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This may be regarded as iatrogenic disease. Most cases occur in patients with Cushing's syndrome who have an adrenocorticotropic hormone (ACTH) secreting pituitary macroadenoma. Such patients have high levels of cortisol which suppress the production of corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus. The normal cortisol feedback mechanism of the hypothalamo-pituitary-adrenal (HPA) axis is thus disturbed, with loss of circadian rhythm and excess cortisol production. Once the patient has had a bilateral adrenalectomy, cortisol levels come down to normal and the production of CRH increases. This in turn sometimes results in the unchecked growth of the pituitary adenoma, leading to Nelson's syndrome. Regulatory gene mutations and mutations in the glucocorticoid receptor may also play a part.
Compression by the tumour can inhibit the release of other pituitary hormones. The level of alpha melanocyte-stimulating hormone (a-MSH) is also very high. This is a derivative of the precursor peptide from which ACTH is derived.The signs and symptoms derive from the pressure of the tumour on surrounding structures and the secondary loss of other pituitary hormones.
Nelson's syndrome is a rare condition that seems to be declining further. This may be related to better management of Cushing's syndrome and pituitary adenomas. Pituitary surgery is used more often but there is still a definite place for adrenalectomy. Even in early series, only 20-40% of patients with a pituitary adenoma who had bilateral adrenalectomy developed Nelson's syndrome. Reported rates of later studies vary from 8-44%.
ACTH-producing tumours are most common in young or middle-aged women and so they are the group most at risk of Nelson's syndrome.
Pregnancy is a predisposing factor.
- In at least 99% of cases there is a history of adrenalectomy.
- Headaches are common with pituitary tumours and are probably the result of stretching of the diaphragma sellae. Features of raised intracranial pressure occur late and are uncommon because they require a tumour large enough to obstruct the flow of cerebrospinal fluid (CSF).
- Hypopituitarism occurs when the hypothalamic-pituitary portal system is disrupted or normal pituitary tissue is destroyed by the tumour:
- It may be partial rather than total. The anterior pituitary is more often involved than the posterior pituitary.
- Often hormone deficiency is incomplete.
- In children and adolescents, note growth and age of puberty.
- In all patients, enquire for symptoms of hypothyroidism, presence of galactorrhoea and polyuria and polydypsia. The last two are due to diabetes insipidus.
- Cushing's syndrome often slows growth in children but operation should return it. If not, investigation is required.
- In women amenorrhoea may be the first sign of pituitary disease. Galactorrhoea is uncommon in men but hyperprolactinaemia often causes erectile dysfunction.
- Visual field defects should be enquired about. They may be too insidious to have been noticed and formal testing might be required. The tumour may also cause diplopia and cranial nerve lesions by involving the oculomotor, trochlear and abducens nerves and also the ophthalmic branch of trigeminal.
- In children and adolescents, note height and weight.
- Hyperpigmentation is usually obvious. A linea nigra is often apparent. This is a dark line from the pubis to the umbilicus. Scars and areolae are pigmented and, as with Addison's disease, pigmentation is more marked in the creases of the hands. Some patients develop hyperpigmentation after bilateral adrenalectomy but do not develop full-blown Nelson's syndrome.
- In adolescents there may be features of delayed puberty. In adult women there may be some regression of breasts or galactorrhoea.
- Hypothyroidism may cause bradycardia but, if adrenal replacement is inadequate, examination of the pulse may show it to be fast but thready. Blood pressure is low with steroid insufficiency but hypertension is common if levels are elevated.
- Check eye movements as the external ocular muscles will be affected if the III, IV or VI cranial nerves are involved. Damage to the ophthalmic division of the trigeminal nerve will impair sensation over the forehead and perhaps corneal reflex.
- Check the fundi, including looking for papilloedema.
- ACTH will be very markedly elevated. One study found that a plasma ACTH concentration above 154 pmol/L occurred only in the subjects with Nelson's syndrome. The ACTH response to CRH is also enhanced but this is not necessary for diagnosis.
