Researchers Report Rare Case of Cushing’s Caused by Bilateral Adrenal Tumors

Cases of adrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome are often caused by unilateral tumors in the adrenal glands, but Indian researchers have now reported a rare case where the condition was caused by tumors in both adrenal glands.

Fewer than 40 cases of bilateral tumors have been reported so far, but an accurate diagnosis is critical for adequate and prompt treatment. Sampling the veins draining the adrenal glands may be a good way to diagnose the condition, researchers said.

The study, “Bilateral adrenocortical adenomas causing adrenocorticotropic hormone-independent Cushing’s syndrome: A case report and review of the literature,” was published in the World Journal of Clinical Cases.

Cushing’s syndrome, a condition characterized by excess cortisol in circulation, can be divided into two main forms, depending on ACTH status. Some patients have tumors that increase the amount of ACTH in the body, and this hormone will act on the adrenal glands to produce cortisol in excess. Others have tumors in the adrenal glands, which produce excess cortisol by themselves, without requiring ACTH activation. This is known as ACTH-independent Cushing’s syndrome.

Among the latter, the disease is mostly caused by unilateral tumors — in one adrenal gland only —  with cases of bilateral tumors being extremely rare in this population.

Now, researchers reported the case of a 31-year-old Indian woman who developed ACTH-independent Cushing’s syndrome because of tumors in both adrenal glands.

The patient complained of weight gain, red face, moon face, bruising, and menstrual irregularity for the past two years. She recently had been diagnosed with high blood pressure and had started treatment the month prior to the presentation.

A physical examination confirmed obesity in her torso, moon face, buffalo hump, thin skin, excessive hair growth, acne, swollen legs and feet, and skin striae on her abdomen, arms, and legs.

Laboratory examinations showed that the woman had an impaired tolerance to glucose, excess insulin, and elevated cortisol in both the blood and urine. Consistent with features of Cushing’s syndrome, cortisol levels had no circadian rhythm and were non-responsive to a dexamethasone test, which in normal circumstances lowers cortisol production.

Because ACTH levels were within normal levels, researchers suspected an adrenal tumor, which led them to conduct imaging scans.

An abdominal computed tomography (CT) scan showed adrenal adenomas in both adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). A magnetic resonance imaging (MRI) scan showed that the pituitary gland (which normally produces ACTH) was normal.

To determine whether both adrenal tumors were producing cortisol, researchers sampled the adrenal veins and compared their cortisol levels to those of peripheral veins. They found that the left adrenal gland was producing higher amounts of cortisol, thought the right adrenal gland was also producing cortisol in excess.

“Our case indicates that adrenal vein [blood] sampling might be useful for obtaining differential diagnoses” in cases of Cushing’s syndrome, researchers stated. Also, they may help design a surgical plan that makes much more sense.”

The tumors were surgically removed — first the left, and three months later the right — which alleviated many of her symptoms. She also started prednisolone treatment, which helped resolve many disease symptoms.

“Bilateral cortisol-secreting tumors are a rare cause of Cushing’s syndrome,” researchers said. So when patients present bilateral adrenal lesions, “it is crucial to make a definitive diagnosis before operation since various treatments are prescribed for different causes,” they said.

The team recommends that in such cases the two tumors should not be removed at the same time, as this approach may cause adrenal insufficiency and the need for glucocorticoid replacement therapy.

From https://cushingsdiseasenews.com/2019/06/27/rare-case-of-cs-due-to-bilateral-tumors-in-the-adrenal-glands/

Laparoscopic Removal of Adrenal Glands Safe for Obese Cushing’s Patients

Laparoscopic adrenalectomy — a minimally invasive procedure that removes the adrenal glands through a tiny hole in the abdomen — can be safely performed in obese patients with Cushing’s syndrome, a retrospective study reports.

The surgery resolved symptoms in 95% of cases, reducing cortisol levels, lowering blood pressure, and leading to a significant loss of weight in morbidly obese patients.

The study, “Minimally invasive approach to the adrenal gland in obese patients with Cushing’s syndrome,” was published in the journal Minimally Invasive Therapy & Allied Technologies.

Cushing’s syndrome results from the prolonged secretion of excess cortisol, the major glucocorticoid hormone. While most cases are caused by tumors in the pituitary gland, up to 27% result from tumors in the adrenal glands.

