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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., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Insulinlike growth factor I (IGF-I) measurement is essential for the diagnosis and management of growth hormone (GH) disorders. However, patient classification may vary substantially according to the assay technique., Objective: We compared individual patient data and classifications obtained with six different IGF-I assay kits in a group of patients with various GH disorders., Design: In this cross-sectional study, we measured IGF-I with six immunoassays in 102 patients with active or treated acromegaly or GH deficiency. IGF-I normative data previously established for the same six assay kits were used to classify the patients (high, low, or normal IGF-I levels), using both raw data and standard deviation scores (SDSs). Pairwise concordance between assays was assessed with Bland-Altman plots and with the percentage of observed agreement and the weighted κ coefficient for categorized IGF-I SDS., Results: We observed marked variability both across each individual's IGF-I raw data and across IGF-I SDS values obtained with each of the six immunoassays. Pairwise concordance between assay values, as assessed with the weighted κ coefficient, ranged from 0.50 (moderate) to 0.81 (excellent)., Conclusion: Even when using normative data obtained in the same large population of healthy subjects and when using calculated IGF-I SDSs, agreement among IGF-I assay methods is only moderate to good. Differences in assay performance must be taken into account when evaluating and monitoring patients with GH disorders. This argues for the use of the same IGF-I assay for a given patient throughout follow-up., (Copyright © 2017 Endocrine Society)

Context: Recently, germline and somatic GPR101 p.(E308D) mutation was found in patients with isolated acromegaly. It is not known whether GPR101 point mutations are associated with other histological types of pituitary adenoma., Objective: We sought germline GPR101 mutations in patients with sporadic pituitary adenomas, and compared the phenotypes of GPR101 mutation carriers and AIP mutation carriers., Design: An observational cohort study performed between 2007 and 2014 in a single referral center., Participants: This prospective study involved 766 unselected patients (413 women) with sporadic pituitary adenomas of all histotypes., Methods: Entire GPR101 and AIP coding sequence were screened for germline mutations., Results: Twelve patients (1.6%) were found to carry the GPR101 p.(E308D) mutation or rare GPR101 variants. The minor allele frequency of the GPR101 mutation and variants was higher in patients with pituitary adenomas than in unaffected individuals included in the Exome Aggregation Consortium database. Three of the six patients with the GPR101 p.(E308D) mutation had adult-onset acromegaly, two had adrenocorticotropin-secreting adenomas, and one had a nonfunctioning macroadenoma. Six patients carried rare GPR101 variants. Germline AIP mutations or rare AIP variants were identified in 32 patients (4.2%). AIP mutation carriers were younger at diagnosis than GPR101 mutation carriers and non carriers. None of the patients harbored mutations in both the GPR101 and AIP genes., Conclusion: Germline GPR101 mutations are very rare in patients with sporadic pituitary adenomas of various histotypes. No digenism with AIP was identified. Further studies are required to establish whether and how genetic variation in GPR101 gene contributes to pituitary tumorigenesis., (© 2016 European Society of Endocrinology.)

Context: Germline mutations of the AIP (aryl-hydrocarbon receptor interacting protein) gene are associated with a predisposition to pituitary adenomas. Such mutations are found in about half of patients with familial acromegaly, but penetrance is incomplete., Objective: We studied the prevalence of germline AIP mutations in a large cohort of patients with apparently sporadic pituitary adenomas., Patients and Setting: A total of 443 patients with pituitary adenomas of all histotypes, who had no familial history of pituitary adenomas or multiple endocrine neoplasia and who were examined at Bicêtre University Hospital, a tertiary referral center, between 2007 and 2010, were enrolled in this prospective study., Methods: The entire coding sequence of the AIP gene was screened for germline mutations. A subgroup of patients were screened for large deletions or duplications of the AIP and MEN1 genes by multiplex ligation-dependent probe amplification., Results: AIP mutations were detected in 16 (3.6%) of the 443 patients, comprising six of 148 patients with acromegaly (4.1%), six of 132 patients with prolactinomas (4.5%), one of 113 patients with nonfunctioning adenomas (0.9%), three of 44 patients with corticotropic adenomas (6.8%), and none of the six patients with thyrotropic adenomas. This is the first report of an AIP mutation leading to a truncated protein in a patient with Cushing's disease. Patients with AIP mutation were younger at diagnosis (24.1 vs. 42.8 yr) and had predominantly macroadenoma (12 of 16). No mutations were found in patients diagnosed after age 40 yr, whereas the prevalence before this age was 7.2% (16 of 222). Studies of seven of the AIP-mutated patients' families showed that one asymptomatic parent carried the same mutation in each case., Conclusion: This large prospective cohort study confirms the very low prevalence of germline AIP mutations in patients with apparently sporadic pituitary adenomas. We propose to limit AIP testing to patients diagnosed before age 40 yr with apparently sporadic large pituitary adenomas, especially GH- or PRL-secreting adenomas.

