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This article is based on reporting that features expert sources.

Adrenal Fatigue: Is It Real?

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You may have heard of so-called 'adrenal fatigue,' supposedly caused by ongoing emotional stress. Or you might have come across adrenal support supplements sold online to treat it. But if someone suggests you have the controversial, unproven condition, seek a second opinion, experts say. And if someone tries to sell you dietary supplements or other treatments for adrenal fatigue, be safe and save your money.

 

(GETTY IMAGES)

 

Physicians tend to talk about 'reaching' or 'making' a medical diagnosis. However, when it comes to adrenal fatigue, endocrinologists – doctors who specialize in diseases involving hormone-secreting glands like the adrenals – sometimes use language such as 'perpetrating a diagnosis,' 'misdiagnosis,' 'made-up diagnosis,' 'a fallacy' and 'nonsense.'

About 20 years ago, the term "adrenal fatigue" was coined by Dr. James Wilson, a chiropractor. Since then, certain practitioners and marketers have promoted the notion that chronic stress somehow slows or shuts down the adrenal glands, causing excessive fatigue.

"The phenomenon emerged from the world of integrative medicine and naturopathic medicine," says Dr. James Findling, a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. "It has no scientific basis, and there's no merit to it as a clinical diagnosis."

 

An online search of medical billing code sets in the latest version of the International Classification of Diseases, or the ICD-10, does not yield a diagnostic code for 'adrenal fatigue' among the 331 diagnoses related either to fatigue or adrenal conditions or procedures.

In a March 2020 position statement, the American Association of Clinical Endocrinologists and American College of Endocrinology addressed the use of adrenal supplements "to treat common nonspecific symptoms due to 'adrenal fatigue,' an entity that has not been recognized as a legitimate diagnosis."

 

The position statement warned of known and unknown health risks of off-label use and misuse of hormones and supplements in patients without an established endocrine diagnosis, as well as unnecessary costs to patients and the overall health care system.

Study after study has refuted the legitimacy of adrenal fatigue as a medical diagnosis. An August 2016 systematic review combined and analyzed data from 58 studies on adrenal fatigue including more than 10,000 participants. The conclusion in a nutshell: "Adrenal fatigue does not exist," according to review authors in the journal BMC Endocrine Disorders.

Adrenal Action

You have two adrenal glands in your body. These small triangular glands, one on top of each kidney, produce essential hormones such as aldosterone, cortisol and male sex hormones such as DHEA and testosterone.

Cortisol helps regulate metabolism: How your body uses fat, protein and carbohydrates from food, and cortisol increases blood sugar as needed. It also plays a role in controlling blood pressure, preventing inflammation and regulating your sleep/wake cycle.

As your body responds to stress, cortisol increases. This response starts with signals between two sections in the brain: The hypothalamus and the pituitary gland, which act together to release a hormone that stimulates the adrenal glands to make cortisol. This interactive unit is called the hypothalamic pituitary adrenal axis.

While some health conditions really do affect the body's cortisol-making ability, adrenal fatigue isn't among them.

"There's no evidence to support that adrenal fatigue is an actual medical condition," says Dr. Mary Vouyiouklis Kellis, a staff endocrinologist at Cleveland Clinic. "There's no stress connection in the sense that someone's adrenal glands will all of a sudden just stop producing cortisol because they're so inundated with emotional stress."

If anything, adrenal glands are workhorses that rise to the occasion when chronic stress occurs. "The last thing in the body that's going to fatigue are your adrenal glands," says Dr. William F. Young Jr., an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota. "Adrenal glands are built for stress – that's what they do. Adrenal glands don't fatigue. This is made up – it's a fallacy."

The idea of adrenal glands crumbling under stress is "ridiculous," Findling agrees. "In reality, if you take a person and subject them to chronic stress, the adrenal glands don't shut down at all," Findling says. "They keep making cortisol – it's a stress hormone. In fact, the adrenal glands are just like the Energizer Bunny – they just keep going. They don't stop."

Home cortisol tests that allow consumers to check their own levels can be misleading, Findling says. "Some providers who make this (adrenal fatigue) diagnosis, provide patients with testing equipment for doing saliva cortisol levels throughout the day," he says. "And then, regardless of what the results are, they perpetrate this diagnosis of adrenal fatigue."

Saliva cortisol is a legitimate test that's frequently used in diagnosing Cushing's syndrome, or overactive adrenal glands, Findling notes. However, he says, a practitioner pursuing an adrenal fatigue diagnosis could game the system. "What they do is: They shape a very narrow normal range, so narrow, in fact, that no normal human subject could have all their saliva cortisol (levels) within that range throughout the course of the day," he says. "Then they convince the poor patients that they have adrenal fatigue phenomena and put them on some kind of adrenal support."

 

Loaded Supplements

How do you know what you're actually getting if you buy a dietary supplement marketed for adrenal fatigue or 'adrenal support' use? To find out, researchers purchased 12 such supplements over the counter in the U.S.

Laboratory tests revealed that all supplements contained a small amount of thyroid hormone and most contained at least one steroid hormone, according to the study published in the March 2018 issue of Mayo Clinic Proceedings. "These results may highlight potential risks for hidden ingredients in unregulated supplements," the authors concluded.

 

Supplements containing thyroid hormones or steroids can interact with a patient's prescribed medications or have other side effects.

"Some people just assume they have adrenal fatigue because they looked it up online when they felt tired and they ultimately buy these over-the-counter supplements that can be very dangerous at times," Vouyiouklis Kellis says. "Some of them contain animal (ingredients), like bovine adrenal extract. That can suppress the pituitary axis. So, as a result, your body stops making its own cortisol or starts making less of it, and as a result, you can actually worsen the condition rather than make it better."

Any form of steroid from outside the body, whether a prescription drug like prednisone or extract from cows' adrenal glands, "can shut off the pituitary," Vouyiouklis Kellis explains. "Because it's signaling to the pituitary like: Hey, you don't need to stimulate the adrenals to make cortisol, because this patient is taking it already. So, as a result, the body ultimately doesn't produce as much. And, so, if you rapidly withdraw that steroid or just all of a sudden decide not to take it anymore, then you can have this acute response of low cortisol."

Some adrenal support products, such as herbal-only supplements, may be harmless. However, they're unlikely to relieve chronic fatigue.

 

Fatigue: No Easy Answers

If you're suffering from ongoing fatigue, it's frustrating. And you're not alone. "I have fatigue," Young Jr. says. "Go to the lobby any given day and say, 'Raise your hand if you have fatigue.' Most of the people are going to raise their hands. It's a common human symptom and people would like an easy answer for it. Usually there's not an easy answer. I think 'adrenal fatigue' is attractive because it's like: Aha, here's the answer."

There aren't that many causes of endocrine-related fatigue, Young Jr. notes. "Hypothyroidism – when the thyroid gland is not working – is one." Addison's disease, or adrenal insufficiency, can also lead to fatigue among a variety of other symptoms. Established adrenal conditions – like adrenal insufficiency – need to be treated.

"In adrenal insufficiency, there is an intrinsic problem in the adrenal gland's inability to produce cortisol," Vouyiouklis Kellis explains. "That can either be a primary problem in the adrenal gland or an issue with the pituitary gland not being able to stimulate the adrenal to make cortisol."

 

Issues can arise even with necessary medications. "For example, very commonly, people are put on steroids for various reasons: allergies, ear, nose and throat problems," Vouyiouklis Kellis says. "And with the withdrawal of the steroids, they can ultimately have adrenal insufficiency, or decrease in cortisol."

Opioid medications for pain also result in adrenal sufficiency, Vouyiouklis Kellis says, adding that this particular side effect is rarely discussed. People with a history of autoimmune disease can also be at higher risk for adrenal insufficiency.

