Diagnosis and management of pituitary adenomas in children and adolescents.

BACKGROUND: Pituitary adenomas (PAs)-also now called pituitary neuroendocrine tumours or Pit-NETS-are rare in children and adolescents and exceptional below the age of 10. Most evidence-based high-quality data are derived from larger studies in adult patients. AIMS: We will review recent knowledge on the epidemiology, clinical features, diagnosis, and treatment modalities of the different types of pituitary adenomas diagnosed in children and adolescents, emphasizing the many reasons why these cases should be discussed within pituitary-specific multidisciplinary teams with experts from both paediatric and adult practice. CONCLUSIONS: Paediatric PA presents multiple peculiarities that may challenge their adequate management. They are overall proportionally larger and more aggressive than in adults, with potential mass effects including hypopituitarism. Hormonal hypersecretion is frequent, resulting in clinical syndromes affecting normal growth and pubertal development. Prolactinomas represent the most frequent subtype of PA found during childhood, followed by adrenocorticotropin (ACTH) and growth hormone (GH)-secreting adenomas, while clinically non-functioning adenomas are exceptionally diagnosed before the age of 16. The occurrence of a pituitary tumour in a young individual should also prompt genetic testing in each case, searching for either germline mutations in one of the known genes that may drive inherited/familial PA (such as the multiple endocrine neoplasia type 1 or MEN1 gene, or the aryl hydrocarbon receptor interacting protein or AIP gene), or for a mosaic activating mutation of GNAS as found in the McCune-Albright syndrome.

Prolactin: structure, receptors, and functions.

Prolactin (PRL) is a 23-kDa protein synthesized and secreted by lactotroph cells of the anterior pituitary gland but also by other peripheral tissues. PRL binds directly to a unique transmembrane receptor (PRLR), and the JAK2/signal transducer and activator of transcription 5 (Stat5) pathway is considered the major downstream pathway for PRLR signaling. To a lesser extent, PRL may be cleaved into the shorter 16-kDa PRL, also called vasoinhibin, whose signaling is not fully known. According to rodent models of PRL signaling inactivation and the identification of human genetic alterations in PRL signaling, a growing number of biological processes are partly mediated by PRL or its downstream effectors. In this review, we focused on PRL structure and signaling and its canonical function in reproduction. In addition to regulating reproductive functions, PRL also plays a role in behavior, notably in initiating nurturing and maternal behavior. We also included recent insights into PRL function in several fields, including migraines, metabolic homeostasis, inflammatory and autoimmune disease, and cancer. Despite the complexity of understanding the many functions of PRL, new research in this field offers interesting perspectives on physiological and pathophysiological processes.

Acromegaly: Incidence, patient characteristics and treatment patterns in a 10-year nationwide retrospective hospital cohort study.

INTRODUCTION: Acromegaly is a multisystemic disease associated with numerous comorbidities, notably cardiovascular disease and cancer. The objective of our study was to estimate the contemporary prevalence and incidence of acromegaly and its complications in a nationwide French retrospective cohort. METHODS: First, the positive predictive value of the ICD-10 acromegaly code E22.0 was checked by individually reviewing 132 medical records from one teaching hospital. Second, to estimate the prevalence of acromegaly, data of patients hospitalized between 2012 and 2021 were extracted from the PMSI French hospital database, using the dedicated ICD-10 code. Third, in a 2015-2020 subset cohort, we estimated the incidence of acromegaly, prevalence of complications and risk ratios of associated comorbidities or complications in subgroups of interest. RESULTS: A total of 7943 adult patients were identified, with a positive predictive value of 87%, resulting in a prevalence of 10.4/100,000 in France. Annual incidence was 0.76/100,000. The most frequent complications were hypertension (43%), sleep apnea (34.3%) and diabetes (31.3%), mostly with onset before diagnosis. Patients with diabetes were at higher risk for most comorbidities: myocardial infarction (odds ratio (OR) 3.14 [1.92-5.13]), ischemic stroke (1.64 [1.18-2.28]) and cancer of any type (1.53 [1.27-1.84]). These risks were partially attenuated after adjustment for other cardiovascular risk factors, becoming respectively 1.52 [0.89-2.59], 0.92 [0.64-1.33] and 1.09 [0.88-1.34]. Treatment involved pituitary surgery in 43% and radiotherapy in 4.6% of patients. CONCLUSION: This study was the first, in a large population, to estimate the contemporary incidence and prevalence of acromegaly in non-selected patients at nationwide level in France. We found higher prevalences of complications than previously reported in tertiary specialized expert centers, probably reflecting suboptimal management in non-selected hospitals, whether specialized or not.