- Thyroxine levels may be low and thyroid-stimulating hormone (TSH) will also be low.
- Gonadotropins and sex hormones may be low. In children growth hormone should be measured.
- Prolactin may well be elevated but not as high as in a prolactin-producing tumour.
- Early morning urine can be tested for specific gravity and, if it is less than 1010, then tests for diabetes insipidus should be undertaken.
- MRI is useful for both detection and to monitor progression of a microadenoma. A gadolinium-enhanced MRI of the pituitary and parasellar region produces excellent images. Experience is, however, required in interpretation.
- Formal perimetry is required for visual fields.
- Adrenal hypoplasia.
- Adrenal insufficiency.
- Congenital adrenal hyperplasia.
- Glucocorticoid therapy and Cushing's syndrome.
- Other causes of skin pigmentation - eg jaundice (also affects the sclerae) and haemochromatosis (more of a bronze colour, may be associated with hepatomegaly and possibly splenomegaly).
The use of MRI has enabled the detection of tumours whilst they are still at the microadenoma stage. This has facilitated early medical treatment and obviated the use of surgery in some cases.
Cabergoline (a dopamine receptor antagonist) has recently been used successfully to induce remission in Nelson's syndrome with decline of ACTH levels and resolution of the microadenoma or macroadenoma.
Octreotide (a parenterally administered somatostatin analogue), cyproheptadine with and without bromocriptine and sodium valproate have also been used with various degrees of success, although they are more effective at controlling ACTH levels than reducing the size of the tumour.
One study reported the successful use of temozolomide after treatment failure with surgery and radiotherapy.
Radiotherapy may be the preferred option for an invasive adenoma showing progression. Fractionated external beam radiotherapy or stereotactic radiosurgery can be used depending on tumour size and location. Modern techniques with high power linear accelerators cause less radiation scatter and so less collateral damage. Radiotherapy is associated with serious long-term problems, including learning and memory difficulties, visual damage and risk of secondary tumours.
Surgery still offers the best chance of cure for tumours that are large, particularly if they are pressing on surrounding structures such as the optic apparatus. Trans-sphenoidal surgery gives the lowest risk of injury of the hypothalamus. If removal is incomplete or where there is invasion, adjunctive irradiation reduces the rate of recurrence and improves the prognosis.
Stereotactic radiosurgery seems very promising. Treatment using protons rather than photons (X-rays) has improved effectiveness and has effected a cure in some patients in whom surgery has been unsuccessful. Use of a gamma knife to focus the radiotherapy beam offers a further refinement.
Long-term assessment of pituitary function is required with hormone replacement therapy as required. Blood pressure should also be monitored.
- Hypopituitarism is very common after treatment, especially if the tumour was large.
- Malignant change in ACTH-producing tumours is rare.
- Lateral extension of the tumour can invade the cavernous sinuses with entrapment or compression of the cranial nerves that cross it. These include the oculomotor, trochlear and abducens nerves and the ophthalmic division of trigeminal. Superior extension of the tumour can compress or invade the optic apparatus or the hypothalamus. Visual symptoms or signs depend upon where the tumour presses.
- During embryogenesis, adrenal cortical cells may migrate along the line of gonadal descent and may even be sequestered in the hilum of the testes, producing adrenal rest tissue. In Nelson's syndrome, this adrenal rest tissue may become stimulated and, if in the testes, it can cause painful testicular enlargement and oligospermia. Rarely, the adrenal rest tissue can produce enough cortisol to produce normal levels or even cause recurrence of Cushing's syndrome.
The prognosis is good, providing there is early recognition. Co-ordination between surgeons and radiotherapists is important. Postoperative aftercare, with adequate monitoring and replacement of hormones, is vital. Epidemiological information is sparse but the available data suggest that the incidence is falling and that modern treatments are helping to reduce morbidity and mortality.
- Bilateral adrenalectomy is said to carry an acceptable risk but follow-up should include awareness of Nelson's syndrome. Monitoring of ACTH level and pituitary MRI are recommended 3-6 months after surgery and regularly thereafter. A high ACTH level one year after adrenalectomy is thought to be predictive of corticotroph tumour progression.
