Think Like a Doctor: Red Herrings Solved!

Posted on January 11, 2026 by MaryO

By LISA SANDERS, M.D.

On Thursday we challenged Well readers to take the case of a 29-year-old woman with an injured groin, a swollen foot and other abnormalities. Many of you found it as challenging as the doctors who saw her. I asked for the right test as well as the right diagnosis. More than 200 answers were posted.

The right test was…

The dexamethasone suppression test,though I counted those of you who suggested measuring the cortisol in the urine.

The right diagnosis was…

Cushing’s disease

More than a dozen of you got the right answer or the right test, but Dr. Davin Quinn, a consultant psychiatrist at the University of New Mexico Hospital, was the first to be right on both counts. As soon as he saw that the patient’s cortisol level was increased, he thought of Cushing’s. And he had treated a young patient like this one some years ago as a second year resident.

The Diagnosis:

Cushing’s disease is caused by having too much of the stress hormone cortisol in the body. Cortisol is made in the adrenal glands, little pyramid shaped organs that sit atop the kidneys. It is normally a very tightly regulated hormone that helps the body respond to physical stress.

Sometimes the excess comes from a tumor in the adrenal gland itself that causes the little organ to go into overdrive, making too much cortisol. More often the excess occurs when a tumor in the pituitary gland in the brain results in too much ACTH, the hormone that controls the adrenal gland.

In the body, cortisol’s most fundamental job is to make sure we have enough glucose around to get the body’s work done. To that end, the hormone drives appetite, so that enough fuel is taken in through the food we eat. When needed, it can break muscle down into glucose. This essential function accounts for the most common symptoms of cortisol excess: hyperglycemia, weight gain and muscle wasting. However, cortisol has many functions in the body, and so an excess of the hormone can manifest itself in many different ways.

Cushing’s was first described by Dr. Harvey Cushing, a surgeon often considered the father of modern neurosurgery. In a case report in 1912, he described a 23-year-old woman with sudden weight gain, mostly in the abdomen; stretch marks from skin too thin and delicate to accommodate the excess girth; easy bruising; high blood pressure and diabetes.

Dr. Cushing’s case was, it turns out, a classic presentation of the illness. It wasn’t until 20 years later that he recognized that the disease had two forms. When it is a primary problem of an adrenal gland gone wild and producing too much cortisol on its own, the disease is known as Cushing’s syndrome. When the problem results from an overgrown part of the pituitary making too much ACTH and causing the completely normal adrenal glands to overproduce the hormone, the illness is called Cushing’s disease.

It was an important distinction, since the treatment often requires a surgical resection of the body part where the problem originates. Cushing’s syndrome can also be caused by steroid-containing medications, which are frequently used to treat certain pulmonary and autoimmune diseases.

How the Diagnosis Was Made:

After the young woman got her lab results from Dr. Becky Miller, the hematologist she had been referred to after seeing several other specialists, the patient started reading up on the abnormalities that had been found. And based on what she found on the Internet, she had an idea of what was going on with her body.

“I think I have Cushing’s disease,” the patient told her endocrinologist when she saw him again a few weeks later.

The patient laid out her argument. In Cushing’s, the body puts out too much cortisol, one of the fight-or-flight stress hormones. That would explain her high blood pressure. Just about everyone with Cushing’s disease has high blood pressure.

She had other symptoms of Cushing’s, too. She bruised easily. And she’d been waking up crazy early in the morning for the past year or so – around 4:30 – and couldn’t get back to sleep. She’d heard that too much cortisol could cause that as well. She was losing muscle mass – she used to have well-defined muscles in her thighs and calves. Not any more. Her belly – it wasn’t huge, but it was a lot bigger than it had been. Cushing’s seemed the obvious diagnosis.

