Adrenal Insufficiency: Primary and Secondary

Posted on November 20, 2016 by MaryO

By Dr Tomislav Meštrović, MD, PhD

Adrenal insufficiency is a condition that develops when most of the adrenal gland is not functioning normally. Primary adrenal insufficiency arises due to the damage of the glands or because of using drugs that halt synthesis of cortisol. On the other hand, secondary adrenal insufficiency stems from processes that inhibit the secretion of the adrenocorticotropic hormone (ACTH) by the hypophysis as a result of a hypothalamic or pituitary pathology. The former is sometimes also referred to as tertiary adrenal insufficiency.

Adrenal insufficiency is still a significant challenge for both patients and their physicians, but also scientists and researchers. In the past decade, long-term studies with adequate follow-up have shown a surge in mortality and morbidity, as well as impaired quality of life in individuals with this condition.

Primary Adrenal Insufficiency

In developed countries, the most common cause of primary adrenal insufficiency is autoimmune adrenalitis, whereas in the developing world tuberculosis is still considered a primary causative factor. Moreover, in young males, an X-linked adrenoleukodystrophy (also known as the less severe form of adrenomyeloneuropathy) must also be considered.

Histopathologically, in autoimmune primary adrenal insufficiency, there is a diffuse mononuclear cell infiltrate that can gradually progress to atrophy. Primary adrenal insufficiency is linked to both cortisol and mineralocorticoid deficiency.

Recent research drew attention to drug-related and infectious causes of adrenal insufficiency. Antifungal agents are known to substantially reduce cortisol synthesis, while imunosuppression associated with human immunodeficiency virus (HIV) has resulted in a resurgence of infectious causes, most notably tuberculous and CMV adrenalitis.

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency has three principal causes: adrenal suppression after exogenous glucocorticoid or ACTH administration, abnormalities of the hypothalamus or pituitary gland that lead to ACTH deficiency, as well as adrenal suppression upon the correction of endogenous glucocorticoid hypersecretion.

Any lesion of the hypophysis or hypothalamus can result in secondary adrenal insufficiency; some of the examples are space-occupying lesions such as adenomas, craniopharyngiomas, sarcoidosis, fungal infections, trauma, and also metastases from distant malignant processes.

The histologic appearance of the adrenal glands in secondary adrenal insufficiency can range from normal to complete atrophy of the cortex (with preserved medulla). In contrast to primary adrenal insufficiency, secondary types are associated with the lack of cortisol, but not mineralocorticoid deficiency.

Clinical Features of Adrenal Insufficiency

The clinical presentation of adrenal insufficiency is related to the rate of onset and severity of adrenal deficiency. In a large number of cases, the disease has a gradual onset, thus the diagnosis can be made only when the affected individual presents with an acute crisis due to an inadequate rise in cortisol secretion during a physiologic stress. Such acute adrenal insufficiency (also known as the Addisonian crisis) is a medical emergency.

On the other hand, the course of chronic adrenal insufficiency is more subtle and insidious, with the predomination of symptoms such as fatigue, weakness, weight loss, diarrhea or constipation, muscle cramps, pain in joints and postural hypotension (low blood pressure). Salt craving and low-grade fever may also be present.

The classic physical finding that can help in differentiating primary from secondary adrenal failure is hyperpigmentation of the skin or the “suntan that does not fade”. Furthermore, patients with secondary adrenal insufficiency may present with additional symptoms related to pituitary disease (e.g., menstrual disturbances, loss of libido, galactorrhea, or hypothyroidism).

Laboratory Findings and Management

In cases of adrenal insufficiency, the complete blood count usually reveals anemia, neutropenia, eosinophilia, and relative lymphocytosis. Common chemical abnormalities include metabolic acidosis and prerenal azotemia, while hyponatremia, hypoglycemia, and hyperkalemia may also be present.

A cosyntropin stimulation test (also known as ACTH or Synacthen test) is required to establish the diagnosis of adrenal insufficiency. Magnetic resonance imaging (MRI) of the hypophysis in secondary adrenal insufficiency and computed tomography (CT) of the adrenal glands in primary adrenal insufficiency can aid in establishing a diagnosis. The adrenal glands appear normal in cases of autoimmune disorder.

