Cyclic Cortisol Production May Lead to Misdiagnosis in Cushing’s

Increased cortisol secretion may follow a cyclic pattern in patients with adrenal incidentalomas, a phenomenon that may lead to misdiagnosis, a study reports.

Since cyclic subclinical hypercortisolism may increase the risk for heart problems, researchers recommend extended follow-up with repeated tests to measure cortisol levels in these patients.

The study, “Cyclic Subclinical Hypercortisolism: A Previously Unidentified Hypersecretory Form of Adrenal Incidentalomas,” was published in the Journal of Endocrine Society.

Adrenal incidentalomas (AI) are asymptomatic masses in the adrenal glands discovered on an imaging test ordered for a problem unrelated to adrenal disease. While most of these benign tumors are considered non-functioning, meaning they do not produce steroid hormones like cortisol, up to 30% do produce and secrete steroids.

Subclinical Cushing’s syndrome is an asymptomatic condition characterized by mild cortisol excess without the specific signs of Cushing’s syndrome. The long-term exposure to excess cortisol may lead to cardiovascular problems in these patients.

While non-functioning adenomas have been linked with metabolic problems, guidelines say that if excess cortisol is ruled out after the first evaluation, patients no longer need additional follow-up.

However, cortisol secretion can be cyclic in Cushing’s syndrome, meaning that clinicians might not detect excess amounts of cortisol at first and misdiagnose patients.

In an attempt to determine whether cyclic cortisol production is also seen in patients with subclinical Cushing’s syndrome and whether these patients have a higher risk for metabolic complications, researchers in Brazil reviewed the medical records of 251 patients with AI — 186 women, median 60 years old — followed from 2006 to 2017 in a single reference center.

Cortisol levels were measured after a dexamethasone suppression test (DST). Dexamethasone is used to stop the adrenal glands from producing cortisol. In healthy patients, this treatment is expected to reduce cortisol levels, but in patients whose tumors also produce cortisol, the levels often remain elevated.

Patients were diagnosed with cyclic subclinical Cushing’s syndrome if they had at least two normal and two abnormal DST tests.

From the 251 patients, only 44 performed the test at least three times and were included in the analysis. The results showed that 20.4% of patients had a negative DST test and were considered non-functioning adenomas.

An additional 20.4% had elevated cortisol levels in all DST tests and received a diagnosis of sustained subclinical Cushing’s syndrome.

The remaining 59.2% had discordant results in their tests, with 18.3% having at least two positive and two negative test results, matching the criteria for cyclic cortisol production, and 40.9% having only one discordant test, being diagnosed as possibly cyclic subclinical Cushing’s syndrome.

Interestingly, 20 of the 44 patients had a normal cortisol response at their first evaluation. However, 11 of these patients failed to maintain normal responses in subsequent tests, with four receiving a diagnosis of cyclic subclinical Cushing’s syndrome and seven as possibly cyclic subclinical Cushing’s.

Overall, the findings suggest that patients with adrenal incidentalomas should receive extended follow-up with repeated DST tests, helping identify those with cyclic cortisol secretion.

“Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk,” the study concluded.

From https://cushingsdiseasenews.com/2019/04/11/cyclic-cortisol-production-may-lead-to-misdiagnosis-in-cushings-study-finds/

Faster Adrenal Recovery May Predict Cushing’s Disease Recurrence

A shorter duration of adrenal insufficiency — when the adrenal gland is not working properly — after surgical removal of a pituitary tumor may predict recurrence in Cushing’s disease patients, a new study suggests.

The study, “Recovery of the adrenal function after pituitary surgery in patients with Cushing Disease: persistent remission or recurrence?,” was published in the journal Neuroendocrinology.

Cushing’s disease is a condition characterized by excess cortisol in circulation due to a tumor in the pituitary gland that produces too much of the adrenocorticotropic hormone (ACTH). This hormone acts on the adrenal glands, telling them to produce cortisol.

The first-line treatment for these patients is pituitary surgery to remove the tumor, but while success rates are high, most patients experience adrenal insufficiency and some will see their disease return.

Adrenal insufficiency happens when the adrenal glands cannot make enough cortisol — because the source of ACTH was suddenly removed — and may last from months to years. In these cases, patients require replacement hormone therapy until normal ACTH and cortisol production resumes.

