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

No Association Between Long-Term Gh Replacement, Comorbidities In Nonfunctioning Pituitary Adenoma

Hammarstrand C, et al. Eur J Endocrinol. 2018;doi:10.1530/EJE-18-0370.

Patients with growth hormone deficiency due to nonfunctioning pituitary adenoma experienced excessive morbidity due to cerebral infarction and sepsis regardless of whether they received long-term GH therapy, whereas treatment was associated with a normal incidence of type 2 diabetes, despite higher BMI and more severe hypopituitarism in treated patients, according to findings from an observational, registry-based study.

“Although growth hormone replacement therapy is well-established and reverses most of the features associated with GH [deficiency], one of the safety concerns is the reduction in insulin sensitivity and the potential risk of developing type 2 diabetes mellitus,” Daniel S. Olsson, MSc, MD, PhD, professor at the Sahlgrenska Academy Institute of Medicine at the University of Gothenburg, Sweden, and colleagues wrote in the study background.

Studies examining whether there is an association have produced mixed results, the researchers wrote, and it remains unknown to what extent GH deficiency — and GH therapy —contribute to the development of type 2 diabetes and other comorbidities, including cerebral infarction, malignant tumors, myocardial infarction or fractures.

Olsson and colleagues analyzed data from 426 patients treated or followed for nonfunctioning pituitary adenoma between 1997 and 2011, selected from the Swedish National Patient Register. Researchers assessed information on tumor treatment, hormone therapy, antihypertensive medication, BMI and duration of GH therapy. For patients with type 2 diabetes, researchers assessed HbA1c values, insulin treatment, oral antidiabetes therapies and lipid-lowering therapies. Researchers followed the cohort through December 2014 or until death. Patients were stratified by use of GH therapy. Researchers calculated standardized incidence ratios (SIRs) based on the observed number of comorbidities among patients with nonfunctioning pituitary adenoma vs. the expected number of comorbidities in the background population.

Within the cohort, 207 patients received GH therapy (145 men) and 219 did not (129 men). Median duration of GH therapy was 11.7 years; mean age at diagnosis was 56 years for treated patients and 65 years for untreated patients. Median follow-up time for treated and untreated patients was 12.2 years and 8.2 years, respectively.

Incidence of cerebral infarction was increased for the whole cohort regardless of GH therapy status, with an SIR of 1.39 (95% CI, 1.03-1.84), and was most evident among 97 patients who underwent radiotherapy, in which 19 cerebral infarctions occurred vs. the expected number of 9.8 (P = .011).

“The study showed an increased overall incidence of cerebral infarction in patients with [nonfunctioning pituitary adenoma] compared to the general population that was related to previous radiotherapy, but not to GH [replacement therapy],” the researchers wrote.

Incidence of myocardial infarction was similar for treated and untreated patients, with SIRs of 1.18 (95% CI, 0.73-1.8) and 1.23 (95% CI, 0.82-1.78), respectively. Incidence of receiving medical treatment for hypertension was also similar between groups.

In assessing incidence of type 2 diabetes, the researchers found that the SIR was higher among untreated patients (1.65; 95% CI, 1.06-2.46) vs. treated patients, who had an SIR similar to the background population (0.99; 95% CI, 0.55-1.63). Treated patients with type 2 diabetes had higher BMI vs. untreated patients with type 2 diabetes (P = .01), according to researchers, and glycemic status was similar among treated and untreated patients.

The incidence of sepsis requiring hospitalization was also similar between treated and untreated patients, with rates for both groups close to double that of the background population (P < .001). Incidence of malignant tumors was not increased for treated or untreated patients when compared against the background population, according to the researchers. – by Regina Schaffer

DisclosuresThe Gothenburg Growth Hormone Database is supported partly through unrestricted grants from Novo Nordisk, Pfizer and Sandoz. Olsson reports he has served as a consultant for Ipsen, Pfizer and Sandoz. Another author reports he has served as a consultant to AstraZeneca and Viropharma/Shire, and received lecture fees from Novo Nordisk, Otsuka and Pfizer.

From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B0739a3a3-f592-4352-93f0-2ee5b5a89251%7D/no-association-between-long-term-gh-replacement-comorbidities-in-nonfunctioning-pituitary-adenoma

ACTH test after adenomectomy may accurately predict Cushing’s disease remission

A plasma adrenocorticotropic hormone suppression test performed shortly after surgical adenomectomy may accurately predict both short- and long-term remission of Cushing’s disease, according to research published in Pituitary.