BRAF and MEK inhibitor targeted therapy in papillary craniopharyngiomas: a cohort study.

OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.

Increase in Testosterone Levels and Improvement of Clinical Symptoms in Eugonadic men With a Prolactin-secreting Adenoma.

Objective: Testosterone concentrations, albeit rarely, may be in the normal range (>3.0 ng/mL) in men with a prolactin-secreting pituitary adenoma (PSPA-nt). The evolution of total, bioavailable testosterone, gonadotropin levels, and that of graded symptoms of testosterone deficiency (TD) are uncertain in these patients. Design: Retrospective case-control longitudinal study at a tertiary referral center. Methods: From 287 men, we selected 25 PSPA-nt men undergoing prolactin normalization (<20.0 ng/mL) during the follow-up. Graded symptoms of TD were investigated by structured interviews. Biochemical changes and TD symptoms were compared to those of a matched cohort of 61 men with pituitary neoplasms and normal testosterone levels (PA-nt). Results: Baseline testosterone levels were similar between PSPA-nt and PA-nt subjects. The prevalence of specific and suggestive symptoms of TD was higher in PSPA-nt (20% and 68%) than in PAnt (3.3 and 29.5%; P = .02 and P = .0015, respectively). At the follow-up, total and bioavailable testosterone levels increased in PSPA-nt but not in PA-nt patients (Δ change: 1.28 ± 2.1 vs0.03 ± 1.5 ng/mL, + 0.33 ± 0.55 vs-0.26 ± 0.60 ng/mL; P = .0028 and P = .0088, respectively). LH and FSH levels also increased in PSPA-nt men (P < .05). Specific and suggestive, but not nonspecific symptoms of TD, improved only in PSPA-nt men (P < .05 for both). Baseline testosterone and LH were the strongest predictors of testosterone improvement in PSPA-nt patients. Conclusion: Despite having normal testosterone levels at baseline, patients with PSPA-nt experience a relief of TD symptoms and an improvement of their pituitary-gonadal axis function following prolactin normalization, especially when baseline TT and LH levels are in the low-normal range.

Diagnosis and management of children and adult craniopharyngiomas: a French Endocrine Society/French Society for Paediatric Endocrinology & Diabetes Consensus Statement.

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.

Clinical and therapeutic implications of cavernous sinus invasion in pituitary adenomas.

Invasion of the cavernous sinus by pituitary adenomas impedes complete surgical resection, compromises biochemical remission, and increases the risk of further tumor recurrence. Accurate preoperative MRI-based diagnosis or intraoperative direct inspection of cavernous sinus invasion are essential for optimal surgical planning and for tailoring postoperative therapeutic strategies, depending on whether a total resection has been achieved, or tumoral tissue has been left in surgically inaccessible locations. The molecular mechanisms underlying the invasive behavior of pituitary adenomas remain poorly understood, hindering the development of targeted therapies. Some studies have identified genes overexpressed in pituitary adenomas invading the cavernous sinus, offering insights into the acquisition of invasive behavior. Their main limitation however lies in comparing purely intrasellar specimens obtained from invasive and non-invasive adenomas. Further, precise anatomical knowledge of the medial wall of the cavernous sinus is crucial for grasping the mechanisms of invasion. Recently, alongside the standard intrasellar surgery, extended endoscopic intracavernous surgical procedures with systematic selective resection of the medial wall of the cavernous sinus have shown promising results for invasive secreting pituitary adenomas. The first- and second-generation somatostatin agonist ligands and cabergoline are used with variable efficacy to control secretory activity and/or growth of intracavernous remnants. Tumor regrowth usually requires surgical reintervention, sometimes combined with radiotherapy or radiosurgery which is applied despite their benign nature. Unraveling the molecular pathways driving invasive behavior of pituitary adenomas and their tropism to the cavernous sinuses is the key for developing efficient innovative treatment modalities that could reduce the need for repeated surgery or radiotherapy.

Personalized Noninvasive Diagnostic Algorithms Based on Urinary Free Cortisol in ACTH-dependant Cushing's Syndrome.

CONTEXT: Current guidelines for distinguishing Cushing's disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients. OBJECTIVE: To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters. DESIGN: Retrospective study. SETTING: University hospitals. PATIENTS: Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation. RESULTS: Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI), .92-.99] in the primary study and .99 [95% CI, .98-1.00] in the validation cohort). The addition of clinical, imaging, and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (C-statistic index .99 [95% CI, .97-1.00]). Three groups were defined based on baseline UFC: < 3 (group 1), 3-10 (group 2), and > 10 × the upper limit of normal (group 3), and they were associated with 0%, 6.1%, and 66.7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group 1, MRI first followed by neck-to-pelvis computed tomography scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value. CONCLUSION: UFC accurately predicts EAS and can serve to define personalized and noninvasive diagnostic algorithms.

