. cigarette smokcardial infarction, and 20 because they gave a history of previous myocardial infarction, and 20 because they smoked a ing, in particular, may considerably enhance the risk variable or unknown number of cigarettes (there were no cases attributable to oral contraceptives. The original data, to whom this applied). This left 1742 controls with a median were insufficient for evaluation of however, adequate age of 36. Musculoskeletal conditions (predominantly orththis hypothesis. In 1977, some independent confirmation opxdic) and trauma accounted for 40%, gastrointestinal disof the association was reported from a cohort orders for 17%, and a large number of conditions for the study.20 The numbers were small, and the result was not remaining 43% of the series (table I). Age-standardised rates of statistically significant. oral-contraceptive use during the month before admission We undertook the present study to confirm the exis(recent use) and of oral-contraceptive use in the more remote tence of the overall association, and more particularly, past (past use) did not differ appreciably in relation to diagnosto estimate the extent to which the effect of oral contratic category. Control for confounding.-When standardised for age, the ceptives might be enhanced by cigarettes. following variables were similar in the two series: ethmc group, religion, marital status, parity, and years of education Patients and Methods (table II). The two groups differed in terms of the geographic Methods of data collection have been described.21 Briefly, areas in which the admitting hospitals were located. In addiwe made telephone contact, every eight to ten days, with coronary-care units of 155 hospitals (Greater Boston, 60; Long Island and the coastal area north of New York, 51; Delaware TABLE I-RATES* OF RECENT AND PAST ORAL CONTRACEPTIVE Valley, 44). Whenever a woman below the age of 50 was (O.C.) USE IN 1742 CONTROLS, ACCORDING TO DIAGNOSIS admitted, we contacted the physician and asked whether the patient had a definite or possible myocardial infarction, according to the diagnostic criteria set by the World Health

larger

overall

.

Organisation.22

,

A nurse interviewed women with definite myocardial infarction in hospital (83%) or at home (17%). As potential controls the nurses interviewed 5 or more women aged less than fifty from the surgical, orthopaedic, and medical services of the same or a nearby hospital. Permission for interview was refused by the physician or patient in 6% of the cases of infarction and 6% of the controls, giving a 94% response-rate. At the interview, menopausal status was determined, and

*

Rates adjusted by the direct method to the age distribution of case; t Use during month preceding admission. $Last use more than 1 month before admission.

745 TABLE II—DISTRIBUTION OF

INFARCTION AND

1742

234

CASES OF MYOCARDIAL

TABLE III-RELATION OF MYOCARDIAL INFARCTION

RECENT*

CONTROLS ACCORDING TO VARIOUS

ORAL CONTRACEPTIVE

(O.C.)

(M.I.) TO

USE

CHARACTERISTICS

rate ratio estimate=4.0; 95% confidence interval=2.5-6.3. Last used within the month before admission.

Summary *

TABLE IV-DOSE OF BY

29

CESTROGEN*

IN ORAL CONTRACEPTIVES USED

CASES OF MYOCARDIAL INFARCTION AND

135

CONTROLS IN

THE MONTH BEFORE ADMISSION

* Rates standardised to the age distribution of cases.

t Ponderal index=weight (lb)/height (in)

tion, cigarette smoking, obesity (weight [1b) × 1000/height [in]2≥40), history of treated diabetes mellitus, history of treated hypertension, history of lipid abnormality, history of treated angina pectoris, and history of pre-eclamptic toxacmia were all more common in the cases. In order to control simultaneously for the possible confounding effects of several factors, we used multiple logistic regression analysis.23 Indicator variables for the following factors were included: age (25-29, 30-34, 35-39, 40-44, 45-49), number of cigarettes smoked per day (0, 1-24, 25), weight (lb)xlOOO/height (in)2 (40), diabetes, lipid ab-

normality, hypertension, angina pectoris, pre-eclamptic mia, and hospital (Boston, New York, Philadelphia).

toxæ-

Results There was no evidence that past use of oral contraceptives was associated with an increased risk of myocardial infarction: 86 of the cases (37%) and 756 of the controls TABLE V-RELATION OF MYOCARDIAL INFARCTION

* Mestranol or ethinylcestradiol.

(43%) had last used oral contraceptives more than one month before admission. Simultaneous adjustment for the effects of all identified potential confounding factors yielded a rate ratio point estimate of 1.2 (95% confidence limits, 0-8-1-7). Further analysis was confined to recent use.