Context: Adequate postoperative management of nonfunctioning pituitary macroadenomas (NFMAs) remains a challenge for the clinician., Objective: To identify predictive factors of NFMA relapse after initial surgery., Patients and Methods: This retrospective study included 142 patients operated for an NFMA in two academic centers (CHU Bicêtre in France and UCL St Luc in Belgium). The rate of tumor relapse, defined as recurrence after total surgical resection or regrowth of a surgical remnant, as well as predictive factors was analyzed., Results: During a mean follow-up of 6.9 years, 10 out of 42 patients (24%) who had complete macroscopic resection of their tumor had recurrence, and 47 out of 100 patients (47%) with a surgical remnant experienced regrowth. The overall relapse rates were 25, 43, and 61% at 5, 10, and 15 years respectively. Invasion of the cavernous sinus, absence of immediate radiotherapy after the first neurosurgery, and immunohistochemical features of the tumor (mainly positive immunostaining for several hormones or for hormones other than gonadotropins) were independent risk factors for tumor relapse. Incomplete excision was only associated with relapse when invasion was withdrawn from the analysis, suggesting that these two factors are closely linked., Conclusion: NFMAs frequently recur/regrow after initial surgery, particularly when tumor is invasive, precluding complete removal. Immunohistochemical features such as positive immunostaining for several hormones or for hormones other than gonadotropins could help to predict undesirable outcomes.

Excessive production of the growth hormone (GH) is responsible for acromegaly. It is related to a pituitary GH-secreting adenoma in most cases. Prevalence is estimated 40-130 per million inhabitants. It is characterised by slowly progressive acquired somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. The rheumatologic, cardiovascular, respiratory and metabolic consequences determine its prognosis. The diagnosis is confirmed by an increased serum GH concentration, unsuppressible by an oral glucose load and by detection of increased levels of insulin-like growth factor-I (IGF-I). Treatment is aimed at correcting (or preventing) tumour compression by excising the disease-causing lesion, and at reducing GH and IGF-I levels to normal values. When surgery, the usual first-line treatment, fails to correct GH/IGF-I hypersecretion, medical treatment with somatostatin analogues and/or radiotherapy can be used. The GH-receptor antagonist (pegvisomant) is helpful in patients who are resistant to somatostatin analogues. Thanks to this multistep therapeutic strategy, adequate hormonal disease control is achieved in most cases, allowing a normal life expectancy.

Background: Serum androgen levels are below normal in patients with benign cortisol-secreting adrenocortical adenomas, owing to ACTH suppression. Associated androgen secretion is usually considered as indicative of malignancy. The objective of the study was to analyse the androgen-producing ability of cortisol-secreting adrenocortical adenomas., Design: Retrospective data collection in a single referral hospital centre., Methods: Dehydroepiandrosterone sulfate (DHEAS), Delta4androstenedione and testosterone concentrations were measured before and after adrenalectomy and then at 6-month intervals in 20 women (eight cortisol-secreting adrenocortical adenomas, six subclinical cortisol-secreting adrenocortical adenomas, and six nonfunctional adenomas)., Results: Before adrenalectomy, serum androgen concentrations were measurable in all women with clinically apparent and subclinical cortisol-secreting adrenocortical adenomas. DHEAS levels were either at the lower end of the normal range or below normal, but were always clearly detectable. Postoperatively, during adrenocortical insufficiency, DHEAS, Delta4androstenedione and testosterone concentrations fell to near the detection limit in all patients with cortisol-secreting adrenocortical adenomas (P = 0.008 for each marker) and showed a similar tendency to fall in all patients with subclinical cortisol-secreting adrenocortical adenomas. Pre- and post-treatment androgen concentrations did not differ in patients with nonfunctional adenomas. Immunohistochemical analysis confirmed CYP17, HSD3B2, SULT2A1 and CYB5 expression by all cortisol-producing tumours. The intensity of CYP17 and SULT2A1 expression was stronger in cortisol-secreting adenomas than in their adjacent normal adrenal tissue., Conclusion: Both clinically apparent and subclinical cortisol-secreting adrenocortical adenomas appear to show moderate autonomous androgen production. Thus, weak androgen secretion in patients with adrenocortical tumours should not necessarily be considered as a sign of malignancy.

