Long-Term Obesity Persists Despite Pituitary Adenoma Treatment In Childhood

Sethi A, et al. Clin Endocrinol. 2019;doi:10.1111/CEN.14146.

January 5, 2020

Obesity is common at diagnosis of pituitary adenoma in childhood and may persist despite successful treatment, according to findings published in Clinical Endocrinology.

“The importance of childhood and adolescent obesity on noncommunicable disease in adult life is well recognized, and in this new cohort of patients, we report that obesity is common at presentation of pituitary adenoma in childhood and that successful treatment is not necessarily associated with weight loss,” Aashish Sethi, MD, MBBS, a pediatric endocrinologist in the department of endocrinology at Alder Hey Children’s Hospital in Liverpool, United Kingdom, and colleagues wrote. “We have reported obesity, and obesity-related morbidity in a mixed cohort of children and young adults previously, but [to] our knowledge, this is the first time this observation has been reported in a purely pediatric cohort.”

In a retrospective study, Sethi and colleagues analyzed clinical and radiological data from 24 white children from Alder Hey Children’s Hospital followed for a median of 3.3 years between 2000 and 2019 (17 girls; mean age at diagnosis, 15 years). Researchers assessed treatment modality (medical, surgical or radiation therapy), pituitary hormone deficiencies and BMI, as well as results of any genetic testing.

Within the cohort, 13 girls had prolactinomas (mean age, 15 years), including 10 macroadenomas between 11 mm and 35 mm in size. Children presented with menstrual disorders (91%), headache (46%), galactorrhea (46%) and obesity (38%). Nine children were treated with cabergoline alone, three also required surgery, and two were treated with the dopamine agonist cabergoline, surgery and radiotherapy.

Five children had Cushing’s disease (mean age, 14 years; two girls), including one macroadenoma. Those with Cushing’s disease presented with obesity (100%), short stature (60%) and headache (40%). Transsphenoidal resection resulted in biochemical cure; however, two patients experienced relapse 3 and 6 years after surgery, respectively, requiring radiotherapy. One patient also required bilateral adrenalectomy.

Six children had a nonfunctioning pituitary adenoma (mean age, 16 years; two girls), including two macroadenomas. These children presented with obesity (67%), visual field defects (50%) and headache (50%). Four required surgical resections, with two experiencing disease recurrence after surgery and requiring radiotherapy.

During the most recent follow-up exam, 13 children (54.1%) had obesity, including 11 who had obesity at diagnosis.

“The persistence of obesity following successful treatment, in patients with normal pituitary function, suggests that mechanisms other than pituitary hormone excess or deficiency may be important,” the researchers wrote. “It further signifies that obesity should be a part of active management in cases of pituitary adenoma from diagnosis.” – by Regina Schaffer

Disclosures: The authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/adrenal/news/online/%7Bde3fd83b-e8e0-4bea-a6c2-99eb896356ab%7D/long-term-obesity-persists-despite-pituitary-adenoma-treatment-in-childhood

BIPSS Diagnostic Method May Cause False Positive in Some Cases of Cyclic Cushing’s Syndrome

A diagnostic technique called bilateral inferior petrosal sinus sampling (BIPSS), which measures the levels of the adrenocorticotropic hormone (ACTH) produced by the pituitary gland, should only be used to diagnose cyclic Cushing’s syndrome patients during periods of cortisol excess, a case report shows.

When it is used during a spontaneous remission period of cycling Cushing’s syndrome, this kind of sampling can lead to false results, the researchers found.

The study, “A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing’s syndrome,” was published in BMC Endocrine Disorders.

Cushing’s syndrome is caused by abnormally high levels of the hormone cortisol. This is most often the result of a tumor on the pituitary gland that produces too much ACTH, which tells the adrenal glands to increase cortisol secretion.

However, the disease may also occur due to adrenal tumors or tumors elsewhere in the body that also produce excess ACTH — referred to as ectopic Cushing’s syndrome.

Because treatment strategies differ, doctors need to determine the root cause of the condition before deciding which treatment to choose.

BIPSS can be useful in this regard. It is considered a gold standard diagnostic tool to determine whether ACTH is being produced and released by the pituitary gland or by an ectopic tumor.

However, in people with cycling Cushing’s syndrome, this technique might not be foolproof.

