Cushing’s Disease Patients with USP8 Mutations More Likely to Achieve Remission After Surgery

Posted on October 24, 2018 by MaryO

Cushing’s disease patients whose pituitary tumors carry a USP8 mutation are more likely to achieve remission after surgery than those without such mutations, a retrospective Italian study found.

The study, “Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas,” was published in the journal Endocrine.

Cushing’s disease is a condition where a tumor on the pituitary gland produces too much of the adrenocorticotropin hormone (ACTH), which will act on the adrenal gland to make cortisol in excess.

While rare, the condition can be life-threatening, as excess cortisol is linked to an increased risk of infections and cardiovascular complications, along with an increased likelihood of obesity and diabetes.

The reasons some patients develop these pituitary adenomas are far from understood, but researchers recently found that some of these patients show mutations in the USP8 gene. These appear to increase EGFR signaling which, in turn, has a stimulatory role for the synthesis of ACTH.

But more than influencing the development of Cushing’s disease, researchers believe the USP8 mutations may also determine response to treatment.

Thus, a team in Italy examined whether patients with USP8 mutations presented different clinical features and responded differently to the standard surgical procedure, called transsphenoidal pituitary surgery.

The study included 92 patients with ACTH-secreting pituitary tumors who received surgery at the neurosurgical department of the Istituto Scientifico San Raffaele in Milan between 1996 and 2016.

“All surgical procedures were performed by the same experienced neurosurgeon, which is one of the most important factors affecting early and late surgical outcome of pituitary adenomas,” researchers explained.

Among study participants, 22 (23.9%) had mutations in the USP8 gene, but these mutations were significantly more common in women than in men — 28.7% vs. 5.3%. Researchers think estrogens — a female sex hormone — may have a role in the development of mutated pituitary tumors.

Overall, the two groups had similar tumor size and aggressiveness and similar ACTH and cortisol levels before surgery. But among those with microadenomas — tumors smaller then 10 mm in diameter — USP8-mutated patients had significantly larger tumor diameters.

After receiving surgery, 81.5% of patients achieved surgical remission — deemed as low cortisol levels requiring glucocorticoid replacement therapy, normal cortisol levels in urine, and normal response to a dexamethasone-suppression test.

But remission rates were significantly higher among those with USP8 mutations — 100% vs. 75.7%. Also, USP8 mutation carriers required steroid replacement therapy for shorter periods, despite ACTH and cortisol levels being similar among the two groups after surgery.

Among patients who entered remission, 12 (16%) saw their disease return. While more patients with USP8 mutations experienced a recurrence — 22.7% vs. 13.2% — this difference was not significant. After five years, 73.8% of UPS8-mutated patients remained alive and recurrence-free, which researchers consider comparable to the 88.5% seen in patients without the mutation.

Researchers also tested sex, age at surgery, and post-surgical ACTH and cortisol levels as possible predictors of disease recurrence, but none of these factors was associated with this outcome.

“ACTH-secreting pituitary adenomas carrying somatic USP8 mutations are associated with a greater likelihood of surgical remission in patients operated on by a single neurosurgeon. Recurrence rates are not related with USP8-variant status,” researchers concluded.

From https://cushingsdiseasenews.com/2018/10/23/cushings-disease-patients-usp8-mutations-more-likely-achieve-remission-after-surgery/

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Most Subclinical Cushing’s Patients Don’t Require Glucocorticoids After Adrenalectomy

Posted on October 23, 2018 by MaryO

Patients with subclinical hypercortisolism, i.e., without symptoms of cortisol overproduction, and adrenal incidentalomas recover their hypothalamic-pituitary-adrenal (HPA) axis function after surgery faster than those with Cushing’s syndrome (CS), according to a study.

Moreover, the researchers found that an HPA function analysis conducted immediately after the surgical removal of adrenal incidentalomas — adrenal tumors discovered by chance in imaging tests — could identify patients in need of glucocorticoid replacement before discharge.

Using this approach, they found that most subclinical patients did not require treatment with hydrocortisone, a glucocorticoid taken to compensate for low levels of cortisol in the body, after surgery.

The study, “Alterations in hypothalamic-pituitary-adrenal function immediately after resection of adrenal adenomas in patients with Cushing’s syndrome and others with incidentalomas and subclinical hypercortisolism,” was published in Endocrine.

The HPA axis is the body’s central stress response system. The hypothalamus releases corticotropin-releasing hormone (CRH) that acts on the pituitary gland to release adrenocorticotropic hormone (ACTH), leading the adrenal gland to produce cortisol.

As the body’s defense mechanism to avoid excessive cortisol secretion, high cortisol levels alert the hypothalamus to stop producing CRH and the pituitary gland to stop making ACTH.

Therefore, in diseases associated with chronically elevated cortisol levels, such as Cushing’s syndrome and adrenal incidentalomas, there’s suppression of the HPA axis.

