Nelson's syndrome is a disorder that occurs in about one in four patients who have had both adrenal glands removed to treat

Cushing's disease Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (spe ...

. In patients with pre-existing adrenocorticotropic hormone (

ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...

)-secreting

pituitary adenoma Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas.bitemporal hemianopsia) and

hyperpigmentation Hyperpigmentation is the darkening of an area of skin or nails caused by increased melanin. Causes Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris.James, William; Ber ...

. The severity of the disease is dependent upon the effect of ACTH release on the skin, pituitary hormone loss from mass compression, as well as invasion into surrounding structures around the pituitary gland. The first case of Nelson's syndrome was reported in 1958 by Dr. Don Nelson. Within the past ten to twenty years, improvements have been made identification and care for patients with

. Techniques such as pituitary

radiation therapy Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radi ...

, ACTH assay, transsphenoidal pituitary surgery, higher resolution

MRIs Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wa ...

, and sampling of the

inferior petrosal sinus The inferior petrosal sinuses are two small sinuses situated on the inferior border of the petrous part of the temporal bone, one on each side. Each inferior petrosal sinus drains the cavernous sinus into the internal jugular vein. Structure The ...

have allowed physicians to pursue routes for Cushing's syndrome therapy prior to consideration of bilateral adrenalectomy. Nelson's syndrome is also referred to as post-adrenalectomy syndrome, a possible result of

adrenalectomy Adrenalectomy (Latin root Ad "near/at" + renal "related to the kidneys" + Greek '' ‑ectomy'' “out-cutting”; sometimes written as ADX for the procedure or resulting state) is the surgical removal of one ( unilateral) or both (bilateral) adr ...

performed for Cushing's disease.

Symptoms and signs

The common symptoms include: * hyper-pigmentation of the skin *

visual disturbances A vision disorder is an impairment of the sense of vision. Vision disorder is not the same as an eye disease. Although many vision disorders do have their immediate cause in the eye, there are many other causes that may occur at other locations in ...

* headaches * abnormally high levels of beta-MSH and

* abnormal enlargements of the

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...

, * interruption of

menstrual cycles The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs ...

in women

Cause

Common causes include bilateral adrenalectomy for the treatment of Cushing's disease and

hypopituitarism Hypopituitarism is the decreased (''hypo'') secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is know ...

. The onset of the disease can occur up to 24 years after bilateral adrenalectomy has been performed, with an average of up to 15 years after. A preventative measure that can be utilized is prophylactic radiotherapy when bilateral adrenalectomy is being performed to prevent Nelson's syndrome from manifesting. Screening can also be done with the help of an

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

in order to visualize the pituitary for tumors. If tumors are not present then an MRI should be performed at intervals. Hyper-pigmentation and fasting ACTH levels within plasma above 154 pmol/L are predictive of Nelson's syndrome after an adrenalectomy. Risk factors include being younger in age and pregnancy.

Mechanism

After a bilateral adrenalectomy is performed cortisol levels are no longer normal. This increases CRH production because it is not suppressed within the hypothalamus anymore. The increased CRH levels promote the growth of the tumor. Mutations with genes and with the

glucocorticoid receptor The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the receptor to which cortisol and other glucocorticoids bind. The GR is expressed in almost every cell in the body and regulates ...

can affect the tumor as well. Furthermore, differences between Nelson syndrome and Cushing's disease have been studied. Particularly Nelson's syndrome differs from Cushing's disease due to the following: secretions from the tumors, replacement of glucocorticoids, and injury to the hypothalamus due to radiation therapy utilized on the patient. The pathophysiology of Nelson's syndrome is not understood very well. Corticotrophinomas are generated from corticotroph cells. Expression of functional CRH and

vasopressin Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then trave ...

V3 receptors increase in number. Additionally, there are two

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every verteb ...

receptors.

Heterozygosity Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

loss in the glucocorticoid receptor can occur in the tumors present in Nelson's syndrome. Overall, not all patients that have had total bilateral adrenalectomy develop Nelson's syndrome, which makes the mechanism harder to understand for such a rare disease. It is not clear whether the adrenalectomy or reduced cortisol secretion causes aggressive tumor growth.

Diagnosis

Common diagnostic techniques include: *

* CAT scans * blood samples. Blood samples are assessed for the absence or presence of aldosterone and cortisol. Physical examinations are also useful in patients to examine vision, skin pigmentation, how the body replaces steroids, and the

cranial nerves Cranial nerves are the nerves that emerge directly from the brain (including the brainstem), of which there are conventionally considered twelve pairs. Cranial nerves relay information between the brain and parts of the body, primarily to and f ...

. Recent advancements in high-resolution MRIs allow for adenomas to be detected during the early stages of Nelson syndrome. Physical examination including height, weight, vital signs, blood pressure, eye examination, thyroid examination, abdominal examination, neurological examination, skin examination, and pubertal staging needs to be assessed. Through blood pressure and pulse readings can indicate hypothyroidism and adrenal insufficiency. Hyper-pigmentation,

hyporeflexia Hyporeflexia is the reduction or absence of normal bodily reflexes (areflexia). It can be detected through the use of a reflex hammer and is the opposite of hyperreflexia. Hyporeflexia is generally associated with a deficit in the lower motor n ...

, and loss of vision can also indicate Nelson's syndrome when assessed together. Specifically for a child who might have Nelson's syndrome, the patient should be questioned about the symptoms of the disease, as well as symptoms of other diseases to narrow down which disease the patient presents with. The patient should be questioned about how often and to what degree headaches, visual disturbances, and symptoms associated with pituitary malfunction occur. Additionally, adrenal steroid replacement should be assessed.

Treatment

Common treatments for Nelson's syndrome include radiation or surgical procedure. Radiation allows for the limitation of the growth of the pituitary gland and the adenomas. If the adenomas start to affect the surrounding structures of the brain, then a micro-surgical technique can be adapted to remove the adenomas in a transsphenoidal (bone at the base of the skull) process. Death may result in development of a locally aggressive

pituitary tumor Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. In the rare case, ACTH-secreting tumors can become

malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

. Morbidity from the disease can occur due to pituitary tissue compression or replacement, and compression of structures that surround the pituitary fossa. The tumor can also compress the optic apparatus, disturb

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

flow, meningitis, and testicular enlargement in rare cases.

Research

Through multiple advancements within the medical field, caregivers have been able to stray away from utilizing bilateral adrenalectomy as the treatment for Cushing's disease. This has decreased the risk of patients presenting with Nelson's syndrome. Alternative treatments for Nelson's syndrome have been discovered. The most utilized technique for Nelson's syndrome has been transsphenoidal surgery. In addition,

pharmacotherapy Pharmacotherapy is therapy using pharmaceutical drugs, as distinguished from therapy using surgery (surgical therapy), radiation (radiation therapy), movement (physical therapy), or other modes. Among physicians, sometimes the term ''medical ther ...

, radiotherapy, and radiosurgery have been utilized accompanying a surgical procedure. Pharmacological drugs can also be given accompanying a transsphenoidal surgery including the following: pasireotide,

temozolomide Temozolomide (TMZ), sold under the brand name Temodar among others, is a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. Text was copied from this source which is © European Medicines Agency. Reproduction ...

and

octreotide Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was ...

. Within rats/mice,

rosiglitazone Rosiglitazone (trade name Avandia) is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutica ...

has been an effective measure, however this has not been discovered in humans yet.

References

External links

{{DEFAULTSORT:Nelson's Syndrome Pituitary disorders Syndromes affecting the endocrine system Rare diseases