Context Osilodrostat's clinical development program mostly enrolled Cushing disease patients. Data in nonpituitary Cushing syndrome (CS) patients are limited. Objective This work aims to evaluate osilodrostat effectiveness and safety in nonpituitary CS in real-world practice in France. Methods A retrospective, observational study (LINC 7; NCT05633953) was conducted in a multicenter institutional practice setting. Data for patients who initiated osilodrostat under the French Autorisation Temporaire d’Utilisation program or, once approved, in routine clinical practice were extracted retrospectively for 36 months or less (2019-2022). Participants included 103 adult nonpituitary CS patients: ectopic adrenocorticotropin secretion (EAS), n = 53; adrenocortical carcinoma (ACC), n = 19; adrenal adenoma (AA), n = 17; and bilateral adrenal nodular disease (BND), n = 14. Forty-three patients remained on osilodrostat throughout the observation period. Median (minimum-maximum) osilodrostat exposure and baseline dose were 177 days (1-1178 days) and 5.0 mg/day (1-60 mg/day), respectively. The main outcome measure was the proportion with mean urinary free cortisol (mUFC) less than or equal to the upper limit of normal (ULN) at Wk 12 (modified intention-to-treat [mITT] population: all enrolled patients with ≥12 weeks' follow-up, excluding patients without Wk 12 mUFC for nonsafety reasons). Results Osilodrostat was initiated and titrated based on investigator judgment. Cortisol decreased by Wk 4, remaining stable thereafter. Twenty-three of 52 patients (mITT, 44.2%; 95% CI, 30.5%-58.7%) had mUFC less than or equal to the ULN at Wk 12 (missing values reported as nonresponders). Forty-five of 52 had Wk 12 mUFC available; the proportions with mUFC less than or equal to the ULN by etiology were as follows: EAS, n = 12/29 (41%); ACC, n = 4/6; AA, n = 1/3; and BND, n = 6/7. The most common (≥15%) treatment-emergent adverse events were adrenal insufficiency (28%) and hypokalemia (18%). Twenty-nine patients (EAS, n = 24; ACC, n = 5) died from adverse events (n = 1 assessed as osilodrostat related by investigator), most commonly neoplasm progression (n = 11). Conclusion Osilodrostat is a suitable treatment for endogenous CS of various nonpituitary etiologies.

The primary treatment for active Cushing’s Syndrome (CS) is the surgical removal of the causative tumor. Alternative therapeutic strategies, particularly pharmaceutical approaches, are required when surgery is not feasible, unsuccessful, or in cases of recurrence. Osilodrostat, an adrenal steroidogenesis inhibitor, is approved in Europe and USA for adult patients with CS. The recommended strategy involves gradual titration to achieve eucortisolism, but this approach has limitations. Delayed disease control can be harmful in severe cases, and frequent clinical and laboratory monitoring may be challenging for some patients or during global health crises. To address these challenges, experts have introduced the block-and-replace (B R) strategy which they consider suitable for selected patients. Due to limited guidance on patient selection and safe implementation, a group of French experts (the authors) who had the opportunity to use osilodrostat outside of clinical trials developed a position statement on B R. They highlight that osilodrostat B R strategy is effective and safe, especially when other treatment options are less beneficial. This position paper, while offering a valuable clinical framework, is expert-driven rather than evidence-based, emphasizing the need for further studies, particularly randomized controlled trials, comparing B R and titration strategies across diverse populations.

