Nelson Syndrome

Updated: Mar 25, 2021
  • Author: Thomas A Wilson, MD; Chief Editor: Robert P Hoffman, MD  more...
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Nelson syndrome (NS) is a potentially life-threatening condition that may develop following bilateral adrenalectomy for the treatment of Cushing disease. It is characterized by a spectrum of signs and symptoms related to the local effects on surrounding structures from an adrenocorticotropin (ACTH)–secreting pituitary macroadenoma after a therapeutic bilateral adrenalectomy, the secondary loss of other pituitary hormones, and the effects of the high serum concentrations of ACTH on the skin. [1] The time interval between the bilateral adrenalectomy and a diagnosis of NS ranges from 0.5–24 years. [2] The first case was reported by Nelson et al in 1958. [3]



Almost all cases of Nelson syndrome follow bilateral adrenalectomy in patients who have Cushing disease due to an adrenocorticotropin (ACTH)–secreting pituitary adenoma. High-resolution magnetic resonance imaging (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.

Studies have demonstrated 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. [4] 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.



Bilateral adrenalectomy

More than 99% of cases of Nelson syndrome arise following bilateral adrenalectomy in a patient with Cushing disease due to an adrenocorticotropin (ACTH)–secreting pituitary adenoma. Other diagnoses should be considered in patients with hyperpigmentation who have not undergone adrenalectomy or in patients who have signs of pituitary or visual dysfunction but without pigmentation.

The most common cause of pigmentation associated with a high ACTH level is primary adrenal insufficiency. This can be either congenital or acquired. Congenital causes of adrenal insufficiency include congenital adrenal hyperplasia or hypoplasia.

Acquired causes of bilateral adrenal insufficiency include Addison disease (autoimmune adrenal failure), adrenoleukodystrophy (in males), infection, and destruction. The patient with acquired adrenal insufficiency may present either acutely with adrenal crisis (eg, vomiting, hypotension, hypoglycemia) or with symptoms of chronic insufficiency, such as fatigue, lethargy, anorexia, nausea, abdominal pain, weight loss, postural hypotension, myalgias, and diarrhea.

Hypopituitarism (without pigmentation)

The presence of a combination of visual disturbance, hypopituitarism, diabetes insipidus, and/or headaches in the absence of hyperpigmentation should arouse the suspicion of a lesion in the region of the pituitary gland or its stalk. The most common childhood tumor in this region is the craniopharyngioma, derived from the remnants of the Rathke pouch, the anlagen of the anterior pituitary gland.

The most frequent hormone-secreting pituitary tumor in childhood is the prolactinoma, which has its peak pediatric incidence in the postpubertal years. Patients usually present with symptoms similar to Nelson syndrome but without evidence of hyperpigmentation. Frequently, arrested puberty and primary or secondary amenorrhea occur with this tumor. Galactorrhea may occur but may be missed unless the areolae are squeezed to express the milk. Prolactin levels are unequivocally elevated. Milder elevation of prolactin (usually < 150 ng/mL) may occur as a result of compression of the pituitary stalk by other space-occupying lesions in the region. Some medications (especially phenothiazines and some anticonvulsants) are dopamine receptor antagonists and may also cause mild hyperprolactinemia (usually < 100 ng/mL).

Even less common are growth–hormone secreting pituitary adenomas that result in excessive growth velocity (pituitary gigantism).

Nonfunctioning pituitary adenomas are extremely rare in children.

Patients with nonpituitary tumors may also present with symptoms of hypopituitarism. These include germ cell tumors that may produce human chorionic gonadotropin (HCG). This protein may stimulate Leydig cells, resulting in gonadotropin–independent precocious puberty in males. Optic gliomas may also result in hypopituitarism. Neurofibromatosis type-1 should be excluded in patients with an optic glioma.



Nelson syndrome is a rare disorder, making accurately determining its incidence difficult. One review indicates that Nelson syndrome may be seen in anywhere from 8-44% of patients who have undergone bilateral adrenalectomy for Cushing disease. [5, 6] This large variance may be explained by shorter follow-up periods in some studies. Osswald and colleagues reported as occurrence of Nelson syndrome in 24% of Cushing disease patients after a median time span of 51 months following bilateral adrenalectomy. [7] Nelson syndrome is less likely in patients without visible tumor at the time of adrenalectomy. [8]

This decline in prevalence may also be attributed to significant improvements in all aspects of the assessment and management of patients with Cushing syndrome in the last 10-20 years. [9] These include introduction of the sensitive adrenocorticotropic hormone (ACTH) assay, the advent of high-resolution magnetic resonance imaging (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.

Sex- and age-related demographics

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

The risk of developing Nelson syndrome appears to be higher in younger individuals than in older individuals. The primary corticotroph adenoma remains in situ after adrenalectomy in patients with Cushing disease. Therefore, both children and adults have a significant risk of developing macroscopic (>1 cm) enlargement of the tumor and hyperpigmentation. [8]



The prognosis for patients with Nelson syndrome is good with early recognition, prompt coordinated treatment with surgeons and radiotherapists, and appropriate hormone replacement. [11] Increased plasma adrenocorticotropic hormone (ACTH) is a strong predictor because of its association with tumor progression. [8] Young age at the time of bilateral adrenalectomy and duration of Cushing disease may also be a predictive factors, but the evidence in the literature is inconsistent. [10] In several studies, high urinary cortisol was associated with Nelson syndrome. [11]

The predominant cause of morbidity from Nelson syndrome is from local tumor extension or invasion. Patients with this disorder become deeply pigmented because the action of ACTH on melanocytes. 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 on the point at which the tumor impinges the optic apparatus.

Although 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.


Potential complications in patients with pituitary macroadenomas include the following:

  • Related to the primary disease: Visual loss, hypopituitarism, and cranial nerve complications

  • Related to surgical intervention: Infection, stroke, hypothalamic damage, hypopituitarism, and visual loss

  • Related to radiotherapy: Hypopituitarism, damage to vision, difficulties with learning or memory, and the risk of developing second tumors


Patient Education

The main educational requirements for patients with Nelson syndrome relate to their need to increase replacement glucocorticoid doses with intercurrent illness, physical stress, or anesthesia and the need for parenteral steroids before anesthesia or with vomiting or severe diarrhea.

Patients receiving other treatment also require education specific to that treatment (eg, administration of growth hormone injections or desmopressin (DDAVP).

All patients on steroid replacement should wear a Medic Alert bracelet or medallion.

If patients have hypogonadotropic hypogonadism, they also require counseling at an appropriate age about the availability of assisted reproduction.

For patient education resources, see the Thyroid and Metabolism Center. Also see Hypopituitarism in ChildrenCushing Syndrome, and Anatomy of the Endocrine System.