Common symptoms of adrenal insufficiency include:

• Fatigue.
• Weight loss.
• Decreased appetite.
• Salt cravings.
• Low blood pressure.
• Abdominal pain.
• Nausea, vomiting or diarrhea.
• Muscle weakness.
• Hyperpigmentation (darkening of the skin).
• Irritability.

Medical tests for adrenal insufficiency start with blood cortisol levels, and tests for the ACTH hormone that stimulates the pituitary gland.

"If the person does not have adrenal insufficiency and they're still fatigued, it's important to get to the bottom of it," Vouyiouklis Kellis says. Untreated sleep apnea often turns out to be the actual cause, she notes.

"It's very important to tease out what's going on," Vouyiouklis Kellis emphasizes. "It can be multifactorial – multiple things contributing to the patient's feeling of fatigue." The blood condition anemia – a lack of healthy red blood cells – is another potential cause.

"If you are fatigued, do not treat yourself," Vouyiouklis Kellis says. "Please seek a physician or a primary care provider for evaluation, because you don't want to go misdiagnosed or undiagnosed. It's very important to rule out actual causes that would be contributing to symptoms rather than ordering supplements online or seeking an alternative route like self-treating rather than being evaluated first."

SOURCES

The U.S. News Health team delivers accurate information about health, nutrition and fitness, as well as in-depth medical condition guides. All of our stories rely on multiple, independent sources and experts in the field, such as medical doctors and licensed nutritionists. To learn more about how we keep our content accurate and trustworthy, read our editorial guidelines.

James Findling, MD

Findling is a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin.

Mary Vouyiouklis Kellis, MD

Vouyiouklis Kellis is a staff endocrinologist at Cleveland Clinic.

William F. Young Jr., MD

Young Jr. is an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota

From https://health.usnews.com/health-care/patient-advice/articles/adrenal-fatigue-is-it-real?

Headaches are a common complaint in patients with pituitary tumors. Although many patients presumably have headaches which are unrelated to their pituitary tumor, there are several important direct and indirect mechanisms by which pituitary tumors may elicit or exacerbate headaches. Pituitary tumors may directly provoke headaches by eroding laterally into the cavernous sinus, which contains the first and second divisions of the trigeminal nerve, by involvement of the dural lining of the sella or diaphragma sella (which are innervated by the trigeminal nerve), or via sinusitis, particularly after transsphenoidal surgery. Headache pain in these situations is typically characterized by steady, bifrontal or unilateral frontal aching (ipsilateral to tumor). In some instances, pain is localized in the midface (either because of involvement of the second division of the trigeminal or secondary to sinusitis).

In contrast to the insidious, subacute development of headaches in most patients with pituitary tumors, patients with pituitary apoplexy may experience acute, severe headaches, perhaps associated with signs and symptoms of meningeal irritation (stiff neck, photophobia), CSF pleocytosis or occulomotor paresis. Routine CT scans of the head occasionally skip the sella, hence the presence of blood or a mass within the sella may not be detected and patients can be misdiagnosed with meningitis or aneurysm. Because pituitary apoplexy represents a neurosurgical emergency, MRI should be used in patients with symptoms suggestive of this disorder. A subacute form of pituitary apoplexy has also been reported. Patients with subacute pituitary apoplexy experience severe and/or frequent headaches over weeks to months and have heme products within the sella on MRI scans.

In most instances, headaches are not attributable to direct effects of the pituitary tumor and indirect causes must be considered. Generally, indirect effects of pituitary tumors are caused by reduced secretion of pituitary hormones and are manifested by promotion of "vascular" headaches (e.g., migraine). The major exception to this rule relates to the potential for acromegalic patients to develop headaches secondary to cervical osteoarthritis. Vascular headaches may be exacerbated in association with disruption of normal menstrual cyclicity and impaired gonadal steroid secretion (e.g., from hyperprolactinemia or gonadotropin deficiency). Hyperprolactinemia, hypothyroidism and hyperthyroidism may also have direct effects, independent of gonadal hormones. Headaches are common in acromegaly, and in the majority of cases the etiology is not well understood.

Finally, drug management of pituitary tumors may inadvertently impact headaches. Octreotide results in extremely rapid headache improvement with patients with acromegaly. The rapid time course suggests it is not due to lowering of GH levels. Octreotide also has a dramatic beneficial effect on migraine and may be producing relief of headache by vascular mechanisms. Occasionally severe headaches surface in acromegalic patients after reduction or discontinuation of octreotide, as a "withdrawal" phenomenon.|

Bromocriptine or other dopamine agonists occasionally trigger severe headaches. When this occurs, it is important to recognize that bromocriptine has been reported as a cause of pituitary apoplexy, and it may be necessary to perform an MRI or CT to rule out infarction or hemorrhage within the pituitary. Once it is established that the patient is not infarcting the pituitary, it is generally safe to treat the headaches symptomatically (not with an ASA containing drug) and consider alternative therapies for the prolactinoma if the problem remains severe.

Pituitary tumor patients with vascular headaches are generally quite responsive to standard prophylactic migraine drugs (e.g., tricyclic antidepressants, verapamil and beta-blockers). It is best to begin therapy with very low-dose medication (e.g., 10 mg of amitriptyline at bedtime) and resist the impulse to escalate the dose rapidly to higher levels. Often patients have an excellent response to 10-30 mg of a tricyclic antidepressant, although it may take up to six or more weeks to reach the ultimate benefit. The choice of tricyclic antidepressant should be based upon the desired side effects (e.g., either more sedation or less sedation) The newer, serotonin-selective antidepressants are generally less effective for headaches than tricyclics, although some patients do respond nicely to these agents. In some cases it may be necessary to use combination therapy (e.g., verapamil plus a tricyclic).

From https://www.massgeneral.org/neurosurgery/treatments-and-services/pituitary-tumors-and-headaches?fbclid=IwAR2iBMjf5VNvw2_ucalXikyIZIh3dJuYu0Kk6P1jhQ2IDnDj9ubkPO4Zl9A

An assessment of free cortisol after a dexamethasone suppression test could add value to the diagnostic workup of hypercortisolism, which can be plagued by false-positive results, according to data from a cross-sectional study.

A 1 mg dexamethasone suppression test (DST) is a standard of care endocrine test for evaluation of adrenal masses and for patients suspected to have endogenous Cushing’s syndrome. Interpretation of a DST is affected by dexamethasone absorption and metabolism; several studies suggest a rate of 6% to 20% of false-positive results because of inadequate dexamethasone concentrations or differences in the proportion of cortisol bound to corticosteroid-binding globulin affecting total cortisol concentrations.

“As the prevalence of adrenal adenomas is around 5% to 7% in adults undergoing an abdominal CT scan, it is important to accurately interpret the DST,” Irina Bancos, MD, associate professor in the division of endocrinology at Mayo Clinic in Rochester, Minnesota, told Healio. “False-positive DST results are common, around 15% of cases, and as such, additional or second-line testing is often considered by physicians, including measuring dexamethasone concentrations at the time of the DST, repeating DST or performing DST with a higher dose of dexamethasone. We hypothesized that free cortisol measurements during the DST will be more accurate than total cortisol measurements, especially among those treated with oral contraceptive therapy.”

Diverse cohort analyzed

Bancos and colleagues analyzed data from adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy) and participants undergoing evaluation for hypercortisolism (n = 196; 16 women on oral contraceptives). The researchers assessed levels of post-DST dexamethasone and free cortisol, using mass spectrometry, and total cortisol, via immunoassay. The primary outcome was a reference range for post-DST free cortisol levels and the diagnostic accuracy of post-DST total cortisol level.

