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.

Growth hormone replacement improved oocyte quality in a patient with hypopituitarism: A study of follicular fluid.

BACKGROUND: Growth hormone (GH) is known to be involved in ovarian folliculogenesis and oocyte maturation. In patients with poor ovarian response without growth hormone deficiency (GHD), adjuvant GH treatment improves in-vitro fertilization (IVF) results. Improvement of oocyte quality in IVF by GH replacement was reported in only a few patients with GHD. We report on a new case with study of follicular fluid. METHODS: A 29-year-old patient with hypopituitarism was referred to our infertility center. She was undergoing hormonal replacement for hypogonadotropic hypogonadism and diabetes insipidus, and did not consider at first GH replacement. Four IVF procedures were performed between 2011 and 2014. Growth hormone replacement (somatotropin 1.1mg/day) was initiated before the fourth IVF procedure and unmasked central hypothyroidism; levothyroxine (75mg/day) was introduced. It took 10 months to reach the treatment objectives for insulin-like growth factor 1 (IGF1), free triiodothyronine (fT3) and free thyroxine (fT4). GH, IGF1 and thyroid hormones were measured in the blood and follicular fluid before and after GH and thyroid hormone replacement. Oocyte and embryo quality were also compared. RESULTS: The first 3 IVF procedures were performed without GH replacement. 62% to 100% of mature oocytes presented one or more morphologic abnormalities: diffuse cytoplasmic granularity, large perivitelline space with fragments, fragmentation of the first polar body, ovoid shape, or difficult denudation. Embryo quality was moderate to poor (grade B to D), and no pregnancy was obtained after embryo transfer. After GH replacement, hormones levels increased in follicular fluid: GH [7.68 vs. 1.39 mIU/L], IGF1 [109 vs. <25ng/mL], fT3 [3.7 vs. 2.5pmol/L] and fT4 [1.45 vs. 0.84ng/mL]. Concomitantly, there was dramatic improvement in oocyte quality (no abnormal morphologies) and embryo quality (grade A), allowing an embryo transfer with successful pregnancy. CONCLUSIONS: This is the first report illustrating changes in hormonal levels in follicular fluid and the beneficial effect of GH replacement on oocyte and embryo quality during an IVF procedure in a patient with hypopituitarism. These results suggest that GH replacement is beneficial for oocyte quality in patients with GHD.

The heart in growth hormone (GH) deficiency and the cardiovascular effects of GH.

Besides its effects on longitudinal growth in childhood and its metabolic effects with consequences on body composition and lipid levels, growth hormone (GH) has important roles on maintaining the structure and function of the normal adult heart. GH/insulin like growth factor-I (IGF-I) also interacts with the vascular system and plays a role in the regulation of vascular tone. GH deficiency (GHD) in adulthood is associated with increased fat mass (particularly visceral) and abnormal lipid profile, which may contribute to the excess cardiovascular mortality observed in patients with panhypopituitarism. Treatment with GH improved body composition (by increasing lean mass and decreasing fat mass) and improved lipid profile. It also has beneficial effects on vascular walls. The improvement in cardiovascular morbidity and mortality induced by GH is less clear as data are scarce and obtained on small populations. The importance of alteration in cardiac morphology and function observed in GHD is debated, particularly when cardiac magnetic resonance is used rather than echocardiography. The effects of treatment with GH on heart function and morphology are modest when studied by echocardiography.

[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.

[Modern Management of Pituitary Adenomas - Current State of Diagnosis, Treatment and Follow-Up]. / Modernes Management von Hypophysenadenomen ­ gegenwärtiger Stand in Diagnostik, Therapie und Nachsorge.

Modern Management of Pituitary Adenomas - Current State of Diagnosis, Treatment and Follow-Up Abstract. Pituitary adenomas (PA) are benign neoplasms originating from parenchymal cells of the anterior pituitary. Tumor mass effect can cause headaches, visual deficits by compression of the optic chiasm, and partial or complete hypopituitarism. Hormone secreting PA can cause several forms of specific syndromes such as Cushing's disease or acromegaly depending on the type of hormone. Endoscopic transsphenoidal resection is the preferred treatment option for most symptomatic or growing PA. Nowadays techniques like high definition intraoperative MRI can assist the surgeon in his goal of maximal safe resection. An exception are prolactinomas which can usually be treated medically with dopamine agonists. Therapy of PA is complex and should be managed in a high-volume center with an interdisciplinary team approach including neurosurgeons and endocrinologists.

Adipsic diabetes insipidus revealing a bifocal intracranial germinoma.

Adipsic diabetes insipidus is a rare complication of intracranial tumors in which impaired antidiuretic hormone secretion is associated with the loss of thirst sensation. Here, we present the case of a patient with bifocal intracranial germinoma, diagnosed due to symptoms mainly caused by adipsic diabetes insipidus. This is, to our knowledge, the first case of adipsic diabetes insipidus revealing an intracranial germinoma reported in the literature. We describe the diagnostic procedures and the three-year follow-up of this patient. Management of intracranial germ-cell tumors is made complex by the wide range of histological features. Although germinomas have a generally better prognosis than most nongerminomatous tumors, they can have severe or even life-threatening presentations. Adipsic diabetes insipidus is one such severe presentation and its rarity can make it difficult to recognize and manage. Awareness of this potential entity is therefore important for clinical practice.

Lessons from monogenic causes of growth hormone deficiency.

Through the multicentric international GENHYPOPIT network, 10 transcription factor genes involved in pituitary development have been screened in more than 1200 patients with constitutional hypopituitarism over the past two decades. The present report summarizes the main lessons learned from this phenotype-based genetic screening: (1) genetically determined hypopituitarism does not necessarily present during childhood; (2) constitutional hypopituitarism may be characterized by a pure endocrine phenotype or by various combinations of endocrine deficits and visceral malformations; (3) syndromic hypopituitarism may also be observed in patients with POU1F1 or PROP1 mutations; (4) in cases of idiopathic hypopituitarism, extensive genetic screening identifies gene alterations in a minority of patients; (5) functional studies are imperfect in determining the involvement of an allelic variant in a specific pituitary phenotype.

[Median congenital fistula of the upper lip associated with Goldenhar syndrome: Report of a case]. / Fistule congénitale médiane de la lèvre supérieure associée à un syndrome de Goldenhar : à propos d'un cas.

AIM OF THE STUDY: We present the case of a patient with Goldenhar syndrome associated with congenital fistula in the middle of philtrum at the upper lip. PATIENTS AND METHODS: The patient was supported from birth for Goldenhar syndrome. Several procedures were performed in childhood to correct a macrostomia and mandibular hypoplasia right. At 14 years old, she has a rhinoplasty to correct a complex nasal malformation. During the procedure, a hole in the upper central incisor inter-space is found. It is extended by a fistula which runs through the front palate towards the vomer rail at the base of the partition. This fistula is blind behind the vomer and can be completely resected. Pathological examination of the resection reveals a squamous lining. RESULTS: The median fistula of the upper lip are extremely rare : less than 30 cases reported in the literature. The unusual run of the fistula and the recent appearance of a pituitary syndrome in this patient makes us look for a continuity between it and Rathke's pocket by computed tomography imaging type. CONCLUSION: The association of Goldenhar syndrome and median congenital fistula of the upper lip was never yet described in the literature. The association with hypopituitarism was suspected with the posterior extension of the malformation, not confirmed by the scanner, but strongly suspected jointly by the neurosurgical and plastic surgery team.