Impact of exenatide on weight loss and eating behavior in adults with craniopharyngioma-related obesity: the CRANIOEXE randomized placebo-controlled trial.

IMPORTANCE: A major issue in the management of craniopharyngioma-related obesity (CRO) is the ineffectiveness of the current therapeutic approaches. OBJECTIVE: To study the efficacy of glucagon-like peptide-1 analogs compared with placebo in adults with obesity CRO. DESIGN: A double-blind multicenter superiority randomized clinical in trial in two parallel arms. SETTING: Eleven French University Hospital Centers. PARTICIPANTS: Adults with CRO (body mass index > 30 kg/m²) without the sign of recurrence of craniopharyngioma in the past year. INTERVENTIONS: Exenatide or placebo injected subcutaneously twice a day during 26 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean change in body weight at week 26 in the intention-to-treat population. Secondary outcomes were eating behavior, calories intake, energy expenditure, cardiovascular, metabolic risk factor, quality of life, and the tolerance profile. RESULTS: At week 26, weight decreased from baseline by a mean of -3.8 (SD 4.3) kg for exenatide and -1.6 (3.8) kg for placebo. The adjusted mean treatment difference was -3.1 kg (95% confidence interval [CI] -7.0 to 0.7, P = 0.11). Results were compatible with a higher reduction of hunger score with exenatide compared with placebo (estimated treatment difference in change from baseline to week 26: -2.3, 95% CI -4.5 to -0.2), while all other outcomes did not significantly differ between groups. Adverse events were more common with exenatide versus placebo, and occurred in, respectively, 19 (95%) participants (108 events) and 14 (70%) participants (54 events). CONCLUSIONS AND RELEVANCE: Combined with intensive lifestyle interventions, a 26-week treatment with exenatide was not demonstrated superior to placebo to treat craniopharyngioma-related obesity.

Diabetes insipidus: Vasopressin deficiency .

Diabetes insipidus is a disorder characterized by hypo-osmotic polyuria secondary to abnormal synthesis, regulation, or renal action of antidiuretic hormone. Recently, an expert group, with the support of patient associations, proposed that diabetes insipidus be renamed to avoid confusion with diabetes mellitus. The most common form of diabetes insipidus is secondary to a dysfunction of the neurohypophysis (central diabetes insipidus) and would be therefore named 'vasopressin deficiency'. The rarer form, which is linked to renal vasopressin resistance (nephrogenic diabetes insipidus), would then be named 'vasopressin resistance'. The etiology of diabetes insipidus is sometimes clear, in the case of a neurohypophyseal cause (tumoral or infiltrative damage) or a renal origin, but in some cases diabetes insipidus can be difficult to distinguish from primary polydipsia, which is characterized by consumption of excessive quantities of water without any abnormality in regulation or action of antidiuretic hormone. Apart from patients' medical history, physical examination, and imaging of the hypothalamic-pituitary region, functional tests such as water deprivation or stimulation of copeptin by hyperosmolarity (induced by infusion of hypertonic saline) can be proposed in order to distinguish between these different etiologies. The treatment of diabetes insipidus depends on the underlying etiology, and in the case of a central etiology, is based on the administration of desmopressin which improves patient symptoms but does not always result in an optimal quality of life. The cause of this altered quality of life may be oxytocin deficiency, oxytocin being also secreted from the neurohypophysis, though this has not been fully established. The possibility of a new test using stimulation of oxytocin to identify alterations in oxytocin synthesis is of interest and would allow confirmation of a deficiency in those patients presenting with diabetes insipidus linked to neurohypophyseal dysfunction.

KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.

IMPORTANCE: A paradoxical increase of growth hormone (GH) following oral glucose load has been described in ∼30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. OBJECTIVE: We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. SETTINGS: We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions. RESULTS: One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. CONCLUSIONS AND RELEVANCE: Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.

A proposed clinical classification for pituitary neoplasms to guide therapy and prognosis.