Irina Bancos

“A group that presents a particular challenge are women treated with oral estrogen,” Bancos told Healio. “In these cases, total cortisol increases due to estrogen-stimulated cortisol-binding globulin production, potentially leading to false-positive DST results. We intentionally designed our study to include a large reference group of women treated with oral contraceptive therapy allowing us to develop normal ranges of post-DST total and free cortisol, and then apply these cutoffs to the clinical practice.”

Researchers observed adequate dexamethasone concentrations ( 0.1 µg/dL) in 97.6% of healthy volunteers and in 96.3% of patients. Among women volunteers taking oral contraceptives, 25.5% had an abnormal post-DST total cortisol measurement, defined as a cortisol level of at least 1.8 µg/dL.

Among healthy volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not taking oral contraceptives, and 79 ng/dL for women taking oral contraceptives.

Compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol level was 87.3% (95% CI, 81.7-91.7). All false-positive results occurred among patients with a post-DST cortisol level between 1.8 µg/dL and 5 µg/dL, according to researchers.

Oral contraceptive use was the only factor associated with false-positive results (21.1% vs. 4.9%; P = .02).

Findings challenge guidelines

Natalia Genere

“We were surprised by several findings of our study,” Natalia Genere, MD, instructor in medicine in the division of endocrinology, metabolism and lipid research at Washington University School of Medicine in St. Louis, told Healio. “First, we saw that with a standardized patient instruction on DST, we found that optimal dexamethasone concentrations were reached in a higher proportion of patients than previously reported (97%), suggesting that rapid metabolism or poor absorption of dexamethasone may play a lower role in the rate of false positives. Second, we found that measurements of post-DST total cortisol in women taking oral contraceptive therapy accurately excluded [mild autonomous cortisol secretion] in three-quarters of patients, suggesting discontinuation of oral contraceptives, as suggested in prior guidelines, may not be routinely necessary.”

Genere said post-DST free cortisol performed “much better” than total cortisol among women treated with oral estrogen.

Stepwise approach recommended

Based on the findings, the authors suggested a sequential approach to dexamethasone suppression in clinical practice.

“We recommend a stepwise approach to enhance DST interpretation, with the addition of dexamethasone concentration and/or free cortisol in cases of abnormal post-DST total cortisol,” Bancos said. “We found dexamethasone concentrations are particularly helpful when post-DST total cortisol is at least 5 µg/dL and free cortisol is helpful in a patient with optimal dexamethasone concentrations and a post-DST total cortisol between 1.8 µg/dL and 5 µg/dL. We believe that DST with free cortisol is a useful addition to the repertoire of available testing for [mild autonomous cortisol secretion], and that its use reduces need for repetitive assessments and patient burden of care, especially in women treated with oral contraceptive therapy.”

PERSPECTIVE

BACK TO TOP 

Ricardo Correa, MD, EsD, FACE, FACP, CMQ

In the evaluation of endogenous Cushing’s disease, the guideline algorithm recommends two of three positive tests — 24-hour free urine cortisol, late midnight salivary cortisol level and 1 mg dexamethasone suppression test, or DST — for diagnosing hypercortisolism. Of those tests, the most accurate to detect adrenal secretion of cortisol when a patient may have an adrenal incidentaloma is the 1 mg DST. The caveat with this specific test is that it is affected by dexamethasone absorption and metabolism and the proportion of cortisol bound to corticosteroid-binding globulin. Up to 20% of these tests report false-positive findings.

This study by Genere and colleagues aimed to determine the normal range of free cortisol during the 1 mg DST. The researchers conducted a prospective, cross-sectional study that included volunteers without adrenal disorders and patients assessed for cortisol excess for clinical reasons.

In the volunteer group, 168 volunteers were enrolled, including 47 women that were taking oral contraceptives. After excluding patients with inadequate dexamethasone levels and other outliers, the post-DST free cortisol maximum level was less than 48 ng/dL for men and women who were not taking oral contraceptive pills and less than 79 ng/dL for women taking oral contraceptive pills.

In the patient group, 100% of post-DST free cortisol levels were above the upper limit of normal among those with a post-DST cortisol of at least 5 µg/dL; however, this was true for only 70.7% of those with post-DST cortisol between 1.8 µg/dL and 5 µg/dL.

This study found that a post-DST free cortisol assessment is helpful in patients with a post-DST total cortisol between 1.8 µg/dL and 5 µg/dL, but was not beneficial for patients with a post-DST total cortisol of less than 1.8 µg/dL or more than 5 µg/dL. Performing free cortisol assessments in this subgroup will reduce the number of false positives.

The authors recommend performing a 1 mg post-DST free cortisol analysis for this subgroup; the levels to confirm cortisol excess are at least 48 ng/dL in men and women not taking oral contraceptive pills and at least 79 ng/dL for women taking oral contraceptive pills. Furthermore, the study presents a stepwise approach algorithm that will be very useful for clinical practice.

Ricardo Correa, MD, EsD, FACE, FACP, CMQ

Endocrine Today Editorial Board Member

Program Director of Endocrinology Fellowship and Director for Diversity

University of Arizona College of Medicine-Phoenix

Phoenix Veterans Affairs Medical Center

Disclosures: Correa reports no relevant financial disclosures.

 

From https://www.healio.com/news/endocrinology/20211117/free-cortisol-evaluation-useful-after-abnormal-dexamethasone-test

I just signed up for this because it may be helpful for researchers at the NIH and elsewhere to learn more about Cushing's, cancer, whatever else they can learn from my history.

Over 35 years ago, I agreed to be a part of a study at NIH so they could learn more about Cushing's.  I consider this to be a larger, easier part of what I did back then.

From my bio: https://cushingsbios.com/2018/10/28/maryo-pituitary-bio/

As luck would have it, NIH (National Institutes of Health, Bethesda, Maryland) was doing a clinical trial of Cushing’s. I live in the same area as NIH so it was not too inconvenient but very scary at first to think of being tested there. At that time I only had a choice of NIH, Mayo Clinic and a place in Quebec to do this then-rare pituitary surgery called a Transsphenoidal Resection. I chose NIH – closest and free. After I was interviewed by the Doctors there, I got a letter that I had been accepted into the clinical trial. The first time I was there was for 6 weeks as an inpatient. More of the same tests.

There were about 12 of us there and it was nice not to be alone with this mystery disease. Many of these Cushies (mostly women) were getting bald, couldn’t walk, having strokes, had diabetes. One was blind, one had a heart attack while I was there. Towards the end of my testing period, I was looking forward to the surgery just to get this whole mess over with. While I was at NIH, I was gaining about a pound a day!

The MRI still showed nothing, so they did a Petrosal Sinus Sampling Test. That scared me more than the prospect of surgery. (This test carries the risk of stroke and uncontrollable bleeding from the incision points.) Catheters were fed from my groin area to my pituitary gland and dye was injected. I could watch the whole procedure on monitors. I could not move during this test or for several hours afterwards to prevent uncontrollable bleeding from a major artery. The test did show where the tumor probably was located. Also done were more sophisticated dexamethasone suppression tests where drugs were administered by IV and blood was drawn every hour (they put a heplock in my arm so they don’t have to keep sticking me). I got to go home for a weekend and then went back for the surgery – the Transsphenoidal Resection. I fully expected to die during surgery (and didn’t care if I did) so I signed my will and wrote last letters to those I wanted to say goodbye to. During the time I was home just before surgery, a college classmate of mine (I didn’t know her) did die at NIH of a Cushing’s-related problem. I’m so glad I didn’t find out until a couple months later!

