Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypophysitis is a chronic inflammation of the pituitary gland of unknown (primary forms) or recognizable (secondary forms) etiology, such as the use of ipilimumab in cancer immunotherapy. Ipilimumab, which blocks the T cell inhibitory molecule CTLA-4 (cytotoxic T lymphocyte antigen-4), induces hypophysitis in about 4% of patients through unknown mechanisms. We first established a model of secondary hypophysitis by repeated injections of a CTLA-4 blocking antibody into SJL/J or C57BL/6J mice, and showed that they developed lymphocytic infiltration of the pituitary gland and circulating pituitary antibodies. We next assessed the prevalence of pituitary antibodies in a cohort of 20 patients with advanced melanoma or prostate cancer, 7 with a clinical diagnosis of hypophysitis, before and after ipilimumab administration. Pituitary antibodies, negative at baseline, developed in the 7 patients with hypophysitis but not in the 13 without it; these antibodies predominantly recognized thyrotropin-, follicle-stimulating hormone-, and corticotropin-secreting cells. We then hypothesized that the injected CTLA-4 antibody could cause pituitary toxicity if bound to CTLA-4 antigen expressed "ectopically" on pituitary endocrine cells. Pituitary glands indeed expressed CTLA-4 at both RNA and protein levels, particularly in a subset of prolactin- and thyrotropin-secreting cells. Notably, these cells became the site of complement activation, featuring deposition of C3d and C4d components and an inflammatory cascade akin to that seen in type II hypersensitivity. In summary, the study offers a mechanism to explain the pituitary toxicity observed in patients receiving ipilimumab, and highlights the utility of measuring pituitary antibodies in this form of secondary hypophysitis.
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PMID:Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. 2469 85

Hypophysitis is a frequent toxic endocrine side-effect of immunotherapy. Prevalence is higher with anti-CTLA-4 antibodies (4-20%) or in association with PD-1 inhibitors (8%). Diagnosis is presumptive, based on poorly specific clinical symptoms (usually, headache and asthenia) and/or hyponatremia and/or at least one pituitary deficit and/or abnormal imaging. Visual disorder or polyuropolydipsic syndrome are exceptional. In decreasing order of frequency, deficits are thyrotropic (86-100%), gonadotropic (85-100%) or corticotropic (50-73%); somatotropin deficit or abnormal prolactin level are rarer. Pituitary MRI in acute phase shows variable moderate increase in pituitary volume, ruling out differential diagnoses, especially pituitary metastasis. Treatment of corticotropin deficiency requires systematic emergency replacement therapy, with the usual modalities, while treatment of other deficits depends on clinical status and progression. Thyrotropin and gonadotropin deficits usually recover, but corticotropin deficiency persists over the long term, requiring education and specialized endocrinologic follow-up. Onset of hypophysitis does not contraindicate continuation of immunotherapy and does not usually require high dose synthetic glucocorticoids.
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PMID:Expert opinion on pituitary complications in immunotherapy. 3012 25

Hypophysitis, secondary to programmed cell death 1 protein (PD1) and programmed cell death 1 ligand 1 (PDL1) inhibitors, were thought to be rare, with only a few studies describing more than one case with long-term follow-up. The aim of the present study was to describe the clinical, laboratory, and morphological characteristics of PD1/PDL1 inhibitor-induced hypophysitis, and its long-term course. This cohort study was conducted at the University Hospital of Lyon, France, with longitudinal follow-up of patients. Seventeen cases of PD1/PDL1 inhibitor-induced hypophysitis were included. The median time to onset of hypophysitis was 28 weeks (range: 10-46). At diagnosis, 16 patients complained of fatigue, 12 of nausea or loss of appetite, while headache was rare. We found no imaging pituitary abnormality. All patients presented adrenocorticotropic hormone (ACTH) deficiency; other pituitary deficiencies were less common (n = 7). At last follow-up (median: 13 months), ACTH deficiency persisted in all but one patient and one patient recovered from gonadotropic deficiency. PD1/PDL1 inhibitor-induced hypophysitis is a clinical entity different from those associated to cytotoxic T-lymphocyte antigen-4 (CTLA4) inhibitors, with less obvious clinical and radiological signs, and probably a different mechanism. The paucity of symptoms demonstrates the need for systematic hormonal follow-up for patients receiving PD1/PDL1 inhibitors.
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PMID:Anti-PD1 and Anti-PDL1-Induced Hypophysitis: A Cohort Study of 17 Patients with Longitudinal Follow-Up. 3306 79