The natural history of treated Cushing's syndrome
Authors: Welbourn R B , Montgomery D A D , Kennedy T L 
Published: March 2007

Abstract
The long-term (2-15 years) results of treatment of a consecutive series of 60 patients with Cushing's syndrome are analysed. Of 41, in whom no evidence of tumour was found initially, 12 were eventually found to have tumours in the pituitary (including 3 suspected), the adrenal, or the bronchus.
Most of the 46 with benign lesions (adrenal hyperplasia, without evidence of malignant tumour, or adrenal adenoma) were treated by adrenalectomy with an operative mortality of 4 per cent. All who survived operation underwent remission. One-quarter died within 3 years, but thereafter the proportion that survived remained fairly constant (between 64 and 76 per cent) up to 15 years. Cushing's syndrome recurred in 11 per cent (3 patients) of those having subtotal adrenalectomy. In each case the recurrence was treated effectively. Two of 9 patients with benign pituitary adenomas were cured by transfrontal hypophysectomy and packing of the fossa with yttrium 90.
Fourteen patients had malignant tumours of the pituitary, the adrenal, or the bronchus and all died within 5 years. Five of these had invasive pituitary tumours which failed to respond to various combinations of hypophysectomy and irradiation.
Arterial hypertension and serious cardiovascular lesions were found initially in 93 per cent and 40 per cent, respectively. Adrenalectomy lowered the pressure effectively and permanently. The average post-operative systolic pressure was about normal and the average diastolic pressure was within 10 mm. Hg of normal. Some cardiovascular lesions resolved, but others persisted or became apparent only later. They were the major cause of death within 1 year of adrenalectomy.
Hypokalaemia (40 per cent) and osteoporosis (47 per cent) resolved after effective treatment of Cushing's syndrome. Diabetes, which was present in 29 per cent, was cured by adrenalectomy when mild, but in only 1 of 3 cases in which it was more severe.
Prepuberal boys had retarded growth but normal ossification, before treatment, and grew rapidly after adrenalectomy. Prepuberal girls (with adrenal carcinomas) were of normal height, but had precocious ossification.
Severe mental abnormality, mainly depression, was present in 20 per cent of patients initially and cleared up completely in those who obtained remission of Cushing's syndrome. Temporary psychiatric symptoms after adrenalectomy were mostly due to adrenal insufficiency or excessive replacement therapy.
Sexual function was impaired in most patients initially and restored after adrenalectomy. Of 8 women who might be expected to bear children after adrenalectomy 6, between them, had 10 pregnancies with 7 live births.
Serious infections were rare initially, but commonly complicated the operation of adrenalectomy. During remission 2 patients developed meningococcal meningitis, which was fatal in 1, and 1 died from encephalitis.
Comparison of the 46 patients with benign lesions in this series (and 12 treated recently) with the 30 reported by Plotz, Knowlton, and Ragan (1952), before the advent of cortisone, reveals a much higher rate of adrenal exploration (91 versus 48 per cent) with a much lower operative mortality (4 versus 29 percent), a greatly increased proportion of patients in remission after 2 years (78 versus 17 per cent), and a higher proportion alive at the time of the report (76 versus 50 per cent).
The best methods of treatment of patients in different aetiological groups are discussed, and the relative advantages and disadvantages of total and subtotal adrenalectomy and of different approaches to the adrenals are considered. Particular emphasis is placed on the early recognition of pituitary tumours and on the need for early radical treatment.