TREATMENT OF THE ADRENOGENITAL SYNDROME WITH CORTISONE

464

synthesis of pantothenic acid and the failure to absorb growth-promoting substances, may be responsible for much of the pathology of Hirschsprung’s disease. Though this is conjecture it is an additional pointer to the fact that the pathology of Hirschsprung’s disease is not yet completely known. REFERENCES

Bodian, M., Stephens, F. D., Ward, B. C. H. (1949) Lancet, i, 6. Hurst, A. F. (1924) Essays and Addresses on Digestive and Nervous Diseases and

on

Addison’s Anaemia and Asthma.

London.

Keith, A. (1915) Brit. J. Surg. 2, 576. Lane, W. A. (1915) Ibid, p. 599. Learmonth, J. R., Markowitz, J. (1930) Amer. J. Physiol. 94, 501. Miles, A. (1923) In Choyce, C. C. System of Surgery. 2nd ed., London ; p. 457. Mutch, N. (1915) Brit. J. Surg. 2, 608. Rankin, F. W., Learmonth, J. R. (1930) Ann. Surg. 92, 710. Stammers, F. A. R. (1932) Brit. J. Surg. 20, 67. Stephens, F. D. (1951) British Surgical Practice Progress. London; p.

163.

Swenson, O., Rheinlander, H. F., Diamond, I. (1949) New Engl. J.

Med. 241, 551. Telford, E. D., Simmins, H. T. (1939) Brit. med. J. ii, 1224. Ward, L. E. B. (1915) Brit. J. Surg. 2, 655.

TREATMENT OF THE ADRENOGENITAL SYNDROME WITH CORTISONE DOUGLAS HUBBLE M.D. Lond., M.R.C.P. DERBYSHIRE

PHYSICIAN, HOSPITAL,

AND

ROYAL

DERBYSHIRE

INFIRMARY,

HOSPITAL

FOR

DERBY

SICK

CITY

CHILDREN

THE manifestations of the adrenogenital syndrome in and women at or after puberty respectively are hirsuties, acne, enlargement of the clitoris, and amenorrhcea or irregular scanty menstruation. Although some of these patients may have a daily excretion of 17-ketosteroids within average limits (5-15 mg.), if the output of 17-ketosteroids is followed over a long period it can be shown in many instances to exceed 20 mg. daily. This increased excretion is intermittent and varies in amount ; it has been reported by Koets (1949) to be greatest in the phase of ovulation, and by Merivale (1951) to be maximal in the luteal phase. The recognition that cortisone depressed adrenocortical function soon led to its use in conditions of adrenocortical excess. Wilkins et al. (1951, 1952) have described its use in eleven children for 5-17 months, and Bartter et al. (1951) have described the results of treatment in three patients. Bishop et al. (1952) and Simpson (1952) have reported its use for a short time in two patients with adrenocortical hyperplasia. In the case reported here a girl, aged 19, with virilism, was studied for ten months, during the last five of which she was treated continuously with cortisone.

girls

varied

(see table). RESULTS

OF TREATMENT

therapeutic results obtained hyperplasia in children. Cortisone will suppress the excessive androgenic activity of the adrenal cortex, and Wilkins et al. suggest that, to sustain an optimal therapeutic effect, the excretion of 17-ketosteroids should be kept less than 8 mg. per twenty-four hours. In the present patient with varying dosage this level was maintained for periods of no longer These

findings

by Wilkins

confirm the

et al. in adrenocortical

than two weeks, and a detailed examination of the records suggests that this level might be permanently

CASE-RECORD

,

The patient, who

mined that the rise or fall of 17-ketosteroids was related to definite intermenstrual phases, nor were the highest levels associated with the increase of pregnanediol in the luteal phase. The other abnormal finding was that on 6 out of 23 occasions the serum-potassium level was lower than normal; the lowest of these six readings was 12-2 mg. per 100 ml. (3-1 m.eq. per litre), and the average 14-5 mg. per 100 ml. (3-7 m.eq. per litre). On three of these occasions the serum. sodium level was above normal : 334, 340. and 344 mg. per 100 ml. (145, 147, and 149 m.eq. per litre). The plasma. chloride level, the alkali reserve, and the urinary output of sodium, potassium, and the chlorides were invariably within accepted average limits. The eosinophil-count was always between 200 and 500 per c.mm. Treatment.-The patient was first given a week’s treatment with 100 mg. of A.C.T.H. daily. This produced an eosinophi]count averaging 60 per c.mm. (ten counts), and an excretion of 17-ketosteroids averaging 24-0 mg. per twenty-four hours (six estimations). The day-time output of urine in the five days preceding A.C.T.H. therapy was 182 oz. (daily average 36-4 oz.) and the nocturnal output 93 oz. (nightly average 18-6 oz.). In the first four days of A.C.T.H. therapy the day-time output was 84 oz. (daily average 21 oz.) and the nocturnal output 144 oz. (nightly average 36 oz.). The daily average serum-potassium level in the first four days of A.C.T.H. therapy was 1,3-9 mg. per 100 ml. (3-6 m.eq. per litre). In the last two days of the week of A.C.T.H. therapy the serum-potassium level was normal and the ratio of diurnal to nocturnal urine was corrected. At the end of five weeks, and before cortisone therapy was started, the patient’s cheeks were shaved and the hair removed was weighed. This was repeated at the end of four further five-week periods, during which the dose and method of administration of cortisone