However, the recovery of adrenal gland function may mean one of two things: either patients have their hypothalamus-pituitary-adrenal axis — a feedback loop that regulates ACTH and cortisol production — functioning normally, or their disease returned.

So, a team of researchers in Italy sought to compare the recovery of adrenal gland function in patients with a lasting remission to those whose disease recurred.

The study included 61 patients treated and followed at the Ospedale Maggiore Policlinico of Milan between 1990 and 2017. Patients had been followed for a median of six years (minimum three years) and 10 (16.3%) saw their disease return during follow-up.

Overall, the median time to recovery of adrenal function was 19 months, but while most patients in remission (67%) had not yet recovered their adrenal function after a median of six years, all patients whose disease recurred experienced adrenal recovery within 22 months.

Among those with disease recurrence, the interval from adrenal recovery to recurrence lasted a median of 1.1 years, but in one patient, signs of disease recurrence were not seen for 15.5 years.

Statistical analysis revealed that the time needed for adrenal recovery was negatively associated with disease recurrence, suggesting that patients with sorter adrenal insufficiency intervals were at an increased risk for recurrence.

“In conclusion, our study shows that the duration of adrenal insufficiency after pituitary surgery in patients with CD is significantly shorter in recurrent CD than in the persistent remission group,” researchers wrote.

“The duration of AI may be a useful predictor for CD [Cushing’s disease] recurrence and those patients who show a normal pituitary-adrenal axis within 2 years after surgery should be strictly monitored being more at risk of disease relapse,” they concluded.

From https://cushingsdiseasenews.com/2019/01/29/faster-adrenal-recovery-may-predict-recurrence-cushings-disease/

Study Supports Midnight Salivary Cortisol Test to Diagnose Cushing’s in Chinese Population

A simple test that measures free cortisol levels in saliva at midnight — called a midnight salivary cortisol test — showed good diagnostic performance for Cushing’s syndrome among a Chinese population, according to a recent study.

The test was better than the standard urine free cortisol levels and may be an alternative for people with end-stage kidney disease, in whom measuring cortisol in urine is challenging.

The study, “Midnight salivary cortisol for the diagnosis of Cushing’s syndrome in a Chinese population,” was published in Singapore Medical Journal.

Cushing’s syndrome, defined by excess cortisol levels, is normally diagnosed by measuring the amount of cortisol in bodily fluids.

Traditionally, urine free cortisol has been the test of choice, but this method is subject to complications ranging from improper collection to metabolic differences, and its use is limited in people with poor kidney function.

Midnight salivary cortisol is a test that takes into account the normal fluctuation of cortisol levels in bodily fluids. Cortisol peaks in the morning and declines throughout the day, reaching its lowest levels at midnight. In Cushing’s patients, however, this variation ceases to exist and cortisol remains elevated throughout the day.

Midnight salivary cortisol was first proposed in the 1980s as a noninvasive way to measure cortisol levels, but its efficacy and cutoff value for Cushing’s disease in the Chinese population remained unclear.

Researchers examined midnight salivary cortisol, urine free cortisol, and midnight serum cortisol in Chinese patients suspected of having Cushing’s syndrome and in healthy volunteers. These measurements were then combined with imaging studies to make a diagnosis.

Overall, the study included 29 patients with Cushing’s disease, and 19 patients with Cushing’s syndrome — 15 caused by an adrenal mass and four caused by an ACTH-producing tumor outside the pituitary. Also, 13 patients excluded from the suspected Cushing’s group were used as controls and 21 healthy volunteers were considered the “normal” group.

The team found that the mean midnight salivary cortisol was significantly higher in the Cushing’s group compared to both control and normal subjects. Urine free cortisol and midnight serum cortisol were also significantly higher than those found in the control group, but not the normal group.

The optimal cutoff value of midnight salivary cortisol for diagnosing Cushing’s was 1.7 ng/mL, which had a sensitivity of 98% — only 2% are false negatives — and a specificity of 100% — no false positives.

While midnight salivary cortisol levels correlated with urine free cortisol and midnight serum cortisol — suggesting that all of them can be useful diagnostic markers for Cushing’s — the accuracy of midnight salivary cortisol was better than the other two measures.

Notably, in one patient with a benign adrenal mass and impaired kidney function, urine free cortisol failed to reach the necessary threshold for a Cushing’s diagnosis, but midnight salivary and serum cortisol levels both confirmed the diagnosis, highlighting how midnight salivary cortisol could be a preferable diagnostic method over urine free cortisol.