In these cases, the standard therapeutic strategy is to remove one or both adrenal glands, a surgical procedure called adrenalectomy. However, because glucocorticoids are key hormones regulating fat metabolism, Cushing’s syndrome patients are known to be prone to obesity, a feature that is often associated with post-operative complications.

In this study, researchers aimed to compare the outcomes of morbidly obese patients versus the mildly obese and non-obese who underwent a minimally invasive procedure to remove their adrenal glands.

The approach, called laparoscopic adrenalectomy, inserts tiny surgical tools through a small hole in the abdomen, along with a camera that helps guide the surgeon.

The study included 228 patients (mean age 53.4 years). Of them, 62 were non-obese, 87 were moderately obese, and 79 were considered morbidly obese. There were 121 patients with tumors in the right adrenal gland, 96 in the left gland, and 11 in both glands.

High blood pressure was the most common symptom, affecting 66.7% of the participants.

Surgery lasted 101 minutes on average, and patients remained in the hospital for a median 4.3 days afterward. Six patients had to be converted into an open surgery because of uncontrollable loss of blood or difficulties in the procedure. Post-surgery complications, most of which were minor, were seen in seven patients.

One patient had blood in the peritoneal cavity and had to have surgery again; another patient had inflammation of the pancreas that required a longer admission.

The analysis showed no statistical differences among the three groups regarding the length of surgery, length of stay in the hospital, or the rate of conversion into open surgery.

However, in obese women, surgeons chose a different surgical incision when removing the left adrenal gland, “suggesting that the distribution of visceral fat in these patients could constitute a drawback for the [standard] approach,” researchers said.

After the surgery, 95% of patients saw their symptoms resolve, including cortisol levels, high blood pressure, and glucose metabolism, and none had a worsening of symptoms in the 6.3 years of follow-up. Obese patients also showed a significant reduction in their weight — 2 kg by 18 months, and 5 kg by the end of follow-up.

Overall, “laparoscopic adrenalectomy is safe and feasible in obese patients affected with Cushing’s disease and it can lead to the resolution of the related symptoms,” researchers said.

The benefits of the surgery in patients with Cushing’s syndrome “could be extended to the improvements and in some cases to the resolution of hypercortisolism related symptoms (i.e. hypertension or even morbid obesity),” the study concluded.

Adapted from https://cushingsdiseasenews.com/2019/02/07/laparoscopic-removal-of-adrenal-glands-safe-for-obese-cushings-patients/

Adrenal Venous Sampling Helps Surgical Decisions in Type of Cushing’s

Cushing’s syndrome patients with tumors on both adrenal glands — which sit on top of the kidneys — could undergo adrenal venous sampling, a procedure where blood samples are taken from both adrenal glands to determine which tumors to remove, researchers suggest.

Their study, “Outcomes of Adrenal Venous Sampling in Patients with Bilateral Adrenal Masses and ACTH-Independent Cushing’s Syndrome,” was published in the World Journal of Surgery. The work was a collaboration between SUNY Upstate Medical University in Syracuse and the University of Pittsburgh.

Cushing’s syndrome, a condition characterized by excess cortisol, can be divided into two main subtypes. In some patients, the disease is dependent on tumors secreting the adrenocorticotropic hormone (ACTH), which stimulates the release of cortisol from the adrenal glands. In others, adrenal tumors are solely responsible for excess cortisol and do not require ACTH for functioning.

ACTH-independent Cushing’s syndrome (AICS), the latter subtype, constitutes about 10% to 15% of endogenous — an overproduction of cortisol within the body — Cushing’s syndrome cases, with cortisol-secreting adenomas in just one gland (unilateral) being the most common cause.

Compared to unilateral adenomas, adrenal tumors in both glands (bilateral) in patients with AICS are difficult to diagnose. Disease management in these rare cases depends on the challenging determination of the lesion’s exact location and of the functional status of the benign tumors (if they are actively secreting cortisol).

Surgical removal of both adrenal glands, also known as bilateral adrenalectomy, “ensures cure of AICS, but leads to permanent corticosteroid dependence and a lifelong risk of adrenal crisis,” investigators explained. Therefore, screening for the presence of unilateral or bilateral adenomas is essential to avoid unnecessary surgery.

“Adrenal venous sampling (AVS) has been reported in a single institutional series … to aid in successful localization of cortisol-secreting adrenal adenomas in patients with bilateral adrenal masses and AICS,” researchers wrote.

Researchers retrospectively assessed the usefulness of AVS in guiding management of patients with bilateral adrenal masses plus AICS.