After an adrenalectomy, which is the surgical removal of one or both adrenal glands, patients often have low cortisol levels (hypocortisolism) and require glucocorticoid replacement therapy.

“Most studies addressing the peri-operative management of patients with adrenal hypercortisolism have reported that irrespective of how mild the hypercortisolism was, such patients were given glucocorticoids before, during and after adrenalectomy,” the researchers wrote.

Evidence also shows that, after surgery, glucocorticoid therapy is administered for months before attempting to test for recovery of HPA function.

For the past 30 years, researchers at the University Hospitals Cleveland Medical Center have withheld glucocorticoid therapy in the postoperative management of patients with ACTH-secreting pituitary adenomas until there’s proof of hypocortisolism.

“The approach offered us the opportunity to examine peri-operative hormonal alterations and demonstrate their importance in predicting need for replacement therapy, as well as future recurrences,” they said.

In this prospective observational study, the investigators extended their approach to patients with subclinical hypercortisolism.

“The primary goal of the study was to examine rapid alteration in HPA function in patients with presumably suppressed axis and appreciate the modulating impact of surgical stress in that setting,” they wrote. Collected data was used to decide whether to start glucocorticoid therapy.

The analysis included 14 patients with Cushing’s syndrome and 19 individuals with subclinical hypercortisolism and an adrenal incidentaloma. All participants had undergone surgical removal of a cortisol-secreting adrenal tumor.

“None of the patients received exogenous glucocorticoids during the year preceding their evaluation nor were they taking medications or had other illnesses that could influence HPA function or serum cortisol measurements,” the researchers noted.

Glucocorticoid therapy was not administered before or during surgery.

To evaluate HPA function, the clinical team took blood samples before and at one, two, four, six, and eight hours after the adrenalectomy to determine levels of plasma ACTH, serum cortisol, and dehydroepiandrosterone sulfate (DHEA-S) — a hormone produced by the adrenal glands.

Pre-surgery assessment of both groups showed that patients with an incidentaloma plus subclinical hypercortisolism had larger adrenal masses, higher ACTH, and DHEA-S levels, but less serum cortisol after adrenal function suppression testing with dexamethasone.

Dexamethasone is a man-made version of cortisol that, in a normal setting, makes the body produce less cortisol. But in patients with a suppressed HPA axis, cortisol levels remain high.

After the adrenalectomy, the ACTH concentrations in both groups of patients increased. This was found to be negatively correlated with pre-operative dexamethasone-suppressed cortisol levels.

Investigators reported that “serum DHEA-S levels in patients with Cushing’s syndrome declined further after adrenalectomy and were undetectable by the 8th postoperative hour,” while incidentaloma patients’ DHEA-S concentrations remained unchanged for the eight-hour postoperative period.

Eight hours after surgery, all Cushing’s syndrome patients had serum cortisol levels of less than 2 ug/dL, indicating suppressed HPA function. As a result, all of these patients required glucocorticoid therapy for several months to make up for HPA axis suppression.

“The decline in serum cortisol levels was slower and less steep [in the incidentaloma group] when compared to that observed in patients with Cushing’s syndrome. At the 6th–8th postoperative hours only 5/19 patients [26%] with subclinical hypercortisolism had serum cortisol levels at ≤3ug/dL and these 5 were started on hydrocortisone therapy,” the researchers wrote.

Replacement therapy in the subclinical hypercortisolism group was continued for up to four weeks.

Results suggest that patients with an incidentaloma plus subclinical hypercortisolism did not have an entirely suppressed HPA axis, as they were able to recover its function much faster than the CS group after surgical stress.

From https://cushingsdiseasenews.com/2018/10/11/most-subclinical-cushings-patients-dont-need-glucocorticoids-post-surgery-study/?utm_source=Cushing%27s+Disease+News&utm_campaign=a881a1593b-RSS_WEEKLY_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_ad0d802c5b-a881a1593b-72451321

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Finding Ways to Deal with Post-surgery Anxieties

Posted on October 20, 2018 by MaryO

Post-traumatic stress disorder (PTSD) following Cushing’s disease is a real issue many of us face. However, we don’t have to let it control our lives — there are ways to cope.

Cushing’s changes us both mentally and physically. We become forgetful. We lose strength. We become someone we don’t recognize in the mirror. We lose hair on our heads and gain it everywhere else. We’re always in pain, and we’re always sick, with no end in sight (or at least it feels that way).

Some days will be trying and seem as if nothing seems to work, no matter what you do. I promise that you’re not alone, and you will make it through those days.

