Cushing's Disease
with Normal Sella : Management

GR Sridhar, Endocrine and Diabetes Centre, Visakhapatnam - 530002.

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Cushings syndrome, or glucocorticoid excess is a generic term, which includes Cushings disease (ie, glucocorticoid excess due to ACTH-secreting pituitary microadenoma). Iatrogenic administration of glucorticoids remains the commonest cause of Cushings syndrome, but Cushings disease accounts for more than three fourth of endogenous Cushings syndrome.

The clinical manifestations of Cushing's syndrome, well known as they are, usually bring the patient to medical attention. The role of increased glucorticoid action can be considered as catabolic in most tissues, which explains why the most prominent manifestations include muscle weakness, bone thinning and skin weakening (2). In addition, the vasculature breaks down and ecchymoses form; inefficient immune system results in opportunistic infection. Insulin antagonism manifests as glucose intolerance.

The diagnosis of Cushings syndrome is suspected on the basis of clinical features, and confirmed by documenting loss of diurnal variations in cortisol concentration, and elevated excretion of free cortisol in the urine. Overnight dexamethasone suppression test, and low dose dexamethasone suppression test can also be used to demonstrate hypercortisolemia.

The differential diagnosis of Cushings syndrome (ie the cause of Cushings syndrome) is made by plasma ACTH, potassium, high-dose dexamethasone test, metyrapone test and corticotropin releasing factor test. Where facilities are available, inferior petrosal sinus canulation along with selective venous sampling for ACTH gives further information. The source of excess glucocorticoids can be imaged by CT/ MRI of pituitary and adrenals, and scintigraphy of the adrenals.

By definition, Cushings disease implies hypercortisolemic state due to pituitary oversecretion of ACTH. Once Cushings syndrome has been diagnosed, the plasma ACTH (elevated), potassium (usually normal), high-dose dexamethasone test (usually suppressible cortisol levels), and CRF stimulation test (further elevation of serum ACTH and cortisol levels) suggest Cushings disease. However, these tests could give both false positive and false negative results. Biochemical Cushings disease must be confirmed by a pituitary adenoma, either on CT scan or MRI imaging. We face here a situation where there is no radiologically demonstrable pituitary tumour, in the face of biochemical features suggestive of ACTH secreting pituitary adenoma.

Cushings disease is often caused by pituitary tumours measuring less than 10 mm in diameter (microadenomas). Interestingly, pituitary adenomas are not found, at either surgery or autopsy in about 20% of patients with Cushings disease. The usual pituitary microadenoma causing Cushings disease is located in the periphery of gland, but rarely it may occur deep in the central wedge of the pituitary and be missed on imaging or at surgery. Given the small size of most pituitary ACTH secreting adenomas, conventional CT scanning of the pituitary can miss a significant proportion of tumours, although MRI improves the pick-up rate.

Difficulties arise in diagnosing Cushings disease rarely, as failure to suppress with high dose dexamethasone, but suppress ACTH with cortisol (6). Similarly, occult ectopic ACTH secreting tumours could account for 10% of ACTH-dependent Cushing's syndrome; ectopic CRH-secreting neoplasia are also another cause of Cushings syndrome with normal sella. Cyclical Cushings disease has also been reported, with periodic hormonogenesis of ACTH and cortisol, with or without ACTH secreting pituitary adenomas.

Petrosal sinus sampling can aid in localisation of pituitary lesions. Catheters are placed in the left and right inferior petrosal sinuses and blood for ACTH is drawn simultaneously from both catherters, and from a peripheral vein. Sequential samples avoid variations from pulsatile hormone secretion. A plasma ACTH concentration gradient (petrosal sinus/ peripheral vein ACTH greater than or equal to 1.6) suggests the pituitary source of ACTH. A right left discrepancy may also help localize ACTH secretion, and help in preoperative localisation of the lesion.

This side localisation is particularly helpful when later at the time or surgery, a tumour cannot be morphologically made out. In such cases, partial resection of the side of the pituitary with the higher ACTH levels usually results in remission of the disease.

Further refinement can be added by administering CRH at the time of the catheterization, which can enhance differences between the right and left sides.

Pituitary surgery is the treatment of choice when the biochemical diagnosis suggests Cushings disease. The possibility of finding pituitary pathological process, and of its being surgically correction occurred in as many as six of 11 patients who did not test typically for biochemical criteria (ie, elevated free cortisol levels a positive metyrapone response, poor suppression with high-dose dexamethasone test).

If biochemical investigations strongly indicate a pituitary lesion but the petrosal sinus sampling cannot lateralize the lesion, and the patient does not desire further children, total hypophysectomy can be done, provided the possibility was discussed with the patient pre-operatively. Should the patient desire further children, alternative therapies may be employed: total adrenalectomy, or medical treatment with cyproherptadine, bromocriptine, aminoglutethimide, metyrapone, ketocanazole or mitotane.

Suggested reading

  1. Cook DM, Loriaux DL. Cushing's syndrome. In (ed) Bardin CW. Current therapy in endocrinology and metabolism. Mosby, St Louis; 1994; pp142-6
  2. Loriaux DL. Cushing's syndrome. In (ed) Wilber JF. The Endocrine Society 41st Postgraduate Assembly; The Endocrine Society, Bethesda; 1989; pp136-51
  3. Aron DC, Findling JW, Tyrell JB. Cushing's disease. Endocrinol Metab Clin North Am 1987;16:705-30
  4. Schteingart DE.Cushings syndrome. Endocrinol Metab Clin North Am 1989;18:311 -38
  5. Carey RM. Suppression of ACTH by cortisol in dexamethasone non-suppressible Cushing's disease. N Engl J Med 1980 ; 302:275-9
  6. Edwards CRW. Adrenocortical diseases. In (eds) Weatherall DJ, Ledingham LGG, Warrell DA. Oxford Textbook of Medicine. Oxford Univ Press, Oxford; 1996; pp1639 -63
  7. Tabarin A, Greselle JF, San Galli F et al. Usefulness of the corticotropin -releasing hormone test during bilateral inferior petrosal simus sampling for the diagnosis of Cushing's disease. J Clin Endocrinol Metab 1991;73:53-9

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