Glucocorticoid replacement in patients with adrenal insufficiency can be lifesaving. Nevertheless, renal crisis is still a threat to patients’ lives, which is why awareness and adequate preventative measures receive increasing attention in the recent years.

Reviewed by Susha Cheriyedath, MSc

From http://www.news-medical.net/health/Adrenal-Insufficiency-Primary-and-Secondary.aspx

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Severe Trauma May Damage The Brain as Well as the Psyche

Posted on October 24, 2016 by MaryO

NOTE: This is only a portion of the article.  Read the entire post at http://www.nytimes.com/1995/08/01/science/severe-trauma-may-damage-the-brain-as-well-as-the-psyche.html?pagewanted=all

Cortisol is a major means the body uses, with adrenaline, to arouse itself so quickly; its action, for example, triggers an increase in blood pressure and mobilizes energy from fat tissue and the liver.

“The dark side of this picture is the neurological effects,” said Dr. Sapolsky. “It’s necessary for survival, but it can be disastrous if you secrete cortisol for months or years on end. We’ve known it could lead to stress-exacerbated diseases like hypertension or adult onset diabetes. But now we’re finding the hippocampus is also damaged by these secretions.”

Studies in animals show that when glucocorticoids are secreted at high levels for several hours or days, there is a detectable effect on memory, though no neuronal death. But with sustained release from repeated stress, “it eventually kills neurons in the hippocampus,” said Dr. Sapolsky. “This has been shown solidly in rats, with the cell biology well understood.”

A parallel effect has long been known among patients with Cushing’s disease, a hormonal condition in which tumors in the adrenal or pituitary glands or corticosteroid drugs used for a prolonged time cause the adrenal glands to secrete high levels of a hormone called ACTHm and of cortisol. Such patients are prone to a range of diseases “in any organ with stress sensitivity,” including diabetes, hypertension and suppression of the immune system, said Dr. Sapolsky.

Cushing’s patients also have pronounced memory problems, especially for facts like where a car was parked. “The hippocampus is essential for transferring such facts from short-term to long-term memory,” said Dr. Sapolsky.

In 1993, researchers at the University of Michigan reported that magnetic resonance imaging had shown an atrophy and shrinkage of the hippocampus in patients with Cushing’s disease; the higher their levels of cortisol, the more shrinkage.

In an apparent paradox, low levels of cortisol in post-trauma victims were found in a separate research report, also in the July issue of The American Journal of Psychiatry. Dr. Rachel Yehuda, a psychologist at Mount Sinai Medical School in New York City, found the lower levels of cortisol in Holocaust survivors who had been in concentration camps 50 years ago and who still had post-traumatic symptoms.

“There are mixed findings on cortisol levels in trauma victims, with some researchers finding very high levels and others finding very low levels,” said Dr. Sapolsky. “Biologically speaking, there may be different kinds of post-traumatic stress.”

In a series of studies, Dr. Yehuda has found that those post-trauma patients who have low cortisol levels also seem to have “a hypersensitivity in cell receptors for cortisol,” she said. To protect itself, the body seems to reset its cortisol levels at a lower point.

The low cortisol levels “seem paradoxical, but both too much and too little can be bad,” said Dr. Yehuda. “There are different kinds of cells in various regions of the hippocampus that react to cortisol. Some atrophy or die if there is too little cortisol, some if there is too much.”

Dr. Yehuda added, “In a brain scan, there’s no way to know exactly which cells have died.”

To be sure that the shrinkage found in the hippocampus of trauma victims is indeed because of the events they suffered through, researchers are now turning to prospective studies, where before-and-after brain images can be made of people who have not yet undergone trauma, but are at high risk, or who have undergone it so recently that cell death has not had time to occur.

Dr. Charney, for example, is planning to take M.R.I. scans of the brains of emergency workers like police officers and firefighters and hopes to do the same with young inner-city children, who are at very high risk of being traumatized over the course of childhood and adolescence. Dr. Pitman, with Dr. Yehuda, plans a similar study of trauma victims in Israel as they are being treated in emergency rooms.

