BLA Instead of Second Pituitary Surgery

One of the problems that can arise with a BLA (bilateral adrenalectomy) instead of a repeat pituitary surgery for Cushing’s recurrence is Adrenal Insufficiency.  Another is Nelson’s Syndrome.

Nelson’s syndrome is a rare disorder that occurs in some patients with Cushing’s disease patients as a result of removing both adrenal glands. In Nelson’s syndrome, the pituitary tumor continues to grow and release the hormone ACTH.

This invasive tumor enlarges, often causing visual loss, pituitary failure and headaches. One key characteristic of Nelson’s disease is dark skin pigmentation, resulting from the skin pigment cells responding to the release of ACTH.


AnchorNelson’s Syndrome: Physiology

Nelson’s syndrome can develop as a result of a specific treatment (bilateral adrenalecomy) for the pituitary disease called Cushing’s disease. The harmful effects of Cushing’s disease are due to the excessive amount of the hormone cortisol produced by the adrenal glands.

To treat Cushing’s disease, your doctor may recommend removing the adrenal glands, during a procedure called a bilateral adrenalectomy. The procedure will stop cortisol production and provide relief. However, the procedure does not treat the actual tumor. Rapid growth of the pituitary tumor can occur.

In about 15-25 percent of patients who had a bilateral adrenalectomy, Nelson’ syndrome develops within one to four years.


Darkening of Skin Color - Nelson's Syndrome SymptomAnchor

Nelson’s Syndrome: Symptoms

The most obvious symptom of Nelson’s syndrome is the darkening of the skin color (hyperpigmentation).

Macroadenomas

Macroadenomas are large pituitary tumors. Large tumors can compress surrounding structures, primarily the normal pituitary gland and optic (visual) pathways, causing symptoms. The symptoms that result from the compression are independent of the effects of excess growth hormone secretion.
This may result in vision problems:

  • Vision loss. This occurs when macroadenomas grow upward into the brain cavity, compressing the optic chiasm.
  • A loss of the outer peripheral vision, called a bitemporal hemianopsia Bitemporal Hemianopsia - Symptom of Nelson's Syndrome
    • When severe, a patient can only see what is directly in front of them.
    • Many patients do not become aware of their visual loss until it is quite severe.
  • Other visual problems can include:
    • Loss of visual acuity (blurry vision), especially if the macroadenoma grows forward and compresses an optic nerve.
    • Colors not perceived as bright as usual

Pituitary Failure or Hypopituitarism

Increased compression of the normal gland can cause hormone insufficiency, called hypopituitarism. The symptoms depend upon which hormone is involved.


AnchorNelson’s Syndrome: Diagnosis

Most patients with Nelson’s syndrome have undergone a bilateral adrenalectomy for the treatment of Cushing’s disease

Diagnostic testing includes:

  • Hormone testing. Typically, the blood ACTH levels are very elevated. Learn more about hormone testing at the UCLA Pituitary Tumor Program.
  • MRI imaging. Magnetic resonance imaging (MRI) scan of the pituitary gland can detect the presence of an adenoma, a pituitary tumor.

AnchorNelson’s Syndrome: Treatment Options

Surgery for Nelson's Syndrome

Treating Nelson’s syndrome effectively requires an experienced team of experts. Specialists at the UCLA’s Pituitary Tumor Program have years of experience managing the complex coordination and care for treatment of Nelsons’ syndrome.

Treatment options include:

AnchorSurgery for Nelson’s Syndrome

Surgical removal of the pituitary adenoma is the ideal treatment; however, it is not always possible. Surgical removal requires advanced surgical approaches, including delicate procedures involving the cavernous sinus.

If surgery is required, typically the best procedure is through a nasal approach. Our neurosurgeons who specialize in pituitary tumor surgery are experts in the minimally invasive expanded endoscopic endonasal technique. This procedure removes the tumor while minimizing complications, hospital time and discomfort. This advanced technique requires specialized training and equipment.

Very large tumors that extend into the brain cavity may require opening the skull (craniotomy) to access the tumor. Our surgeons are also experts in the minimally invasive “key-hole” craniotomy, utilizing a small incision hidden in the eyebrow.