Following are a list of ways to deal with post-surgery scares:

  • Therapy/counseling: If you can afford it, talk with a professional about your health worries and how your anxiety affects you. It takes the burden off your caregivers who don’t like to see you suffer because they care so much.
  • Journaling: Journaling is a therapeutic and inexpensive way to let out your worries. Documenting your anxieties can help you keep track of how your thought processes are changing. Writing out your stresses is cathartic. Give it a try — if you haven’t already.
  • Yoga or any light exercise: If you’re in the early stages of recovery, you shouldn’t go straight back to the gym — working out is a stressor on the body. Light yoga, such as restorative yoga, in which you practice stretching, deep breathing, and relaxation, will help your mind and body to recover. Light walks are amazing for the brain and body post-surgery.
  • Delve into things you enjoy: Read, cook, go for walks, sit outside, etc. Do whatever feeds your soul and keeps your mind free from negative thoughts. Feeding your soul is one sure way to keep your mind and body happy and healthy.
  • Other ideas from the CushieWiki
  • Please share your ideas in the comments on this post or on the message boards. 

Adapted from https://cushingsdiseasenews.com/2018/10/19/cushings-post-surgery-anxieties-ptsd-post-traumatic-stress-disorder-journaling-yoga-therapy/

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

Rare Prostate Cancer Associated with Cushing’s Syndrome

Posted on October 17, 2018 by MaryO

A patient with depression developed Cushing’s syndrome (CS) because of a rare ACTH-secreting small cell cancer of the prostate, a case study reports.

The case report, “An unusual cause of depression in an older man: Cushing’s syndrome resulting from metastatic small cell cancer of the prostate,” was published in the “Lesson of the Month” section of Clinical Medicine.

Ectopic CS is a condition caused by an adrenocorticotropic hormone (ACTH)-secreting tumor outside the pituitary or adrenal glands. The excess ACTH then acts on the adrenal glands, causing them to produce too much cortisol.

Small cell cancer is more common in older men, those in their 60s or 70s. Sources of ectopic ACTH synthesis arising in the pelvis are rare; nonetheless, ACTH overproduction has been linked to tumors in the gonads and genitourinary organs, including the prostate.

Still, evidence suggests there are less than 30 published cases reporting ectopic CS caused by prostate cancer.

Researchers from the Southern Adelaide Local Health Network and the Royal Adelaide Hospital in Australia described the case of an 84-year-old man who complained of fatigue, back pain, and lack of appetite.

Blood tests revealed mildly elevated prostate-specific antigen (PSA) and creatinine levels, which could indicate the presence of prostate cancer and impaired kidney function, respectively.

The patient had a history of locally invasive prostate cancer even though he didn’t experience any symptoms of this disease.

Ultrasound examination showed an enlarged prostate plus obstructed ureters — the tubes that carry urine from the kidney to the bladder. To remove the obstruction, doctors inserted a thin tube into both ureters and restored urine flow.

After the procedure, the man had low levels of calcium, a depressed mood, and back pain, all of which compromised his recovery. Imaging of his back showed no obvious reason for his complaints, and he was discharged.

Eight days later, the patient went to the emergency room of a large public hospital because of back pain radiating to his left buttock. The man also had mild proximal weakness on both sides. He was thinner, and had low levels of calcium, high blood pressure and serum bicarbonate levels, plus elevated blood sugar. In addition, his depression was much worse.

A psychiatrist prescribed him an antidepressant called mirtazapine, and regular follow-up showed that his mood did improve with therapy.

A computed tomography (CT) scan revealed a 10.5 cm tumor on the prostate and metastasis on the lungs and liver. Further testing showed high serum cortisol and ACTH levels, consistent with a diagnosis of Cushing’s syndrome.

But researchers could not identify the ACTH source, and three weeks later, the patient died of a generalized bacterial infection, despite treatment with broad-spectrum antibiotics.

An autopsy revealed that the cancer had spread to the pelvic sidewalls and to one of the adrenal glands. Tissue analysis revealed that the patient had two types of cancer: acinar adenocarcinoma and small cell neuroendocrine carcinoma — which could explain the excess ACTH.

Cause of death was bronchopneumonia, a severe inflammation of the lungs, triggered by an invasive fungal infection.

Investigators believe there are things to be learned from this case, saying, “Neither the visceral metastases nor aggressive growth of the pelvic mass noted on imaging were typical of prostatic adenocarcinoma. [Plus], an incomplete diagnosis at death was the precipitant for a post-mortem examination. The autopsy findings were beneficial to the patient’s family and treating team. The case was discussed at a regular teaching meeting at a large tertiary hospital and, thus, was beneficial to a wide medical audience.”

Although a rare cause of ectopic ACTH synthesis, small cell prostate cancer should be considered in men presenting with Cushing’s syndrome, especially in those with a “mystery” source of ACTH overproduction.

“This case highlights the importance of multidisciplinary evaluation of clinical cases both [before and after death], and is a fine example of how autopsy findings can be used to benefit a wide audience,” the researchers concluded.

https://cushingsdiseasenews.com/2018/10/16/rare-prostate-cancer-prostate-associated-cushings-syndrome-case-report/

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

Posted on October 2, 2018 by MaryO

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

Filed under: adrenal, Cushing's, Treatments | Tagged: , , | Leave a comment »

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