Expert opinion on pituitary complications in immunotherapy

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

French Endocrine Society Guidance on endocrine side-effects of immunotherapy

The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPI). However, the use of ICPI has a risk of side-effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side-effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side-effects in oncology using \u27Common terminology criteria for adverse events\u27 (CTCAE) and the difficulties in applying this to endocrine side-effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side-effects (high-dose corticosteroids, contra-indicated in ICPI for example), and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high dose glucocorticoid intake

Pre-surgical medical treatment, a major prognostic factor for long-term remission in acromegaly

PurposeTo determine whether pre-surgical medical treatment (PSMT) using long-acting Somatostatin analogues in acromegaly may improve long-term surgical outcome and to determine decision making criteria.MethodsThis retrospective study included 110 consecutive patients newly diagnosed with acromegaly, who underwent surgery in a reference center (Marseille, France). The mean long-term follow-up period was 51.436.5 (median 39.4) months. Sixty-four patients received PSMT during 3-18 (median 5) months before pituitary surgery. Remission was defined at early (3 months) evaluation and at last follow-up by GH nadir after oral glucose tolerance test<0.4 mu g/L and normal IGF-1.ResultsPretreated and non-pretreated groups were comparable for the main confounding factors except for higher IGF-1at diagnosis in PSMT patients. Remission rates were significantly different in pretreated or not pretreated groups (61.1% vs. 36.6%, respectively at long-term evaluation). In multivariate analysis, PSMT was significantly linked to 3 months (p<0.01) and long-term remission (p<0.01). Duration of PSMT was not significantly different in cured or non-cured patients, at both evaluation times. PSMT appeared to be more beneficial for patients with an invasive tumor. No patient with a tumor greater than 18mm or mean GH level exceeding 35ng/mL at diagnosis was cured by surgery alone (vs. 8 and 9 patients in the pretreated group, respectively). Patients with PSMT showed more transient mild hyponatremia after surgery.Conclusions p id=Par4 PSMT significantly improved short and long-term remission in patients with acromegaly, independent of its duration, especially in invasive adenomas

[Clinical and genetic aspects of combined pituitary hormone deficiencies]

International audienceDEFINITION: Congenital hypopituitarism is characterized by multiple pituitary hormone deficiency, including somatotroph, thyrotroph, lactotroph, corticotroph or gonadotroph deficiencies, due to mutations of pituitary transcription factors involved in pituitary ontogenesis. INCIDENCE: Congenital hypopituitarism is rare compared with the high incidence of hypopituitarism induced by pituitary adenomas, transsphenoidal surgery or radiotherapy. The incidence of congenital hypopituitarism is estimated to be between 1:3000 and 1:4000 births. CLINICAL SIGNS: Clinical presentation is variable, depending on the type and severity of deficiencies and on the age at diagnosis. If untreated, main symptoms include short stature, cognitive alterations or delayed puberty. DIAGNOSIS: A diagnosis of combined pituitary hormone deficiency (CPHD) must be suspected when evident causes of hypopituitarism (sellar tumor, postsurgical or radioinduced hypopituitarism...) have been ruled out. Clinical, biological and radiological work-up is very important to better determine which transcription factor should be screened. Confirmation is provided by direct sequencing of the transcription factor genes. AETIOLOGY: Congenital hypopituitarism is due to mutations of several genes encoding pituitary transcription factors. Phenotype varies with the factor involved: PROP1 (somatolactotroph, thyrotroph, gonadotroph and sometimes corticotroph deficiencies; pituitary hyper and hypoplasia), POU1F1 (somatolactotroph and thyrotroph deficiencies, pituitary hypoplasia), HESX1 (variable pituitary deficiencies, septo-optic dysplasia), and less frequently LHX3 (somatolactotroph, thyrotroph and gonadotroph deficiencies, limited head and neck rotation) and LHX4 (variable pituitary deficiencies, ectopic neurohypophysis, cerebral abnormalities). MANAGEMENT: An appropriate replacement of hormone deficiencies is required. Strict follow-up is necessary because patients develop new deficiencies (for example late onset corticotroph deficiency in patients with PROP1 mutations). GENETIC COUNSELLING: Type of transmission varies with the factor and the mutation involved (recessive transmission for PROP1 and LHX3, dominant for LHX4, autosomal or recessive for POU1F1 and HESX1). PROGNOSIS: It is equivalent to patients without pituitary deficiencies if treatment is started immediately when diagnosis is confirmed, and if a specialized follow-up is performed

Evaluation of an individualized education program in pituitary diseases: a pilot study

International audienceThe low prevalence of pituitary diseases makes patient autonomy crucial, and self-management programs should be more common. Objectives To assess the efficacy of an education program for patients with pituitary diseases in terms of patients’ quality of life, satisfaction and goal attainment. Design and methods Adult patients with pituitary disorders were recruited in a tertiary referral center and chose at least three of eight possible sessions on various topics, from disease management to psychosocial issues. Patients were included if they attended at least three sessions between 2012 and 2016 and completed the initial, final, and follow-up questionnaires. Data on quality of life (SF36), satisfaction and goal attainment were analyzed. Results Fifty-three patients were included (33 women; mean age, 53.5 years). There were a significant quality of life improvements in terms of physical and psychic limitation scores at the final assessment that persisted at follow-up evaluation. Most patients reached their objectives, especially those on sharing experiences and improving autonomy and self-confidence. More than half set new objectives at the end of the program, the most popular one being to reinforce their knowledge of their pituitary disease, its evolution and treatment (17.1% of patients). The mean overall satisfaction score was 3.75/4. At follow-up evaluation, patients reported improved self-management of pituitary disease (3.6/5) and improved self-efficacy (3.8/5). Conclusion Individualizing the educational objectives of patients with pituitary disease improves the way they live with their disease. If confirmed in other cohorts, this approach could become the gold standard for education programs in rare endocrine diseases

[Genetic aspects of growth hormone deficiency].