“MSC is a simple and non-invasive tool that does not require hospitalization. Our results confirmed the accuracy and reliability of [midnight salivary cortisol] as a diagnostic test for [Cushing’s syndrome] for the Chinese population,” the investigators said.

The team also noted that its study is limited: the sample size was quite small, and Cushing’s patients tended to be older than controls, which may have skewed the results. Larger studies will be needed to validate these results in the future.

From https://cushingsdiseasenews.com/2019/01/10/midnight-salivary-cortisol-test-helps-diagnose-cushings-chinese-study-shows/

Mutations in Two Genes, USP48 and BRAF, Linked to Cushing’s Disease

Mutations in USP48 and BRAF genes contribute to the overproduction of adrenocorticotropin (ACTH) hormone by the pituitary gland and consequent development of Cushing’s disease, a study shows, linking these genes to the disease for a first time.

The study, “Identification of recurrent USP48 and BRAF mutations in Cushing’s disease,” published in the journal Nature Communications, also identified a possible treatment for patients with BRAF-related mutations.

Cushing’s disease is a condition characterized by excessive cortisol levels that, if left untreated, can lead to serious cardiovascular problems, infections, and mood disorders. It usually arises from benign pituitary tumors that produce too much of ACTH hormone, which in turn stimulates the adrenal glands to secrete cortisol.

It is still not clear why some people develop these tumors, but studies have pointed to mutations in the USP8 gene as a possible cause. They are present in 35%–62% of all tumor cases, and influence treatment response and long-term outcomes.

But major disease drivers in people whose tumors have no evidence of  USP8 mutations are unknown. Recognizing this gap, researchers in China examined tumor tissue samples from 22 patients with pituitary ademonas but a normal USP8 gene.

Their analysis revealed four genes that were recurrently mutated, including two — BRAF and USP48 — never before reported in this disease setting. Then, looking at 91 samples from patients, researchers found BRAF mutations in 17% of cases and USP48 mutations in 23% of patients.

These mutations were also found in patients with USP8-mutant pituitary tumors, but at a much lower rate — 5.1% for BRAF and 1.2% for USP48 mutations.

However, mutations in these two genes were not seen in patients with pituitary tumors producing other hormones, suggesting they are “unique genetic signatures of [ACTH-producing] adenomas,” the researchers wrote.

The team also found that BRAF and USP48 mutations activate signaling pathways that lead to the production of proopiomelanocortin (POMC), which is the precursor of ACTH.

“ACTH overproduction is a hallmark of Cushing’s disease and appears to be frequently induced by mutations in genes that tightly regulate POMC gene transcription in the pathogenesis of this disease,” investigators wrote.

Patients with BRAF and USP48 mutations had significantly higher levels of midnight plasma ACTH and midnight serum cortisol, compared to patients without these mutations. Tumor size, however, was similar among the two groups.

Interestingly, the team found that the BRAF inhibitor Zelboraf (vemurafenib) effectively reduced ACTH production in cells from ACTH-producing pituitary tumors. Zelboraf, marketed by Genentech, is approved in the U.S. and Europe to treat cancers with BRAF mutations, and findings suggest it may be a good therapeutic candidate for some people with Cushing’s disease.

“The mutational status of BRAFUSP8, and USP48 in corticotroph adenomas may be used in the future to characterize the molecular subtypes and guide targeted molecular therapy,” the researchers suggested.

From https://cushingsdiseasenews.com/2018/11/20/mutations-in-usp48-braf-genes-contribute-for-cushings-disease-study-finds/

Stress, cortisol and weight gain

If you’ve got your finger on the pulse of health trends, it’s likely you’ve been hearing the current buzzwords “cortisol creates belly fat” and “cortisol causes muscle wasting and fat storage.” These are the type of catch phrases that gain momentum every few years. And although some of the fads and trends showing up seasonally in fitness are myths, this caution about chronically elevated cortisol is true. Cortisol is also deeply connected with the dangers of chronic inflammation, which I described in another article, “Inflammation Creates Diseases.”

Like many hormones, cortisol has an effect on a wide variety of functions in the body. Although it’s getting particularly demonized lately, cortisol serves some very important and positive functions in the body. It’s an essential component of the flight or flight response, so it gives us energy, focus, strength, motivation and courage. But, like with sugar or caffeine, it comes with a crash that feels like an emotional, psychological and physical drain. Cortisol is important for survival, but we didn’t evolve to have high levels of it all the time.

