Donald Nelson, MD(b. 1925-): an endocrinologist born in Salt Lake City, Utah attended medical school at the University of Utah graduating in 1947. His work mainly focused on glucocorticoids and he published “ACTH-producing pituitary tumors following adrenalectomy for Cushing Syndrome” in the Annals of Internal Medicine in 1960. The syndrome he described now bares his name.

Nelson’s Syndrome: denotes a constellation of signs and symptoms secondary to adrenocorticotropin (ACTH) secreting pituitary macroadenomas following therapeutic bilateral adrenalectomy. The syndrome results from tumor mass effects and the increased production of proopiomelanocortin (POMC) from which ?-melanocyte stimulating hormone (MSH) and ACTH are derived.

Pathophysiology: Patients suffering from Cushing Disease secondary to ACTH-secreting pituitary adenomas often undergo bilateral adrenalectomy in efforts to normalize cortisol levels. Subsequently, the negative feedback on CRH provided by cortisol is removed and levels of CRH begin to rise. CRH exerts a tropic effect on the adenoma causing it to grow, thus enabling the tumor to produce increasing amounts of POMC, ACTH and MSH.

Clinical Manifestations of Nelson’s Syndrome: Hypopituitarism results when the hypothalamic-pituitary portal system is disrupted or normal pituitary tissue is destroyed by the tumor. The anterior pituitary is more commonly involved than the posterior pituitary and interruption of function can be evaluated by changes in growth, galactorrhea, polyuria, polydipsia, symptoms of hypothyroidism and pubertal delay in adolescents.

Growth (GH, TSH): While a child’s growth curve may flatten over time due to hypercorotisolemia, growth should trend toward normal following adrenalectomy. If normalization does not occur, levels of growth and thyroid hormones should be measured. Decreased levels of either hormone may reflect a disruption of pituitary function. Weight and height measurements should be performed over time.

Central hypothyroidism (TSH): Typically this condition is demonstrated by poor growth, but may less commonly result in mild cold intolerance, constipation, slowing of mentation, change in face shape or weight gain. On physical exam, one may have slowed pulses. In addition, the thyroid gland should be examined for enlargement to exclude autoimmune hypothyroidism as it may also result in the above physical findings.

Pubertal Delay (FSH): In girls, if breast tissue has begun to develop, examination may reveal regression due to hypoestrogenism secondary to decreased FSH. Levels of testosterone will also drop resulting in testicular and scrotal changes in boys.
Galactorrhea: (prolactin) If portal circulation is disrupted, hypothalamic inhibition of pituitary prolactin production is interrupted. Hyperprolactinemia may result in galactorrhea. However, this may only result if breasts have previously been stimulated by estrogen. Thus, the absence of galactorrhea does no rule out hyperprolactinemia.
Polyuria/Polydipsia: (ADH) First, glucocorticoids are needed for appropriate water excretion. If post adrenalectomy hormone replacement is inadequate central DI may be masked. Central DI typically presents as nocturia accompanied by dilute first morning urine, polyuria and polydipsia. Early morning urine should have an osmolality greater than 600-700 mOsm/kg or a specific gravity greater than 1.010.

The pituitary adenoma may also exert mass effects on surrounding structures. Stretching of the diaphragma sella commonly results in headaches. A large tumor may cause obstruction of the foramen of Monro obstructing the flow of CSF, causing an increase in intracranial pressure. Given the position of the pituitary adenoma in relation to the optic chiasm, visual disturbances may also be expected. Deficits will reflect where the tumor is impinging on the optic apparatus. Full assessment of visual acuity in each eye is essential.
Increased Production of POMC results in the increased productions of its derivatives; ACTH and MSH. Elevated MSH levels result in hyperpigmentation of the skin. Examination of the skin may reveal a linea nigra (pigmented line) that is present in the midline extending from the pubis to the umbilicus. Scars, gingivae and the areolae are also hyperpigmented. An abdominal exam should be used to rule out hepatosplenomegaly as hemochromatosis may also result in hyperpigmentation.

Treatment: Medical management alone is rarely curative as 99% of Nelson Syndrome cases are due to pituitary macroadenoma. Drugs used unsuccessfully in efforts to control growth include Octreotide, cyproheptadine and sodium valproate. Radiotherapy is a useful treatment in reducing the tumor, but is associated with memory difficulties, radiation induced visual damage and secondary tumors. Surgical care provides the greatest chance for cure. The goal of surgery is to remove all macroscopic tumor tissue without compromising vital structures. Adjuvant irradiation reduces tumor unable to be removed during surgery, reduces the rate of recurrence and improves prognosis.

References:
1. George P. Chrousos, MD, Antony Lafferty, MB ChB, eMedicine, “Nelson’s Syndrome” pages 1-16. Updated: January 24, 2002

2. BG Firkin, JA Whitworth, Dictionary of Medical Eponyms, 2nd Edition. Page 282
The Parthenon Publishing Group International Publishers in Medicine, Science and Technology. 1996