OBJECTIVE:The aim of the study was to investigate bone comorbidities and their management in patients included in the European Register on Cushing's syndrome (ERCUSYN). DESIGN:A retrospective multicentric cohort study and on-line survey. METHODS:We analyzed the prevalence of osteoporosis (OP) and fractures among 1682 patients with Cushing's syndrome (CS), at initial evaluation and during follow-up. All the ERCUSYN partners received a survey addressing bone disease management in CS. RESULTS:Seven hundred and sixty-six patients (45%) had DXA examination at baseline, of whom 157 (21%) presented OP at spine and 103 (13%) at hip. Risk factors for OP were older age (P=0.038) and lower BMI (P=0.022). An X-ray was performed in 492 (29%) patients and fracture was detected in 87 (18%). Risk factors for fractures at baseline were male sex (P<0.001), muscle weakness (P=0.026) and bone mineral density (BMD) at hip indicating OP (P=0.026). During follow-up, spine BMD deterioration was more common in older patients (P=0.005) and in those with diabetes mellitus (P=0.024), while worsening of hip BMD was more frequent in patients with hypopituitarism (P=0.021), diabetes mellitus (P=0.034), on levothyroxine substitution (P=0.008) and those less often treated with anti-osteoporotic agents (P=0.022). The survey evidenced significant heterogeneity in terms of timing of bone evaluation and treatment initiation. CONCLUSIONS:A significant number of patients with CS experienced OP and fractures. Clinical factors may help to select patients at the highest risk. There are currently no standards of care for the management of bone complications in CS across Europe.

BACKGROUND:Children carrying germline RET mutations associated with multiple endocrine neoplasia type 2 (MEN2) are at high risk of developing medullary thyroid carcinoma (MTC). Prophylactic-intent thyroidectomy is recommended during childhood to prevent progression to advanced disease. Genotype-based recommendations combined with calcitonin measurements allow more individualized surgical timing. However, performing thyroidectomy at very young ages may expose children to long-term morbidity, particularly permanent hypoparathyroidism. METHODS:We conducted a retrospective national multicenter cohort study within the French Groupe d'Étude des Tumeurs Endocrines, including children younger than 15 years who underwent prophylactic-intent total thyroidectomy between 2010 and 2020 in the absence of clinically apparent structural disease. Data collected included RET genotype, age at surgery, preoperative calcitonin values interpreted relative to each laboratory's upper limit of normal, surgical procedures performed, histopathologic findings, postoperative complications, and clinical status at last follow-up. RESULTS:Sixty-four children (61 MEN2A, 3 MEN2B) underwent surgery at a median age of 4.6 years (interquartile range [IQR] = 3.2-8.3 years). Preoperative calcitonin was elevated in 44% of evaluable patients. Histopathology demonstrated C-cell hyperplasia in 52% and micro-MTC in 34%, while lymph node metastases were rare (3%). After a median follow-up of 6 years (IQR = 2.4-8.5 years), no patient had persistent structural disease. One patient had persistent moderate biochemical disease without structural evidence of MTC, although follow-up duration limits definitive long-term oncologic outcomes. Postoperative morbidity was notable: hypoparathyroidism occurred in 31% of patients and was permanent in 16%, predominantly among children operated before age 5 years. CONCLUSIONS:In this national contemporary cohort, prophylactic-intent thyroidectomy in pediatric MEN2 was associated with excellent short-term oncologic outcomes but also with a substantial rate of permanent hypoparathyroidism, particularly in very young children. These findings underscore the importance of multidisciplinary evaluation of both the timing and extent of surgery in expert centers.

Medical treatment of hypercortisolism may be necessary for a high proportion of patients with Cushing syndrome (CS), including those who are not candidates for curative surgery. It may also be used in the presurgical period when hypercortisolism is severe, as long-term treatment following surgical failure or recurrence after surgery, or while waiting for the effects of pituitary radiation in Cushing disease. Currently available medical treatments include adrenal steroidogenesis inhibitors that block cortisol secretion (ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, and etomidate), drugs that modulate pituitary ACTH secretion (pasireotide and cabergoline), and drugs that block peripheral glucocorticoid receptors (mifepristone). In addition, there are other medical treatments in development that target pituitary signaling pathways, ACTH or its adrenal receptor, or the conversion of cortisol from cortisone by 11ßHSD1. Steroidogenesis inhibitors can be administered using either a titration or a block-and-replace approach. Titration requires adjusting the daily drug dose with the aim of normalizing circulating cortisol levels, whereas the block-and-replace strategy uses higher drug doses to fully suppress endogenous cortisol production, followed by glucocorticoid supplementation. In this review, we summarize the main indications for medical treatment in CS, the mechanism of drug action, efficacy, recommended doses, and safety of the currently available drugs, as well as potential future treatments. We also discuss titration and block-and-replace approaches for control of hypercortisolism and provide recommendations for the use and monitoring of medical treatment in CS, including patients with endogenous hypercortisolism in special situations such as pregnancy, cyclic CS, and mild autonomous cortisol secretion.