Researchers reported the case of a 43-year-old woman who had rapidly cycling Cushing’s syndrome, meaning she had periods of excess cortisol with Cushing’s syndrome symptoms — low potassium, high blood pressure, and weight gain — followed by normal cortisol levels where symptoms resolved spontaneously.

In general, the length of each period can vary anywhere from a few hours to several months; in the case of this woman, they alternated relatively rapidly — over the course of weeks.

After conducting a series of blood tests and physical exams, researchers suspected of Cushing’s syndrome caused by an ACTH-producing tumor.

The patient eventually was diagnosed with ectopic Cushing’s disease, but a BIPSS sampling performed during a spontaneous remission period led to an initial false diagnosis of pituitary Cushing’s. As a result, the woman underwent an unnecessary exploratory pituitary surgery that revealed no tumor on the pituitary.

Additional imaging studies then identified a few metastatic lesions, some of which were removed surgically, as the likely source of ACTH. However, the primary tumor still hasn’t been definitively identified. At the time of publication, the patient was still being treated for Cushing’s-related symptoms and receiving chemotherapy.

There is still a question of why the initial BIPSS result was a false positive. The researchers think that the likely explanation is that BIPSS was performed during an “off phase,” when cortisol levels were comparatively low. In fact, a later BIPSS performed during a period of high cortisol levels showed no evidence of ACTH excess in the pituitary.

This case “demonstrates the importance of performing diagnostic tests only during the phases of active cortisol secretion, as soon as first symptoms appear,” the researchers concluded.

From https://cushingsdiseasenews.com/2020/01/02/cushings-syndrome-case-study-shows-drawback-in-bipss-method/

Risk for thrombotic events high after Cushing’s syndrome surgery

Approximately 20% of a cohort of adults with Cushing’s syndrome experienced at least one thrombotic event after undergoing pituitary or adrenal surgery, with the highest risk observed for those undergoing bilateral adrenalectomy, according to findings from a retrospective analysis published in the Journal of the Endocrine Society.

“We have previously showed in a recent meta-analysis that Cushing’s syndrome is associated with significantly increased venous thromboembolic events odds vs. the general population, though the risk is lower than in patients undergoing major orthopedic surgery,” Maria Fleseriu, MD, FACE, professor of neurological surgery and professor of medicine in the division of endocrinology, diabetes and clinical nutrition in the School of Medicine at Oregon Health & Science University and director of the OHSU Northwest Pituitary Center, told Healio. “However, patients undergoing many types of orthopedic surgeries have scheduled thromboprophylaxis, especially postsurgery, which is not the standard of care in patients with Cushing’s syndrome. In this study, we wanted to look in more detail at the rates of all thrombotic events, both arterial and venous, in patients at our specialized pituitary center over more than a decade.”

In a retrospective, longitudinal study, Fleseriu and colleagues analyzed data from 208 individuals with Cushing’s syndrome undergoing surgical (pituitary, unilateral and bilateral adrenalectomy) and medical treatment at a single center (79.3% women; mean age at presentation, 45 years; mean BMI, 33.9 kg/m²; 41.8% with diabetes). Individuals with severe illness and immediate mortality were excluded. Thromboembolic events (myocardial infarction, deep venous thrombosis [DVT], and pulmonary embolism or stroke) were recorded at any point up until last patient follow-up. Researchers assessed all patients who received anticoagulation in the immediate postoperative period and up to 3 months after surgery, recording doses and complications for anticoagulation.

Within the cohort, 39 patients (18.2%) experienced at least one thromboembolic event (56 total events; 52% venous), such as extremity DVT (32%), cerebrovascular accident (27%), MI (21%), and pulmonary embolism (14%). Of those who experienced a thromboembolic event, 40.5% occurred within 60 days of surgery.

Researchers found that 14 of 36 patients who underwent bilateral adrenalectomy experienced a thromboembolic event, for an OR of 3.74 (95% CI, 1.69-8.27). Baseline 24-hour urinary free cortisol levels did not differ for patients with or without thromboembolic event after bilateral adrenalectomy.

“Despite following these patients over time, results almost surprised us,” said Fleseriu, also an Endocrine Today Editorial Board Member. “The risk of thromboembolic events in patients with Cushing’s syndrome was higher than we expected, approximately 20%. Many patients had more than one event, with higher risk at 30 to 60 days postoperatively. Use of a peripherally inserted central catheter line clearly increased risk of upper extremity DVT.”