Dr. Yehuda held out some hope for people who have suffered through traumatic events. “It’s not necessarily the case that if you’ve been traumatized your hippocampus is smaller,” she said. She cited research with rats by Dr. Bruce McEwen, a neuroscientist at Rockefeller University, showing that atrophied dendritic extensions to other cells in the hippocampus grew back when the rats were given drugs that blocked stress hormones.

Dr. Sapolsky cited similar results in patients with Cushing’s disease whose cortisol levels returned to normal after tumors were removed. “If the loss of hippocampal volume in trauma victims is due to the atrophy of dendrites rather than to cell death, then it is potentially reversible, or may be so one day,” he said.

NOTE: This is only a portion of the article.  Read the entire post at http://www.nytimes.com/1995/08/01/science/severe-trauma-may-damage-the-brain-as-well-as-the-psyche.html?pagewanted=all

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Causes of Cushing’s Syndrome

Posted on October 2, 2016 by MaryO

Cushing’s syndrome—also referred to as hypercortisolism—is fairly rare. However, researchers have boiled down a few key causes of Cushing’s syndrome, which you’ll read about below.

The cause of Cushing’s syndrome boils down to: Your body is exposed to too much cortisol. There are a few ways that this over-exposure can happen, including taking certain medications and having a tumor on your pituitary gland or adrenal gland.

Can Taking Corticosteroids Cause Cushing’s Disease?
One particular type of medication can cause Cushing’s syndrome: corticosteroids. But rest assured: Not all steroid medications cause Cushing’s syndrome. It’s more common to develop Cushing’s syndrome from steroids you take in pill form or steroids you inject. Steroid creams and steroids you inhale are not common causes of Cushing’s syndrome.

Some steroid medications have the same effect as the hormone cortisol does when produced in your body. But as with an excessive production of cortisol in your body, taking too much corticosteroid medications can, over time, lead to Cushing’s syndrome.

It’s common for people with asthma, rheumatoid arthritis, and lupus to take corticosteroids. Prednisone (eg, Deltasone) is an example of a corticosteroid medication.

Other Cushing’s Disease Causes
Your body can over-produce cortisol or adrenocorticotropic hormone (ACTH). The pituitary gland secretes ACTH, which is in charge of stimulating the adrenal glands to produce cortisol, and the adrenal glands are responsible for releasing cortisol into the bloodstream.

Cortisol performs important tasks in your body, such as helping to maintain blood pressure and regulate how your body metabolizes proteins, fats, and carbohydrates, so it’s necessary for your body to maintain normal levels of it.

The following can cause excessive production of cortisol or ACTH, leading to Cushing’s syndrome.

  • Pituitary gland tumors: A benign (non-cancerous) tumor of the pituitary gland can secrete an excess amount of ACTH, which can cause Cushing’s syndrome. Also known as pituitary adenomas, benign tumors of the pituitary gland affect women 5 times more often than men.
  • Adrenal gland tumors: A tumor in one of your adrenal glands can lead to Cushing’s syndrome by causing too much cortisol to enter your bloodstream. Most of these tumors are non-cancerous (called adrenal adenomas).

    Cancerous adrenal tumors—called adrenocortical carcinomas—are relatively rare. These types of tumors typically cause extremely high levels of cortisol and very rapid development of symptoms.

  • Other tumors in the body: Certain tumors that develop outside the pituitary gland can also produce ACTH. When this happens, it’s known as ectopic ACTH syndrome. Ectopic means that something is in an abnormal place or position. In this case, only the pituitary gland should produce ACTH, so if there is a tumor producing ACTH and it isn’t located on the pituitary, it’s ectopic.

    It’s unusual to have a tumor that secretes ACTH outside the pituitary. These tumors are usually found in the pancreas, lungs, or thyroid, and they can be benign or malignant (cancerous).

    The most common forms of ACTH-producing tumors are small cell lung cancer, which accounts for about 13% of all lung cancer cases, and carcinoid tumors—small, slow-growing tumors that arise from hormone-producing cells in various parts of the body.

  • Familial Cushing’s syndrome: Although it’s rare, Cushing’s syndrome can develop from an inherited tendency to have tumors on one or more of your endocrine glands. Some inherited conditions, such as multiple endocrine neoplasia (MEN 1), can involve tumors that over-produce cortisol or ACTH, leading to Cushing’s syndrome.