AnchorRadiation Therapy for Nelson’s Syndrome

Radiation Therapy for Nelson's SyndromeRadiation therapy can be effective in controlling the growth of the tumor. However, if you received radiation therapy in the past, additional radiation may not be safe.

Our Pituitary Tumor Program offers the latest in radiation therapy, including stereotactic radiosurgery. This approach delivers a highly focused dose of radiation to the tumor while leaving the surrounding brain structures unharmed (with the exception of the normal pituitary gland).

One consequence of radiation treatment is that it can cause delayed pituitary failure. This typically occurs several years after treatment, and continued long-term follow-up with an endocrinologist is important. You may require hormone replacement therapy.

Medical Therapy for Nelson’s Syndrome

Medication for Nelson's SyndromeMedical therapies for the treatment of Nelson’s syndrome are currently limited, but include:

  • Somatostatin-analogs (SSAs). These medications are typically used to treat acromegaly. A small number of Nelson’s syndrome patients may respond.
  • Cabergoline. This medication is typically used to treat prolactinomas; you may require a very high dose.
  • Temozolomide. This is a type of chemotherapy used to treat primary brain tumors called glioblastoma.

If you require medication to treat Nelson’s syndrome, our endocrinologists will monitor you closely.

From http://pituitary.ucla.edu/body.cfm?id=53

 

Effects of Cushing’s syndrome on the human brain

Cushing’s syndrome (CS) is characterized by excessive exposure to cortisol, and is associated with both metabolic and behavioural abnormalities even after biochemical cure. Andela et al conducted a systematic review of literature available in the PubMed, Embase, Web of Knowledge, and Cochrane databases evaluating structural and functional changes in the brain identified by magnetic resonance imaging in CS patients. They also reviewed potential associations between brain characteristics and disease status, cognitive functioning, psychopathology, and general well-being.

They found CS has profound effects on the human brain including abnormalities in structural grey matter, possibly white matter and neurochemical and functional alterations. After correction of hypercortisolism, the structural and neurochemical alterations improve substantially and correlate with improvements in clinical and behavioural outcomes. Nevertheless, abnormalities in both grey- and white matter are not completely reversible at long-term remission and are accompanied by psychological symptoms and impairments in cognitive functioning.

The full review by Andela et al. is published in the European Journal of Endocrinology 2015 173, DOI:10.1530/EJE-14-1101

From http://www.ese-hormones.org/news/article.aspx?articleid=9306

Experts recommend tumor removal as first-line treatment for Cushing’s syndrome

The Endocrine Society today issued a Clinical Practice Guideline (CPG) on strategies for treating Cushing’s syndrome, a condition caused by overexposure to the hormone cortisol.

The CPG, entitled “Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline,” was published online and will appear in the August 2015 print issue of the Journal of Clinical Endocrinology and Metabolism (JCEM), a publication of the Endocrine Society.

Cushing’s syndrome occurs when a person has excess cortisol in the blood for an extended period, according to the Hormone Health Network. When it is present in normal amounts, cortisol is involved in the body’s response to stress, maintains blood pressure and cardiovascular function, keeps the immune system in check, and converts fat, carbohydrates and proteins into energy. Chronic overexposure to the hormone can contribute to the development of cardiovascular disease, infections and blood clots in veins.

People who take cortisol-like medications such as prednisone to treat inflammatory conditions, including asthma and rheumatoid arthritis, can develop Cushing’s syndrome. The high cortisol levels return to normal when they stop taking the medication. This is called exogenous Cushing’s syndrome.

In other cases, tumors found on the adrenal or pituitary glands or elsewhere in the body cause the overproduction of cortisol and lead to the development of Cushing’s syndrome. The Clinical Practice Guidelines focus on this form of the condition, known as endogenous Cushing’s syndrome.

“People who have active Cushing’s syndrome face a greater risk of death – anywhere from nearly twice as high to nearly five times higher – than the general population,” said Lynnette K. Nieman, MD, of the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, MD, and chair of the task force that authored the guideline. “To reduce the risk of fatal cardiovascular disease, infections or blood clots, it is critical to identify the cause of the Cushing’s syndrome and restore cortisol levels to the normal range.”