Among 197 patients who underwent surgery, 50 (25.38%) received anticoagulation after surgery with 2% experiencing bleeding complications.

“We clearly need to understand more about what happens in patients with Cushing’s syndrome for all comorbidities, but especially thrombosis, and find the factors that predict higher risk and use anticoagulation in those patients,” Fleseriu said. “We have shown that among patients who had anticoagulation, risks were minimal. We also have to think more about timelines for these thromboembolic events and the duration of anticoagulation, and probably to expand it up to 30 to 60 days postoperatively if there are no contraindications, especially for patients undergoing bilateral adrenalectomy.”

Fleseriu cautioned that the findings do not necessarily suggest that every individual with Cushing’s syndrome needs anticoagulation therapy, as the study was retrospective. Additionally, sex, age, BMI, smoking status, estrogen or testosterone supplementation, diabetes and hypertension — all known factors for increased thrombosis risk among the general population — were not found to significantly increase the risk for developing a thromboembolic event, Fleseriu said.

“As significantly more patients have exogenous Cushing’s syndrome than endogenous Cushing’s syndrome and many of these patients undergo surgeries, we hope that our study increased awareness regarding thromboembolic risks and the need to balance advantages of thromboprophylaxis with risk of bleeding,” Fleseriu said. – by Regina Schaffer

For more information:

Maria Fleseriu, MD, FACE, can be reached at fleseriu@ohsu.edu.

Disclosure: Fleseriu reports she has received research funding paid to her institution from Novartis and Strongbridge and has received consultant fees from Novartis and Strongbridge.

 

From  https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7Bce267e5a-0d32-4171-abc8-34369b455fcf%7D/risk-for-thrombotic-events-high-after-cushings-syndrome-surgery

Cortisol Levels Predict Remission in Cushing’s Patients Undergoing Transsphenoidal Surgery

In patients with Cushing’s disease, removing the pituitary tumor via an endoscopic transsphenoidal surgery (TSS) leads to better remission rates than microscopic TSS, according to new research.

But regardless of surgical approach, plasma cortisol levels one day after surgery are predictive of remission, researchers found.

The study, “Management of Cushing’s disease: Changing trend from microscopic to endoscopic surgery,” was published in the journal World Neurosurgery.

Because it improves visualization and accessibility, endoscopic TSS has been gaining popularity over microscopic TSS to remove pituitary tumors in Cushing’s disease patients. Yet, although this surgery has been associated with high remission rates, whether it outperforms microscopic surgery and determining the factors affecting long-term outcomes may further ease disease recurrence after TSS.

A team with the All India Institute of Medical Sciences addressed this topic in 104 patients who underwent surgery from January 2009 to June 2017. Among these patients, 47 underwent microscopic surgery and 55 endoscopic surgery. At presentation, their ages ranged from 9 to 55 (mean age of 28). Also, patients had been experiencing Cushing’s symptoms over a mean duration of 24 months.

Eighty-seven patients showed weight gain. Hypertension (high blood pressure) and diabetes mellitus were among the most common co-morbidities, found in 76 and 33 patients, respectively. Nineteen patients had osteoporosis and 12 osteopenia, which refers to lower-than-normal bone mineral density.

As assessed with magnetic resonance imaging, 68 patients had a microadenoma (a tumor diameter smaller than one centimeter) and 27 had a macroadenoma (a tumor one centimeter or larger). Only two patients had an invasive pituitary adenoma.

Two patients with larger tumors were operated on transcranially (through the skull). The surgery resulted in total tumor removal in 90 cases (86.5%). A blood loss greater than 100 milliliter was more common with endoscopic than with microscopic TSS.

Ten patients developed transient diabetes inspidus, two experienced seizures after surgery, and six of nine patients with macroadenoma and visual deterioration experienced vision improvements after TSS.

The incidence of intraoperative leak of cerebrospinal fluid — the liquid surrounding the brain and spinal cord — was 23.2%, while that of post-operative leak was 7.7% and was more common in microadenoma than macroadenoma surgery (9.8% vs. 5.0%).

Seventeen patients were lost to follow-up and two died due to metabolic complications and infections. The average follow-up was shorter for endoscopic than with microscopic surgery (18 months vs. 35 months).