Growth hormone deficiency (GHD) is a rare endocrine disorder responsible for growth failure. In the absence of an identified secondary cause, a genetic etiology can be identified, affecting genes involved in hypothalamo-pituitary growth hormone (GH) regulation or in pituitary development itself. The anterior pituitary gland arises from the oral ectoderm and is regulated by neuroectodermal signaling and transcription factors that ensure proper differentiation of hormone-producing cells. GH secretion is stimulated by growth hormone-releasing hormone (GHRH) and ghrelin, with mutations in their respective receptors (GHRHR, GHSR) contributing to isolated GHD (IGHD). Mutations in GH1, encoding GH itself, are the main genetic cause of IGHD. GHD can also arise from mutations in transcription factor genes such as POU1F1, PROP1, IGSF1 or TBX19 or in genes involved in early brain development such as GLI2, LHX3 or HESX1, potentially leading to syndromic presentations with multi-organ involvement. Understanding the genetic basis of GHD is essential to improving diagnostic strategies, genetic counseling and the development of targeted therapies. Although animal models have been fundamental for understanding pituitary ontogenesis, emerging tools such as human pituitary organoids now offer the promise of dissecting human-specific regulatory mechanisms that cannot be fully captured in traditional animal models. This review aims to provide a comprehensive overview of all known genetic causes of GHD, with a particular focus on the underlying molecular mechanisms and their associated phenotypes.

Glucocorticoids (GCs) are essential endocrine regulators coordinating stress responsiveness, metabolic flexibility, inflammatory resolution, and circadian physiology. While acute GC fluctuations are adaptive, sustained exposure (arising from psychosocial stress, circadian disruption, obesity, chronic inflammation, neoplasms, or steroid therapy) elicits pleiotropic effects that overlap with biological aging. Prolonged GC signaling intersects with multiple hallmarks of aging by altering nutrient sensing, suppressing autophagy, impairing mitochondrial quality control, and promoting cellular senescence. In this context, the GC-responsive polypeptide ACBP/DBI (acyl-coenzyme A [CoA]-binding protein/diazepam-binding inhibitor) has emerged as a stress-induced inhibitor of macroautophagy that amplifies several metabolic and immune consequences of GC excess linked to aging phenotypes. Clinically, chronic GC elevation is associated with earlier and more severe manifestations of age-related diseases, including metabolic syndrome, osteoporosis, sarcopenia, neurodegeneration, cardiovascular disease, immunosenescence, and cancer. Here, we review mechanistic links between GC signaling and systemic aging and discuss strategies to mitigate the age-accelerating consequences of persistent GC exposure.

Introduction: Isolated growth hormone deficiency (IGHD) involves multiple genes, yet characterization of its mutational landscape and genotype-phenotype correlations remains limited. The aim of this study was to analyze a large cohort of patients with genetic IGHD and describe associated genotypes and phenotypes. Methods: Descriptive study of IGHD patients with an identified genetic cause was referred for targeted NGS panel analysis through the GENHYPOPIT network between 2017 and 2024, and complementary targeted family analysis. Results: Among 205 patients with IGHD, 23 (11.2%) had a pathogenic (P) or likely pathogenic (LP) variant. The average age at diagnosis was 3.9 years, and 47% of patients had pituitary hypoplasia. Seventy percent of variants were in GH secretion genes, 39% in GH1, mostly with autosomal dominant transmission, 13% in GHRHR, and 18% in GHSR, with autosomal dominant or recessive inheritance and incomplete penetrance. Variants in genes involved in pituitary development were rarer (30% of variants). The most commonly affected pituitary development gene was GLI2 (13%). GLI2 variants were always associated with pituitary stalk interruption syndrome. The remaining variants were in POU1F1 (9%), HESX1 (4%), and SOX3 (4%). We report 10 new P or LP variants. Family analyses (n = 30) broadened the genotype-phenotype correlation, identified de novo variants, as well as the first ever reported case of GH1 mosaicism. Conclusion: Our study broadens the spectrum of genetic variations associated with IGHD. In most cases, the implicated gene is involved in GH secretion, but our results highlight that IGHD can also be caused by genes involved in pituitary development. These findings confirm the importance of genetic analysis in IGHD, to improve patient management and genetic counselling.