If you think you could have Cushing’s syndrome or you have questions about the causes of Cushing’s syndrome, talk to your doctor immediately.

Written by | Reviewed by Daniel J. Toft MD, PhD, adapted from  http://www.endocrineweb.com/conditions/cushings-syndrome/cushings-syndrome-causes

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Experimental Drug Improves Cushing’s Disease

Posted on August 12, 2016 by MaryO

International phase 3 trial is largest study ever of rare endocrine disorder

A new investigational drug significantly reduced urinary cortisol levels and improved symptoms of Cushing’s disease in the largest clinical study of this endocrine disorder ever conducted.

Results of the clinical trial conducted at centers on four continents appear in the March 8 issue of the New England Journal of Medicine and show that treatment with pasireotide cut cortisol secretion an average of 50 percent and returned some patients’ levels to normal.

“Cushing’s disease is a rare disorder, with three to five cases per million people. It can affect all ages and both genders but is most common in otherwise healthy young women,” says Harvard Medical School Professor of Medicine Beverly M.K. Biller of the Massachusetts General Hospital (MGH) Neuroendocrine Unit, senior author of the study.

“Often misdiagnosed, Cushing’s is associated with a broad range of health problems – causing physical changes, metabolic abnormalities, and emotional difficulties – and if not controlled, significantly increases patients’ risk of dying much younger than expected,” Biller says.

Cushing’s disease, one of several conditions that lead to Cushing’s syndrome, is characterized by chronically elevated secretion of the hormone cortisol. The disease is caused by a benign pituitary tumor that oversecretes the hormone ACTH, which in turn induces increased cortisol secretion by the adrenal glands.

Symptoms of Cushing’s syndrome include weight gain, hypertension, mood swings, irregular or absent periods, abnormalities of glucose processing (insulin resistance, glucose intolerance, and type 2 diabetes), and cardiovascular disease. Because those symptoms are associated with many health problems, physicians may not consider the rare possibility of Cushing’s. The diagnosis can be difficult to make and usually requires the expertise of an endocrinologist. Because cortisol levels normally fluctuate during the day, a single blood test is unlikely to identify chronic elevation, and thus the most common diagnostic test measures a patient’s 24-hour urinary output.

First-line treatment for Cushing’s disease is surgical removal of the ACTH-secreting tumor, which leads to remission in 65 to 90 percent of patients. But symptoms return in 10 to 30 percent of those patients, requiring repeat surgery, radiation therapy, or treatment with drugs that interfere with part of the cortisol control system. Until last month, there was no specific FDA-approved medical treatment for Cushing’s syndrome; the newly approved drug mifepristone should benefit some patients, but it does not affect the pituitary source of the condition or reduce cortisol levels.

The current phase 3 trial of pasireotide — the first drug that blocks ACTH secretion by binding to somatostatin receptors on the pituitary tumor — was sponsored by Novartis Pharma. The trial enrolled 162 patients at 62 sites in 18 countries. Nearly 85 percent of participants had either persistent disease that had not responded to surgery or had recurrent disease; the other 15 percent were recently diagnosed but not appropriate candidates for surgery.

Participants were randomly assigned to two groups, one starting at two daily 600-microgram injections of pasireotide and the other receiving 900-microgram doses. Three months into the 12-month trial, participants whose urinary cortisol levels remained more than twice the normal range had their dosage levels increased. During the rest of the trial, dosage could be further increased, if necessary, or reduced if side effects occurred.

At the end of the study period, many patients had a significant decrease in their urinary cortisol levels, with 33 achieving levels within normal range at their original dosage by month six of the trial. Participants whose baseline levels were less than five times the upper limit of normal were more likely to achieve normal levels than those with higher baseline levels, and the average urinary cortisol decrease across all participants was approximately 50 percent. Many Cushing’s disease symptoms decreased, and it became apparent within the first two months whether or not an individual was going to respond to pasireotide.