In the CPG, the Endocrine Society recommends that the first-line treatment for endogenous Cushing’s syndrome be the removal of the tumor unless surgery is not possible or unlikely to address the excess cortisol. Surgical removal of the tumor is optimal because it leaves intact the hypothalamic-pituitary-adrenal axis, which is integral to the body’s central stress response.

Other recommendations from the CPG include:

  • Tumors should be removed by experienced surgeons in the following situations:— A tumor has formed on one or both of the two adrenal glands.— A tumor that secretes adrenocorticotropic hormone (ACTH) – the hormone that signals the adrenal glands to produce cortisol – has formed somewhere in the body other than the adrenal or pituitary gland.

    — A tumor has formed on the pituitary gland itself.

  • Patients who continue to have high levels of cortisol in the blood after surgery should undergo additional treatment.
  • People who had an ACTH-producing tumor should be screened regularly for the rest of their lives for high cortisol levels to spot recurrences.
  • If patients’ cortisol levels are too low following surgery, they should receive glucocorticoid replacement medications and be educated about adrenal insufficiency, a condition where the adrenal glands produce too little cortisol. This condition often resolves in 1-2 years.
  • Morning cortisol and/or ACTH stimulation tests, or insulin-induced hypoglycemia, can be used to test for the recovery of the hypothalamic-pituitary-adrenal axis in people who have low cortisol levels after surgery. Once the tests results return to normal, glucocorticoid replacement can be stopped.
  • People who have undergone pituitary surgery should be re-evaluated for other pituitary hormone deficiencies during the post-operative period.
  • Patients who have a pituitary tumor and have undergone surgery to remove both adrenal glands should be regularly evaluated for tumor progression using pituitary MRIs and tests for ACTH levels.
  • Radiation therapy may be used to treat a pituitary tumor, especially if it is growing. While awaiting the effect of radiation, which may take months to years, treatment with medication is advised.
  • To assess the effect of radiation therapy, the patient’s cortisol levels should be measured at 6- to 12-month intervals.
  • Medications may be used to control cortisol levels as a second-line treatment after surgery for a pituitary gland tumor, as a primary treatment for ACTH-secreting tumors that have spread to other parts of the body or suspected ACTH-secreting tumors that cannot be detected on scans. Medications also can be used as adjunctive treatment to reduce cortisol levels in people with adrenal cortical carcinoma, a rare condition where a cancerous growth develops in the adrenal gland.
  • People with Cushing’s syndrome should be treated for conditions associated with the disease, such as cardiovascular disease risk factors, osteoporosis and psychiatric symptoms.
  • Patients should be tested for recurrence throughout their lives except in cases where the person had a benign adrenal tumor removed.
  • Patients should undergo urgent treatment within 24 to 72 hours of detecting excess cortisol if life-threatening complications such as serious infection, pulmonary thromboembolism, cardiovascular complications and acute psychosis are present.

More information: The Hormone Health Network offers resources on Cushing’s syndrome at www.hormone.org/questions-and-answers/2012/cushing-syndrome

Bilateral Adrenal Incidentalomas May Have Different Etiology Than Unilateral

MedicalResearch.com Interview with:
Quan-Yang Duh MD
Chief, Section of Endocrine Surgery
UCSF Medical Center

Medical Research: What is the background for this study? What are the main findings?

Dr. Quan-Yang Duh: At UCSF we have a monthly Adrenal Conference (involving surgeons, endocrinologists and radiologists) to discuss patients we are consulted for adrenal tumors. About 30% of these are for incidentally discovered adrenal tumors (versus those found because of specific indications such as clinical suspicion or genetic screening). Of these 15-20% has bilateral adrenal tumors.

The evaluation of unilateral incidentaloma has been very well studied and many national guidelines have been published with specific management recommendations. So during our monthly adrenal conference, we have a routine “script” for evaluation and recommendations (rule out metastasis by looking for primary cancer elsewhere, rule out pheochromocytoma and Cushing, resect secreting tumors or large tumors, and if no operation recommended repeat scan in 6 months, etc.). This “script” has worked very well for patients with unilateral incidentaloma.