While most individuals with familial medullary thyroid carcinoma (fMTC) carry RET mutations, in some instances the causative mutations remain unknown. We studied two related families with RET -negative fMTC in 21 affected individuals through linkage analysis, exome/genome sequencing, and high-density array comparative genomic hybridization. We identified a novel heterozygous 40kb intragenic SLC30A9 deletion which segregated with the disease in all affected individuals. The mutant transcript escaped nonsense-mediated decay and resulted in the production of N-terminally truncated proteins via translation reinitiation from in-frame AUG codons located downstream of the deletion. These proteins showed increased stability and their expression in an MTC cell line increased cell proliferation and clonogenic capacity, supporting an oncogenic role. These findings expand the genetic background of fMTC beyond RET mutations and implicate translation reinitiation in the etiology of cancer susceptibility syndromes secondary to structural genomic variants.

Although radiation therapy is used less frequently in the treatment of functioning and nonfunctioning pituitary adenomas, it still plays a role to control volume and secretion. Radiation therapy remains to be considered in the therapeutic algorithm for these diseases, as mentioned in all recent national and international guidelines. Recent studies have focused on the use of stereotactic approaches, either given as a single dose or as a fractionated one. However, some patients may still benefit from conformal fractionated radiotherapy. The choice among these procedures is currently based mainly on adenoma's profile in terms of size, quality of the radiological definition, invasiveness, and aggressiveness, as well as local availability. Endocrine efficacy in functioning pituitary adenomas and tumor control in nonfunctioning pituitary adenomas seem equivalent regardless of the technique. This review will try to determine whether gender should also be considered as a predictive factor of efficacy and toxicity.

BACKGROUND:Adrenocortical carcinoma (ACC) is a rare cancer. The French ENDOCAN-COMETE network was established in 2009 to coordinate care locally and nationally, and to promote research and education on malignant adrenal tumors. Evidence demonstrating the benefits of this organization is currently lacking. PATIENTS AND METHODS:Patients diagnosed with ACC between 2010 and 2017 were identified from the French Network of Cancer Registries (FRANCIM). Patients were categorized based on referral to the ENDOCAN-COMETE network as either referred at diagnosis (R-ACC) or not referred, or referred late (nR-ACC). Median overall survival (OS) and OS rates at 1, 5, and 10 years were compared between the R-ACC and nR-ACC groups after adjustment for prognostic parameters. RESULTS:A total of 134 patients with ACC were identified from the FRANCIM registries, corresponding to an incidence of 1.4 cases per million person-years. Ten patients were excluded because of insufficient information regarding their health care pathway. The final analysis included 124 patients (mean age, 53.6 years; female-to-male ratio, 2:1). At diagnosis, 45.2% had European Network for the Study of Adrenal Tumours (ENSAT) stage I-II disease, 48.4% had stage III-IV disease, and 6.4% had an unknown stage; endocrine and/or tumour-related symptoms were present in 62.9% of patients. Among the analyzed patients, 87 (70%) were R-ACC, whereas 37 (30%) were nR-ACC. In patients with localized stage I-II ACC, OS rates were significantly higher in the R-ACC group than in the nR-ACC group: 1-year OS was 92% versus 85%, 5-year OS was 81% versus 55%, and 10-year OS was 75% versus 35%, respectively. This survival advantage remained significant after adjustment for prognostic factors (hazard ratio, 3.9; P=.026). In contrast, among patients with advanced ACC, OS rates were similar between the 2 groups. CONCLUSIONS:Our study demonstrates an OS benefit for patients with stage I-II ACC who were referred early to specialized centers within the ENDOCAN-COMETE network. The combined use of the French cancer registries and dedicated national networks provides the strongest evidence to date demonstrating the impact of such a network.

