Comparative Biology of Skin (Proceedings of a Symposium held at the Zoological ... H. J. J. Leenen, C. Leering, P. Muntendam, P. J. Stolk and W. van Zeben.
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Cushing's Syndrome and Pregnancy A Case Report D. BLUMSOHN,
E. H. MUNYADZIWA,
S. K. DAJIE,
SUMMARY The literature on Cushing's syndrome associated wth pregnancy is reviewed, and a case of this rare association is reported. The patient had an adrenal adenoma. Investigations and interpretation of stimulation and suppression tests are discussed. Cortisol metabolism in normal pregnancy is referred to.
S. Afr. med. J., 53, 338 (1978).
Patients with Cushing's syndrome have a high incidence of infertility, associated with disturbed menstrual function and ovulation.,,2 OnJy 24 patients with the syndrome who have faJlen pregnant have been reported,"lS and most of these pregnancies ended in abortion, premature birth or stiUbirth. This report documents a case of florid Cushing's syndrome associated with pregnancy. An adrenocortical adenoma was successfully removed and the patient was cured at 18 wee)cs' gestation. Unfortunately, this was foHowed by an abortion 3 weeks later.
CASE REPORT A 25-year-old Black woman presented at Tembisa Hospital with a short history of shortness of breath, palpitations and cough, and a l·month history of easy bruising. She had rounded moon facies and obesity of the trunk, but not Tembisa Hospital, Olifantsfontein, Tvl D. BLUMSOHN, LB. B.CH., DIP. MED., Principal Physician E. H. MUNYADZIWA, M.B. CH.B., Senior Medical Officer S. K. DAJIE, M.B. B.S., Senior Medical Officer R. C. SHER, M.B. CH.B., Registrar D. K. PRAJAPAT, M.B. B.S., F.R.C.S., Su-rgeon Date received: 29 August 1977.
D. K. PRAJAPAT
R. C. SHER,
of the arms and legs. She had a dorsal neck 'hump', acne, hirsutism and purple striae over the abdomen, buttocks and thighs. There were. bruises. This was a classic case of florid Cushing's syndrome, and when, at our request, the patient produced a photograph of herself taken at the age of 18, we noticed that the change was remarkable and absolutely diagnostic. On direct questioning, she admitted to a 6-year history of progressive weight gain and obesity, weakne,ss and backache, and a very irregular menstrual cycle with long periods of amenorrhoea. She had had no menstruaJ period for the preceding 4 months. She had had no previous pregnancies, and did not know whether she was pregnant or not. She had also complained of abdominal pain, vomiting and melaena for a short while. On examination she was very distressed, dyspnoeic and orthopnoeic. She was not cyanosed, but the jugular venous pressure was elevated and there were crepitations throughout both lung fields. The pulse was 140/min, the blood pressure 210/130 mmHg, and there was cardiomegaly and left ventricular failure. Her urine contained protein but no glucose. A 14 - 16week pregnant uterus was detected on examination, and latex test for chorionic gonadotrophin was persistently positive, confirming pregnancy. Chest radiographs showed cardiomegaly and congestive changes in the lung fields, and skull radiographs revealed a normal pituitary fossa. Full blood count was normal, as were urea and electrolytes. A glucose tolerance test was indicative of diabetes. Treatment was starte,d with digitalis and diuretics for cardiac failure, and the blood pressure was lowered with methyldopa. Once Cushing's syndrome was suspected, minimal laboratory diagnostic criteria had to be met. Plasma cortisol levels were all elevated, and there was loss of the normal
TABLE I. EXPECTED RESPONSES TO DEXAMETHASONE SUPPRESSION, ACTH STIMULATION AND METYRAPONE Response to high dose dexamethasone Pituitary lesion
Benign adenoma Adrenal carcinoma Ectopic ACTH syndrome
Response to metyrapone
Response to ACTH
Excretion of 17-hydroxycorti costeroids