“Cushing’s disease is caused by hypersecretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma, resulting in hypercortisolism,” Erik Uvelius, MD, of the department of clinical sciences, Skåne University Hospital, Lund University, Sweden, and colleagues wrote in the study background. “Surgical adenomectomy is the first line of treatment. Postoperative remission is reported in 43% to 95% of cases depending on factors such as adenoma size, finding of pituitary adenoma on preoperative MRI and surgeons’ experience. However, there is no consensus on what laboratory assays and biochemical thresholds should be used in determining or predicting remission over time.”

In the study, the researchers retrospectively gathered data from medical records of 28 patients who presented with Cushing’s disease to Skåne University Hospital between November 1998 and December 2011, undergoing 45 transsphenoidal adenomectomies.

On postoperative days 2 and 3, oral betamethasone was administered (1 mg at 8 a.m., 0.5 mg at 2 p.m., and 0.5 mg at 8 p.m.). Researchers assessed plasma cortisol and plasma ACTH before betamethasone administration and again at 24 and 48 hours, and measured 24-urinary free cortisol on postoperative day 3.

At 3 months postoperatively and then annually, plasma concentrations of morning cortisol and ACTH along with urinary-free cortisol and/or a low-dose dexamethasone suppression test were evaluated at the endocrinologists’ discretion. The researchers defined remission as lessening of clinical signs and symptoms of hypercortisolism, as well as laboratory confirmation through the various tests.

The researchers used Youden’s index to establish the cutoff with the highest sensitivity and specificity in predicting remission over the short term (3 months) and long term (5 years or more). Clinical accuracy of the different tests was illustrated through the area under curve.

The study population consisted of mainly women (71%), with a median age of 49.5 years. No significant disparities were seen in age, sex or surgical technique between patients who underwent a primary procedure and those who underwent reoperation. Two of the patients were diagnosed with pituitary carcinoma and 11 had a macroadenoma. ACTH positivity was identified in all adenomas and pathologists confirmed two cases of ACTH-producing carcinomas.

Of the 28 patients, 12 (43%) demonstrated long-term remission at last follow-up. Three patients were not deemed in remission after primary surgery but were not considered eligible for additional surgical intervention, whereas 13 patients underwent 17 reoperations to address remaining disease or recurrence. Four patients demonstrated long-term remission after a second or third procedure, equaling 16 patients (57%) achieving long-term remission, according to the researchers.

The researchers found that both short- and long-term remission were most effectively predicted through plasma cortisol after 24 and 48 hours with betamethasone. A short-term remission cutoff of 107 nmol/L was predicted with a sensitivity of 0.85, specificity of 0.94 and a positive predictive value of 0.96 and AUC of 0.92 (95% CI, 0.85-1). A long-term remission cutoff of 49 nmol/L was predicted with a sensitivity of 0.94, specificity of 0.93, positive predictive value of 0.88 and AUC of 0.98 (95% CI, 0.95-1). This cutoff was close to the suppression cutoff for the diagnosis of Cushing’s disease, 50 nmol/L. The cutoff of 25 nmol/L showed that the use of such a strict suppression cutoff would cause a low level of true positives and a higher occurrence of false negatives, according to the researchers.

“A 48 h 2 mg/day betamethasone suppression test day 2 and 3 after transsphenoidal surgery of Cushing’s disease could safely predict short- and long-term remission with high accuracy,” the researchers wrote. “Plasma cortisol after 24 hours of suppression showed the best accuracy in predicting 5 years’ remission. Until consensus on remission criteria, it is still the endocrinologists’ combined assessment that defines remission.” – by Jennifer Byrne

DisclosuresThe authors report no relevant financial disclosures.

From https://www.healio.com/endocrinology/neuroendocrinology/news/in-the-journals/%7B0fdfb7b0-e418-4b53-b59d-1ffa3f7b8cd3%7D/acth-test-after-adenomectomy-may-accurately-predict-cushings-disease-remission

Pregnant Women with Hypertension and Hypercortisolism May Have Cushing’s

Pregnant woman with hypertension and significant signs of hypercortisolism (high cortisol levels) may have Cushing’s disease, according to a new case report.