La connaissance sur l’ontogenèse hypophysaire et la régulation en hormone croissance a progressé à partir de 4 modèles de souris dont le nanisme est secondaire à des mutations spontanées, soit des mutations sur le gène POU1F1 (souris Snell et Jackson), sur le gène PROP1 (souris Ames) et sur le gène GHRHR (souris Little). Puis, les modèles de souris transgéniques ont permis d’établir le rôle crucial de plusieurs protéines, non seulement dans le développement hypophysaire mais également dans le développement cérébral. Du fait de la conservation de l’ontogenèse chez les vertébrés, l’identification du rôle de ces protéines permettait en retour d’identifier de nouvelles causes génétiques chez des patients présentant des déficits touchant la lignée somatotrope mais également les autres lignées hypophysaires parfois dans un tableau syndromique. Les progrès dans la compréhension des déficits hypophysaires se sont donc appuyés sur la conservation de l’ontogenèse hypophysaire chez les vertébrés et soulignent l’importance de certains modèles animaux qui ont permis d’avoir accès à cette toute petite glande, mesurant 7 à 8mm de diamètre chez l’humain, et si cruciale pour la physiologie endocrinienne. Au cours de l’ontogenèse hypophysaire, les 5 phénotypes cellulaires sont issus d’une même cellule souche d’origine ectodermique qui, sous l’influence de facteurs de transcription et de facteurs neurohypothalamiques, se différencient pour aboutir à leur différenciation terminale en cellule somatotrope, lactotrope, thyréotrope gonadotrope et corticotrope à e17 chez la souris et e51 chez l’humain. Des altérations génétiques de ces facteurs hypophysaires ou neurohypothalamiques sont responsables d’un déficit hormonal touchant une ou plusieurs lignées chez l’humain.

Acromegaly is a chronic endocrine disorder characterized by excessive growth hormone (GH) secretion. It is typically caused by a pituitary tumor that secretes GH. Understanding the precise mechanisms that lead to tumorigenesis and GH hypersecretion is important for anticipating the comorbidities induced by the disease and defining the most appropriate treatment for both the hypersecretion and the comorbidities. This chapter will thus focus on the physiology of the normal GH axis, the mechanisms of GH-secreting tumorigenesis, and how GH induces comorbidities such as hypertension, sleep apnea, and diabetes. We will not discuss the currently available treatments or their effects on comorbidities. However, clarifying the pathophysiology can lead to a better understanding of the available therapeutic options.

Treatment of acromegaly includes surgery followed by chronic medical therapy for persistent growth hormone (GH) excess, and, in some patients, radiation. Treatment is aimed at biochemical normalization, which improves survival and comorbidities. However, many patients experience lifelong burden related to persistent acromegaly manifestations and adverse treatment effects. Long-acting somatostatin receptor ligand (SRL) therapy with octreotide or lanreotide has been the cornerstone of management. Pasireotide long-acting release, a somatostatin receptor multiligand, achieves more favorable biochemical control rates but is associated with an increased risk of hyperglycemia. Pegvisomant, a GH receptor antagonist, can be used as monotherapy or in combination with SRLs. The spectrum of medical therapy has expanded with the advent of oral octreotide capsules; the oral selective somatostatin receptor subtype 2 agonist, paltusotine; and monthly self-administered subcutaneous octreotide. This review outlines the updates to current acromegaly treatment options and their impact on patient outcomes.