November 3, 1987, the surgeon, Dr. Ed Oldfield, cut the gum above my front teeth under my upper lip so there is no scar. He used tiny tools and microscopes. My tumor was removed successfully. In some cases (not mine) the surgeon uses a plug of fat from the abdomen to help seal the cut. Afterwards, I was in intensive care overnight and went to a neurology ward for a few days until I could walk without being dizzy. I had some major headaches for a day or two but they gave me drugs (morphine) for those. Also, I had cotton plugs in my nostrils. It was a big day when they came out. I had diabetes insipidus (DI) for a little while, but that went away by itself – thank goodness!

I had to use a foam product called “Toothies” to brush my teeth without hitting the incision. Before they let me go home, I had to learn to give myself an injection in my thigh. They sent me home with a supply of injectable cortisone in case my level ever fell too low (it didn’t). I was weaned gradually off cortisone pills (scary). I now take no medications. I had to get a Medic Alert bracelet. I will always need to tell medical staff when I have any kind of procedure – the effects of my excess cortisone will remain forever.

I went back to the NIH for several follow-up visits of a week each where they did all the blood and urine testing again. After a few years NIH set me free. Now I go to my “outside” endocrinologist every year for the dexamethasone suppression test, 24-hour urine and regular blood testing.

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Any condition that causes the adrenal gland to produce excessive cortisol results in the disorder Cushing's syndrome. Cushing syndrome is characterized by facial and torso obesity, high blood pressure, stretch marks on the belly, weakness, osteoporosis, and facial hair growth in females.

Cushing's syndrome has many possible causes including tumors within the adrenal gland, adrenal gland stimulating hormone (ACTH) produced from cancer such as lung cancer, and ACTH excessively produced from a pituitary tumors within the brain. ACTH is normally produced by the pituitary gland (located in the center of the brain) to stimulate the adrenal glands' natural production of cortisol, especially in times of stress.

When a pituitary tumor secretes excessive ACTH, the disorder resulting from this specific form of Cushing's syndrome is referred to as Cushing's disease.

As an aside, it should be noted that doctors will sometimes describe certain patients with features identical to Cushing's syndrome as having 'Cushingoid' features. Typically, these features are occurring as side effects of cortisone-related medications, such as prednisone and prednisolone.

Published:November 18, 2021DOI:https://doi.org/10.1016/S2213-8587(21)00291-6

To investigate whether adrenal vascular cells and possibly steroid-producing cells are direct targets of SARS-CoV-2, we examined SARS-CoV-2 presence in adrenal gland tissues obtained from the 40 patients with COVID-19 (appendix pp 1–3). Adrenal tissues from patients who died before the COVID-19 pandemic were used as negative controls to validate antibody specificity. Using a monoclonal antibody (clone 1A9; appendix p 11), we detected SARS-CoV-2 spike protein in adrenocortical cells in 18 (45%) of 40 adrenal gland tissues (figure B; appendix p 12). In the same number of adrenal tissues (18 [45%] of 40), we have detected SARS-CoV-2 mRNA using in situ hybridisation (ISH; figure A; appendix p 12). The concordance rate between immunohistochemistry and ISH methods was 90% (36/40). Scattered and rather focal expression pattern of SARS-CoV-2 spike protein was found in the adrenal cortex (figure A and B; appendix p 12). In addition, SARS-CoV-2 expression was confirmed in 15 out of 30 adrenal gland tissues of patients with COVID-19 by multiplex RT-qPCR (appendix pp 6–7). The concordance between ISH, immunohistochemistry, and RT-qPCR techniques for SARS-CoV-2 positivity was only 23%, which is a technical limitation of our study possibly reflecting the low number of virus-positive cells. However, when considering triple-negative samples, an overall 53% consensus was found (appendix pp 7–8).

The endocrine system is a complex network of glands and organs. It uses hormones to control and coordinate your body's metabolism, energy level, reproduction, growth and development, and response to injury, stress, and mood. The following are integral parts of the endocrine system:

• Hypothalamus. The hypothalamus is located at the base of the brain, near the optic chiasm where the optic nerves behind each eye cross and meet. The hypothalamus secretes hormones that stimulate or suppress the release of hormones in the pituitary gland, in addition to controlling water balance, sleep, temperature, appetite, and blood pressure.

• Pineal body. The pineal body is located below the corpus callosum, in the middle of the brain. It produces the hormone melatonin, which helps the body know when it's time to sleep.

• Pituitary. The pituitary gland is located below the brain. Usually no larger than a pea, the gland controls many functions of the other endocrine glands.

• Thyroid and parathyroid. The thyroid gland and parathyroid glands are located in front of the neck, below the larynx (voice box). The thyroid plays an important role in the body's metabolism. The parathyroid glands play an important role in the regulation of the body's calcium balance.

• Thymus. The thymus is located in the upper part of the chest and produces white blood cells that fight infections and destroy abnormal cells.

• Adrenal gland. An adrenal gland is located on top of each kidney. Like many glands, the adrenal glands work hand-in-hand with the hypothalamus and pituitary gland. The adrenal glands make and release corticosteroid hormones and epinephrine that maintain blood pressure and regulate metabolism.

• Pancreas. The pancreas is located across the back of the abdomen, behind the stomach. The pancreas plays a role in digestion, as well as hormone production. Hormones produced by the pancreas include insulin and glucagon, which regulate levels of blood sugar.

• Ovary. A woman's ovaries are located on both sides of the uterus, below the opening of the fallopian tubes (tubes that extend from the uterus to the ovaries). In addition to containing the egg cells necessary for reproduction, the ovaries also produce estrogen and progesterone.

• Testis. A man's testes are located in a pouch that hangs suspended outside the male body. The testes produce testosterone and sperm.

Purpose: This study aimed to identify predictive factors and to develop a predictive model for adrenal insufficiency (AI) related to topical corticosteroids use.

Methods: The research was conducted using a cross-sectional design. Adult patients with dermatological conditions who had been prescribed topical steroids for at least 12 months by the dermatology outpatient departments of the Faculty of Medicine, Chiang Mai University from June through October 2020 were included. Data on potential predictors, including baseline characteristics and laboratory investigations, were collected. The diagnoses of AI were based on serum 8AM cortisol and low-dose ACTH stimulation tests. Multivariable logistic regression was used for the derivation of the diagnostic score.

Results: Of the 42 patients, 17 (40.5%) had AI. The statistically significant predictive factors for AI were greater body surface area of corticosteroids use, age < 60 years, and basal serum cortisol < 7 μg/dL. In the final predictive model, duration of treatment was added as a factor based on its clinical significance for AI. The four predictive factors with their assigned scores were: body surface area involvement 10– 30% (20), > 30% (25); age < 60 years old (15); basal serum cortisol of < 7 μg/dL (30); and duration of treatment in years. Risk of AI was categorized into three groups, low, intermediate and high risk, with total scores of < 25, 25– 49 and ≥ 50, respectively. The predictive performance for the model was 0.92 based on area under the curve.

Conclusion: The predictive model for AI in patients using topical corticosteroids provides guidance on the risk of AI to determine which patients should have dynamic ACTH stimulation tests (high risk) and which need only close follow-up (intermediate and low risk). Future validation of the model is warranted.

Keywords: adrenal insufficiency, topical corticosteroids, predictive model, skin diseases

Introduction

Topical corticosteroids are frequently used for inflammatory skin diseases owing to their anti-inflammatory and immunosuppressive effects. Common indications for use include diseases such as psoriasis, eczema, atopic dermatitis, and vitiligo.¹ In clinical practice, a variety of delivery vehicles and potencies of topical corticosteroids are used.¹ Prolonged and/or inappropriate use of topical corticosteroids can lead to adverse side effects.² These adverse side effects can be categorized as cutaneous and systemic side effects. The most common cutaneous side effect is skin atrophy. Systemic side effects include hypothalamic-pituitary-adrenal (HPA) axis suppression, glaucoma, hyperglycemia and hypertension.³

One of the most worrisome adverse side effects from the use of topical corticosteroids is adrenal insufficiency (AI) resulting from HPA axis suppression. Topically applied corticosteroids can be absorbed systemically through the skin and can suppress the HPA axis.^4–8 This adverse outcome, the inability to increase cortisol production after stress, can lead to adrenal crisis, which is potentially life-threatening. Tests that are normally used to diagnose or exclude AI include serum morning cortisol and the dynamic ACTH stimulation test.⁹

Secondary AI from percutaneous absorption of topical corticosteroids is less common than with parenteral or oral administration. The cumulative doses and the durations of oral corticosteroid therapy associated with HPA axis suppression have been well documented.¹⁰ Data regarding the dose and duration of oral corticosteroids and HPA axis suppression have similarly been well established. A study by Curtis et al reported that the use of oral prednisolone >7.5 mg/day for an extended period (>3 weeks) was linked to this adverse event, and that the incidence increased with duration.¹⁰ However, corresponding data for topical corticosteroids has been limited. The degree of risk of HPA axis suppression from topical corticosteroids use is associated with the level of percutaneous absorption which, in turn, depends on numerous factors including the age of the patient (younger patients are more susceptible), body surface area treated, quantity of topical corticosteroids used, potency of the drug, duration of therapy, body region of application, the associated compounds used, eg, urea or salicylic acid, the characteristics of the diseased skin, the degree of impairment of skin integrity, and the coexistence of hepatic and/or renal disease.^11–13 One study reported that HPA axis suppression occurs when high potency steroids are administered at a cumulative dose per week of >50 g.²

Presently, there is a lack of data on predictive factors for AI and no predicative model of the relationship between secondary AI resulting from HPA axis suppression and topical corticosteroids use. A simple predictive model which could help preclude and predict the risk of AI which incorporates both demographic and biochemical data could potentially reduce the number of dynamic ACTH stimulation tests performed. This study aimed to identify potential predictive factors and to design an easy-to-use model for predicting the risk of AI following topical corticosteroids use in dermatological patients.

Materials and Methods

This cross-sectional study was conducted with 42 patients who were seen at the dermatology outpatient departments at the Faculty of Medicine, Chiang Mai University Hospital over a 5-month period (June – October 2020). The study protocol was approved by the Faculty of Medicine, Chiang Mai University, Ethical Committee (Ethical number: MED-2563-07037). Recruited participants were adult dermatological patients (≥18 years) who had used topical corticosteroids for at least 12 months. Patients with pituitary or adrenal diseases, pregnant women and patients who had been treated with either systemic corticosteroids or other local corticosteroids were excluded. Those who meet all the inclusion criteria gave their informed consent prior to the study. This study was conducted in accordance with the Declaration of Helsinki.

Adrenal Function Evaluation

Adrenal function was evaluated by serum morning (8 AM) cortisol and the low-dose ACTH stimulation test. Patients were instructed to suspend use of topical corticosteroids for at least 24 hours before serum morning cortisol measurement and ACTH stimulation tests. In those with serum morning cortisol between 3 and 17.9 µg/dL, ACTH stimulation tests were performed on the same day between 9–11AM to either exclude or diagnose AI. Serum cortisol concentrations were measured at 8 AM 0 (basal cortisol) as well as 20 and 40 minutes after 5 µg ACTH was administered intravenously.

Data Collection

Epidemiological data collected included gender, age, blood pressure, underlying dermatologic diseases, other underlying diseases, body surface area involvement, sensitive area involvement, topical corticosteroid potency, amount and duration of topical corticosteroids use, symptoms of AI and the presence of Cushingoid features. Biochemical data included serum cortisol at 8 AM, 0 (basal cortisol) and at 20 and 40 minutes after ACTH intravenous injection, serum creatinine, electrolytes and albumin. Serum cortisol levels were measured by electrochemiluminescence assay (ECLIA) (Elecsys^® Cortisol II assay, Roche Diagnostics GmbH, Mannheim, Germany).

Definitions

An 8AM cortisol level of ❤️ µg/dL or a peak serum cortisol level of <18 µg/dL at 20 or 40 minutes after an ACTH stimulation test was defined as having AI.¹⁴ Sensitive area involvement included the axilla, groin, face and genitalia. Topical corticosteroids are classified by potency based on a skin vasoconstriction assay, and range from ultra-high potency (class I) to low potency (class VII).¹⁵ Since some patients had concurrently used more than one class of corticosteroids in one treatment period, the new variable potency·dose·time (summary of corticosteroids potency (I–VII)¹⁶ multiplied by total doses (mg) of corticosteroids use and multiplied by duration (months) of corticosteroids use) was created. Symptoms of AI included lethargy, nausea and vomiting, orthostatic hypotension and significant weight loss. Significant weight loss was defined as a loss of 5% of body weight in one month or a loss of 10% over a period of six months.¹⁷ Having Cushingoid features was defined as at least one of the excess glucocorticoid features, eg, easy bruising, facial plethora, proximal myopathy, striae, dorsocervical fat pad, facial fullness, obesity, supraclavicular fullness, hirsutism, decreased libido and menstrual abnormalities.

Statistical Analysis

All statistical analyses were performed using Stata 16 (StataCorp, College Station, Texas, USA). Categorical variables are reported as frequency and percentage, while continuous variables are reported as mean ± standard deviation or median and interquartile range (IQR), according to their distribution. For univariable comparison, Fisher’s exact probability test was used for categorical variables, and the independent t-test or the Mann–Whitney U-test was used for continuous variables. p-values less than 0.05 were considered statistically significant.

Multivariable logistic regression was used in the derivation of the prediction model for AI. Predictors with significant p-values in the univariable analysis were included in the multivariable model. We also included age and treatment duration in the model due to the clinical significance of those factors.^4,18 The clinical collinearity among the predictors was also evaluated before the selection of the predictors. We generated a weighted score for each predictor by dividing the logit coefficient of the predictor by the lowest coefficient in the model. The discriminative ability of the final multivariable model was assessed using the area under the receiver operating characteristics (ROC) curve. The calibration of the scores was evaluated using the Hosmer-Lemeshow goodness-of-fit test, where a p-value >0.01 was considered a good fit. For clinical applicability, the appropriate cut-off points for the scores were identified based on sensitivity and specificity. We identified one cut-off point with high sensitivity for ruling out AI and another cut-off point with high specificity for ruling in AI. The positive predictive value for each score category with its corresponding confidence interval were presented. A sample size of at least 25 patients with at least 5 patients with AI was estimated to give 80% power at the 5% significance level.⁴ There was no missing data in this study.

Results

Baseline characteristics and biochemical investigations are shown in Table 1. Forty-two patients with dermatological diseases were included in this study. Of these, 17 patients (40.5%) had AI of whom 5 (29.4%) were female. The mean age of the group was 56.5 ±15.4 years, the mean duration of treatment was 10.1 ± 6 years, and the majority of patients had psoriasis (n = 14, 82.4%). There was no significant difference in sex, age, duration of treatment, potency dose-time, comorbidities, or underlying skin disease between the AI and non-AI groups. The average body surface area of corticosteroids use was significantly higher in patients with AI than in the non-AI group (27.5 ±18.7 m² and 10.7 ±11.7 m², p < 0.001, respectively). Basal serum cortisol levels were significantly lower in the AI group (6.52 ± 4.04 µg/dL) than in the non-AI group (10.48 ± 3.45 µg/dL, p 0.003). Although lower serum morning cortisol levels were observed in the AI group, the difference was not statistically significant (5.24 ± 4.65 µg/dL vs 13.39 ± 15.68 µg/dL, p = 0.069). Three patients were identified as having Cushingoid features. All patients with Cushingoid features had AI.

 

Table 1 Comparison of Clinical Characteristics Between Patients with a History of Topical Corticosteroids Use for at Least 12 Months Who Were Diagnosed with Adrenal Insufficiency and Those without Adrenal Insufficiency (n = 42)

 

Based on the multivariate logistic regression analysis (shown in Table 2), the significant predictive factors for AI in patients who used topical corticosteroids for more than 12 months were body surface area of corticosteroids use of 10–30% and >30% (POR 18.9, p =0.042, and POR 59.2, p = 0.035, respectively), age less than 60 years (POR 13.8, p = 0.04), and basal serum cortisol of <7 µg/dL (POR 131.5, p = 0.003). Only serum basal cortisol was included in the final multivariable model as there was clinical collinearity among serum morning cortisol and basal cortisol as well as 20- and 40-minute cortisol measurements.

 

Table 2 Multivariable Model for Prediction of Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38)

 

Predictive risk score was created to determine the probability of patients having AI using the aforementioned three significant predictive factors from the multivariable analysis (Table 2). As previous studies have demonstrated that duration of treatment is a strong predictive factor for AI in corticosteroid users,^4,18 this factor was also incorporated in the model. The transformed score for body surface area, age and basal serum cortisol had a range of 0 to 30. For treatment duration, the transformed score was based on cumulative years of treatment. The total score was categorized into three groups: low, intermediate, and high risk (Table 3).

 

Table 3 Accuracy of the Score to Rule in and Rule Out Adrenal Insufficiency in Patients with a History of Topical Corticosteroids Use for at Least 12 Months (n = 38)

 

The cut-off point of ≥50 suggests high risk for developing AI with a sensitivity of 46.2% and a specificity of 100%, a score of <25 suggests a low risk with a sensitivity of 100% and a specificity of 52%, and a score between 25 and 49 indicates an intermediate risk of having AI. The ROC curve for the model assessing predictive performance which included all significant factors had an AuROC of 0.92 (Figure 1). The Hosmer-Lemeshow goodness-of-fit test revealed non-statistically significant results (p = 0.599), indicating that our newly derived scoring system fits the data well.

 

Figure 1 Model discrimination via receiver operating characteristic curve in patients with a history of topical corticosteroids use for at least 12 months (n = 42).

 

Discussion

The present study proposes an easy-to-use predictive model for AI following topical corticosteroids use in dermatological patients based on demographic and biochemical factors. The accuracy of the model shows an excellent diagnostic accuracy of 92% based on AuROC. Currently, the diagnosis of AI in dermatological patients with topical corticosteroids use involves multiple steps including screening for serum morning cortisol followed by dynamic ACTH stimulation testing. The proposed simple predictive model, which requires only three demographic data items (age, body surface area of corticosteroids use, duration of use) and one biochemical test (serum basal cortisol), could potentially reduce the number of dynamic ACTH stimulation tests performed, resulting in cost- and time-saving for both patients and health-care facilities.

Based on the proposed cut-off points, we suggest screening of individuals at high risk for having AI, including serum morning cortisol and the ACTH stimulation tests to confirm a diagnosis of AI. If there is evidence of AI, the patient should begin to receive treatment for AI to reduce future complications. For those in the low-risk group, only clinical follow-up should be carried out. In the intermediate-risk group, we recommend regular and close biochemical follow-up including serum morning cortisol and clinical follow-up for signs and symptoms of AI. Signs and symptoms that should raise a high index of suspicion for AI include significant weight loss, nausea and/or vomiting, orthostatic hypotension and lethargy. However, this proposed predictive model was studied in adults and cannot simply be generalized and extrapolated to children or infants.

In our study, 40.5% of the patients were determined to have AI. A previous meta-analysis by Broersen et al reported the percentage of patients with AI secondary to all potencies of topical corticosteroids based on a review of 15 studies was 4.7%, 95% CI (1.1–18.5%).¹⁹ The higher prevalence of AI in our study could be a result of differences in patients’ baseline characteristics, eg, duration of treatment, corticosteroids potency and body surface area involvement.

In the predictive model, we incorporated both clinical and biochemical factors which are easy to obtain in actual clinical practice. Some of those predictive factors have been previously reported to be linked to AI. Body surface area of corticosteroids use larger than 10% found to be significantly related to AI, especially in patients with a lesion area of over 30%. This finding is consistent with a study by Kerner et al which suggests the extent of surface area to which the corticosteroids are applied may influence absorption of the drug.²⁰ Regarding the age of the patients, our study found that individuals over 60 years old tended to be at high risk of AI following topical corticosteroids therapy. The underlying explanation is that the stratum corneum acts as a rate-limiting barrier to percutaneous absorption as the stratum corneum in younger individuals is thinner than in older people. Diminished effectiveness of topical corticosteroid treatment in older people was demonstrated in a study by Malzfeldt et al.²¹ Even though serum basal cortisol is not recommended as a standard test to diagnose AI, a prior study reported that it can be considered as an alternative choice to diagnose AI when serum morning cortisol results are not available. In fact, it has been reported that there is no difference in diagnostic accuracy between serum morning cortisol and basal cortisol²² which supports our finding that serum basal cortisol <7 µg/dL is one of the significant factors related to AI.

The final model found no statistically significant relationship between the incidence of AI and the duration of corticosteroids treatment. However, we decided to include this factor in the final model since previous publications have reported that the duration of treatment is a relevant risk factor for developing AI following continuous topical corticosteroids use. The duration of AI events has been reported to vary between 2 weeks to 18 months.^4,18 Additionally, a case report of AI demonstrated that 5 years of topical corticosteroids use can cause AI.⁶ Together, this suggests that patients with a longer duration of topical corticosteroids use are at increased risk of AI, especially those who also have other risk factors. Although both potency and dosage of topical corticosteroids have been reported to be significantly linked to HPA axis suppression, the present study found only a non-significance link. This could be the result of the small sample size as well as of other factors, eg, body surface area involvement and serum cortisol levels, which could have masked the association between potency and dosage of topical corticosteroids with HPA suppression.

To the best of our knowledge, this study is the first to use these novel predictive factors to develop a predictive model for AI in patients using topical corticosteroids. This model has multiple potential implications. First, the model uses clinical and biochemical factors which are obtainable in many institutes. Second, the model’s risk score provides good diagnostic accuracy in terms of both sensitivity and specificity. Finally, each of the predictive factors in the model has an underlying pathophysiological explanation and is not due simply to chance.

There are some limitations in this study. First, the sample size is relatively small, although it does offer sufficient statistical power for each of the predictive factors. Second, further external validation is needed to validate the predictive performance of the model. Third, the cut-off level of serum cortisol after ACTH stimulation test was based on the older generation of ECLIA assay. There was a study proposed that the cut-off for serum cortisol in the newer generation of cortisol assay should be lower (~14–15 µg/dL) than the previous one (18 µg/dL).²³ However, this proposed cut-off has not yet been established in the current guideline for AI. In the future, if the newer cut-off for serum cortisol will have been employed in the standard guideline, our predictive model may lead to overdiagnosis of AI.

Conclusions

The proposed predictive model uses both demographic and biochemical factors to determine the risk of AI in dermatological patients following topical corticosteroids use with a high level of diagnostic accuracy. This model has advantages in terms of a reduction in the number of dynamic ACTH stimulation tests needed, thus saving time and resources. Additionally, it can provide guidance to clinical practitioners regarding which patients should be closely followed up for development of AI. Future external validation of this predictive model is warranted.

Acknowledgments

The authors are grateful to Lamar G. Robert, PhD and Chongchit S. Robert, PhD for editing the manuscript.

Disclosure

The authors report no conflict of interest in this work.

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9. Ospina NS, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700

10. Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum. 2006;55(3):420–426. doi:10.1002/art.21984

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13. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency: clinical implications. Am J Clin Dermatol. 2002;3(3):141–147. doi:10.2165/00128071-200203030-00001

14. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389. doi:10.1210/jc.2015-1710

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An updated guideline for the treatment of Cushing’s disease focuses on new therapeutic options and an algorithm for screening and diagnosis, along with best practices for managing disease recurrence.

Despite the recent approval of novel therapies, management of Cushing’s disease remains challenging. The disorder is associated with significant comorbidities and has high mortality if left uncontrolled.

“As the disease is inexorable and chronic, patients often experience recurrence after surgery or are not responsive to medications,” Shlomo Melmed, MB, ChB, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, and an Endocrine Today Editorial Board Member, told Healio. “These guidelines enable navigation of optimal therapeutic options now available for physicians and patients. Especially helpful are the evidence-based patient flow charts [that] guide the physician along a complex management path, which usually entails years or decades of follow-up.”

Shlomo Melmed

The Pituitary Society convened a consensus workshop with more than 50 academic researchers and clinical experts across five continents to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, participants reviewed data from January 2015 to April 2021 on screening and diagnosis; surgery, medical and radiation therapy; and disease-related and treatment-related complications of Cushing’s disease, all summarized in recorded lectures. The guideline includes recommendations regarding use of laboratory tests, imaging and treatment options, along with algorithms for diagnosis of Cushing’s syndrome and management of Cushing’s disease.

Updates in laboratory, testing guidance

If Cushing’s syndrome is suspected, any of the available diagnostic tests could be useful, according to the guideline. The authors recommend starting with urinary free cortisol, late-night salivary cortisol, overnight 1 mg dexamethasone suppression, or a combination, depending on local availability.

If an adrenal tumor is suspected, the guideline recommends overnight dexamethasone suppression and using late-night salivary cortisol only if cortisone concentrations can also be reported.

The guideline includes several new recommendations in the diagnosis arena, particularly on the role of salivary cortisol assays, according to Maria Fleseriu, MD, FACE, a Healio | Endocrine Today Co-editor, professor of medicine and neurological surgery and director of the Pituitary Center at Oregon Health & Science University in Portland.

Maria Fleseriu

“Salivary cortisol assays are not available in all countries, thus other screening tests can also be used,” Fleseriu told Healio. “We also highlighted the sequence of testing for recurrence, as many patients’ urinary free cortisol becomes abnormal later in the course, sometimes up to 1 year later.”

The guideline states combined biochemical and imaging for select patients could potentially replace petrosal sinus sampling, a very specialized procedure that cannot be performed in all hospitals, but more data are needed.

“With the corticotropin-releasing hormone stimulation test becoming unavailable in the U.S. and other countries, the focus is now on desmopressin to replace corticotropin-releasing hormone in some of the dynamic testing, both for diagnosis of pseudo-Cushing’s as well as localization of adrenocorticotropic hormone excess,” Fleseriu said.

The guideline also has a new recommendation for anticoagulation for high-risk patients; however, the exact duration and which patients are at higher risk remains unknown.

“We always have to balance risk for clotting with risk for bleeding postop,” Fleseriu said. “Similarly, recommended workups for bone disease and growth hormone deficiency have been further structured based on pitfalls specifically related to hypercortisolemia influencing these complications, as well as improvement after Cushing’s remission in some patients, but not all.”

New treatment options

The guideline authors recommended individualizing medical therapy for all patients with Cushing’s disease based on the clinical scenario, including severity of hypercortisolism. “Regulatory approvals, treatment availability and drug costs vary between countries and often influence treatment selection,” the authors wrote. “However, where possible, it is important to consider balancing cost of treatment with the cost and the adverse consequences of ineffective or insufficient treatment. In patients with severe disease, the primary goal is to treat aggressively to normalize cortisol concentrations.”

Fleseriu said the authors reviewed outcomes data as well as pros and cons of surgery, repeat surgery, medical treatments, radiation and bilateral adrenalectomy, highlighting the importance of individualized treatment in Cushing’s disease.

“As shown over the last few years, recurrence rates are much higher than previously thought and patients need to be followed lifelong,” Fleseriu said. “The role of adjuvant therapy after either failed pituitary surgery or recurrence is becoming more important, but preoperative or even primary medical treatment has been also used more, too, especially in the COVID-19 era.”

The guideline summarized data on all medical treatments available, either approved by regulatory agencies or used off-label, as well as drugs studied in phase 3 clinical trials.

“Based on great discussions at the meeting and subsequent emails to reach consensus, we highlighted and graded recommendations on several practical points,” Fleseriu said. “These include which factors are helpful in selection of a medical therapy, which factors are used in selecting an adrenal steroidogenesis inhibitor, how is tumor growth monitored when using an adrenal steroidogenesis inhibitor or glucocorticoid receptor blocker, and how treatment response is monitored for each therapy. We also outline which factors are considered in deciding whether to use combination therapy or to switch to another therapy and which agents are used for optimal combination therapy.”

Future research needed

The guideline authors noted more research is needed regarding screening and diagnosis of Cushing’s syndrome; researchers must optimize pituitary MRI and PET imaging using improved data acquisition and processing to improve microadenoma detection. New diagnostic algorithms are also needed for the differential diagnosis using invasive vs. noninvasive strategies. Additionally, the researchers said the use of anticoagulant prophylaxis and therapy in different populations and settings must be further studied, as well as determining the clinical benefit of restoring the circadian rhythm, potentially with a higher nighttime medication dose, as well as identifying better markers of disease activity and control.

“Hopefully, our patients will now experience a higher quality of life and fewer comorbidities if their endocrinologist and care teams are equipped with this informative roadmap for integrated management, employing a consolidation of surgery, radiation and medical treatments,” Melmed told Healio.

TAMPA, Fla., Nov. 3, 2021 /PRNewswire/ -- The Carling Adrenal Center, a worldwide destination for the surgical treatment of adrenal tumors, becomes the first center to offer adrenal vein sampling and curative surgery in one visit.

Cortisol is a hormone which produced by the adrenal gland (cortex) to control blood sugar. The production of cortisol is triggered by the pituitary hormone ACTH. Cortisol is a glucocorticoid which stimulates an increase in blood glucose. Cortisol will also stimulate the release of amino acids from muscle tissue and fatty acids from adipose tissue. The amino acids are then converted in the liver to glucose (for use by the brain). The fatty acids can be used by skeletal muscles for energy (rather than glucose) thereby freeing up glucose for selective utilization by the brain. Cortisol levels are often measured to evaluate the function of the pituitary or adrenal glands. Some of the cortisol is metabolized by the liver to produce 17 hydroxycorticosteroids, which is then excreted in the urine.

The primary stress hormone. Cortisol is the major natural GLUCOCORTICOID (GC) in humans.

Synthetic cortisol, also known as hydrocortisone, is used as a drug mainly to fight allergies and inflammation.

Physiology
The amount of cortisol present in the serum undergoes diurnal variation, with the highest levels present in the early morning, and lower levels in the evening, several hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. Changed patterns of the serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of temperature. There is also significant individual variation, although a given person tends to have consistent rhythms.

Cortisol also inhibits the secretion of corticotropin releasing hormone (CRH), resulting in feedback inhibition of ACTH secretion. Some researchers believe that this normal feedback system may break down when animals are exposed to chronic stress.

In normal release, cortisol has widespread actions which help restore homeostasis after stress. It acts as a physiological antagonist to insulin by promoting gluconeogenesis, breakdown of lipids, and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased blood glucose concentrations, resulting in increased glycogen formation in the liver (Freeman, 2002). It also increases blood pressure. In addition, immune and inflammatory cells have their responses to stress attenuated by cortisol, and the hormone thus lowers the activity of the immune system. Bone formation is also lowered by cortisol.

These normal endogenous functions are the basis for the physiological consequences of chronic stress - prolonged cortisol secretion causes muscle wastage, hyperglycemia, and suppresses immune / inflammatory responses. The same consequences arise from long-term use of glucocorticoid drugs.

Also, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning. However, short-term exposure of cortisol helps to create memories; this is the proposed mechanism for storage of flash bulb memories.

Pharmacology
As an oral or injectable drug, cortisol is also known as hydrocortisone. It is used as an immunosuppressive drug, given by injection in the treatment of severe allergic reactions such as anaphylaxis and angioedema, in place of prednisolone in patients who need steroid treatment but cannot take oral medication, and peri-operatively in patients on long-term steroid treatment to prevent an Addisonian crisis.

It is given by topical application for its anti-inflammatory effect in allergic rashes, eczema and certain other inflammatory conditions. It may also be injected into inflamed joints resulting from diseases such as gout.

Compared to prednisolone, hydrocortisone is about 1/4th the strength. Dexamethasone is about 40 times stronger than hydrocortisone. For side effects, see corticosteroid and prednisolone.

A certain amount of cortisol is necessary for life. Without cortisol even a small amount of stress will kill you. Addison's disease is a disease which causes low cortisol levels, and which is treated by cortisol replacement therapy.

Cortisol...

• helps maintain blood pressure and cardiovascular function;
• helps slow the immune system's inflammatory response;
• helps balance the effects of insulin in breaking down sugar for energy; and
• helps regulate the metabolism of proteins, carbohydrates, and fats.

 

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Sparrow Pharmaceuticals is an emerging biopharma company on a mission to help patients suffering from an excess of corticosteroids, with a focus on Cushing’s syndrome, autonomous cortisol secretion (ACS), and polymyalgia rheumatica (PMR).

Cushing’s and ACS are both caused by an excess of cortisol produced by tumors. Patients with Cushing’s can present physically with a fatty hump between their shoulders, a rounded face, and pink or purple stretch marks on their skin. Cushing’s syndrome and ACS can both result in high blood pressure, bone loss, type 2 diabetes, weight gain, and mood, cognition, and sleep disorders. Any of those symptoms may be side effects for patients with conditions such as PMR who rely on long-term treatment with corticosteroid medications such as prednisone.

“Cushing’s syndrome impacts around 20,000 patients in the U.S. alone,” says David Katz, Chief Scientific Officer for Sparrow. “Approximately 50% of those patients can be cured by surgery, but some will develop another tumor years later. ACS is an under-recognized condition, but it may affect up to 3 million patients in the U.S. There are also around 2 million people in the U.S. who rely on long-term use of corticosteroid medications to control autoimmune diseases and other conditions.”

The treatments being developed by Sparrow are based on recognition that cortisol and corticosteroid medications are activated in certain tissues such as the liver, bone, fat, and brain, where in excess they act to cause toxicity. The company’s investigational drugs inhibit HSD-1, the enzyme responsible for that activation.

Sparrow is about to launch a Phase 2 trial for Cushing’s syndrome. In early 2022 the company will also begin two additional Phase 2 trials for ACS and PMR, a common autoimmune disease in elderly patients. PMR is an arthritic syndrome characterized by a phenomenon known as claudication, which means the more you use a limb, the more it hurts and the harder it is to use. “For example, the more a PMR patient walks, the more painful and stiff their legs will become,” says Katz. “If they're trying to do anything with their arms, the arms will get stiffer and more painful. The disease is pretty debilitating in terms of physical function. The only approved treatment for PMR is steroids, which have side effects such as diabetes, hypertension, osteoporosis, and fractures.”

Unknown Clinical Challenges

Katz is excited about the clinical trials for ACS and PMR because no sizable interventional trials have been reported in either of those conditions.

“We're going into a completely new area, and we don't know what we're going to encounter in terms of patient recruitment and retention,” says Katz. “There is also no strong precedent for how to get approval for a drug in these conditions. The only treatment indicated for PMR is steroids, and that came without any efficacy clinical trials. There are no drugs approved for ACS. It’s hard to anticipate the challenges we will face when we are in an area that is very new.”

Patient centricity is a topic that is very important to Katz, and he spends a lot of time thinking about how to make trials a more pleasant experience for patients by limiting the burden placed on them. He notes that can sometimes be a difficult trade-off because of the procedures that must be performed to meet regulatory standards.

“In Cushing’s syndrome clinical care and clinical trials, the standard way for someone's cortisol level to be measured is a 24-hour urine collection,” states Katz. “That involves looking at the amount of cortisol in the urine over a 24-hour period. That collection is inconvenient and burdensome, and the patient must then carry it somewhere to be analyzed.”

Sparrow hopes to shift that collection to a spot urine sample, like what patients would experience during a physical. The patient would urinate into a cup and hand it off to a clinic employee for analysis. The process would be much simpler and less burdensome for the patient. Sparrow will first need to prove that in a clinical trial the spot sample will work as well or better than the 24-hour collection. Subjects in the initial clinical trials will have to contribute the 24-hour collections so that Sparrow can demonstrate that future patients will not need to do so.

The Future of Endocrinology

Katz has a positive outlook on the future of endocrinology. Sparrow’s leading drug candidate, SPI-62, is an oral, small-molecule HSD-1 inhibitor. In four clinical trials, it demonstrated potent targeting of HSD-1 in both the brain and liver, and significantly lowered cortisol levels in the liver. The studies also showed a favorable safety and tolerability profile.

“If we are successful at developing SPI-62, I believe it will change the field of endocrinology,” says Katz. “We aim to shift the focus in Cushing’s syndrome to intracellular cortisol as the main driver of symptoms. What I mean by that is if we find that SPI-62 substantially reduces symptoms and that the degree of inhibition of our target HSD-1 correlates well with clinical improvement, then we can get to a new standard of care. We can potentially get rid of the 24-hour urine collections, which will be a big relief to patients. Additionally, many of today's drugs have a side effect called adrenal insufficiency, which results when the drugs either reduce cortisol too much or completely block activity. Many of today's drugs also require frequent monitoring and dose titration to prevent adrenal insufficiency. We believe that with HSD-1 inhibition we might avoid adrenal insufficiency as well.”

Katz is hopeful patients treated with SPI-62 will not require monitoring and dose titration. That proof will take years and lots of clinical trials. Sparrow may also produce the first targeted therapy for ACS. That could improve the recognition of ACS as a prevalent form of hypercortisolism and a substantial cause of morbidity and mortality.

“ACS is probably the most under-recognized condition in endocrinology based on recent epidemiological studies,” adds Katz. “It's possible that as few as 3% of patients who have ACS actually have a diagnosis.  That is shocking for a condition that is associated with a lot of cardiometabolic and bone morbidity, negative effects on mood and cognition, sleep, and muscle strength, and is associated with excess mortality. We want to bring attention to this condition by bringing out a targeted therapy to treat a spectrum of symptoms by getting to the root cause of them.”

From https://www.clinicalleader.com/doc/sparrow-pharmaceuticals-hopes-to-change-the-future-of-endocrinology-0001