According to hormone.org, cortisol isn’t only a stress hormone: “Because most bodily cells have cortisol receptors, it affects many different functions in the body. Cortisol can help control blood sugar levels, regulate metabolism, help reduce inflammation and assist with memory formulation. It has a controlling effect on salt and water balance and helps control blood pressure. In women, cortisol also supports the developing fetus during pregnancy. All of these functions make cortisol a crucial hormone to protect overall health and well-being.”

There are many symptoms of chronically elevated cortisol levels. With that said, the way a spike of cortisol gives you a jolt of energy is by raising blood sugar. It does this by way of gluconeogenesis. This literally means “creating new sugar,” and it happens by way of breaking protein down into amino acids that are then turned into sugar by the liver. What is a large source of protein in the body? Yep, muscles. This is what is meant by “cortisol causes muscle loss.” This in turn contributes to muscle weakness. Whereas normal levels of cortisol help to regulate blood sugar levels by breaking down only a little muscle (which can be replaced with exercise), excessive levels cause muscle wasting.

Why does cortisol cause fat gain? Remember those cortisol receptors most cells have? Fat cells have four times as many, so they are particularly responsive to cortisol. Okay, remember all that glucose the cortisol surge dumped into your blood for energy? Well, that also came with an insulin response to get your blood sugar levels back down, and insulin causes energy storage. And where do you store the energy? Yep, in those hypersensitive fat cells that cortisol just turned on. And what happens when you have too much insulin over time? Yep, diabetes. Also, another reason stress can cause emotional and/or binge eating is because cortisol also fires up your sense of purpose, as well as your appetite. So now stress has made you feel motivated…to eat.

Emotionally and psychologically, chronically high cortisol can exacerbate depression, anxiety, irritability and lack of emotional control. Cortisol triggers a release of tryptophan oxygenase. This enzyme breaks down tryptophan. Tryptophan is required for creating serotonin. Serotonin gives us the ability to feel happiness, and it also affects appetite, sleep and sexual desire. Since extended exposure to high levels of cortisol inhibits the production of serotonin, all the symptoms of low serotonin become problematic (decreased appetite, insomnia, impotence, etc.). In short, prolonged stress causes depression.

Cortisol also plays a role in the circulatory system. It manipulates blood pressure by acting as a diuretic. Excess cortisol causes an electrolyte imbalance, whereby sodium is retained, but potassium is excreted. Let me take you back to your high school biology days: Muscles fire because of the sodium potassium pump. The sodium potassium pump also effects the firing of nerves, including those impulses that cause your heart to beat and your kidneys to take in water for filtration. That sodium potassium pump is important throughout the entire body, across many of its biological functions. Because cortisol increases the concentration of sodium in your body, it has a direct impact on your blood pressure. Remember why excess salt can cause high blood pressure? Because it contains sodium. For all these reasons and more, chronically elevated cortisol also causes muscle weakness (ironic, since short bursts of it temporarily increase strength).

Cortisol has other effects on minerals. According to the Hindawi Journal of Sports Medicine, “Cortisol triggers bone mineral resorption (removal) in order to free amino acids for use as an energy source through gluconeogenesis. Cortisol indirectly acts on bone by blocking calcium absorption, which decreases bone cell growth.” As you can see, excess cortisol causes osteoporosis. It also exacerbates other bone mineral density diseases, which means cortisol can leave you literally brittle with stress.

Practically anything can become a stressor in the right conditions, and fight or flight is our only biological response to stress. Some triggers of stress include conflict, worry, alcohol and drug consumption, processed foods, excess exercise (especially prolonged and repeated sessions of low-level steady-state cardio training), sleep deprivation, thirst and hunger. As much as possible, protect yourself from stress with rest, relaxation, meditation, play time and healthy foods full of antioxidants, which reduce inflammation and thus the risks for practically all diseases.

Jack Kirven completed the MFA in Dance at UCLA, and earned certification as a personal trainer through NASM. His wellness philosophy is founded upon integrated lifestyles as opposed to isolated workouts. Visit him at jackkirven.com and INTEGRE8Twellness.com.

Adapted from https://goqnotes.com/61597/stress-cortisol-and-weight-gain/

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