Excretion of 17-ketosteroids
50% fall urinary 17-hydroxycorticosteroids None None
Rise
Exaggerated
High
High
None None
Variable None
High High
Normal Very high (4x)
None
Variable
Minimal
Very high (4x)
High
Other
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diurnal variation. In fact, nearly all the levels exceeded the highest measurable - 43 ,p,g/lOO ml (normal values at 08hOO are 6 - 24 ,p.g/l00 ml, at 16hOO 4 - 18 ,fLg/lOO ml, and 3 - 14 ,p.g/l00 ml at 24hOO). In all forms of Cushing's syndrome. patients demonstrate some degree of autonomous secretion of excessive amounts of cortisol. If the administration of slightly supraphysiological amounts of a glucocorticoid will not suppress the pituitary-adrenal axis in an otherwise unstressed individual, then the diagnosis IS certain. As a suppression test, dexamethasone 1 mg was given orally at midnight, and plasma cortisol was measured at 08hOO. The level was above 43 iflg/1OO ml on two occasions, confirming the diagnosis. The 24-hour urinary 17-hydroxycorticosteroid excretion was 27;2 mg (normal 4 - 18 mg). The urinary 17-ketosteroids in 24 hours was 19 mg and 20 mg (normal 4,5 - 20 mg). Once the diagnosis of Cushing's syndrome had be,en confirmed, we attempted to establish its aetiology. Immunoassay of ACrn was not available, so we studied the steroid excretion pattern and response of the pituitary-adrenal axis to physiological manipulation. In Table I the expected responses to dexamethasone suppression, ACTH stimulation and to metyrapone (Metopirone) (an 11-hydroxylase inhibitor) in each of the conditions which cause Cushing's syndrome are shown. Table n shows the results in our patient, and explains the methods. We thought that an adre,nocortical adenoma was the most likely diagnosis, because (i) there was a lack of plasma cortisol suppression by dexamethasone; (ii) there was no response to metyrapone; (iit) there was positive ACTH stimulation of 24-hour urinary 17-hydroxycorticosteroids; and (iv) 17-ketosteroids were normal or only slightly elevated. Radiological techniques to demonstrate an adenoma could not be undertaken because of the early pregnancy. Because of the severity of the hypertension and its complications, the. abnormal glucose tolerance and the poor general state of the patient, surgery was planned. The. patient was treated with steroids before, during and after the operation. Both adrenal glands were examined at surgery and a large benign adenoma was found on the right side. The remaining right adrenal tissue and the left adrenal gland did not appear atrophic. The tumour, which was removed, was 3 cm in length with a mass of 18 g. Histological examination showed two cell types orginating from both the zone fasciculata and the zone reticularis. This was a cortical adenoma. The pregnancy was confirmed at surgery. Recovery was uneventful. ACTH was given for 3 days to stimulate possible atrophic or suppressed adrenal remnants. Beta-adrenergic stimulants were given to delay possible abortion or premature labour, but the patient unexpectedly aborted a 500-g fetus some 3 weeks later. Adrenocortical function is now normal, plasma electrolytes are normal, plasma cortisol is normal and there are normal responses to both dexamethasone suppression and AClH stimulation. The patient is now normote,nsive and takes no hypotensive drugs or diuretics. Vomiting was the only symptom which persisted, and after the abortion a
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of infertility,'" and we believe that our patient may be the 25th pregnant woman with Cushing's syndrome to be reported.
barium meal revealed a large duodenal ulcer, presumably accounting for her symptoms of abdominal pain, vomiting and melaena on admission. No doubt this was related to the high le,vels of endogenous cortisol. This appears to be healing with medical therapy.
