Mortality in adults with hypopituitarism

Posted on April 5, 2016 by MaryO

endo2016

 

April 04, 2016

Oral Session: Pituitary Patients and Outcomes

Mortality in adults with hypopituitarism: A systematic review and meta-analysis

S Jasim, F Alahdab, A Ahmed, S Tamhane, TB Nippoldt, H Murad

Summary: The purpose of this study was to review existing literature on mortality in hypopituitarism and determine possible predictors of this outcome to help create clinical practice guidelines. Premature mortality may be associated with hypopituitarism, and the risk of hypopituitarism is higher in women and patients diagnosed at a younger age, concluded researchers.

Methods:

  • Researchers conducted a comprehensive search of multiple databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus.
  • Using a predefined protocol, they selected eligible studies that evaluated patients with hypopituitarism and reported mortality estimates.
  • Reviewers, independently and in duplicate, extracted data and assessed the risk of bias.

Results:

  • A total of 12 studies (published 1996 to 2015) that reported on 23515 patients were included in this review.
  • Compared to the general population, hypopituitarism was associated with an overall excess mortality (weighted SMR of 1.52; 95% CI: 1.14- 2.04), P=0.000.
  • The following were independent risk factors for increased mortality: younger age at diagnosis, female gender, diagnosis of craniopharyngioma, radiation therapy, transcranial surgery, DI, and hypogonadism.

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ6AA1CEC190F5428EA690616DAA054518/57001/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ENDO2016&nonus=0

Filed under: Cushing's, Meetings and Conferences, pituitary, Rare Diseases | Tagged: , , , , | Leave a comment »

Cushing’s disease associated with USP8 mutations

Posted on April 5, 2016 by MaryO

endo2016

 

April 04, 2016

Oral Session: Pituitary Patients and Outcomes

Cushing’s disease associated with USP8 mutations

RR Correa, FR Faucz, A Angelousi, N Settas, P Chittiboina, MB Lodish, CA Stratakis

Summary: In Cushing’s disease (CD), pituitary corticotroph adenomas secrete excessive adrenocorticotropic hormone (ACTH), resulting in hypercortisolism. Often, the genetic pathogenesis of CD remains unknown, but recent studies have shown that the ubiquitin-specific protease 8 gene (USP8) is frequently mutated in CD. This gene codes for a protein deubiquitinase that inhibits the lysosomal degradation of the epidermal growth factor receptor. Researchers determined that pediatric patients with USP8 mutations were predominantly female and presented with higher ACTH levels than control patients.

Methods:

  • To further study the prevalence of mutations in USP8, researchers sequenced the complete USP8-coding and surrounding intronic regions in 97 patients with diagnosed CD by Sanger sequencing of germline DNA (n=97) and tumor DNA (n=50).
  • They analuzed biochemical and clinical characteristics in all the patients with predicted (by in silico analysis) damaging USP8 mutations and it was compared to patients without the mutation (control).

Results:

  • Overall researchers identified 18 (18.5%) patients with corticotroph adenomas who had USP8mutations, 13 with germline mutation, 2 with a germline and a new somatic mutation, and 5 with somatic mutation only.
  • All the somatic mutations that were not present at the germline level were mutations in the previously described hotspot.
  • Female-to-male ratio in the patients with USP8 mutations was 3.5:1 compared to the control ratio of 1:1 (P=0.05).
  • The mean age was 13 years old (range 6-18) and 72% (13/18) were whites.
  • Three of the mutant tumors were macroadenomas (≥ 1 cm) and 15 were microadenomas (< 1 cm).
  • In cases, mean basal plasma ACTH was 53.2±28.5 pg/mL and 39.6±19.1 pg/mL in the control group (P=0.02).
  • Researchers did not note any statistically significant differences in cortisol levels between the groups.

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Decreased prefrontal functional brain response in women with Cushing’s syndrome in remission

Posted on April 5, 2016 by MaryO

endo2016

 

April 03, 2016

Poster Session: Cushing’s Syndrome and Primary Adrenal Disorders

Decreased prefrontal functional brain response in women with Cushing’s syndrome in remission

O Ragnarsson, A Stomby, P Dahlqvist, JA Evang, M Ryberg, T Olsson, J Bollerslev, L Nyberg, G Johannsson

Summary: Neuropsychiatric symptoms including impairment of memory, attention, and executive function are important features of Cushing’s syndrome (CS). Notably, patients with CS in remission commonly demonstrate residual cognitive dysfunction, which has been suggested to be linked to incomplete recovery of neuronal function. Researchers sought to assess whether functional brain responses are altered during cognitive testing in patients with CS in remission. During episodic memory, women with CS in long-term remission have reduced functional brain responses in the prefrontal cortex and in the hippocampus.