The doctor was skeptical. He had seen Cushing’s before, and this patient didn’t match the typical pattern. She was the right age for Cushing’s and she had high blood pressure, but nothing else seemed to fit. She wasn’t obese. Indeed, she was tall (5- foot-10) and slim (150 pounds) and athletic looking. She didn’t have stretch marks; she didn’t have diabetes. She said she bruised easily, but the endocrinologist saw no bruises on exam. Her ankle was still swollen, and Cushing’s can do that, but so can lots of other diseases.

The blood tests that Dr. Miller ordered measuring the patient’s ACTH and cortisol levels were suggestive of the disease, but many common problems — depression, alcohol use, eating disorders — can cause the same result. Still, it was worth taking the next step: a dexamethasone suppression test.

Testing, Then Treatment:

The dexamethasone suppression test depends on a natural negative feedback loop whereby high levels of cortisol suppress further secretion of the hormone. Dexamethasone is an artificial form of cortisol. Given in high doses, it will cause the level of naturally-occurring cortisol to drop dramatically.

The patient was told to take the dexamethasone pills the night before having her blood tested. The doctor called her the next day.

“Are you sure you took the pills I gave you last night?” the endocrinologist asked her over the phone. The doctor’s voice sounded a little sharp to the young woman, tinged with a hint of accusation.

“Of course I took them,” she responded, trying to keep her voice clear of any irritation.

“Well, the results are crazy,” he told her and proposed she take another test: a 24-hour urine test.

Because cortisol is eliminated through the kidneys, collecting a full day’s urine would show how much cortisol her body was making. So the patient carefully collected a day’s worth of urine.

A few days later, the endocrinologist called again: her cortisol level was shockingly high. She was right, the doctor conceded, she really did have Cushing’s.

An M.R.I. scan revealed a tiny tumor on her pituitary. A couple of months later, she had surgery to remove the affected part of the gland.

After recovering from the surgery, the patient’s blood pressure returned to normal, as did her red blood cell count and her persistently swollen ankle. And she was able to once again sleep through the night.

Red Herrings Everywhere:

As many readers noted, there were lots of findings that didn’t really add up in this case. Was this woman’s groin sprain part of the Cushing’s? What about the lower extremity swelling, and the excess red blood cell count?

In the medical literature, there is a single case report of high red blood cell counts as the presenting symptom in a patient with Cushing’s. And with this patient, the problem resolved after her surgery – so maybe they were linked.

And what about the weird bone marrow biopsy? The gastritis? The enlarged spleen? It’s hard to say for certain if any of these problems was a result of the excess cortisol or if she just happened to have other medical problems.

Why the patient didn’t have the typical symptoms of Cushing’s is easier to explain. She was very early in the course of the disease when she got her diagnosis. Most patients are diagnosed once symptoms have become more prominent

By the time this patient had her surgery, a couple of months later, the round face and belly characteristic of cortisol excess were present. Now, two years after her surgery, none of the symptoms remain.

From http://well.blogs.nytimes.com/2014/01/17/think-like-a-doctor-red-herrings-solved/?_php=true&_type=blogs&_r=0

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Insights on Diagnosing and Managing Cushing’s Syndrome

Posted on August 18, 2024 by MaryO

Cushing’s syndrome, or endogenous hypercortisolemia, is a rare condition that both general practice clinicians and endocrinologists should be prepared to diagnose and treat. Including both the pituitary and adrenal forms of the disease, the Endocrine Society estimates that the disorder affects 10 to 15 people per million every year in the United States. It is more common in women and occurs most often in people between the ages of 20 and 50.

Even though Cushing’s remains a rare disease, cortisol recently made waves at the American Diabetes Association 84th Scientific Session. A highlight of the meeting was the initial presentation of data from the CATALYST trial, which assessed the prevalence of hypercortisolism in patients with difficult-to-control type 2 diabetes (A1c 7.5+).

CATALYST is a prospective, Phase 4 study with two parts. In the prevalence phase, 24% of 1,055 enrolled patients had hypercortisolism, defined as an overnight dexamethasone suppression test (ODST) value greater than 1.8 µg/dL and dexamethasone levels greater than 140 µg/dL. Results of CATALYST’s randomized treatment phase are expected in late 2024.

