Pituitary and adrenal disorders induced by immune checkpoint inhibitors.

Over the past decade, the development of ICI (immune checkpoint inhibitors) has constituted a revolution in the treatment of many cancers, but with a specific toxicity profile including endocrine IRAEs (immune-related adverse events). As the indications for these molecules are constantly increasing due to their efficacy, it is important that endocrinologists and oncologists know how to detect, manage and monitor this type of toxicity. Many guidelines and recommendations have been proposed in the last few years for the management of endocrinopathies. French guidelines on immunotherapy-related endocrine IRAEs were published in 2018, with a specific algorithm for hypophysitis and primary adrenal insufficiency (PAI), based on clinical suspicion followed by biochemical and imaging evaluation, and are still relevant today. Here we present the general pathophysiological mechanisms of these toxicities, and discuss the incidence, diagnosis, treatment, progression, management and monitoring of pituitary and adrenal disorders in patients treated by immunotherapy, with emphasis on hypophysitis, which is much more frequent than PAI with this type of molecule. We also highlight several key points, such as the need for emergency treatment by hydrocortisone with the possibility of continuing immunotherapy in these endocrinopathies, and the long-term persistence of corticotropin or adrenal deficiency in most cases, requiring specific "hydrocortisone education". These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

Covid-19, the thyroid and the pituitary - The real state of play.

Thyroid and pituitary disorders linked to the coronavirus SARS-CoV-2, responsible for the COVID-19 epidemic, are mainly due to direct infection of the endocrine glands by the virus and to cell damage induced by the immune response. The two most frequent thyroid complications of COVID-19 are low T3 syndrome, or "non-thyroidal illness syndrome" (NTIS), and thyroiditis. Studies among in-patients with COVID-19 have shown that between one out of six and half of them have a low TSH level, related to NTIS and thyroiditis, respectively, sometimes found in the same patient. In NTIS, the decrease in free T3 concentration correlates with the severity of the infection and with a poor prognosis. Assessment of thyroid function in patients after a COVID-19 infection, shows normalization of thyroid function tests. Thyroiditis linked to COVID-19 can be divided into two groups, which probably differ in their pathophysiology. One is "destructive" thyroiditis occurring early in infection with SARS-CoV-2, with a severe form of COVID-19, usually observed in men. It is often asymptomatic and associated with lymphopenia. The other is subacute thyroiditis occurring, on average, one month after the COVID-19 episode, usually in clinically symptomatic women and associated with moderate hyperleukocytosis. Post-infection, one quarter to one third of patients remain hypothyroid. An Italian study demonstrated that low TSH in patients hospitalized for COVID-19 was associated with prolonged hospitalization and a higher mortality risk. Pituitary diseases associated with SARS-CoV-2 infection are much rarer and the causal relationship more difficult to ascertain. Several cases of pituitary apoplexy and diabetes insipidus during COVID-19 infection have been reported. Hyponatremia occurs in 20-50% of patients admitted to hospital for COVID-19. The prevalence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) amongst these hyponatremic cases is difficult to determine. These endocrine complications may influence the prognosis of infection with SARS-CoV-2. Although they rarely require specific treatment, it is important that endocrinologists recognize them to ensure appropriate management, particularly in the acute phase.

[Checkpoint inhibitors-induced hypophysitis]. / Hypophysites induites par les immunothérapies anti-néoplasiques.

Checkpoint inhibitors immunotherapy is more and more prescribed in oncology, causing new immune related endocrine adverse events. Hypophysitis occurs in approximately 10 % of patients treated with anti-CTLA4. It occurs two to three months after initiation of the immunotherapy. The initial presentation is characterized, in typical forms, by the association of headache, asthenia and hyponatremia. Hormonal exploration usually shows ACTH, gonadotropic and thyrotropic deficiencies. ACTH deficiency may be life-threatening and requires urgent supplementation, without awaiting for biological results. MRI is warranted in order to exclude differential diagnoses, such as pituitary metastases. Hypophysitis induced by anti-PD1/PDL1 seems to be a different nosologic entity characterized by a later onset and a less symptomatic presentation. Biologically ACTH deficiency seems to be constant and permanent, and often isolated. Treatment requires high-dose steroids only in case of severe tumor syndrome (resistant headache, visual disturbance) or acute decompensation of ACTH deficiency. Patients always need lifelong hormonal supplementation of pituitary deficits and must be followed and educated specifically. Immunotherapy can be delayed during the acute phase, but can be secondarily continued if there is an oncological benefit. As it is a pauci-symptomatic but potentially life-threatening complication, biological screening must be systematic in patients treated with checkpoint inhibitors.

[Interdisciplinary Management of Sellar Masses]. / Interdisziplinäres Management von Hypophysentumoren.