Methods:

  • Included in this study were 19 women previously treated for CS (14 Cushing’s disease and 5 cortisol producing adrenal adenomas) and 19 controls, matched for age, gender, and education.
  • The median (interquartile range) remission time was 7 (6-10) years.
  • Researchers studied brain activity with functional magnetic resonance imaging during an episodic-memory face-name task.
  • The primary regions of interest were the prefrontal cortex and the hippocampus.
  • A voxel wise comparison of functional brain responses in patients and controls was performed, and an uncorrected P < 0.001 was considered significant.

Results:

  • During memory encoding, patients displayed lower functional brain responses in the left and right prefrontal gyrus (Brodmann areas [BA] 44, 45, and 46) as well as the right inferior occipital gyrus (BA 18) compared to controls (P < 0.001 for all).
  • Patients displayed lower functional brain responses in several brain areas including the prefrontal, parietal, occipital, and cerebellar cortices bilaterally during memory retrieval.
  • The most predominant difference was found in the right prefrontal cortex (BA 46 and 48; P < 0.001).
  • Reduced functional response in left dorsolateral prefrontal cortex was seen for patients during both encoding and retrieval.
  • Researchers compared the functional brain responses in four hippocampal clusters that were significantly activated during memory encoding among all participants (P < 0.05, FDR).
  • Patients had a trend toward lower functional brain responses in the left anterior hippocampus compared to controls (P=0.05).

From http://www.mdlinx.com/endocrinology/conference-abstract.cfm/ZZ6AA1CEC190F5428EA690616DAA054518/56991/?utm_source=confcoveragenl&utm_medium=newsletter&utm_content=abstract-list&utm_campaign=abstract-ENDO2016&nonus=0

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Osilodrostat for Cushing’s

Posted on November 12, 2015 by MaryO

The study looked at a drug to treat Cushing’s disease. The article, in the journal Pituitary, is called Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing’s disease.
Fleseriu M, Pivonello R, Young J, Hamrahian AH, Molitch ME, Shimizu C, Tanaka T, Shimatsu A, White T, Hilliard A, Tian C, Sauter N, Biller BM, Bertagna X.
Pituitary. 2015 Nov 5. [Epub ahead of print]

Abstract

PURPOSE:
In a 10-week proof-of-concept study (LINC 1), the potent oral 11β-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing’s disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing’s disease.

METHODS:
Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 × ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 × ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC ≤ ULN. Main efficacy endpoint was the proportion of responders (UFC ≤ ULN or ≥50 % decrease from baseline) at weeks 10 and 22.

RESULTS:
Overall response rate was 89.5 % (n/N = 17/19) at 10 weeks and 78.9 % (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC ≤ ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels.

CONCLUSIONS:
Osilodrostat treatment reduced UFC in all patients; 78.9 % (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated.

KEYWORDS:
11β-hydroxylase; Cortisol; Cushing’s; LCI699; Osilodrostat

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Pituicytoma and Cushing’s Disease in a 7-Year-Old Girl: A Mere Coincidence?

Posted on November 9, 2015 by MaryO

Paola Cambiaso, Donato Amodio, Emidio Procaccini, Daniela Longo, Stefania Galassi, Francesca Diomedi Camassei, Marco Cappa

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Abstract

Pituicytoma is a tumor extremely rare in childhood, with only 4 cases reported in literature. It is thought to arise from the specialized glial elements called “pituicytes.” The association of pituicytoma and Cushing’s disease (CD) has been described only once so far, in an adult patient.

A 7-year-old girl was referred for clinical signs of hypercortisolism, and a diagnosis of CD was made. MRI revealed 2 pathologic areas in the pituitary gland. The patient underwent surgery, with microscopic transsphenoidal approach, and a well-circumscribed area of pathologic tissue was identified and removed. Surprisingly, histologic and immunohistochemical study provided unequivocal evidence of pituicytoma. No pituitary adenoma could be identified.

For persistent hypercortisolism, the patient necessitated transsphenoidal endoscopic reintervention and 2 other lesions were removed. By immunohistological examination, these lesions were confirmed to be corticotropin-secreting adenoma. Unfortunately, there was no postoperative decrease in corticotropin and cortisol levels, and the patient underwent bilateral laparoscopic adrenalectomy.

Considering that we report a second case of association of pituicytoma and corticotropin-secreting adenoma, that CD is infrequent, and pituicytoma is extremely rare in childhood, the coexistence of these 2 tumors should not be considered a mere coincidence. To date, there is no conclusive evidence about the origin of these different subtypes of pituitary tumors. This case supports the hypothesis that these tumors share a common progenitor cell, which could be the folliculostellate cell.

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