The report, titled “A Case of Cushing’s Syndrome in Pregnancy,” was published in the Iranian Journal of Medical Sciences.

While Cushing’s rarely occurs in women during pregnancy, high cortisol levels can lead to major complications for both the mother and the fetus, such as premature birth and high fetal mortality.

However, it can be difficult to diagnose pathological hypercortisolism in these women as the symptoms might resemble other diseases that commonly occur during pregnancy, such as preeclampsia (high blood pressure during pregnancy) and gestational diabetes.

Unfortunately, there are no effective long-term medical therapies for Cushing’s. The most definitive therapy is the surgical removal of the pituitary or adrenal adenoma, if that is the case of hypercortisolism.

The case report details that a 29-year old women in the 27th week of pregnancy presented to the Ghaem Hospital clinic in Mashhad, Iran, with edema, weakness, and hypertension. Her symptoms also included truncal obesity, moon face (her face had a rounded appearance), purple steria on her upper and lower limbs and abdomen, excessive edema, and wet skin.

At first, she was hospitalized for suspected preeclampsia, but the diagnosis was later excluded.

The patient’s hormonal profile showed high levels of 24-hour urine cortisol. There were also low levels of adrenocorticotropic hormone (ACTH), which results from a negative feedback due to excessive cortisol. However, plasma cortisol is generally elevated during pregnancy, and therefore may not be the best method for diagnosis.

An abdominal ultrasonography revealed a well-defined mass in the right adrenal gland.

While hospitalized, the patient experienced two crises of blood pressure, and while preeclampsia was ruled out, the physicians could find no more plausible explanation than eclampsia (the onset of seizures in a women with preeclampsia).

Since eclampsia was suspected, the physicians terminated the pregnancy at 28th week of gestation using misoprostol. The woman delivered a male infant weighing 1.94 pounds.

Two days after birth, the physicians conducted a computed tomography (CT) scan and again found a mass in the right adrenal gland.

As a result, the patient underwent a laparoscopic right adrenalectomy to remove the mass one week after giving birth. The patient’s blood pressure normalized and cortisol levels declined. Her condition remained stable after surgery.

“Cushing’s syndrome should be considered in hypertensive pregnant patients with remarkable signs of hypercortisolism,” the researchers concluded. “The best results would be achieved through a collaboration between obstetricians, endocrinologists, and surgeons.”

From https://cushingsdiseasenews.com/2017/12/19/pregnant-women-hypertension-hypercortisolism-may-have-cushings-disease/

Delayed complications after transsphenoidal surgery for pituitary adenomas

World Neurosurg. 2017 Oct 5. pii: S1878-8750(17)31710-2. doi: 10.1016/j.wneu.2017.09.192. [Epub ahead of print]

Abstract

Perioperative complications after transsphenoidal surgery for pituitary adenomas have been well documented in the literature; however, some complications can occur in a delayed fashion postoperatively and reports are sparse about their occurrence, management, and outcome.

Here, we describe delayed complications after transsphenoidal surgery and discuss the incidence, temporality from the surgery, and management of these complications based on the findings of studies that reported delayed postoperative epistaxis, delayed postoperative cavernous carotid pseudoaneurysm formation and rupture, vasospasm, delayed symptomatic hyponatremia (DSH), hypopituitarism, hydrocephalus, and sinonasal complications.

Our findings from this review revealed an incidence of 0.6-3.3% for delayed postoperative epistaxis at 1-3 weeks postoperatively, 18 reported cases of delayed carotid artery pseudoaneurysm formation at 2 days to 10 years postoperatively, 30 reported cases for postoperative vasospasm occurring 8 days postoperatively, a 3.6-19.8% rate of DSH at 4-7 days postoperatively, a 3.1% rate of new-onset hypopituitarism at 2 months postoperatively, and a 0.4-5.8% rate of hydrocephalus within 2.2 months postoperatively.

Sinonasal complications are commonly reported after transsphenoidal surgery, but spontaneous resolutions within 3-12 months have been reported. Although the incidence of some of these complications is low, providing preoperative counseling to patients with pituitary tumors regarding these delayed complications and proper postoperative follow-up planning is an important part of treatment planning.

KEYWORDS:

carotid pseudoaneurysm; cerebrospinal fluid leak; delayed complications; epistaxis; hydrocephalus; hyponatremia; hypopituitarism; pituitary; sinonasal complication; transsphenoidal surgery; tumor

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