- Routine pituitary irradiation after bilateral adrenalectomy is no longer recommended.
- A study from Italy found that the occurrence of Nelson's syndrome was significantly related to the pretreatment urinary cortisol level and the presence of pituitary adenoma at previous pituitary surgery. Previous pituitary surgery, even if unsuccessful, appeared to protect against relapse. The results indicate that relapse after cure by either pituitary surgery or irradiation is a considerable clinical problem that increases over time. The findings suggest importance to the clinical presentation of patients and indicate subgroups that are at high risk for relapse after pituitary surgery or irradiation and for developing Nelson's syndrome after bilateral adrenalectomy.
Although Cushing's syndrome dates back to Harvey Cushing's paper in 1932, Nelson's syndrome goes back only to 1960 and the author has failed to reach the pages of the 'whonamedit.com' website.
Further reading & references
- Munir A, Newell-Price J; Nelson's Syndrome. Arq Bras Endocrinol Metabol. 2007 Nov;51(8):1392-6.
- Wilson T et al; Nelson Syndrome, eMedicine, May 2009
- Biller BM, Grossman AB, Stewart PM, et al; Treatment of ACTH-dependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab. 2008 Apr 15;.
- Imai T, Funahashi H, Tanaka Y, et al; Adrenalectomy for treatment of Cushing syndrome: results in 122 patients and long-term follow-up studies. World J Surg. 1996 Sep;20(7):781-6; discussion 786-7.
- Pereira MA, Halpern A, Salgado LR, et al; A study of patients with Nelson's syndrome. Clin Endocrinol (Oxf). 1998 Oct;49(4):533-9.
- Bahurel-Barrera H, Assie G, Silvera S, et al; Inter- and intra-observer variability in detection and progression assessment with MRI of microadenoma in Cushing's disease patients followed up after bilateral adrenalectomy. Pituitary. 2008 Apr 17;.
- Moyes VJ, Alusi G, Sabin HI, et al; Treatment of Nelson's syndrome with temozolomide. Eur J Endocrinol. 2009 Jan;160(1):115-9. Epub 2008 Nov 4.
- Petit JH, Biller BM, Yock TI, et al; Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. J Clin Endocrinol Metab. 2008 Feb;93(2):393-9. Epub 2007 Nov 20.
- Mauermann WJ, Sheehan JP, Chernavvsky DR, et al; Gamma Knife surgery for adrenocorticotropic hormone-producing pituitary adenomas after bilateral adrenalectomy. J Neurosurg. 2007 Jun;106(6):988-93.
- Wright-Pascoe R, Charles CF, Richards R, et al; A clinico-pathological study of Cushing's syndrome at the University Hospital of the West Indies and a review of the literature. West Indian Med J. 2001 Mar;50(1):55-61.
- Chapuis Y, Pitre J, Conti F, et al; Role and operative risk of bilateral adrenalectomy in hypercortisolism. World J Surg. 1996 Sep;20(7):775-9; discussion 779-80.
- Assie G, Bahurel H, Coste J, et al; Corticotroph tumor progression after adrenalectomy in Cushing's Disease: A reappraisal of Nelson's Syndrome. J Clin Endocrinol Metab. 2007 Jan;92(1):172-9. Epub 2006 Oct 24.
- Sonino N, Zielezny M, Fava GA, et al; Risk factors and long-term outcome in pituitary-dependent Cushing's disease. J Clin Endocrinol Metab. 1996 Jul;81(7):2647-52.
- Moshang T Jr; Cushing's disease, 70 years later. and the beat goes on. J Clin Endocrinol Metab. 2003 Jan;88(1):31-3.
- Nelson DH, Meakin JW, Thorn GW; ACTH-producing pituitary tumors following adrenalectomy for Cushing's syndrome. Ann Intern Med. 1960 Mar;52:560-9.
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Dr Laurence Knott
Dr Laurence Knott