Adult growth hormone deficiency (GHD) is associated with increased adiposity, reduced lean mass, adverse lipid profile, decreased bone density and impaired quality of life. Growth hormone (GH) replacement therapy provides significant metabolic, cardiovascular, musculoskeletal and psychological benefit. Traditional stimulation tests, such as the insulin tolerance and glucagon tests, are gold-standards for diagnosis, but the oral macimorelin test offers a safe, reliable and well-tolerated alternative. GH replacement should be titrated to achieve age-appropriate insulin-like growth factor 1 (IGF-1) levels. Monitoring should address potential side-effects, including glucose intolerance and fluid retention. Long-acting growth hormone (LAGH) formulations, such as somapacitan, lonapegsomatropin and somatrogon, now enable weekly administration, improving adherence while maintaining efficacy and safety comparable to daily therapy. Early evidence suggests enhanced patient satisfaction and similar metabolic outcomes. Ongoing longitudinal studies are essential to clarify long-term safety.

The discovery of RET as the primary driver of hereditary medullary thyroid cancer in multiple endocrine neoplasia syndrome drastically changed the diagnosis, management, and prognosis of patients with this rare endocrine tumor. First, from a diagnostic viewpoint, RET testing within families became possible, ruling out unnecessary follow-up for negative patients and proposing an adapted surveillance protocol for positive patients. Second, large-scale epidemiological studies paved the way for early "prophylactic" thyroidectomy, rendering a historically fatal disease curable. RET identification also allowed for proper screening of pheochromocytoma and primary hyperparathyroidism. Lastly, RET identification enabled the synthesis of new, highly effective, and well-tolerated specific inhibitors, which changed the outcome for patients with metastatic disease. The RET discovery is thus a perfect example of how gene discovery can transform the fate of a rare syndrome, and this is what will be described in this short review.

AIMS:Hypophysitis is an inflammation of the pituitary gland or stalk. There are no standardized guidelines for diagnosis and treatment. The present study investigated the role of surgery in diagnosing and treating hypophysitis. PATIENT AND METHODS:A retrospective observational study was conducted in the University referral hospital of Marseille, France. Patients over 15 years of age diagnosed with histologically proven hypophysitis between January 1st, 1994 and October 31st, 2023 were included. Additionally, a literature review was performed, focusing on cases with surgical and/or medical management, during the same period. Immune checkpoint inhibitor-related hypophysitis was not included. RESULTS:In 9 of our 61 patients (14.5%), surgery was indicated mainly for visual disorder (75%). Four showed suspected adenoma. All patients recovered visual function. There was no endocrine improvement. The literature review of surgical management, with 21 studies, included 289 operated patients (40% due to misdiagnosis of adenoma, and 40% for visual impairment). After surgery, 20% developed new endocrine deficits, while 13% showed hormonal improvement. Visual improvement was seen in 80-90% of cases. Non-endocrine complications were rare (5%). The literature review of all forms of management included 661 patients from 22 studies. Glucocorticoids improved endocrine deficits in 30% of cases, and worsened pituitary function in 2%. Patients managed by monitoring had a lower incidence of new deficits than patients managed by surgery. CONCLUSION:In hypophysitis not related to immune checkpoint inhibitors, surgery should not be performed systematically. It may be indicated in patients with severe visual impairment unresponsive to glucocorticoids or in situations of diagnostic uncertainty after complete medical assessment. In other cases, surgery seems to worsen pituitary function more than glucocorticoids or conservative follow-up, restricting its role to these specific cases after multidisciplinary discussion.

PURPOSE:The 2022 WHO classification states no histological grading exists to assess pituitary adenoma (PA) aggressiveness. The European Society of Endocrinology refers to the term "unusually rapid growth rate" when defining an aggressive PA. This study aimed to evaluate three-dimensional volume growth rate (3DVGR) in multiple PAs and correlate it with tumor progression and histopathology. METHODS:Patients with growing or proliferative PAs who underwent surgery were retrospectively selected. Gadolinium-enhanced 3D T1-weighted MRI was required. RESULTS:A total of 76 3DVGR measurements were performed on 50 nonproliferative and 25 proliferative PAs, with median 3DVGRs of 21.2%/year and 60.2%/year, respectively (P < .0001). ROC analysis (AUC 0.992, P < .001) defined three 3DVGR groups: <50%/year, ≥50%, and <80%/year, ≥80%/year with a median PFS of 99.0, 39.0, and 7.0 months, respectively. In tumors with 3DVGR <50%/year, proliferative status had no significant progression-free survival impact (P = .381). In contrast, proliferative tumors with 3DVGR ≥50%/year had worse outcomes than those with 3DVGR <50%/year (P < .001). In multivariate analysis, only 3DVGR ≥50%/year predicted early progression (P < .001), unlike proliferative status. Combining 3DVGR ≥80%/year or 50% ≤3DVGR < 80%/year with Ki67 ≥ 8% identified 12 PAs with a median PFS of 8.5 months vs 64 months in others. CONCLUSION:PA proliferation may be categorized as: <10%/year: non and/or slowly progressive, 10-49%/year: slowly progressive, 50-79%/year: progressive, ≥80%/year: highly progressive. 3DVGR appears to be a valuable tool to evaluate PA proliferation alongside histology.

The knowledge in the pituitary ontogeny and in the growth hormone regulation started from 4 models of dwarf mice with spontaneous mutations, the Snell and Jackson carrying mutations in the POU1F1 gene, Ames in PROP1 gene and Little mice in GHRHR gene. Transgenic mouse models enabled to establish the crucial role of several proteins not only in pituitary development but also in brain development. Given the conservation of ontogeny in vertebrates, the identification of the role of these proteins in turn enabled the identification of new genetic causes in patients with pituitary deficiency affecting not only the somatotroph lineage but also the other pituitary lineages, sometimes in a syndromic context. The progress in the knowledge on pituitary deficiencies was based at the beginning on the conservation of pituitary ontogeny in vertebrates and highlights the interest of some animal models to have access to this tiny gland measuring 7 to 8 mm in diameter in humans and so crucial to human endocrine physiology. During pituitary ontogeny, the 5 cellular phenotypes are derived from the same ectodermal stem cell which, under the control of transcription and neurohypothalamic factors, differentiate to achieve their terminal differentiation into somatotroph, lactotroph, thyreotroph gonadotroph and corticotroph cells at e17 in mice and e51 in humans. Genetic alterations in these pituitary or neurohypothalamic factors are responsible for hormonal deficiency affecting one or several lineages in humans. During pituitary ontogeny, the 5 cellular phenotypes are derived from the same ectodermal stem cell which, under the control of transcription factors and neurohypothalamic factors, differentiate to achieve their terminal differentiation into somatotroph, lactotroph, thyreotroph gonadotroph and corticotroph cells at e17 in mice and e51 in humans. Genetic alterations in these pituitary or neurohypothalamic factors are responsible for hormonal deficiency affecting one or several lineages in humans.

Aggressive and metastatic pituitary neuroendocrine tumors constitute a rare, yet biologically distinct group of lesions, marked by rapid growth, therapeutic resistance, and unpredictable clinical behavior. Despite their rarity, they contribute disproportionately to morbidity due to the absence of reliable prognostic and therapeutic frameworks. Recent evidence has reframed aggressiveness as a multidimensional process shaped by somatic variants, chromosomal instability, and epigenetic remodeling. Recurrent alterations in ATRX, TP53, and SF3B1; widespread copy number losses; and lineage-specific methylation and transcriptomic profiles help delineate tumors with early malignant potential. Single-cell and immune profiling studies reveal proliferative, migratory, and immunoevasive subpopulations that may underpin variable clinical trajectories and treatment responses. Clinically, temozolomide remains the only systemic therapy with consistent benefit, while immune checkpoint inhibitors, anti-VEGF agents, and peptide receptor radionuclide therapy show emerging efficacy in selected settings. Progress will rely on harmonizing diagnostic criteria, integrating molecular and imaging biomarkers, and embedding translational endpoints into clinical trials. Together, these advances define a path toward more precise recognition and management of aggressive pituitary tumors.