Background: The pituitary tumour transforming gene (pttg) plays a central role in pituitary tumorigenesis, but PTTG protein expression is poorly documented and its relationship with tumour cell proliferation and the prognosis of pituitary adenomas is unclear., Aim: The aim of this study was to evaluate the immunohistochemical expression of PTTG and Ki-67 in 45 human pituitary adenomas according to the tumour histotype, aggressiveness and persistence/recurrence status., Patients and Methods: The tumours comprised 37 macroadenomas and 8 microadenomas. Twenty patients experienced disease persistence or recurrence after transsphenoidal surgery. Disease recurrence was observed in 16 patients, 8-72 months after surgery., Results: No PTTG or Ki-67 expression was detected in normal pituitary tissue. In pituitary adenomas, tumour nuclei were positive for PTTG and Ki-67 in 89 and 98% of samples, respectively, and there was a strong correlation between the expression of the two proteins (P < 0.001). By the ROC curves method, a PTTG score of 3.3% was the best cut-off for distinguishing between recurrent and nonrecurrent pituitary adenomas (P < 0.05; sensitivity 60%; specificity 76%). A 2.9% cut-off was obtained for both PTTG (P < 0.01; sensitivity 77%; specificity 71%) and Ki-67 (P < 0.05; sensitivity 85%; specificity 64%) among patients with more than 1 year of follow-up. Neither PTTG nor Ki-67 expression was influenced by the maximal tumour diameter, tumour grade, age, gender or presurgical medical treatment. Both PTTG and Ki-67 tumour score > 2.9% identified a subgroup of patients with a significantly higher recurrence-free interval (P < 0.01). By multivariate analysis, a > 2.9% Ki-67 tumour score was the best predictor of pituitary tumour persistence/recurrence after surgery (chi(2) = 8.2, P < 0.01)., Conclusion: PTTG is expressed in approximately 90% of pituitary tumours of different histotypes but with a high variability from one case to another. As expected, PTTG expression parallels that of Ki-67 and both are correlated to a more aggressive behaviour. However, a 2.9% Ki-67 cut-off proved to be the most reliable biological marker for predicting the recurrence potential of these tumours, when an adequate postsurgical follow-up is considered.