Recent

Last use within the month before admission.

of oral

contraceptives (table in)

was con-

all ages, and the summary rate ratio estimate24 was 4.0, with 95% confidence limits of 2.5 and 6.3.25 After simultaneous adjustment for all identified potential confounding factors, the rate ratio estimate was 4.1. For women who were not known to be predisposed (90 cases and 539 controls), the rate ratio estimate was 5 6. Dosages of mestranol, or ethinylcestradiol, were simi-

sistently

more common

in the

(M.I.) TO RECENT ORAL CONTRACEPTIVE (O.C.) CIGARETTE SMOKING

’

use

USE*

cases at

ACCORDING TO AGE AND

746 TABLE VI-SEPARATE AND COMBINED EFFECTS OF ORAL

CONTRACEPTIVE

(O.C.)

USE AND CIGARETTE SMOKING IN

RELATION TO MYOCARDIAL INFARCTION: RATIO

*

ESTIMATES*

(95%

AGE-ADJUSTED

CONFIDENCE

RATE

LIMITS)

Estimates derived from table V

t Reference category.

lar in those cases and controls who used oral contraceptives (table IV). The mean duration of use, standardised by the direct method to the age distribution of the cases who used oral contraceptives, was 6.8years in 28 cases and 6.7 years in 126 controls for whom the duration was known. In table v women are classified by age and according to three levels of cigarette smoking (none, 1-24 per day, and 25 per day). The age-adjusted rate ratio estimates for recent oral contraceptive users were 4.5in nonsmokers, 1.2 in light smokers, and 4.3 in heavy smokers. In table vi, which is derived from the data displayed in table v, rate ratio estimates, adjusted for age by the Mantel-Haenszel method,24 are given (together with their 95% confidence limits)25 for the separate and combined effects of oral-contraceptive use and cigarette smoking. The comparisons in the table refer to women who did not use oral contraceptives or smoke cigarettes. For nonsmokers who used oral contraceptives, the rate ratio estimate was 4.5; for those who smoked 25 or more cigarettes per day but did not use oral contraceptives, the estimate was 7 8; for those who used oral contraceptives and smoked heavily, the rate ratio estimate was 39, with a lower 95% per cent confidence limit of 22. Estimates in table vi did not change materially after simultaneous adjustment for confounding.

Discussion The present study is large enough to provide a more estimate of the overall effect of oral-contraceptive use than has previously been possible, and more notably, it permits a detailed evaluation of the suggestion that the effect of oral-contraceptive use on the risk of myocardial infarction is materially enhanced by

precise

cigarette smoking. Our findings suggest

that the rate of myocardial infarction is increased some fourfold among women using oral contraceptives. They also give strong evidence that the combination of smoking 25 or more cigarettes per day, together with oral-contraceptive use, increases the rate at least twentyfold, and more probably, about fortyfold. There are insufficient data in our study to evaluate possible modification of the effect of oral contraceptives by factors other than cigarette smoking.

Although

our

subjects

were

routinely questioned

about all drugs used before admission, we cannot rule out the possibility that there may have been some bias in recording oral-contraceptive use. At the time of collecting the data, the nurses, and many of the patients, were aware of the hypothesis. However, all subjects in this study were questioned within days or weeks of

admission, and recall of

recent

oral-contraceptive

use

has been shown to be quite accurate .21,2’1 Selection bias is unlikely to have influenced our results since we interviewed 94% of the potential cases and controls. Our study did not include women whose illness was fatal. However, studies of fatal infarction13,14,20 suggest that our results cannot be explained by a greater tendency for women to survive an infarction if they use oral contraceptives. Factors that may have been related to oral contraceptive use as well as to myocardial infarction were controlled, and bias due to confounding is an unlikely explanation of our findings. Our results concerning the overall effect of oral contraceptives accord with the British findings."-" We found an association of similar magnitude for recent use, and none for discontinued use. This suggests that these agents have a relatively acute thrombogenic effect, as would be expected.4,5 We found no evidence of increasing risk with increasing duration of use, even though oral contraceptives tend to raise blood-pressureza and may accelerate atherogenesis.29 There was no evidence that the risk of infarction varied according to the dosage of ethinyloestradiol or mestranol. This, however, may simply reflect the very low usage-rates of preparations containing less than 50 µg of either compound. Our results differ from those reported by Jick et al. 30,31 Whereas we estimated a rate ratio of 5.6 for oralcontraceptive users who did not have predisposing conditions, the corresponding point estimate in their study was 15. In Jick’s study, the loss of potential cases of myocardial infarction from the initial sampling frame was 85%. Such a high rate of attrition could have biased the results if willingness to collaborate, among the remaining 15%, was influenced by oral-contraceptive use.