Among the remaining 85 cases, 65 (76.5%) experienced remission, as defined by a morning cortisol level under 5.0 μg/dL, restored circadian rhythm (the body’s internal clock, typically impaired in Cushing’s patients), and suppression of serum cortisol to below 2 μg/dl after overnight dexamethasone suppression test.

The remission rate was 54.5% in pediatric patients and was higher with endoscopic than with microscopic TSS (88.2% vs. 56.6%). Also, patients with microadenoma showed a trend toward more frequent remission than those with macroadenoma (73.2% vs. 64.3%).

Ten of the remaining 20 patients experienced disease recurrence up to 28 months after surgery. Sixteen cases revealed signs of hypopituitarism, or pituitary insufficiency, which were managed with replacement therapy.

A subsequent analysis found that morning cortisol level on day one after surgery was the only significant predictor of remission. Specifically, a one-unit increase in cortisol lowered the likelihood of remission by 7%. A cortisol level lower than 10.7 μgm/dl was calculated as predicting remission.

Overall, the study showed that “postoperative plasma cortisol level is a strong independent predictor of remission,” the researchers wrote, and that “remission provided by endoscopy is significantly better than microscopic approach.”

From https://cushingsdiseasenews.com/2019/09/24/cortisol-levels-predict-remission-cushings-patients-undergoing-transsphenoidal-surgery/

ACTH Levels After Surgery Help Predict Remission, Recurrence in Cushing’s

Levels of adrenocorticotropic hormone (ACTH) in circulation after pituitary surgery may help predict which Cushing’s disease patients will achieve early remission and which will eventually see the disease return, a study shows.

Also, the earlier that patients reached their lowest peak of ACTH levels, the better their long-term outcomes.

The study, “Prognostic usefulness of ACTH in the postoperative period of Cushing’s disease,” was published in the journal Endocrine Connections.

Removing the pituitary tumor through a minimally invasive surgery called transsphenoidal surgery is still the treatment of choice for Cushing’s disease patients. But not all patients enter remission, and even among those who do, a small proportion will experience disease recurrence.

While cortisol levels have been suggested as a main predictor of remission and recurrence, there is no consensus as to which cutoff point should be used after surgery, or the best time for measuring this hormone.

Because Cushing’s disease is caused by an ACTH-producing tumor in the pituitary gland, and ACTH has a short half-life (approximately 10 minutes), it is expected that ACTH levels drop markedly within a few hours after surgery.

Thus, a group of researchers in Spain aimed to determine whether blood levels of ACTH could be useful for predicting remission of Cushing’s disease both immediately after surgery (defined as less than 72 hours) and in the long term.

Researchers analyzed 65 patients with Cushing’s disease who had undergone transsphenoidal surgery (seven required a second intervention) between 2005 and 2016. Remission within three months was seen in 56 of 65 cases; late disease recurrence was seen in 18 of 58 cases.

Investigators measured the ACTH nadir concentration (defined as the lowest concentration) and the time taken to reach nadir levels after surgery, as well as the plasma ACTH concentration before hospital discharge.

While ACTH levels had no predictive value, the team found that people who went into remission had significantly lower ACTH nadir levels and ACTH levels at discharge. On the other hand, levels of ACHT nadir and at discharge were significantly higher for people who experienced a relapse, compared to those who remained in remission.

Using artificial intelligence algorithms, the researchers further found that ACTH nadir, ACTH at discharge, and cortisol nadir values were all of great relevance to predict remission within three months.

Analysis indicated that using a cutoff point of 3.3 pmol/L of ACTH after surgery and before discharge gave the best sensitivity and specificity for predicting a patient’s prognosis.

Researchers further found that the time patients took to reach their ACTH nadir, regardless of nadir levels, also influenced their outcomes. In fact, patients reaching this nadir in less than than 46 hours more likely achieved early remission.

And taking longer than 39 hours to reach the ACTH nadir was significantly more frequent in patients who experienced recurrence. This indicates that the time to ACTH nadir is an important measure for prognosis.

“In the immediate postoperative period of patients with [Cushing’s disease], the ACTH concentration is of prognostic utility in relation to late disease remission,” the researchers said.

Overall, “we propose an ACTH value <3.3 pmol/L as a good long-term prognostic marker in the postoperative period of CD. Reaching the ACTH nadir in less time is associated to a lesser recurrence rate,” the study concluded.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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