Nine women (age 51-73) with bilateral adrenal masses and AICS were included in the study. All subjects had undergone AVS at the University of Pittsburgh Medical Center from 2008 to 2016. None of the patients had apparent symptoms of Cushing’s syndrome.

“Samples were obtained for testing of epinephrine [also called adrenaline] and cortisol from both [adrenal veins] and the external iliac vein. Multiple samples were obtained to ensure adequate sampling,” they wrote.

Adrenal glands produce cortisol and epinephrine, among other hormones, which are critical for maintaining good health. In AICS, there’s an overproduction of both hormones that’s independent on the release of ACTH, which is produced by the brain’s pituitary gland.

Successful adrenal venous sampling was achieved in eight women. “One patient with unsuccessful catheterization had [other additional diseases] and passed away from unrelated reasons,” researchers reported.

AVS results indicated that all patients had bilateral cortisol-secreting adenomas.

“Surgical management was strongly influenced by adrenal mass size. However, AVS may have influenced surgical decision-making in some cases, particularly when minimal difference in size was noted in adrenal mass sizes,” they reported.

Six women underwent adrenalectomy: three had the gland with larger size mass removed (unilateral type of surgery); two had both glands removed; and one had the right gland removed followed by the left one, five months later, due to continuous hormonal overproduction without experiencing symptoms of Cushing’s syndrome.

Evidence suggests that removal of the larger adrenal mass in patients with bilateral cortisol-secreting adenomas improves Cushing’s syndrome presentation.

In theory, unilateral adrenalectomy reduces cortisol production through the removal of the oversecreting mass. Because of this, unilateral adrenalectomy of the larger adrenal mass was chosen in half of this study’s surgical cases, instead of bilateral adrenalectomy.

Tissue analysis revealed multiple-lump masses, also known as macronodular adrenal hyperplasia (MAH), in all six surgical cases.

In addition, computed tomography (CT) scan findings were predictive of bilateral MAH, with scans showing evidence of one or multiple nodules on one or both adrenal glands.

“To the best of our knowledge, this is the second study to evaluate the utility of AVS in guiding management of patients with bilateral adrenal masses and AICS,” investigators said.

The first study was by Young and included 10 patients with a more severe presentation of Cushing’s syndrome and other individual characteristics, which contributed to the differences in results, compared to the current study. In Young’s study, half the subjects had unilateral adrenal masses.

Patients with bilateral cortisol-secreting masses frequently have a milder form of Cushing’s syndrome, which corroborates researchers’ findings.

Despite suggesting that adrenal venous sampling is useful in excluding a unilateral adenoma as the cause of AICS, this study’s sample size is small.

“More data are needed before AVS can be advocated as essential for management of patients with bilateral adrenal masses and AICS,” researchers concluded.

From https://cushingsdiseasenews.com/2018/10/02/adrenal-venous-sampling-helps-surgical-decisions-type-cushings-syndrome/?utm_source=Cushing%27s+Disease+News&utm_campaign=a990429aad-RSS_WEEKLY_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_ad0d802c5b-a990429aad-72451321

MEKT1 Could Be a Potential New Therapy for Treating Cushing’s Disease

MEKT1, a type of therapy called a PPAR-γ agonist, acts to reduce levels of the adrenocorticotropic hormone and could be a potential new therapy for Cushing’s disease, according to researchers.

Their study, “Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells,” was published in the journal PPAR Research.

Cushing’s disease is caused by a tumor in the pituitary gland — generally a type of tumor called an adenoma that produces high levels of adrenocorticotropic hormone (ACTH).

ACTH causes the adrenal glands to make too much cortisol, leading to the classic symptoms associated with Cushing’s disease.

PPAR-gamma (PPAR-γ) is a transcription factor protein (meaning it regulates the levels of certain genes by acting through other proteins), and is seen in high levels in the normal human pituitary and in ACTH-secreting pituitary adenomas.

The Pomc gene is a precursor molecule to ACTH. While it is known that PPAR-γ plays a role in regulating Pomc levels, its mechanism has not yet been clarified in pituitary cells.

PPAR-γ agonists — agents that activate PPAR-γ — include the medications rosiglitazone and pioglitazone, both of which are used to treat type 2 diabetes. Some studies have shown that rosiglitazone and pioglitazone have an effect on Pomc suppression, which would lead to lower levels of ACTH and help treat patients with Cushing’s disease.