Elena Christofides, MD, FACE, founder of Endocrinology Associates, Inc., in Columbus, OH, believes the CATALYST results will be a wake-up call for both physicians and patients seeking to advocate for their own health. “This means that nearly 1 in 4 patients with type 2 diabetes have some other underlying hormonal/endocrine dysfunction as the reason for their diabetes, or significant contribution to their diabetes, and they should all be screened,” she said. “All providers need to get comfortable with diagnosing and treating hypercortisolemia, and you need to do it quickly because patients are going to pay attention as well.”

In Dr. Christofides’ experience, patients who suspect they have a hormonal issue may start with their primary care provider or they may self-refer to an endocrinologist. “A lot of Cushing’s patients are getting diagnosed and treated in primary care, which is completely appropriate. But I’ve also met endocrinologists who are uncomfortable diagnosing and managing Cushing’s because it is so rare,” she said. “The important thing is that the physician is comfortable with Cushing’s or is willing to put in the work get comfortable with it.”

According to Dr. Christofides, the widespread popular belief that “adrenal fatigue” is causing millions of Americans to feel sick, tired, and debilitated may be creating barriers to care for people who may actually have Cushing’s. “As physicians, we know that adrenal fatigue doesn’t exist, but we should still be receptive to seeing patients who raise that as a concern,” said Dr. Christofides. “We need to acknowledsalige their lived experience as being very real and it can be any number of diseases causing very real symptoms. If we don’t see these patients, real cases of hypercortisolemia could be left undiagnosed and untreated.”

Dr. Christofides, who also serves as a MedCentral Editor-at-Large, said she reminds colleagues that overnight dexamethasone suppression test (ODST) should always be the first test when you suspect Cushing’s. “While technically a screening test, the ODST can almost be considered diagnostic, depending on how abnormal the result is,” she noted. “But I always recommend that you do the ODST, the ACTH, a.m. cortisol, and the DHEAS levels at the same time because it allows you to differentiate more quickly between pituitary and adrenal problems.”

Dr. Christofides does see a place for 24-hour urine collection and salivary cortisol testing at times when diagnosing and monitoring patients with Cushing’s. “The 24-hour urine is only positive in ACTH-driven Cushing’s, so an abnormal result can help you identify the source, but too many physicians erroneously believe you can’t have Cushing’s if the 24-hour urine is normal,” she explained. “Surgeons tend to want this test before they operate and it’s a good benchmark for resolution of pituitary disease.” She reserves salivary cortisol testing for cases when the patient’s ODST is negative, but she suspects Cushing’s may be either nascent or cyclical.

Surgical resection has long been considered first-line treatment in both the pituitary and adrenal forms of Cushing’s. For example, data shared from Massachusetts General Hospital showed that nearly 90% of patients with microadenomas did not relapse within a 30-year period. A recent study found an overall recurrence rate of about 25% within a 10-year period. When reoperation is necessary, remission is achieved in up to 80% of patients.

As new medications for Cushing’s syndrome have become available, Dr. Christofides said she favors medical intervention prior to surgery. “The best part about medical therapy is you can easily stop it if you’re wrong,” she noted. “I would argue that every patient with confirmed Cushing’s deserves nonsurgical medical management prior to a consideration of surgery to improve their comorbidities and surgical risk management, and give time to have a proper informed consent discussion.”

In general, medications to treat Cushing’s disease rely on either cortisol production blockade or receptor blockade, said Dr. Christofides. Medications that directly limit cortisol production include ketoconazole, osilodrostat (Isturisa), mitotane (Lysodren), levoketoconazole (Recorlev), and metyrapone (Metopirone). Mifepristone (Korlym, Mifeprex) is approved for people with Cushing’s who also have type 2 diabetes to block the effects of cortisol. Mifepristone does not lower the amount of cortisol the body makes but limits its effects. Pasireotide (Signifor) lowers the amount of ACTH from the tumor. Cabergoline is sometimes used off-label in the US for the same purpose.