REFERENCES I. Hunt. A. B. and McConahey, W. M. (1953): Amer. J. Obstet. Gynec.• 66, 970. 2. Parra, A. and Cruz-Krohn, J. (1966): Amer. J. Med., 40, 961. 3. Cope. O. and Raker, J. W. (1955): ew Eng!. J. Med., 253, 119. 4. Birke, G .. Franksson, C., Gernzell, C. A. et al. (1959): Acta c.hir. scand., 117, 233. 5. Greenblatt, R. B.. Scarpa-Smith. C. and Mells, J. C. (1959): Ferti!. and Steril., 10. 323. 6. Bergman. P., Ekman. H .. Hakansson, B. et al. (1960): Acta endoer. (Kbh.). 35. 293. 7. MacGregor. W. G., Spencer. A. G. and Swyer. G. T. M. (1960): J. Obstet. Gynaec. Brit. Cwlth. 67, 465. 8. And reoli , C. (1962): Minerva ginec., 14, 139. 9. Litowsky, D. and Ford. R. V. (1962): Amer. J. Obstet. Gynec., 83, 756. 10. Eisenstein. A. B., Karsh, R. and Gail. T. (1963): J. c1in. Endocr., 23, 971. 11. Kreines. K., Perin. E. and Salzer. R. (1964): Ibid .• 24. 75. 12. Bank, H .• Beer, R .• Lunenfeld. B. et al. (1964): Ibid., 25. 359. 13. Molinalto. G. M. and Olivetti, M. (1964): Minerva med., 55, 1191. 14. Wieland, R. G., Shaffer, M. B. jun. and Glove, R. (1971): Amer. J. Obstet. Gynec.. 38, 841. 15. Lee. R. and Rapoport. A. (1972): J. Amer. med. Ass.. 221, 392. 16. Grimes. E. M., Fayez. J. A. and Miller. G. L. (1973): Obstet. and Gynec., 42, 550. 17. Anderson. K. J. and Waiters. W. A. W. (1976): Aust. N.Z. J. Obstet. Gynaec.. 46. 225. 18. Anevlavis, E. S. and Schletter, F. E. (1976): J. Amer. med. Ass.• 236, 589. 19. Gemzell, C. A. (1953): J. c1in. Endocr., 13, 898. 20. Schteingart. D. E. (1967): Clin. Obstet. Gynaec.. 10, 88. 21. Wilber. J. F. (1968): Med. Clin. N. Amer., 52, 253.
DISCUSSION Early in normal pregnancy, 17-hydroxycorticosteroid and cortisol levels start increasing; they reach a le,vel about 7 times the normal value immediately after delivery and then drop off, returning to the pre-pregnancy level by the 6th postpartum day."'''' Plasma cortisol levels in normal pregnancy 'often approach those found in non-pregnant patients with Cushing's syndrome. Despite increased bound and free plasma cortisol levels in normal pregnancy, clinical features of hypercorticism are rarely seen, suggesting that a change in reactivity to cortisol may render it biologically less effective in pregnancy."'·2l The exaggerated response of plasma cortisol levels to ACTH stimulation in pregnancy suggests either an increased sensitivity of the adrenal cortex or a delay in the turnover of cortisol. Patients with Cushing's syndrome have a high incidence
Books Received Comparative Biology of Skin (Proceedings of a Symposium held at the Zoological Society of London on 30 and 31 October 1975). Ed. by R. I. C. Spearman. Pp. xvii + 427. Illustrated. £14,80. London: Academic Press. 1977. Directory of On-Going Research in Cancer Epidemiology. (IARC Scientific Publications No. 17.) Ed. by C. S. Muir and G. Wagner. Pp. xii + 599. Sw. Fr. 25,-. Geneva: World Health Organization. 1977. Available from Van Schaik's Bookstore (Ply) Ltd, PO Box 724, Pretoria, 0001. Gastroenterology. 2nd ed. By I. A. D. Bouchier. Pp. x £4,50. London: Bailliere Tindall. 1977.
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Boeke Ontvang Euthanasie. (De ederlandse Bibliotheek der Geneeskunde, Deel ill.) By P. V. Admiraal, Th. Beemer, J. C. van Es, F. van Heek, H. J. Heering, T. I. Gerlings-Huurman, H. J. J. Leenen, C. Leering, P. Muntendam, P. J. Stolk and W. van Zeben. Pp. 269. f65,00. Leiden: StaReu's Wetenschappelijke Uitgeversmaatschappij. 1977. Bacteriology, Virology and Immunity. 10th ed. By F. S. Stewart and T. S. L. Beswick. Pp. vii + 486. Illustrated. London: Bailliere Tindall. 1977.
374.
A Medical Biochemistry for the Tropics. By J. K. Candlish. Pp. x + 254. £5,50. London: Bailliere Tindall. 1977.
Forensische Pathologie. (De Nederlandse Bibliotheek der Geneeskunde, Deel 109.) By J. Zeldenrust. Pp. 336. Illustrated. f87,50. Leiden: Stafleu's Wetenschappelijke Uitgeversmaatschappij. 1977.
Introduction to Anesthesia. The Principles of Safe Practice. 5th ed. By R. D. Dripps, J. E. Eckenhoff and L. D. Vandam. Pp. xvi + 557. Illustrated. RI7,40. Philadelphia: W. B. Saunders. 1977.
