Excerpt from Nelson Syndrome

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Background

Nelson syndrome refers to a spectrum of symptoms and signs arising from an adrenocorticotropin (ACTH)–secreting pituitary macroadenoma after a therapeutic bilateral adrenalectomy. The spectrum of clinical features observed relates to the local effects of the tumor on surrounding structures, the secondary loss of other pituitary hormones, and the effects of the high alpha-melanocyte–stimulating hormone (a-MSH), another derivative of proopiomelanocortin (POMC, the precursor peptide from which ACTH is derived) on the skin. The first case was reported by Nelson et al in 1958.

Pathophysiology

Almost all cases of Nelson syndrome follow bilateral adrenalectomy in patients who have Cushing disease due to an ACTH-secreting pituitary adenoma. Recently, high-resolution MRI has allowed for detection of microadenomas at an early phase of Nelson syndrome. Most adenomatous corticotropes still retain their responsiveness to corticotropin-releasing hormone (CRH). Following bilateral adrenalectomy and normalization of cortisol levels that had suppressed hypothalamic CRH production, an increase in CRH occurs, which then has a trophic effect on the tumor, stimulating its growth. Regulatory gene mutations and mutations in the glucocorticoid receptor may also be important in determining tumor behavior.

Recent studies demonstrate the difference in the mechanism of increased ACTH secretion in Nelson syndrome and untreated Cushing disease. Detailed analyses delineate marked ACTH secretory burst mass amplification and anomalous regularity of successive pulse size and timing in Nelson syndrome, compared with Cushing disease or controls. Authors of these studies speculate that these distinctions are due to unique tumoral secretory properties, concurrently required glucocorticoid replacement, and/or hypothalamic injury associated with prior radiotherapy in Nelson syndrome.

Frequency

International

Nelson syndrome is a rare disorder, making accurately determining its incidence difficult. A recent review indicates that Nelson syndrome may be seen in anywhere from 8-44% of patients who have undergone bilateral adrenalectomy for Cushing disease. Fewer series were published in the 1990s than in the 1980s, suggesting that the syndrome is becoming increasingly less common. This decline in prevalence can be attributed to significant improvements in all aspects of the assessment and management of patients with Cushing syndrome in the last 10-20 years. These include introduction of the sensitive ACTH assay, the advent of high-resolution MRI, the availability in some centers of inferior petrosal sinus sampling, the refinement of the transsphenoidal pituitary surgery, and advances in pituitary radiation therapy, which have made bilateral adrenalectomy a less attractive therapy for Cushing disease.

Even in early series, only 20-40% of patients with a pituitary adenoma who had bilateral adrenalectomy developed Nelson syndrome. Younger age and pregnancy appeared to be risk factors. The former possibly represents a bias because younger patients have a longer time for tumor growth to occur and symptoms to become manifest.

Mortality/Morbidity

• The predominant cause of morbidity from Nelson syndrome is from local tumor extension or invasion. Patients with this disorder become deeply pigmented because of excess a-MSH, another derivative of POMC. Malignant transformation of ACTH-secreting Nelson tumors has been reported, although this is very rare. Morbidity in Nelson syndrome may be due to loss of pituitary function because of compression or replacement of normal pituitary tissue or compression of structures adjacent to the pituitary fossa by the tumor. Lateral extension of the tumor may result in invasion of the cavernous sinuses and entrapment or compression of the cranial nerves that traverse it (the oculomotor, trochlear, and abducens nerves and the ophthalmic division of the trigeminal). Superior extension of the tumor can lead to compression or invasion of the optic apparatus or the hypothalamus. The visual symptoms or signs observed depend upon the point at which the tumor impinges the optic apparatus.
• While headaches are common and are probably due to stretching of the dura of the diaphragma sellae by the tumor, obstruction of cerebrospinal fluid (CSF) flow is rare because this requires the tumor to be sufficiently large enough to obstruct the foramen of Monro in the third ventricle. Dural invasion with CSF leak and meningitis has been reported, although it is a rare complication.
• During embryogenesis, adrenal cortical cells may migrate along the line of gonadal descent and may even be sequestered in the hilum of the testes, giving rise to adrenal rest tissue. In Nelson syndrome, this adrenal rest tissue may become stimulated. When in the testes, it can result in painful testicular enlargement and oligospermia. Rarely, the adrenal rest tissue can produce sufficient cortisol to normalize levels or even cause recurrence of Cushing syndrome.

Race

No data on this issue exist.

Sex

Corticotroph adenomas are observed predominantly in females; thus, Nelson syndrome is more common in women than men.

Age

Corticotroph adenomas are observed predominantly in young and middle-aged women. The risk of developing Nelson syndrome appears to be higher in younger individuals than in older individuals.

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