The pituitary origin of ACTH secretion in ACTH-dependent hypercortisolism can be difficult to assess, as magnetic resonance imaging (MRI) frequently fails to identify ACTH-secreting microadenomas or, on the contrary, may give false positive images of microadenomas. The choice of therapeutic option for patients with such normal MRI findings is controversial. Some groups propose routinely pituitary surgery, whereas others consider that neurosurgical exploration may be less successful and more harmful, and therefore prefer other types of management. The aim of this study was to compare surgical outcomes between patients with Cushing's disease (CD) and normal vs. positive pituitary MRI findings. Fifty-four patients (44 women and 10 men) with CD, operated on after 1996 in two centers (Kremlin-Bicêtre and Bordeaux) and followed postoperatively during a mean period of 19.9 +/- 22.7 months (range, 1-89 months), were enrolled in this retrospective study. Twenty-eight patients had normal pituitary MRI findings, and the pituitary origin of ACTH was established by bilateral petrosal sinus sampling in all of these cases. Twenty-six patients had positive MRI findings clearly showing a microadenoma. The two groups were not significantly different in terms of the sex ratio, age, frequency of hypertension, or diabetes, basal 24-h urinary free cortisol levels and follow-up. All of the patients were operated on by two experienced neurosurgeons using the same surgical protocol. Selective adenomectomy was performed when a tumor was identified, and subtotal hypophysectomy was performed when the lesion was uncertain or when no tumor was found during surgical exploration. Respectively, 50% and 84% of patients with normal and positive MRI results underwent adenomectomy (P < 0.05). A pituitary adenoma (confirmed by pathological examination) was found at surgery in 53% and 88% of patients in the normal and positive MRI groups, respectively (P < 0.05). The early surgical success rate (combining patients with corticotropic deficiency and patients with eucortisolism) was similar in the normal and positive MRI groups (78% and 88%, respectively; P = 0.85). The recurrence rate was lower in the normal MRI group, but the difference did not reach statistical significance (9% vs. 30%; P = 0.07). The final remission rate at the last visit was similar in the normal and positive MRI groups (72% and 61%, respectively; P = 0.29). Postoperative complications were also similar: 10 patients (36%) with normal MRI and five patients (20%) with positive MRI had at least one postoperative complication (surgical and/or pituitary deficiency; P = 0.12). Thus, the outcome of pituitary surgery in CD appears to be similar regardless of whether pituitary MRI shows a microadenoma. We recommend neurosurgical pituitary exploration as the first-line treatment of CD, provided that the pituitary origin of ACTH secretion is confirmed by bilateral petrosal sinus sampling in patients with normal pituitary MRI findings.

Objective: The diagnostic impact of chromogranin A (CgA) measurement has been studied in various neuroendocrine tumours (NET) such as pheochromocytomas, gastrinomas and neuroblastomas. Clinically nonfunctioning pituitary adenomas (NFPA) are generally diagnosed on tumoural symptoms or hypopituitarism and, except for gonadotrophins and their free subunits which may be increased in the case of gonadotrophinomas, markers of endocrine secretory activity are lacking not only for diagnostic purpose but also in the postoperative follow-up of these patients. As the presence of CgA has been demonstrated by immunohistochemistry in pituitary adenomas, we performed this study to further assess the sensitivity of CgA measurement in sporadic pituitary adenomas using a new, specific, sandwich immunoassay., Subjects: We first completed a basal normative data set obtained using this assay by studying four healthy men (49 +/- 13 years old), five healthy premenopausal women (35.8 +/- 7.5 years old) and five healthy postmenopausal women (49.1 +/- 4.6 years old) basally and after TRH administration. Twenty-seven patients [12 men (64.2 +/- 11.8 years), even premenopausal women (38.4 +/- 5.7 years) and eight postmenopausal women (67.7 +/- 10.3 years)] with NFPA, 15 acromegalic patients [nine men (45 +/- 13.3 years), six women (52 +/- 14.9 years)] and 19 patients with a prolactin-secreting adenoma [four men (41.2 +/- 18 years) and 15 women (31.2 +/- 7.5 years), with a macroadenoma (n = 11) or a microadenoma (n = 8)] had basal and TRH-stimulated measurement of CgA. A gonadotrophin-releasing hormone (GnRH)-stimulation test was also performed in two, four and four patients, respectively. All patients had sporadic pituitary adenomas., Measurements: Serum CgA was measured using a solid-phase two-site immunoradiometric assay based on monoclonal antibodies that bind to two distinct contiguous epitopes within the 145-245 region of CgA., Results: Mean basal CgA concentration in 14 normal subjects was 80.2 ng/ml (SD: 31.7; range 19-124). A cut-off value for normal range was thus set at 125 ng/ml. TRH injection did not change significantly the CgA levels, peak values remaining less than 124 ng/ml. Three out of 27 subjects with NFPA (11%) had elevated basal CgA levels (576, 143, 241 ng/ml, respectively). Serum levels of CgA were not influenced by TRH in any of the NFPA subjects (including those three with increased basal levels). One out of 15 acromegalic patients (6.6%) and one out of 19 hyperprolactinemic patients (5.2%) had elevated serum basal CgA which did not significantly increase after TRH administration. In the remaining patients TRH-tests did not modify CgA levels. GnRH administration did not modify CgA levels., Conclusions: CgA serum levels measurement, assessed with a novel assay, does not provide a helpful marker for the clinical management of functioning and NFPA.

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

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. [ABSTRACT FROM AUTHOR]