International audienceCongenital growth hormone deficiency (GHD) is a rare cause of growth delay. It should be suspected when other causes of hypopituitarism (sellar tumor, postsurgical or radioinduced hypopituitarism, etc.) have been ruled out. GHD can be isolated (IGHD) or associated with at least one other pituitary hormone deficiency (CPHD) including thyrotroph, lactotroph, corticotroph, or gonadotroph deficiencies. CPHD is caused by mutations of genes coding for pituitary transcription factors involved in pituitary ontogenesis or in the hypothalamic-pituitary axis. Clinical presentation varies, depending on the type and severity of GHD, the age at diagnosis, the association with other pituitary hormone deficiencies, or extrapituitary malformations. Clinical, biological, and radiological work-up is very important to determine for which transcription factor the patient should be screened. There is a wide variety of phenotypes depending on the transcription factor involved: PROP1 (somatolactotroph, thyrotroph, gonadotroph, and sometimes corticotroph deficiencies ; pituitary hyper- or hypoplasia), POU1F1 (somatolactotroph and thyrotroph deficiencies, pituitary hypoplasia), HESX1 (variable pituitary deficiencies, septo-optic dysplasia), and less frequently LHX3 (somatolactotroph, thyrotroph, and gonadotroph deficiencies, deafness, and limited head and neck rotation), LHX4 (variable pituitary deficiencies, ectopic neurohypophysis, cerebral abnormalities), and OTX2 (variable pituitary deficiencies, ectopic neurohypophysis, ocular abnormalities). Mutations of PROP1 remain the first identified cause of CPHD, and as a consequence the first to be sought. POU1F1 mutations should be looked for in the postpubertal population presenting with GH/TSH deficiencies and no extrapituitary malformations. Once genetic diagnosis has been concluded, a strict follow-up is necessary because patients can develop new deficiencies (for example, late-onset corticotroph deficiency in patients with PROP1 mutations). Identification of gene defects allows early treatment of pituitary deficiency and prevention of their potentially lethal consequences. If untreated, the main symptoms include short stature, cognitive alterations, or delayed puberty. An appropriate replacement of hormone deficiencies is therefore required. Depending on the type of transmission (recessive transmission for PROP1 and LHX3, dominant for LHX4, autosomal dominant or recessive for POU1F1 and HESX1), genetic counseling might be proposed. Genotyping appears highly beneficial at an individual and familial level

Meningiomas in patients with long-term exposition to progestins: Characteristics and outcome

International audienceThe aim of this study was to describe progestin-associated meningiomas' characteristics, outcome and management

Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms

International audienceBACKGROUND: Pituitary stalk interruption syndrome (PSIS) is a particular entity in the population of patients with hypopituitarism. Only rare cases have a known genetic cause. OBJECTIVES: i) To compare subgroups with or without extra-pituitary malformations (EPM) in a cohort of PSIS patients to identify predictive factors of evolution, ii) to determine the incidence of mutations of the known pituitary transcription factor genes in PSIS. Study design We analyzed features of 83 PSIS patients from 80 pedigrees and screened HESX1, LHX4, OTX2, and SOX3 genes. RESULTS: PSIS had a male predominance and was rarely familial (5%). Pituitary hypoplasia was observed only in the group with EPM. Multiple hormone deficits were observed significantly more often with versus without EPM (87.5 vs 69.5% respectively). Posterior pituitary location along the stalk was a significant protective factor regarding severity of hormonal phenotype. A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial PSIS. CONCLUSION: PSIS patients with EPM had a more severe hormonal disorder and pituitary imaging status, suggesting an antenatal origin. HESX1 or LHX4 mutations accounted for <5% of cases and were found in consanguineous or familial cases

A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism.

International audienceCONTEXT: LHX4 is a LIM homeodomain transcription factor involved in pituitary ontogenesis. Only a few heterozygous LHX4 mutations have been reported to be responsible for congenital pituitary hormone deficiency. SUBJECTS AND METHODS: A total of 136 patients with congenital hypopituitarism associated with malformations of brain structures, pituitary stalk, or posterior pituitary gland was screened for LHX4 mutations. RESULTS: Three novel allelic variants that cause predicted changes in the protein sequence of LHX4 (2.3%) were found (p.Thr99fs, p.Thr90Met, and p.Gly370Ser). On the basis of functional studies, p.Thr99fs mutation was responsible for the patients' phenotype, whereas p.Thr90Met and p.Gly370Ser were likely polymorphisms. Patients bearing the heterozygous p.Thr99fs mutation had variable phenotypes: two brothers presented somato-lactotroph and thyrotroph deficiencies, with pituitary hypoplasia and poorly developed sella turcica; the youngest brother (propositus) also had corpus callosum hypoplasia and ectopic neurohypophysis; their father only had somatotroph deficiency and delayed puberty with pituitary hyperplasia. Functional studies showed that the mutation induced a complete loss of transcriptional activity on POU1F1 promoter and a lack of DNA binding. Cotransfection of p.Thr99fs mutant and wild-type LHX4 failed to evidence any dominant negative effect, suggesting a mechanism of haploinsufficiency. We also identified prolactin and GH promoters as potential target genes of LHX4 and found that the p.Thr99fs mutant was also unable to transactivate these promoters. CONCLUSIONS: The present report describes three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. It also extends the phenotypical heterogeneity associated with LHX4 mutations, which includes variable anterior pituitary hormone deficits, as well as pituitary and extrapituitary abnormalities