No comprehensive classification system that guides prognosis and therapy of pituitary adenomas exists. The 2022 WHO histopathology-based classification system can only be applied to lesions that are resected, which represent few clinically significant pituitary adenomas. Many factors independent of histopathology provide mechanistic insight into causation and influence prognosis and treatment of pituitary adenomas. We propose a new approach to guide prognosis and therapy of pituitary adenomas by integrating clinical, genetic, biochemical, radiological, pathological, and molecular information for all adenomas arising from anterior pituitary cell lineages. The system uses an evidence-based scoring of risk factors to yield a cumulative score that reflects disease severity and can be used at the bedside to guide pituitary adenoma management. Once validated in prospective studies, this simple manageable classification system could provide a standardised platform for assessing disease severity, prognosis, and effects of therapy on pituitary adenomas.

Prognostic Impact of Hypothalamic Perforation in Adult Patients With Craniopharyngioma: A Cohort Study.

CONTEXT: Outcome of craniopharyngioma is related to its locoregional extension, which impacts resectability and the risk of surgical complications. To maximize resection and minimize complications, optic tract localization, temporal lobe extension, and hypothalamic involvement are essential factors for surgical management. OBJECTIVE: To assess the outcome of craniopharyngiomas depending on their relation to the hypothalamus location. METHODS: We conducted a retrospective analysis of 79 patients with a craniopharyngioma who underwent surgery from 2007 to 2022. Craniopharyngiomas were classified in 3 groups, depending on the type of hypothalamus involvement assessed by preoperative magnetic resonance imaging: infra-hypothalamic (type A, n = 33); perforating the hypothalamus (type B, n = 40); and supra-hypothalamic (type C, n = 6). Surgical strategy was guided by the type of hypothalamic involvement, favoring endonasal approaches for type A and type B, and transcranial approaches for type C. RESULTS: Long-term disease control was achieved in 33/33 (100%), 37/40 (92%), and 5/6 (83%) patients in type A, B, and C, respectively. In type B, vision was improved in 32/36 (89%) patients, while hypothalamic function was improved, stable, or worsened in 6/40 (15%), 32/40 (80%), and 2/40 (5%) patients, respectively. Papillary craniopharyngiomas were found in 5/33 (15%), 9/40 (22%), and 3/6 (50%) patients in types A, B, and C, respectively. In 4 patients, BRAF/MEK inhibitors were used, with significant tumor shrinkage in all cases. CONCLUSION: Craniopharyngiomas located below the hypothalamus or perforating it can be safely treated by transsphenoidal surgery. For supra-hypothalamic craniopharyngiomas, postoperative results are less favorable, and documenting a BRAF mutation may improve outcome, if targeted therapy was efficient enough to replace surgical debulking.

Differentiating pathologic parathyroid glands from thyroid nodules on neck ultrasound: the PARATH-US cross-sectional study.

Background: Neck ultrasound (US) is a widely used and accessible operator-dependent technique that helps characterize thyroid nodules and pathologic parathyroid glands (PPGs). However, thyroid nodules may sometimes be confused with PPGs. PARATH-US study aims at identifying US characteristics to differentiate PPGs from thyroid nodules, as there is no study, at present, which directly compares the US features of these two common neoplasms. Methods: PARATH-US is a single-center study that was conducted at a tertiary referral center, including consecutive lesions from patients undergoing neck US examination from 2016 to 2022. Findings: 176 PPGs (158 patients: serum calcium levels 2.91 [IQR 2.74-3.05] mmol/L, PTH levels 173 [112-296] ng/L) were compared to 232 size- and volume-matched thyroid nodules (204 age- and sex-matched patients). The morphologic patterns, echoic content and vascular status were all different between PPGs and thyroid neoplasms (p < 0.01 for all comparisons). The combined parameters maximally discriminated PPGs from thyroid nodules (OR, 7.6; 95% CI: 3.4, 17.1, p < 0.0001). When applying risk stratification systems developed for thyroid malignancies, 58-63% of PPGs were classified as high-risk lesions. Parathyroid adenomas had larger sizes and volumes than hyperplasias (p = 0.013 and p = 0.029). Serum calcium and PTH levels were significantly correlated with PPG size and volume (p < 0.0001 for all comparisons). Interpretation: We demonstrate the presence of distinct US characteristics in PPGs, which help differentiate them from thyroid nodules. When mistaken for thyroid nodules, PPGs bear high-risk US features. When dealing with high-risk cervical lesions detected on US, a PPG should be suspected, and an assessment of calcium levels recommended to avoid unnecessary invasive procedures. Funding: CYTO-TRAIN, C2022DOSRH053, funded by the French Regional Health Agency.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

Impact of Cushing's syndrome on the gonadotrope axis and testicular functions in men.