me from the dermatological of the Derbyshire Royal Infirmary by Dr. P. D. C. Kinmont for investigation of hirsuties. complained of an excessive growth of hair on her face since the age of 15, more marked on the cheeks than on the lip and chin (see figure). She shaved three or four times a year. Her menses started at the age of 13 and were irregular during the first two years, with periods of amenorrhœa lasting three or four months. From the age of 1;3 to that of 17 the intervals between periods were about a month, but during the last year usuallv 31-33 days. On examination the patient had a few hairs round the areola: of the nipples and a rnale distribution of hair on the abdomen. The growth of hair on the back and on the legs There was a moderate amount of acne on the was excessive. face and back. The labia minora were reported by a gynæand the cologist (Mr. N. L. Edwards) to be clitoris to be enlarged. Investigantions.—A tumour of the adrenal cortex was excluded, and the usual endocrine functions were investigated and found to be within average limits except in two aspects. The urinary excretion of 17-ketosteroids was intermittently greater than usual. In 25 estimations done in five months the average daily excretion was 15-2 mg. per twenty-four hours, the lowest figure being 7.0 mg. and the highest 33 mg. per twenty-four hours. It could not be deterwas

referred to

department

hypertrophied,

Extent of patient’s facial hair.

465 RESULTS OF CORTISONE THERAPY

-

5First weeks5Second weeks

Third

i Fourth 5 weeks

5 weeks

weeksFifth

checked against estimations made on other patients on the same day, they were frequently estimated by different methods, and they were usually duplicated in two laboratories. In another patient with adrenocortical hyperplasia

being investigated

now

a

similar

hypokalæmia

has been

observed : A

school-mistress, aged 24, complained that a considerable of hair had been present on her face since adolescence.

growth

She had a male distribution of hair on her abdomen. Her menarche was at the age of 18, and her menses are scanty, short, and irregular. Her breasts are normally developed, and her clitoris is moderately enlarged. Her average daily excretion, determined each day for 23 days, was 21-3 mg., the lowest daily value being 11 mg. and the highest 30 mg. The average daily serum-potassium level in a month was 14-3 mg. per 100 ml. (3-7 m.eq. per litre), and the average of seven daily serum-potassium levels obtained in another laboratory in the same period was 14-4 mg. per 100 ml. (3-7m.eq. per

Jlethod of administration 1, 25 mg. by injection twice daily. 2(a) 2 weeks, 50ing. orally (? =25mg. by injection). (b) 3 weeks, 25 mg. by injection daily. 3(a) 1 week, 25 mg. by injection twice daily. (b)4 weeks, 50 mg. by injection on alternate days. 4(a) 2 weeks, 50 mg. by injection on alternate days. (b) 2 weeks, 25 mg. twice daily. (c) 1 week, 100 mg. on alternate days.

sustained with a daily injection of 50 mg. or an injection of 100 mg. on alternate days. The same dose by mouth was ineffective, and Wilkins et al. advise that, for an

equal suppressive action, the oral route requires three times the amount given by injection.

two

or

It will be seen from the table that there is a rough correlation between the amount of hair growth, the dose of cortisone, and the amount of 17-ketosteroids excreted. It is shown that the rate of excessive hair growth can be about halved, but that it can be completely suppressed by cortisone therapy is as yet uncertain. MODE OF ACTION

It is assumed that cortisone suppresses adrenocortical activity by opposing the action of A.C.T.H. Bartter et al. suggest that the androgenic excess may be due to a relative insufficiency of 11,17-oxysteroid production (which is the major opponent and regulator of A.C.T.H. secretion) with a consequent excessive secretion of A.C.T.H.