Following surgery, people with Cushing’s need replacement steroids until their adrenal function resumes, when replacement steroids must be tapered. But Dr. Christofides said she believes that all physicians who prescribe steroids should have a clear understanding of when and how to taper patients off steroids.

“Steroid dosing for therapeutic purposes is cumulative in terms of body exposure and the risk of needing to taper. A single 2-week dose of steroids in a year does not require a taper,” she said. “It’s patients who are getting repeated doses of more than 10 mg of prednisone equivalent per day for 2 or more weeks multiple times per year who are at risk of adrenal failure without tapering.”

Physicians often underestimate how long a safe, comfortable taper can take, per Dr. Christofides. “It takes 6 to 9 months for the adrenals to wake up so if you’re using high-dose steroids more frequently, that will cause the patient to need more steroids more frequently,” she explained. “If you’re treating an illness that responds to steroids and you stop them without tapering, the patient’s disease will flare, and then a month from then to 6 weeks from then you’ll be giving them steroids again, engendering a dependence on steroids by doing so.”

When developing a steroid taper plan for postoperative individuals with Cushing’s (and others), Dr. Christofides suggests basing it on the fact that 5 mg of prednisone or its equivalent is the physiologic dose. “Reduce the dose by 5 mg per month until you get to the last 5 mg, and then you’re going to reduce it by 1 mg monthly until done,” she said. “If a patient has difficulty during that last phase, consider a switch to hydrocortisone because a 1 mg reduction of hydrocortisone at a time may be easier to tolerate.”

Prednisone, hydrocortisone, and the other steroids have different half-lives, so you’ll need to plan accordingly, adds Dr. Christofides. “If you do a slower taper using hydrocortisone, the patient might feel worse than with prednisone unless you prescribe it BID.” She suggests thinking of the daily prednisone equivalent of hydrocortisone as 30 mg to allow for divided dosing, rather than the straight 20 mg/day conversion often used.

What happens after a patient’s Cushing’s has been successfully treated? Cushing’s is a chronic disease, even in remission, Dr. Christofides emphasized. “Once you have achieved remission, my general follow-up is to schedule visits every 6 months to a year with scans and labs, always with the instruction if the patient feels symptomatic, they should come in sooner,” she said.

More on Cushing’s diagnosis and therapies.

https://www.medcentral.com/endocrinology/cushings-syndrome-a-clinical-update

Filed under: adrenal, adrenal crisis, Cushing's, Diagnostic Testing, pituitary, Treatments | Tagged: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , | Leave a comment »

Cushing’s Disease Treatment Market to Witness an Outstanding Growth by 2017 – 2025

Posted on March 2, 2017 by MaryO

Cushing disease is caused by tumour in the pituitary gland which leads to excessive secretion of a hormone called adrenocorticotrophic (ACTH), which in turn leads to increasing levels of cortisol in the body. Cortisol is a steroid hormone released by the adrenal glands and helps the body to deal with injury or infection. Increasing levels of cortisol increases the blood sugar and can even cause diabetes mellitus. However the disease is also caused due to excess production of hypothalamus corticotropin releasing hormone (CRH) which stimulates the synthesis of cortisol by the adrenal glands.

The condition is named after Harvey Cushing, the doctor who first identified the disease in 1912. Cushing disease results in Cushing syndrome. Cushing syndrome is a group of signs and symptoms developed due to prolonged exposure to cortisol.

Signs and symptoms of Cushing syndrome includes hypertension, abdominal obesity, muscle weakness, headache, fragile skin, acne, thin arms and legs, red stretch marks on stomach, fluid retention or swelling, excess body and facial hair, weight gain, acne, buffalo hump, tiredness, fatigue, brittle bones, low back pain, moon shaped face etc.