Interdisciplinary Management of Sellar Masses Abstract. Sellar masses may present with an impairment of pituitary function (hypopituitarism), hormone hypersecretion (prolactinoma, acromegaly, glucocorticoid excess) or neurological symptoms (visual impairment, headache). An increasing number of them is discovered as an incidentaloma. Among the various entities, benign pituitary adenomas and cystic lesions are most frequently encountered. The work-up includes a laboratory evaluation for hormone hyper- or hyposecretion and an MRI of the pituitary gland. If the optic chiasm is compromised, a visual field examination is mandatory. Except for prolactinomas, symptomatic sellar masses are usually resected via an endoscopic transsphenoidal approach. If a total resection is not feasible because of the invasion of surrounding structures, debulking to relieve pressure from the optic chiasm is the primary goal and radiotherapy may be considered. Residual hormone excess can be treated medically. In the early postoperative period special attention to the development and treatment of disordered body water homeostasis and hypopituitarism is crucial. Interdisciplinary work-up and decision making are of utmost importance and will offer the best management.

[Immunotherapy-induced endocrinopathies: Insights from the 2018 French Endocrine Society Guidelines]. / Endocrinopathies induites par l'immunothérapie : synthèse du consensus 2018 de la Société française d'endocrinologie.

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 guidance document on ICPI-related endocrine toxicity. In this paper, we summarize the main insights of experts' opinions, from an oncologist viewpoint: initial screening, monitoring, emergency situations for which immediate management by the oncologist is crucial, as well as the roles of the interactions between oncologists and endocrinologists. These points will be detailed for each endocrinopathy, i.e., dysthyroidism, hypophysitis, fulminant diabetes and primary adrenal insufficiency. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. Finally, the CTCAE (Common terminology criteria for adverse events) recommendations will be discussed in view of the relatively easy management of such endocrine side-effects.

[Autoimmune hypophysitis associated with new anti-cancer immunotherapies]. / L'hypophysite auto-immune, complication des nouvelles immunothérapies anticancéreuses.

Recently developed immunotherapeutic agents, like anti-cytotoxic T lymphocyte antigen 4 antibody (CTLA4), anti-programmed cell death 1 (PD1) or anti-programmed cell death-ligand 1 (PDL1), have demonstrated substantial potential for the treatment of a variety of malignancies. Autoimmune side effects from these agents are diverse and can include multiple endocrinopathies like immunotherapy induced hypophysitis (IH). These toxicities appear to be more frequent in patients receiving anti-CTLA4 antibody compared to PD1/PDL1 agents. The diagnosis of IH is generally based on the presence of new hypopituitarism without an alternative etiology and radiographic pituitary enlargement or not while on treatment with Immunotherapy. Patients with IH frequently present non-specifics symptoms like headache, fatigue or weakness. ACTH and TSH deficiencies are more frequent. TSH and gonadotrophin deficiencies may be reversible but ACTH deficiency appears permanent. Glucocorticoid and thyroid hormone replacement should be instituted early after the diagnosis of IH, androgen replacement can be deferred initially and discussed by the patient. High-dose glucocorticoid does not improve the outcome of IH and should be reserved for patients with persistent severe headache, severe hyponatremia or visual defects. Patient education, early identification by measuring TSH, free thyroxine, morning ACTH and cortisol levels before each treatment cycle and proper treatment are the core of IH management.

Diabetes insipidus and pregnancy.

Diabetes insipidus (DI) is a rare complication of pregnancy. It is usually transient, being due to increased placental production of vasopressinase that inactivates circulating vasopressin. Gestational, transient DI occurs late in pregnancy and disappears few days after delivery. Acquired central DI can also occur during pregnancy, for example in a patient with hypophysitis or neuroinfundibulitis during late pregnancy or postpartum. Finally, pre-existing central or nephrogenic DI may occasionally be unmasked by pregnancy. Treatment with dDAVP (desmopressin, Minirin(®)) is very effective on transient DI of pregnancy and also on pre-existing or acquired central DI. Contrary to vasopressin, dDAVP is not degraded by vasopressinase. Nephrogenic DI is insensitive to dDAVP and is therefore more difficult to treat during pregnancy if fluid intake needs to be restricted.

Hypophysitis in 2014.

Hypophysitis is a rare pathology. As clinical symptoms and radiologic signs are non-specific, the diagnostic is difficult. Hypophysitis's pathogenesis remains obscure but new histological and etiological variants have recently been reported. Primary hypophysitis is the main form. For the first time, hypophysitis in ANCA-associated vasculitides has been reported. An entity of immunoglobulin G4 related plasmatic hypophysitis has been described and well-defined diagnostic criteria are proven. Monoclonal antibodies directed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4), investigated in metastatic cancer, can induce hypophysitis. Hypophysitis's pathogenesis remains obscure but several candidate pituitary autoantigens have been described in the last decade, although none has proven useful as a diagnostic tool.

[Current update on hypophysitis]. / Quoi de neuf dans les hypophysites?

Hypophysitis is a rare disorder. As clinical manifestations and radiologic signs are non specific, the diagnosis is difficult. Pathogenesis of hypophysitis remains largely unknown but new histological and etiological variants have been recently reported. Primary hypophysitis is the main form. For the first time, hypophysitis in ANCA-associated vasculitides has been reported. An entity of IgG4 related plasmatic hypophysitis has been described and well-defined diagnostic criteria have been proposed. Monoclonal antibodies directed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4), investigated in metastatic cancer, can induce hypophysitis. Several candidate pituitary auto-antigens have been described in the last decade, although none has proven to be useful as a diagnostic tool.