Our findings have implications mainly for older premenopausal women. In the U.S.A. the incidence of myocardial infarction in women begins to rise after about

the age of 35 years, and we have estimated21 that incidence-rates might be of the order of 20 and 40 per 100 000 women per year at the ages of 40 to 44, and 45 to 49, respectively. Therefore the annual incidence of myocardial infarction in older premenopausal women who smoke heavily and use oral contraceptives is likely to be considerable. Finally, our data support the suggestion18 that in societies where smoking is rare, the relative disadvantage of oral contraceptive use may be less severe, even among older premenopausal women. Without the teamwork of the nurses, staff, and physicians in 155 in the north-east of the U.S.A. this study could not have been done. Carol Enseki was the programme coordinator, Jacquelyn Smith, the assistant coordinator, and the following nurses arranged and conducted the interviews: Marygrace Barber, Geraldine Christie, Mary Galatio, Dorothy Gray, Margaret Imbro, Barbara Lauchle, Linda McGeary, Joan Metz, Susan Ober, Carol Palmer, and Linda Paradis. We thank Patricia Dattwyler and Marguerite Angelom for their important contributions to the study, and Leonard Gaetano for his help. This work was supported by contract no. N01-HD-6-2849 from the National Institute of Child Health and Human Development, contract no. 223-76-3016 from the Food and Drug Administration, contract no. N01-CP-71029 and NO 1-CB-74099 from the National Cancer Institute, and by a grant m aid from Hoffman La Roche, Inc.

hospitals located

Requests for reprints should be addressed to S. S., Drug EpidemiolUnit, 10 Moulton Street, Cambridge, Massachusetts 0213S.

ogy

U.S.A.

747

IMPAIRED HYPOTHALAMIC CONTROL OF PROLACTIN SECRETION IN MASSIVE OBESITY P. G. KOPELMAN T. R. E. PILKINGTON

N. WHITE L. S. JEFFCOATE

Department of Medicine, St. George’s Hospital and Medical School, and Department of Endocrinology, Chelsea Hospital for Women, London Intravenous insulin tolerance tests and

Summary

thyrotropin-releasing hormone (T.R.H.) stimulation tests were performed in nine massively obese women and six lean female controls and the prolactin, growth hormone, and cortisol responses were measured. A combined pituitary function test (insulin, T.R.H., and gonadotropin-releasing hormone) was performed in eleven other massively obese women. In the obese women to whom insulin was given separately there was no prolactin release, and growth hormone and cortisol responses were impaired. T.R.H. stimulation produced a prolactin response which was subnormal. These changes were not apparent in the obese women in whom a combined pituitary function test was performed. The results suggest an alteration of hypothalamic function in massive obesity.

Introduction A DISORDER of hypothalamic function is suspected in human obesity but the impaired growth-hormone response to insulin-induced hypoglycxmia is the only evidence for this.l,2 We attempted to obtain further inforDR SHAPIRO AND OTHERS: REFERENCES

1. Jordan, W. M. Lancet, 1961, ii, 1146. 2. Vessey, M. P. in Risks, Benefits and Controversies in Fertility Control edited by J. J. Sciarra, G. I. Zatuchni and J. J. Speidel); p. 113. Hagerstown, Maryland 1978. 3. Stolley, P. D. ibid. p. 122. 4. Dugdale, M., Masi, A. T. Effects of the Oral Contraceptive on Blood Clotting, Second report on the Oral Contraceptive Advisory Committee on Obstetrics and Gynecology, Food and Drug Administration; p. 43, Washington, D.C., Government Printing Office, 1969. 5 Dugdale, M., Masi, A. T. J. chron. Dis. 1971, 23, 775 6 Inman, W.H.W., Vessey, M. P. Br. med. J. 1968, ii, 193. 7 Vessey, M. P., Doll, R. ibid. 1969, ii, 651. 8 Inman, W. H. W., Vessey, M. P., Westerholm, B., Egelund, A. ibid. 1970, ii, 203. 9. Fischer, A. J., Mosbech, J. Ugeskr Laeger, 1970, 132, 2480. 10 11 12 13 14 15 16 17

about hypothalamo-pituitary function in massively obese patients by studying prolactin release. Prolactin release in people of normal weight is stimulated by insulin-induced hypoglycxmia3 and by intravenous thyrotropin-releasing hormone (T.R.H.), which acts directly on pituitary cells.’ We therefore performed, either separately or in combination, intravenous insulin tolerance and T.R.H. stimulation tests in obese patients, and compared the prolactin, growth hormone, and cortisol responses observed with those seen in lean controls.

mation

Oliver, M. F. Br. med J. 1970, ii, 210.