However, the benefits of PPAR-γ agonists in the treatment of Cushing’s disease are still controversial.

Researchers examined the effects of a new PPAR-γ agonist, MEKT1, on Pomc levels and ACTH secretion using a mouse pituitary tumor-derived cell line called AtT20 cells. They also compared its effects with the well-established PPAR-γ agonists rosiglitazone and pioglitazone.

AtT20 cells were treated with either MEKT1, rosiglitazone, or pioglitazone at various concentrations ranging from 1 nM to 10 μM (micrometers) for 24 hours.

Results showed that 10 μM of MEKT1 significantly inhibited Pomc gene levels compared to rosiglitazone and pioglitazone. Additionally, ACTH secretion from AtT20 cells was also significantly inhibited by the agonist.

To see if it worked to decrease Pomc levels by acting specifically on PPAR-γ, researchers eliminated the PPAR-γ protein using a technique called siRNA knockdown. In this case, the effects of MEKT1 on Pomc levels were significantly halted.

It is known that other proteins, such as Nur77, Nurr1, and Tpit activate Pomc levels by binding to the promoter region of Pomc — the area of the gene responsible for activating gene levels.

To determine whether these proteins could be targeted by MEKT1, researchers also looked at levels of Nur77, Nurr1, and Tpit. The PPAR-γ agonist was found to significantly suppress the levels of the three genes that encode these proteins.

“Although clinical trials of MEKT1 are needed to determine its drug efficacy in the future, it can be speculated that MEKT1 is much more effective than the previously recognized PPAR-γ agonists rosiglitazone, and pioglitazone for the suppression of Pomc expression/ACTH secretion from our in vitro [laboratory] research,” they added.

Results from this study suggest MEKT1 could be a potential new therapy for the treatment of Cushing’s disease.

From https://cushingsdiseasenews.com/2018/06/12/mekt1-could-be-potential-therapy-treatment-cushings-disease/

Case Report Shows Rare Adrenal Tumors Associated with Cushing’s Disease

Pituitary tumors that produce too much adrenocorticotropic hormone (ACTH) have been associated with the development of rare tumors on the adrenal glands, called adrenal myelolipomas, for the first time in a case report.

The study, “Case report of a bilateral adrenal myelolipoma associated with Cushing disease,” was published in the journal Medicine.

Myelolipomas, composed of mature fat cells and blood-forming cells, are usually asymptomatic and do not produce hormones. In many cases, these tumors are detected by accident when patients undergo imaging scans for other conditions.

The cause of these tumors is unknown, but due to their benign nature, they do not spread to other parts of the body. However, they can grow up to 34 centimeters (about 13 inches), leading to tissue death and hemorrhage.

Researchers at Soon Chun Hyang University College of Medicine in Seoul, Korea, described the case of a 52-year-old man with myelolipoma possibly caused by an ACTH-secreting pituitary tumor.

During a routine checkup, researchers detected a mass in the patient’s spleen. Further abdominal evaluations identified tissue lesions in both adrenal glands consistent with myelolipoma. Besides the masses, the patient did not show any other Cushing-associated physical characteristics.

However, the patient’s ACTH levels were two times higher than the normal upper limit. Cortisol levels were also increased and unresponsive to low-dose dexamethasone treatment.

No additional lesions were found that could help explain the high ACTH and cortisol levels. But analysis of blood samples collected from the veins draining the pituitary glands revealed the right gland was producing too much ACTH, strongly suggesting Cushing’s disease.

Both the left adrenal gland and pituitary tumor were surgically removed. The samples collected during surgery confirmed the benign nature of the adrenal tumors, and the diagnosis of abnormal, ACTH-positive pituitary gland tissue.

Three days after the surgeries, hormone levels were back to normal. But a follow-up evaluation five months later again showed increased ACTH levels. Cortisol levels, however, were normal.

For the next seven years, the patient was evaluated every six months. During a five-year period, the size of the right adrenal gland was found to have grown. Imaging analysis confirmed the existence of small, new lesions in both pituitary glands.

“This case confers valuable information about the clinical course of adrenal myelolipoma associated with Cushing disease,” the researchers said. It also “supports the notion that ACTH can be associated with the development of bilateral adrenal myelolipomas.”

From https://cushingsdiseasenews.com/2018/03/08/bilateral-adrenal-myelolipoma-associated-with-cushing-disease-case-report/

%d bloggers like this: