Pituitary adenomas (PAs) are rare in children and adolescents. Despite their typically benign histology, these tumors raise significant clinical challenges because they occur during critical developmental windows, impacting growth, puberty, and long-term quality of life. This review aims to focus on the sex-specific patterns in the epidemiology, clinical presentation, and outcomes of pediatric PAs. Prolactinomas are the most frequent subtype, showing a marked post-pubertal female predominance. Adolescent girls typically present early with endocrine symptoms like amenorrhea, whereas boys are often diagnosed after a longer delay, bearing larger, more aggressive macroadenomas and presenting mass-effect symptoms such as headaches and visual disturbance. In Cushing disease (CD), a striking sex reversal occurs in epidemiology. A male predominance is observed in pre-pubertal children, which progressively shifts toward a female predominance during late adolescence. Furthermore, CD seems to affect boys more severely than girls. Pediatric growth hormone excess also displays distinct genetic sex-specificities, with X-linked acrogigantism (X-LAG) predominantly affecting infant girls and somatotroph macroadenomas related to AIP mutations appearing more frequently in adolescent boys. While management strategies are often extrapolated from adult data, the pediatric population exhibits higher rates of treatment resistance and a greater risk of long-term hypopituitarism. Recognizing these sex-related biological and clinical differences is essential for early diagnosis and the implementation of personalized therapeutic approaches to preserve future general health, fertility and quality of life.

The role of transsphenoidal surgery in the management of prolactinomas remains debated in the era of dopamine agonist therapy. This descriptive study evaluated the long-term endocrine outcomes of transsphenoidal surgery in a highly selected single-center surgical cohort. We retrospectively reviewed all patients who underwent transsphenoidal surgery for prolactinomas at a tertiary referral center between September 1995 and July 2015. Biochemical remission was defined as normalization of serum prolactin levels 6 months after surgery. Persistent disease and recurrence were assessed during long-term follow-up. The analysis was descriptive and all subgroup comparisons were exploratory. Fifty-five patients were included (47 women and 8 men; median age, 30 years), comprising 35 microprolactinomas (64

Giant prolactinomas are rare pituitary tumors characterized by extremely high prolactin levels and extensive extrasellar invasion. While dopamine agonists are usually effective, they may require months to normalize prolactin. We report a 47-year-old premenopausal woman presenting with new-onset temporal epilepsy and secondary amenorrhea. Assessments revealed marked hyperprolactinemia (mean serum prolactin concentration, 3902 ng/mL [SI: 169.8 nmol/L]) (reference range, 5.0-30.0 ng/mL [SI: 0.22-1.30 nmol/L]), and an invasive 47 × 43 × 50 mm adenoma extending into the right temporal lobe. After initiating cabergoline (0.25 mg/day), serum prolactin dropped to 802 ng/mL (SI: 34.9 nmol/L) within 18 hours and normalized by day 4 (12.7 ng/mL [SI: 0.55 nmol/L]). Polyethylene glycol recovery excluded macroprolactinemia. Despite ultra-rapid biochemical remission, magnetic resonance imaging at 3 and 6 months revealed no tumor shrinkage despite increasing cabergoline to a maximal tolerated dose of 0.75 mg/week. The patient remained seizure free and resumed normal menses. This case illustrates a striking dissociation between hormonal sensitivity and a lack of radiological regression.

OBJECTIVE:This analysis describes the evolution of health-related quality of life (HRQoL) over 36 weeks of metyrapone treatment in the PROMPT study, identifying patterns of early, delayed improvement, or persistence using item-level resolution. DESIGN AND METHODS:Longitudinal analysis of patient-reported outcomes from PROMPT (NCT02297945), a prospective, open-label, multicountry study of metyrapone in 49 evaluable adults with confirmed endogenous CS. HRQoL was assessed with the CushingQoL (0-100; higher = better QoL) and Tübingen CD-25 (0-100; higher = worse QoL) at weeks 4, 12, 24, and 36. Item-level analyses characterized the pattern and timing of improvement. Within-patient changes were assessed using the Wilcoxon signed-rank test. RESULTS:Both questionnaires demonstrated significant overall improvement by week 36: CushingQoL increased by 10.4 points (P < .001; 44.7% with ≥10-point improvement), and Tübingen CD-25 decreased by -7.8 points (P = .01). Early responses (by week 12) involved eating behaviour and depression symptoms. Delayed improvements (consolidating at weeks 24-36) were observed in sexual activity, environment, and social domains. Bodily restrictions (-4.3 points, P = .203) and cognition (-6.8 points, P = .143) did not show improvement over the study period. Item-level analysis identified a cluster of symptoms, predominantly psychological health anxiety and physical appearance concerns, where burden remained elevated throughout the 36 weeks despite cortisol normalization. CONCLUSIONS:Metyrapone treatment is associated with meaningful, progressive HRQoL improvements across multiple symptom domains over 36 weeks, with a pattern consistent with rapid cortisol-mediated relief (eating, mood), delayed recovery in social and sexual domains, and persistent residual burden in symptom clusters likely driven by incomplete phenotypic reversal within the study timeframe.

Dopamine agonists (DA) are an effective first-line treatment for prolactinomas, achieving high rates of prolactin normalization, gonadal recovery and tumor shrinkage. However, chronic DA therapy also has many downsides, including common short-term side effects such as nausea and dizziness, the risk of impulse control or emotional disorders, and the need for cardiac valvular monitoring at high doses. This duality of beneficial and adverse DA effects has led clinicians to more frequently attempt treatment reduction and withdrawal. In this review, we will summarize the evidence and determine the most appropriate DA withdrawal strategies in premenopausal and post-menopausal women, in men, and in children and adolescents. We will discuss surveillance protocols after withdrawal and therapeutic strategies in case of recurrence. In order to understand why remission remains unachievable in most patients, future research must elucidate the underlying cellular pathways governing the biological and radiological response to DA.

CONTEXT:Menopause is thought to have beneficial effects in women with prolactinoma, potentially offering a higher chance for successful dopamine agonist (DA) withdrawal. However, strong evidence supporting this remains limited. OBJECTIVE:To assess the impact of menopause on prolactinoma evolution and recurrence after DA withdrawal. DESIGN:Retrospective study. SETTING:Two tertiary academic hospitals. PATIENTS:We retrospectively analyzed data from 99 women undergoing menopause (Mp, defined as 12 months of amenorrhea, low estradiol, and FSH > 25 U/L) while still on DA treatment for a prolactinoma (mean age at diagnosis: 37.9 ± 8.1 years). The tumors were microadenomas in 67 cases and macroadenomas in 32 (12 invasive). RESULTS:In postmenopausal women continuing DA at stable doses, median prolactin levels decreased significantly from 18.0 µg/L before Mp to 9.8 µg/L 3 to 6 months after Mp (n = 71, P = .05) and to 7.9 µg/L after 24 months (n = 45, P < .001). Coronal surface also decreased significantly from 16.5 to 8.2 mm² at 24 months (n = 34, P < .01). DA treatment was successfully discontinued in 56 women, all meeting stringent criteria for discontinuation, with 41 (73%) remaining in remission over a median follow-up of 29 months. Recurrence occurred in 15 women (27%), mostly within the first year after DA withdrawal. Prolactin concentration measured 3 to 6 months after DA discontinuation was the only independent predictor of recurrence. Estrogen-progestin replacement therapy, given in 23 women, did not influence prolactinoma outcome. CONCLUSION:We confirm that menopause has a beneficial effect on the evolution of prolactinomas. When fulfilling stringent criteria for DA withdrawal, two-thirds of postmenopausal women can expect sustained remission, and recurrences are generally mild and asymptomatic.

Context: Equivocal or negative pituitary magnetic resonance imaging (MRI) findings pose a significant challenge in the management of persistent or recurrent Cushing disease (CD), compromising the chances of success of further transsphenoidal surgery (TSS). Objective: To determine the diagnostic utility of C-11-methionine (C-11-MET) positron emission tomography/computerized tomography (PET/CT) in localizing residual or relapsing corticotroph adenoma. Methods: We retrospectively analyzed the results of all C-11-MET PET/CT performed at 2 tertiary medical centers between May 2002 and November 2023 in 22 patients with persistent/recurrent CD after initial TSS and equivocal/negative pituitary MRI. In 15 cases, C-11-MET PET/CT images were also co-registered with high-resolution 3D T1 or FLAIR MRI pituitary imaging. Results: Of 22 patients (18 female; mean age 36 years at diagnosis; mean initial tumor maximum diameter 6.5 mm), 13 had a suspect anomaly on conventional MRI and 9 had a negative MRI. Maximal metabolic activity in the suspect area (SUVmaxT) was found in 14 patients (63.5%; 5/9 patients with negative pituitary MRI and 9/13 with equivocal findings). Based on positive imaging, 12 patients underwent repeat TSS, successful in 7, while 2 patients underwent Gamma Knife radiosurgery (GKRS), both resulting in remission (total remission rate of 64%). Among the 5 patients not cured by TSS, the presence of corticotroph adenoma in the resected tissue was found in 3 cases. Positive C-11-MET PET/CT had a detection rate accuracy of 86% (12/14). Of the 8 PET-negative patients, 2 underwent exploratory TSS, with no remission, and 2 underwent GKRS, with 1 long-term remission. Conclusion: C-11-MET PET/CT imaging can provide valuable diagnostic information to detect a corticotroph microadenoma in more than half of patients with persistent/recurrent CD and equivocal or negative MRI findings, allowing targeted TSS or radiosurgery with a global success rate of 64% in the selected subgroup with positive imaging.

Ectopic ACTH secretion is a rare, severe condition covering a wide spectrum of tumors of different location and aggressiveness. The usual poor prognosis of patients with ectopic ACTH secretion requires prompt management. We report a case of a patient with high surgical risk and intolerance to cortisol-lowering drug, in which hypercortisolism was successfully treated with radiofrequency ablation of a lung carcinoid tumor. A 78-year-old woman was referred for a rapidly progressive ACTH-dependent Cushing syndrome (CS). Biological tests suggested the presence of CS due to ectopic ACTH production. Imaging studies detected an 11-mm left upper pulmonary lobe nodule. A computed tomography-guided biopsy of the lesion confirmed a well-differentiated ACTH-positive carcinoid tumor with a Ki67 index <10%. The patient started therapy with ketoconazole but developed severe gastrointestinal side effects. Because of a very high surgical risk, lung resection was prohibited. Radiofrequency ablation of the lung carcinoid tumor was performed without major complication. The procedure allowed a progressive control of hypercortisolism with rapid improvement of CS that persists after 1 year. We show that radiofrequency ablation may be an efficient alternative treatment for the management of high surgical risk patients with ectopic ACTH syndrome secondary to a well-differentiated lung carcinoid tumor.

BACKGROUND:Cushing's syndrome (CS) is associated with increased metabolic and cardiovascular (CV) risk factors and morbidities. Evidence-based guidelines for the management of these issues in active or remitted CS are not available, so best practice is derived from guidelines developed for the general population. We aimed to evaluate the awareness and practice variation for CV comorbidities of CS across Reference Centres (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). METHODS:A dedicated online survey was distributed from June 2022 to December 2022 to Endo-ERN RCs with recognized expertise in adrenal and/or pituitary diseases. RESULTS:19 centres provided complete responses to the survey, accounting for an estimated pool of around one thousand chronically cared CS patients across Europe. Most ERN experts consider patients with CS at high CV risk irrespectively of remission status. Preoperative cortisol-lowering treatment was a common practice, especially for severe cases, and deemed effective in reducing CV risk by many. Most comorbidities were regularly evaluated at diagnosis and during follow-up, although a lack of provocative testing to diagnose diabetes (used only in 26% of RCs) was evidenced. A strict glycaemic control was encouraged although its target differed. On the contrary, a less stringent approach to dyslipidaemia and overweight emerged. Preferred initial compounds for patients presenting comorbidities were angiotensin converting enzyme inhibitors, metformin and statins; lifestyle changes were preferred over drugs to control weight excess after cure. Screening for asymptomatic vascular disease was performed routinely and regularly repeated during follow-up by only half of the centres. Important heterogeneity in some responses emerged, especially regarding the effect of remission or medical treatment on comorbidities and CV risk. DISCUSSION:Our survey highlights the awareness of ERN experts on management of metabolic and CV risk factors or disease in CS. Most of them use the current European guidelines and apply strategies for high CV risk patients, although not all these recommendations were fully followed. Since several CV risk factors seem to persist after disease remission, they should be adequately and promptly addressed. Population-specific studies are required to identify the optimal management of CV and metabolic comorbidities of CS patients.

OBJECTIVE:We evaluated the safety and efficacy of metyrapone treatment for Cushing's syndrome (CS). DESIGN:International, prospective, single-arm, open-label study. METHODS:Fifty adults with endogenous CS (either unsuitable for or uncontrolled after surgery) and 3 urinary free cortisol (UFC) concentrations each ≥1.5-fold the upper limit of normal (ULN) were enrolled. After 12 weeks of metyrapone titration, participants with mean 24 h UFC (mUFC) ≤ 2-fold ULN could enter a 24-week extension phase. Safety was assessed, and doses adjusted at weeks 1-5, 8, 12, and 24. Pre-defined endpoints included normalization of mUFC at weeks 12 (primary), 24, and 36, and proportion of "responders" (normalization or ≥50% decrease of baseline mUFC), time to eucortisolemia, salivary cortisol day-curve, and quality of life (QoL). RESULTS:Of the 49 evaluable participants, 47 completed the 12-week visit; 40 were evaluated at week 24 and 35 at week 36. The primary endpoint was met in 46.9% of participants (95% CI 32.5%-61.7%), with efficacy maintained at week 24 (52.5%; 95% CI 37.5%-67.1%) and week 36 (48.6%; 95% CI 33.0%-64.4%). The responder rates were 80.9%, 77.5%, and 71.4% at weeks 12, 24, and 36, respectively. Forty-seven participants (94%) developed mild-to-moderate adverse events (AEs), mostly during the first 12 weeks and most commonly nausea (38%), fatigue (26%), and headache (22%); 8 experienced severe AEs. Six participants developed reversible adrenal insufficiency during titration. Clinical features and QoL improved. CONCLUSION:Metyrapone is a safe and effective treatment for endogenous CS.

Introduction:Adrenal venous sampling (AVS) is considered the gold standard test for primary aldosteronism (PA) subtyping. Considering the limited availability of this challenging procedure, we propose a noninvasive score predicting unilateral (UPA) or bilateral (BPA) form of PA in order to reduce the need for AVS. Material and methods:The score was retrospectively developed from a cohort of 72 patients who underwent AVS (21 patients with BPA and 51 with UPA) at Cliniques Universitaires Saint Luc between 1993 and 2021. Another multicenter cohort of 130 patients who underwent AVS (67 patients with BPA and 63 with UPA) served as external validation. Results:Four predictive parameters of UPA highlighted by logistic regression analysis were integrated into the KASAI score: minimal serum potassium value, supine resting aldosteronemia, aldosteronemia at the end of the saline infusion test, and results of adrenal imaging. Depending on the results, 0, 1, or 3 points were assigned to each parameter. In both cohorts, a score greater than 9/12 identified UPA and a score less than 4/12 identified BPA with 100% specificity, while performing AVS remained indicated for scores between 4 and 9. The score may have avoided AVS in 40% of patients in the primary cohort and in 42% of patients in the validation cohort. The area under the ROC curve for discrimination of UPA from BPA was 0.81 (95% CI, 0.70-0.90) in the primary cohort and 0.86 (95% CI, 0.80-0.90) in the validation cohort. Conclusion:We propose a new biological-radiological score that could simplify the diagnostic assessment of PA.

Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors.

The diagnosis and management of Cushing’s disease (CD) during pregnancy are challenging. Only a few cases of mixed pituitary adenomas secreting prolactin and ACTH have been reported, and none during pregnancy. We report the case of a 30-year-old woman who presented with galactorrhea, weight gain, hypertension, prediabetes, dorsal fat pad, and abdominal striae. Initial biochemical investigations revealed hyperprolactinemia with increased ACTH but no biochemical signs of hypercortisolism. Pituitary MRI showed a 10 mm pituitary adenoma, which was first considered a prolactinoma potentially co-secreting ACTH. Surgery was indicated, but the patient did not undergo treatment immediately due to lack of health insurance. Cabergoline monotherapy was initiated, with close follow-up advised until regularization of social status in Belgium. The patient was then lost to follow-up and presented 15 months later because of an early pregnancy with treatment-resistant hypertension. Biochemical evaluation during the first trimester led to the suspicion of ACTH-dependent cortisol excess and showed hyperprolactinemia despite ongoing cabergoline treatment. She underwent transsphenoidal surgery at 16 weeks of pregnancy, and pathological examination showed a single adenoma with two different cell components staining for PRL/PIT1 and ACTH/TPIT, respectively. Surgery was successful, the patient developed corticotrope insufficiency, and was able to stop antihypertensive drugs. Because of failed induction of labor (for gestational insulin-requiring diabetes), she underwent cesarean section at 39 weeks of pregnancy and gave birth to a healthy boy with no maternal or neonatal complications. Adrenal insufficiency recovered 12 months after surgery. Genetic testing for MEN1 and AIP was negative.

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.

Introduction: Lipodystrophy syndromes are rare diseases characterized by a generalized or partial lipoatrophic morphotype and metabolic complications. Data on health-related quality of life and impact of genetic lipodystrophy on social or psychological well-being are lacking. Patients and Methods: Patients with genetic lipodystrophy were recruited throughout the French national reference network for rare diseases of insulin secretion and insulin sensitivity. Patients completed a self-reported questionnaire exploring their physical, psychological, and social well-being and perceived impact of the disease. Descriptive analyses and comparison with general population norms were conducted. Results: Of 175 eligible patients, 109 (84% of women) were included, either with familial partial (n = 93) or congenital generalized (n = 16) lipodystrophy. Health-related quality of life based on physical and mental scores was significantly decreased compared to the French general population of similar age and gender (P < .001 for both). Forty-one percent of patients reported moderate or severe depression and 69% dealt with chronic pain. Half of respondents had taken tranquilizers, sleeping pills, or antidepressants over their life. Female participants with genetic lipodystrophy were more frequently unemployed due to health issues as compared to the general population. Social discrimination was highly prevalent (73%), coming, in 34% of cases, from health professionals. More than half of affected women reported a very negative impact of lipodystrophy on body image, significantly associated with depressive symptoms. Conclusion: This study highlights the need of psychosocial support in patients with lipodystrophy. An integrated approach and evaluation of psychological and physical symptoms by physicians should be made available to organize specialized care and set up specific therapeutic educational programs.