Symptoms vary from individual to individual depending upon the disease duration, age and gender of the patient.  Disease diagnosis is done by measuring levels of cortisol in patient’s urine, saliva or blood. For confirming the diagnosis, a blood test for ACTH is performed. The first-line treatment of the disease is through surgical resection of ACTH-secreting pituitary adenoma, however disease management is also done through medications, Cushing disease treatment market comprises of the drugs designed for lowering the level of cortisol in the body. Thus patients suffering from Cushing disease are prescribed medications such as ketoconazole, mitotane, aminoglutethimide metyrapone, mifepristone, etomidate and pasireotide.

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Cushing’s disease treatment market revenue is growing with a stable growth rate, this is attributed to increasing number of pipeline drugs. Also increasing interest of pharmaceutical companies to develop Cushing disease drugs is a major factor contributing to the revenue growth of Cushing disease treatment market over the forecast period. Current and emerging players’ focuses on physician education and awareness regarding availability of different drugs for curing Cushing disease, thus increasing the referral speeds, time to diagnosis and volume of diagnosed Cushing disease individuals. Growing healthcare expenditure and increasing awareness regarding Cushing syndrome aids in the revenue growth of Cushing’s disease treatment market. Increasing number of new product launches also drives the market for Cushing’s disease Treatment devices. However availability of alternative therapies for curing Cushing syndrome is expected to hamper the growth of the Cushing’s disease treatment market over the forecast period.

The Cushing’s disease Treatment market is segment based on the product type, technology type and end user

Cushing’s disease Treatment market is segmented into following types:

By Drug Type

  • Ketoconazole
  • Mitotane
  • Aminoglutethimide
  • Metyrapone
  • Mifepristone
  • Etomidate
  • Pasireotide

By End User

  • Hospital Pharmacies
  • Retail Pharmacies
  • Drug Stores
  • Clinics
  • e-Commerce/Online Pharmacies

Cushing’s disease treatment market revenue is expected to grow at a good growth rate, over the forecast period. The market is anticipated to perform well in the near future due to increasing awareness regarding the condition. Also the market is anticipated to grow with a fastest CAGR over the forecast period, attributed to increasing investment in R&D and increasing number of new product launches which is estimated to drive the revenue growth of Cushing’s disease treatment market over the forecast period.

Depending on geographic region, the Cushing’s disease treatment market is segmented into five key regions: North America, Latin America, Europe, Asia Pacific (APAC) and Middle East & Africa (MEA).

North America is occupying the largest regional market share in the global Cushing’s disease treatment market owing to the presence of more number of market players, high awareness levels regarding Cushing syndrome. Healthcare expenditure and relatively larger number of R&D exercises pertaining to drug manufacturing and marketing activities in the region. Also Europe is expected to perform well in the near future due to increasing prevalence of the condition in the region.

Asia Pacific is expected to grow at the fastest CAGR because of increase in the number of people showing the symptoms of Cushing syndrome, thus boosting the market growth of Cushing’s disease treatment market throughout the forecast period.

Some players of Cushing’s disease Treatment market includes CORCEPT THERAPEUTICS, HRA Pharma, Strongbridge Biopharma plc, Novartis AG, etc. However there are numerous companies producing branded generics for Cushing disease. The companies in Cushing’s disease treatment market are increasingly engaged in strategic partnerships, collaborations and promotional activities to capture a greater pie of market share.

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From http://www.medgadget.com/2017/03/cushings-disease-treatment-market-to-witness-an-outstanding-growth-by-2017-2025-persistence-market-research.html 

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Exophthalmos and Cushing’s Syndrome

Posted on February 4, 2015 by MaryO

A woman experienced red, irritated and bulging eyes. She saw an ophthalmologist who strongly suspected Graves’ ophthalmopathy. However, the patient did not have and never had hyperthyroidism.

