Nelson's Syndrome: A Narrative Review

Abstract

Nelson's syndrome (NS) is an uncommon disease occurring as a complication of bilateral adrenalectomy (BLA) in patients with persistent Cushing's disease (CD) due to an adrenocorticotropin-producing pituitary tumor. The first reports of this syndrome were done in the 50s, although its pathophysiology is still not understood. Every year, between 1.8 and 2.6 cases are thought to occur per million people. It is characterized by hyperpigmentation, elevated adrenocorticotropic hormone (ACTH) plasma levels, and typical signs and symptoms related to pituitary adenomas, such as visual deficits due to optic pathway compression or decreased hormone production from the adenohypophysis. NS represents a challenge due to the lack of accepted diagnostic criteria and the complexity of its treatment. Moreover, the development of stereotactic radiosurgery (SRS) in the last few years has become an essential but controversial strategy for this syndrome. This review presents a comprehensive overview of NS.

Keywords: cushing’s syndrome; nelson’s syndrome; acth; cushing’s disease; pituitary adenoma.

Figure 1. Pituitary gland

The pituitary gland is located in the center of the skull base. The gland rests on the pituitary fossa and is separated from the rest of the skull by the sellar diaphragm, which has a central foramen that is crossed by the pituitary stalk. The latter is a cylindrical structure, which is formed mainly by axons that connect the posterior lobe of the pituitary gland with the hypothalamus. Image credit: The authors of the current study.

Figure 2. Distribution of cells in the pituitary gland

In the anterior lobe of the pituitary, different types of cells are responsible for the manufacture of various hormones. About 20% of the anterior pituitary cells are lactotrophs that secrete prolactin (PRL), and about 50% are somatotroph cells that create growth hormone (GH). Corticotrophs account for 15% of the anterior pituitary cells and are in charge of producing adrenocorticotropic hormone (ACTH), and up to 10% are gonadotroph cells that generate luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Thyrotrophs produce thyroid-stimulating hormone (TSH) and represent about 5% of the anterior pituitary, being the least prevalent cell type. Image credit: The authors of the current study.

Figure 3. Hypothalamic-pituitary-adrenal axis

Corticotroph cells are regulated by corticotropin-releasing hormone (CRH), produced in the paraventricular nucleus of the hypothalamus, whose activation is governed by a positive feedback system repressed by glucocorticoids from the adrenal glands. Corticotroph cells produce proopiomelanocortin, which is a precursor molecule of adrenocorticotropic hormone (ACTH) that is converted by proteolytic enzymes. Image credit: The authors of the current study.

Figure 4. Hypothalamic-pituitary-adrenal axis altered in Nelson's syndrome

Surgical resection of the adrenal gland is designed to reduce hypercortisolemia in patients with Cushing's disease (CD) by breaking the feedback loop. The tumor that eventually develops and gives rise to Nelson's syndrome is believed to originate from the corticotropic cells that caused CD. Image credit: The authors of the current study.