The present patient showed no evidence of 11,17-oxysteroid insufficiency (including her response to a water load, to intravenous insulin, and to stress). Moreover, though A.C.T.H. 100 mg. daily produced an effect on 17-ketosteroid output and serum-potassium levels of the same order as had appeared intermittently in the preliminary control periods, it produced in addition a profound and sustained eosinopenic response. Clearly 11,17-oxysteroid production was not deficient in this patient either under ordinary conditions or in response to A.C.T.H.

’

POSSIBILITIES

OF THERAPY

the treatment of adrenocortical hyperplasia in female pseudohermaphroditism or in macrogenitosomia præcox in boys, is undeniably first-class therapy, it is uncertain whether adrenocortical hyperplasia occurring at puberty and after justifies continued treatment with cortisone. The suppression of the signs of virilism-hirsuties, menstrual disturbance, acne, and so on-may seem to be an inadequate reward for the frequent injections of a potentially hazardous substance. On the other hand, few conditions cause more distress to girls in adolescence and in young womanhood than does virilism, and, when cortisone is more freely available, such therapy, carefully controlled, may justifiably be practised. This condition is by no means rare and, since its effective treatment will require about 20 g. of cortisone a year, such therapy is not immediately

Though

in

childhood, whether

practicable.

SUMMARY

The treatment of a patient with the adrenogenital syndrome (virilism) with cortisone- for five months is

described. The amount of cortisone required for the suppression of excessive androgenic activity was about 50 mg. daily. This dosage slowed the rate of facial hair-growth by about half. The finding of intermittent hypokalaemia in this patient and in another with the adrenogenital syndrome is reported. This parallels the potassium deficit which sometimes occurs in the adrenocortical (Cushing’s)

syndrome.

DISTURBANCE OF ELECTROLYTES

It has long been recognised that adrenocortical hyperplasia in infants may be accompanied by excessive loss of sodium and that, though this is corrected as the child grows older, it tends to recur during infections. hi Cushing’s syndrome a low serum-potassium level is sometimes seen ; and this may be sufficiently severe to produce the hypochlortemic alkalosis which is now recognised to follow a potassium deficit. It is assumed that this hypokalæmia is due to the excessive production of a steroid with a deoxycortone-like action. In this levels presumably patient the low resulted from the same cause. Occasionally this hypokalaemia was accompanied by a serum-sodium level above normal ; but, although examined on scores of occasions, no reduction of plasmachloride level and no increase of CO2-combining beyond average limits were recorded. The hypokalæmia was not accompanied by fatigue, muscle weakness. or electrocardiographic This lack of correlation is now widely recognised. Since this observation of hypokalæmia in the adrenogenital syndrome has apparently not been made before, great care was taken to ensure that these results were accurate. They were

serum-potassium

power

change.

litre).

This paper is the report of a great deal of investigation, much of it here unrecorded, conducted by several technicians. The chemical investigations were made in the laboratory of the Derbyshire Royal Infirmary (Dr. G. R. Osborn) by Mr. J. A. Allen, Miss A. Matthews, B.sc., and Miss J. Pegg, B.se. The duplication of the potassium estimations was done in the laboratory at the Sheffield Royal Infirmary (Dr. A. Jordan) by Mr. D. A. Podmore, A.R.i.c., Miss K. P. M. Groocock, The estimation of B.sc., and Miss M. C. O’Connell, B.sc. 17-ketosteroids was done by Mr. F. Mitchell, B.sc., in the laboratory of the Jessop Hospital for Women, Sheffield (Dr. G. C. Paine). To all these chemists my thanks are due. Dr. Harold Tulloh and Dr. Barbara Green, my housephysicians, and Miss L. M. Edwards, mv ward-sister, gave me much help. I am indebted to the Medical Research Council for the A.C.T.H. and the cortisone. REFERENCES

Bartter, F. C., Albright, F., Forbes, A. P., Leaf, A., Dempsey, E., Carroll, E. (1951) J. clin. Invest. 30, 237. Bishop, P. M. F., Bray, B. M., de Mowbray, R. R.. Menvale, W. H. H., Vaughan-Morgan, J. (1952) Lancet, i, 1287. Koets, P. (1949) J. clin. Endocrinol. 9, 795. Merivale, W. H. H. (1951) J. clin. Path. 4, 78. Simpson, S. L. (1952) Lancet, ii, 91. Wilkins, L., Gardner, L. I., Crigler, J. F. jun., Silverman, S. H., Migeon, C. J. (1952) J. clin. Endocrinol. 12, 257. Lewis, R. A., Klein, R.. Gardner, L. I., Crigler, J. F. jun., Rosemberg, E., Migeon, C. J. (1951) Ibid, 11, 1. —