However, we were less certain when we made recommendations about bilateral incidentalomas because there was very little literature or guidelines written about it. We had some gut feelings, but we were not sure that we were recommending the right things. We needed more data. That was the main reason for the study.

What we found in our study was that although the possible subclinical diseases were the same – hypercortisolism and pheochromocytoma, the probabilities were different. The patients with bilateral incidentalomas were more likely to have subclinical Cushing’s and less likely to have pheochromocytomas than those with unilateral incidentalomas.

Medical Research: What should clinicians and patients take away from your report?

Dr. Quan-Yang Duh: The work up for bilateral adrenal incidentalomas is similar to that for unilateral incidentalomas. However, patients with bilateral incidentalomas are more likely to have subclinical Cushing’s and less likely to have pheochromocytoma. This difference should be kept in mind when clinicians evaluating these patients.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Quan-Yang Duh: Because our study used data that were from patients who were referred to us to be discussed at our Adrenal Conference, there is likely to be a selection bias (probably higher proportion with clinically significant diseases). It would be interesting to prospectively study ALL patients with adrenal  from a radiology department and see whether our results are confirmed.

Citation:

What Genes are Related to Cushing’s Disease?

genetic

 

The genetic cause of Cushing disease is often unknown. In only a few instances, mutations in certain genes have been found to lead to Cushing disease. These genetic changes are called somatic mutations. They are acquired during a person’s lifetime and are present only in certain cells. The genes involved often play a role in regulating the activity of hormones.

Cushing disease is caused by an increase in the hormone cortisol, which helps maintain blood sugar levels, protects the body from stress, and stops (suppresses) inflammation. Cortisol is produced by the adrenal glands, which are small glands located at the top of each kidney. The production of cortisol is triggered by the release of a hormone called adrenocorticotropic hormone (ACTH) from the pituitary gland, located at the base of the brain. The adrenal and pituitary glands are part of the hormone-producing (endocrine) system in the body that regulates development, metabolism, mood, and many other processes.

Cushing disease occurs when a noncancerous (benign) tumor called an adenoma forms in the pituitary gland, causing excessive release of ACTH and, subsequently, elevated production of cortisol. Prolonged exposure to increased cortisol levels results in the signs and symptoms of Cushing disease: changes to the amount and distribution of body fat, decreased muscle mass leading to weakness and reduced stamina, thinning skin causing stretch marks and easy bruising, thinning of the bones resulting in osteoporosis, increased blood pressure, impaired regulation of blood sugar leading to diabetes, a weakened immune system, neurological problems, irregular menstruation in women, and slow growth in children. The overactive adrenal glands that produce cortisol may also produce increased amounts of male sex hormones (androgens), leading to hirsutism in females. The effect of the excess androgens on males is unclear.

Most often, Cushing disease occurs alone, but rarely, it appears as a symptom of genetic syndromes that have pituitary adenomas as a feature, such as multiple endocrine neoplasia type 1 (MEN1) or familial isolated pituitary adenoma (FIPA).

Cushing disease is a subset of a larger condition called Cushing syndrome, which results when cortisol levels are increased by one of a number of possible causes. Sometimes adenomas that occur in organs or tissues other than the pituitary gland, such as adrenal gland adenomas, can also increase cortisol production, causing Cushing syndrome. Certain prescription drugs can result in an increase in cortisol production and lead to Cushing syndrome. Sometimes prolonged periods of stress or depression can cause an increase in cortisol levels; when this occurs, the condition is known as pseudo-Cushing syndrome. Not accounting for increases in cortisol due to prescription drugs, pituitary adenomas cause the vast majority of Cushing syndrome in adults and children.

Read more about familial isolated pituitary adenoma.

 

How do people inherit Cushing disease?

Most cases of Cushing disease are sporadic, which means they occur in people with no history of the disorder in their family. Rarely, the condition has been reported to run in families; however, it does not have a clear pattern of inheritance.

The various syndromes that have Cushing disease as a feature can have different inheritance patterns. Most of these disorders are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

From http://ghr.nlm.nih.gov/condition/cushing-disease

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