STUDY QUESTION: Does Cushing's syndrome (CS) differently affect the gonadotrope axis and testicular functions (GA/TF) according to the hypercortisolism intensity and underlying etiology? SUMMARY ANSWER: Endogenous cortisol excess caused by CS leads to varying degrees of hypogonadotropic hypogonadism (HH) with more severe GA/TF impairment and altered spermatogenesis in men with intense hypercortisolism associated with paraneoplastic/ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS). WHAT IS KNOWN ALREADY: CS is very rarely studied in men due to its lower prevalence in men than in women. In a few old reports focusing exclusively on a limited number of men with Cushing's disease (CD), the occurrence of hypogonadism was reported. However, a detailed assessment of the impact of CS on the GA/TF in a significant series of patients has not been performed. Yet, hypogonadism could worsen CS-associated comorbidities such as osteoporosis and myopathy. To date, the full spectrum of GA/TF impairment in men with CS of different etiologies and intensity remains unknown. STUDY DESIGN, SIZE, DURATION: In this monocentric study, 89 men with CS diagnosed at a tertiary endocrine university center (Bicêtre, Paris Saclay) between January 1990 and July 2021 were evaluated and compared to 40 normal men of similar age. PARTICIPANTS/MATERIALS, SETTING, METHODS: The CS patient cohort of 89 men included 51 with CD, 29 with EAS and 9 with CS of adrenal origin i.e. (ACTH-independent CS (AI-CS)). They all had frank hypercortisolism, with increased 24 h-urinary-free cortisol (24 h-UFC) in two separate samples. A case-control study was performed focusing on pituitary gonadotrope function and testicular sex steroids and peptides. An additional set of six CS men had an evaluation including semen analysis. In a subgroup of 20 men with available data after CS remission, a longitudinal analysis was conducted to assess the reversibility of GA/TF defects. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to controls, men with CS had significantly lower total testosterone (TT), bioavailable TT, and free TT (P < 0.0001). Hypogonadism, defined as serum TT levels <3.0 ng/ml, was present in 83% of men with EAS, in 61% of men with CD, and in 33% of men with AI-CS. Low-normal LH concentrations in the included men with hypercortisolism indicated HH. Serum sex hormone-binding globulin levels were moderately decreased in men with CD (P = 0.01 vs controls). Among the CS men, those with EAS had significantly lower TT, LH, and FSH levels than those with CD or AI-CS. When compared to controls, patients with EAS were the only group exhibiting a significant decrease in both serum FSH (P = 0.002) and the testicular peptides inhibin B (P < 0.0001) and anti-Müllerian hormone (P = 0.003). Serum INSL3 levels were significantly lower in men with CD than in the controls (P = 0.03). Of note, 24 h-UFC and ACTH were inversely and significantly associated with the majority of reproductive hormones including LH, FSH, TT, and inhibin B. Following successful curative therapy, reproductive assessment at a mean of 6.0 ± 4.3 years showed a significant increase in serum TT (P < 0.0001) and plasma LH (P = 0.02) levels, indicating a reversal of HH in 75% of the affected males. Among the six patients with available semen analysis, the two EAS cases exhibited a decrease in Sertoli cell peptides associated with a severe oligozoospermia, which completely normalized following removal of the source of hypercortisolism. LIMITATIONS, REASONS FOR CAUTION: The potential bias due to the retrospective design is counteracted by the analysis of the largest male CS cohort to date as well as the use of stringent inclusion and exclusion criteria. Due to the low number of patients with semen analysis in this study, further research is needed to unravel the full spectrum of spermatogenesis defects in men with CS. WIDER IMPLICATIONS OF THE FINDINGS: This work reveals the variable spectrum of reproductive impact in men with CS. We demonstrate that GA/TF impairment depends on the intensity of hypercortisolism which in turn is related to the underlying etiology. The causal link between hypercortisolism and GA/TF impairment was attested by its reversibility in most patients after CS remission. The wider implications of our findings lie in the potential generalization to a much commoner entity, iatrogenic CS due to chronic exposure to exogenous glucocorticoids. STUDY FUNDING/COMPETING INTEREST(S): Several research grants were attributed to J.Y.: (i) a grant from Programme Hospitalier de Recherche Clinique (PHRC # P081212 HYPOPROTEO); (ii) a grant from the French Association of Patients with Adrenal Diseases ('Association surrénales'); and (iii) independent Investigator Research Grants from HRA Pharma, Novartis and Recordati Pharma. A SICPA Foundation grant (Lausanne, Switzerland) allowed protected research time for G.E.P. The above sponsors were not involved in any part of the study. The authors have no competing or other conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.