Indeed, she had primary hypothyroidism optimally treated with levothyroxine. Her thyroid stimulating hormone level was 1.197 uIU/mL.

An MRI of the orbits showed normal extraocular muscles without thickening, but there was mild proptosis and somewhat increased intraorbital fat content. Both thyroid-stimulating immunoglobulins as well as thyrotropin receptor antibodies were negative.

The patient presented to her primary care physician a few months later. She had experienced a 40-lb weight gain over only a few months and also had difficult-to-control blood pressure.

After failing to respond to several antihypertensive medications, her primary care physician astutely decided to evaluate for secondary causes of hypertension. A renal ultrasound was ordered to evaluate for renal artery stenosis, and the imaging identified an incidental right-sided adrenal mass. A CT confirmed a 3.4-cm right-sided adrenal mass. Her morning cortisol was slightly high at 24.7 ug/dL (4.3 – 22.4) and her adrenocorticotropic hormone was slightly low at 5 pg/mL (10-60).

At this point I saw the patient in consultation. She definitely had many of the expected clinical exam findings of Cushing’s syndrome, including increased fat deposition to her abdomen, neck, and supraclavicular areas, as well as striae. Her 24-hour urine cortisol was markedly elevated at 358 mcg/24hrs (< 45) confirming our suspicions.

She asked me, “Do you think that my eye problem could be related to this?”

“I’ve not heard of it before,” I replied, “but that doesn’t mean there can’t be a connection. Wouldn’t it be wonderful if your eyes got better after surgery?”

The patient underwent surgery to remove what fortunately turned out to be a benign adrenal adenoma.

When we saw her in follow-up 2 weeks later, her blood pressures were normal off medication and her eye symptoms had improved. I had a medical student rotating with me, so I suggested that we do a PubMed literature search.

The first article to come up was a case report titled “Exophthalmos: A Forgotten Clinical Sign of Cushing’s Syndrome.” Indeed, not only did Harvey Cushing describe this clinical finding in his original case series in 1932, but others have reported that up to 45% of patients with active Cushing’s syndrome have exophthalmos.

The cause is uncertain but is theorized to be due to increased intraorbital fat deposition. Unlike exophthalmos due to thyroid disease, the orbital muscles are relatively normal — just as they were with our patient.

Some of you may have seen exophthalmos in your Cushing’s patients; however, this was the first time I had seen it. Just because one has not heard of something, does not mean it could never happen; no one knows everything. “When in doubt, look it up” is a good habit for both attending physicians and their students.

For more information:

Giugni AS, et al. Case Rep Endocrinol. 2013; 2013: 205208.

From http://www.healio.com/endocrinology/adrenal/news/blogs/%7B779bf3e5-e1da-459e-af27-955c9b4274a5%7D/thomas-b-repas-do-facp-face-cde/exophthalmos-and-cushings-syndrome

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Cushing’s Awareness Challenge: Day 9

Posted on April 9, 2014 by MaryO

cushings-women

Another of Robin’s fine awareness graphics.  I had all these symptoms except Type 2 Diabetes.

After my pituitary surgery, I had diabetes mellitus for a while but that went away.

It was the easy bruising that finally got me diagnosed.

In 1986 I started bruising incredibly easily. I could touch my skin and get a bruise.

On New Year’s Day of 1987 I started bleeding under the skin. My husband made circles around the outside perimeter each hour with a marker, like the rings of a tree. When I went to my Internist the next day he was shocked at the size. He now thought I had a blood disorder so he sent me to a Hematologist/Oncologist.

Fortunately, the Hematologist/Oncologist ran a twenty-four hour urine test and really looked at me. Both he and his partner recognized that I had Cushing’s. Of course, he was sure that he did the diagnosis. No matter that I had been pursuing this with other doctors for 3 years.

However, he couldn’t help me any further so the Hematologist referred me to an Endocrinologist and I was finally on the way to my diagnosis.

 

maryo colorful zebra

 

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