Transient gastrointestinal discomfort, known to be associated with medications in the same family as pasireotide, was an expected side effect. Another side effect was elevated glucose levels in 73 percent of participants, something not seen to the same extent with other medications in this family. These elevated levels will require close attention, because many Cushing’s patients already have trouble metabolizing glucose. Biller explains, “Those patients who already were diabetic had the greatest increases in blood sugar, and those who were pre-diabetic were more likely to become diabetic than those who began with normal blood sugar. However, elevations were even seen in those who started at normal glucose levels, so this is real and needs to be monitored carefully.”

Additional trials of pasireotide are in the works, and a phase 3 study of a long-acting version of the drug was recently announced. Biller notes that the potential addition of pasireotide to available medical treatments for Cushing’s disease would have a number of advantages. “It’s very important to have medications that work at different parts of the cortisol control system – which is the case for the currently used medications that work at the adrenal gland level; pasireotide, which works at the pituitary gland; and mifepristone, which blocks the action of cortisol at receptors in the body. Having more options that work in different ways is valuable because not all patients respond to one medicine and some may be unable to tolerate a specific drug’s side effects.

“As we have more drugs available to treat Cushing’s,” Biller adds, “I think in the long run we may start using combinations of drugs, which is the approach we use in some patients with acromegaly, another disorder in which a pituitary tumor causes excess hormone secretion. Ultimately, we hope to be able to give lower doses leading to fewer overall side effects, but that remains to be determined by future studies.”

Annamaria Colao, University of Naples, Italy, is the lead author of the report. Additional co-authors are Stephan Petersenn, University of Duisberg-Essen, Germany; John Newell-Price, University of Sheffield, U.K.; James Findling, Medical College of Wisconsin, Milwaukee; Feng Gu, Peking Union Medical College Hospital, Beijing; Mario Maldonado, Ulrike Schoenherr, and David Mills, Novartis Pharma; and Luiz Roberto Salgado, University of São Paulo Medical School, Brazil.

From http://dailyrecords.us/experimental-drug-improves-cushings-disease/

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New Diagnostic Criteria for Subclinical Hypercortisolism using Postsurgical Hypocortisolism

Posted on August 12, 2016 by MaryO

Clin Endocrinol (Oxf). 2016 Jun 24. doi: 10.1111/cen.13145. [Epub ahead of print]

 

Abstract

OBJECTIVE:

There is no consensus on the biochemical diagnostic criteria for subclinical hypercortisolism (SH). Using parameters related to the hypothalamic-pituitary-adrenal axis, we aimed to develop a diagnostic model of SH for predicting postsurgical hypocortisolism and metabolic complications.

DESIGN:

Prospective and cross-sectional, observational, multicentre study in Korea.

METHODS:

After exclusion of overt Cushing’s syndrome, adrenal incidentaloma (AI) patients who underwent unilateral adrenalectomy (n = 99) and AI patients (n = 843) were included. Primary outcome was defined as the presence of postsurgical hypocortisolism; secondary outcome was the presence of ≥4 complications (components of the metabolic syndrome and low bone mass). Postsurgical hypocortisolism was determined on the fifth postsurgery day using the ACTH stimulation test.

RESULTS:

Thirty-three of the 99 patients developed postsurgical hypocortisolism. Analysis of the presurgery overnight 1-mg dexamethasone suppression test (1-mg DST) showed that all patients with cortisol levels of >138 nmol/l experienced postsurgical hypocortisolism, whereas those with levels of ≤61 nmol/l did not. The models of (i) 1-mg DST >138 nmol/l or (ii) >61 nmol/l with the presence of one among low levels of ACTH and dehydroepiandrosterone-sulphate had the highest accuracy (89·9%, P < 0·001) and odds ratio [OR 111·62, 95% confidence interval (CI) 21·98-566·74, P < 0·001] for predicting postsurgical hypocortisolism. Finally, patients with the same criteria in the 843 AI patients showed the highest risk for having ≥4 complications (OR 3·51, 95% CI 1·84-6·69, P < 0·001), regardless of gender, age, body mass index and bilaterality.

CONCLUSIONS:

Our proposed model is able to accurately predict subtle cortisol excess and its chronic manifestations in AI patients.

© 2016 John Wiley & Sons Ltd.

PMID:
27341314
DOI:
10.1111/cen.13145

From http://www.ncbi.nlm.nih.gov/pubmed/27341314

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