Radford, D. J., Oliver, M. F. ibid. 1973, iii, 428. Oliver, M. F. ibid. 1974, iv, 253. Mann, J. I., Inman, W. H. W. ibid. 1975, ii, 245. Mann, J. I., Vessey, M. P., Thorogood, M., Doll, R. ibid. 1975, ii, 241. Mann, J I., Thorogood, M., Waters, W. E., Powell, C. ibid. 1975, iii, 631. Mann, J. I., Inman, W. H. W., Thorogood, M. ibid. 1976, ii, 445. Mann, J. I., Doll, R., Thorogood, M., Vessey, M. P., Waters, W. E. Br. J. prev soc. Med. 1976, 30, 94. 18 Jain, A. K. Am.J. Obstet Gynec. 1976, 126, 301. 19 Ory, H W. J. Am. med. Ass. 1977, 237, 2619. 20 Royal College of General Practitioners’ Oral Contraception Study, Lancet,

1977, ii, 727.

21. Slone, D., Shapiro, S., Rosenberg, L., Kaufman, D. W., Hartz, S. C., Rossi, A. C, Stolley, P. D., Miettinen, O. S. New Engl. J. Med. 1978, 298, 1273. 22 Ischæmic Heart Disease Registers: Report of the Fifth Working Group, Copenhagen, World Health Organisation, 1971.

23 Truett, J., Cornfield, J., Kannel, W. A. J. chron. Dis. 1967, 20, 511. 24 Mantel, N, Haenszel, W. J. natn. Cancer Inst. 1959, 22, 719. 25 Miettinen, O. S. Am. J. Epidem. 1976, 103, 226. 26 Glass, R, Johnson, B., Vessey, M. P. Br. J. prev. soc. Med. 1974, 28, 273. 27 Stolley, P. D., Tonascia, J. A., Tockman, M. S., Sartwell, P. E., Rutledge, A H, Jacobs, M P Am. J. Epidem. 1975, 102, 197. 28 Laragh, H. Am. J. Obstet. Gynec. 1971, 109, 210. 29

Stokes, T, Wynn, V. Lancet, 1971, ii, 677. 30 bek H., B., Rothman, K. J. J. Am. med. Ass. 1978, 239, 1403. 31 Lck H, Dinan, B., Herman, R., Rothman, K. J. ibid. 1978, 240, 2548.

Dinan,

Patients and Methods The following subjects were studied: nine obese women (mean 240 % ideal body-weight [i.s.w.], range 200-290 %; mean age 33, range 26-49) in whom an intravenous insulin tolerance test (0-15 units/kg soluble insulin) and an intravenous T.R.H. stimulation test (200 µg) were performed on different occasions, and in random order; six female volunteers (mean weight 100 % I.B.w., range 90-105 %; mean age 24, range 19-28) who also had an insulin tolerance test (0-1 units/kg soluble insulin) and T.R.H. test (200 fLg) on separate occasions; eleven obese women (mean weight 220 % I.B.W., range 180-270 %; mean age 34, range 17-56) to whom a combined injection of soluble insulin (0-15 units/kg), T.R.H. (200 µg), and gonadotropin-releasing hormone (100 ug) was given. I.B.W. was defined as the midpoint of the weight range for medium frame size as listed by the Metropolitan Life Insurance Company Table. Obese subjects were studied in hospital on a weight-maintaining diet and informed consent was obtained for the investigations. None was taking any medication. Each test was performed in the morning after an overnight fast and subjects rested for at least 30 min after the insertion of an intravenous cannula, through which the blood-samples were drawn. Blood was taken at 30 min intervals for 2 h after insulin and for 1 h after T.R.H. Blood-glucose fell to less than 40% of the fasting level after insulin and this fall was accompanied by symptoms in all the subjects. Each sample was immediately centrifuged and the plasma was frozen and stored at -20 ° C until assay. Growth hormone, prolactin, and cortisol were measured by specific radioimmunoassays (R.I.A.). The standard used in the growth hormone R.I.A. was I.R.P. 66/217, and the prolactin standard was I.R.P. 75/504.

weight

Results All values are given in relation to basal values (100 %), and are mean maximum increments + standard error of the mean (s.E.M.). The Student’st test of statistical significance was used for all significance calculations. Basal Hormone Concentrations Mean + S.E.M. concentrations of hormones in the basal samples from the twenty obese subjects were prolactin 370 + 60 mi.u./l, growth hormone 2.4+_05 mi.u./l, and cortisol 506:t34 nmol/1. In the six lean controls basal concentrations were prolactin 330+_60 mi.u./l, growth hormone 3.2±0.5 mi.u./l, and cortisol 325+ 59 nmol/1. Prolactin and growth hormone results were not significantly different in the two groups, but in the the basal plasma-cortisol was higher (n