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Background: Patients with acromegaly require lifelong medication; a longer dosing interval would reduce treatment burden. This study investigated the pharmacokinetics, pharmacodynamics and safety profile of a new prolonged-release formulation (PRF) of lanreotide every 12 weeks. Research design and methods: In this multicenter, open-label, dose-ascending study, cohorts of nine patients with acromegaly received single doses of lanreotide PRF according to a 3 + 3 + 3 scheme in order to determine the maximum tolerated dose (MTD). Following a 12-week treatment period, patients were followed up for a further 12 weeks. Serum lanreotide, insulin-like growth factor-1 and growth hormone concentrations were analyzed. Adverse events were monitored throughout the study. Results: The MTD was not reached. Peak lanreotide serum concentration values were similar in all cohorts, whereas area under the curve values from time zero to 85 days increased but were not dose-proportional. The apparent elimination half-life of lanreotide PRF was approximately 54–63 days, in line with the expected prolonged-release characteristics. Growth hormone and insulin-like growth factor-1 levels were generally stable. Conclusions: The safety and tolerability profile was in-line with the known safety profile of lanreotide autogel. Lanreotide PRF was well tolerated and the pharmacokinetic profile suggests that a dosing interval of 12 weeks could be achievable. Clinical trial registration: www.clinicaltrials.gov identifier is NCT02396953; EudraCT 2014–002389-62.

Objective T2-signal intensity and somatostatin (SST) receptor expression are recognized predictors of therapy response in acromegaly. We investigated the relationship between these predictors and the hormonal and tumoral responses to long-acting pasireotide (PAS-LAR) therapy, which were also compared with responsiveness to first-generation somatostatin receptor ligands (SRLs). Design The PAPE study is a cohort study. Methods We included 45 acromegaly patients initially receiving SRLs, followed by combination therapy with pegvisomant, and finally PAS-LAR. We assessed tumor volume reduction (≥25% from baseline), IGF-1 levels (expressed as the upper limit of normal), and T2-weighted MRI signal and SST receptor expression of the adenoma. Results Patients with significant tumor shrinkage during PAS-LAR showed higher IGF-1 levels during PAS-LAR (mean (S.D.): 1.36 (0.53) vs 0.93 (0.43), P = 0.020), less IGF-1 reduction after first-generation SRLs (mean (S.D.): 0.55 (0.71) vs 1.25 (1.07), P = 0.028), and lower SST2 receptor expression (median (IQR): 2.0 (1.0–6.0) vs 12.0 (7.5–12.0), P = 0.040). Overall, T2-signal intensity ratio was increased compared with baseline (mean (S.D.): 1.39 (0.56) vs 1.25 (0.52), P = 0.017) and a higher T2-signal was associated with lower IGF-1 levels during PAS-LAR (β: −0.29, 95% CI: −0.56 to −0.01, P = 0.045). A subset of PAS-LAR treated patients with increased T2-signal intensity achieved greater reduction of IGF-1 (mean (S.D.): 0.80 (0.60) vs 0.45 (0.39), P = 0.016). Conclusions Patients unresponsive to SRLs with a lower SST2 receptor expression are more prone to achieve tumor shrinkage during PAS-LAR. Surprisingly, tumor shrinkage is not accompanied by a biochemical response, which is accompanied with a higher T2-signal intensity.

Gigantism has always been the subject of interest among the general public due to connotations of otherworldly strength and abilities. Until quite recently, the study of gigantism as an illness has not received concerted scientific attention, probably due to its very rare nature. International collaborative research has now led to significant advances in the understanding of the molecular mechanisms responsible for some forms of excessively tall stature. The clinical presentation of pituitary gigantism will be detailed here with emphasis on the specific aspects that are typical to the different genetic causes underlying the disease.

Introduction: Acromegaly is a rare disease due to growth hormone (GH)-secreting pituitary adenoma. GH and IGF-1 levels are usually congruent, indicating either remission or active disease, however a discrepancy between GH and IGF-1 may occur. We aimed to evaluate the outcome of acromegalic comorbidities in patients with congruent GH and/or IGF-1 levels vs discordant biochemical parameters. Methods: Retrospective analysis of the data of 3173 patients from the Liège Acromegaly Survey (LAS) allowed to include 190 patients from 8 tertiary referral centers across Europe, treated by surgery, with available data concerning diabetes mellitus (DM) and hypertension (HT) both at diagnosis and at last follow-up. We recorded for all the patients the number of antihypertensive and antidiabetic drugs used at the first evaluation and at last follow-up. Results: Ninety-nine patients belonged to the REM group (Concordant parameters), sixty-five patients were considered as GHdis and 26 patients were considered as IGF-1dis. At diagnosis, 63 patients (33.1%) had HT and 54 patients had DM (28.4%). There was no statistically significant difference in terms of number of anti-HT and anti-diabetic drugs at diagnosis versus last follow-up (mean duration=7.3+/-4.5years) between all 3 groups. Discussion: The results highlight that the long-term outcome of acromegaly does not tend to be more severe in patients with biochemical discordance in comparison with patients considered as in remission on the basis of concordant biological parameters, suggesting that patients with biochemical discordance do not require a closer follow-up.

Context First-generation somatostatin receptor ligands (fg-SRLs) represent the mainstay of medical therapy for acromegaly, but they provide biochemical control of disease in only a subset of patients. Various pretreatment biomarkers might affect biochemical response to fg-SRLs. Objective To identify clinical predictors of the biochemical response to fg-SRLs monotherapy defined as biochemical response (insulin-like growth factor (IGF)-1 ≤ 1.3 × ULN (upper limit of normal)), partial response (>20% relative IGF-1 reduction without normalization), and nonresponse (≤20% relative IGF-1 reduction), and IGF-1 reduction. Design Retrospective multicenter study. Setting Eight participating European centers. Methods We performed a meta-analysis of participant data from 2 cohorts (Rotterdam and Liège acromegaly survey, 622 out of 3520 patients). Multivariable regression models were used to identify predictors of biochemical response to fg-SRL monotherapy. Results Lower IGF-1 concentration at baseline (odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.72–0.95 IGF-1 ULN, P = .0073) and lower bodyweight (OR = 0.99, 95% CI 0.98–0.99 kg, P = .038) were associated with biochemical response. Higher IGF-1 concentration at baseline (OR = 1.40, (1.19–1.65) IGF-1 ULN, P ≤ .0001), the presence of type 2 diabetes (oral medication OR = 2.48, (1.43–4.29), P = .0013; insulin therapy OR = 2.65, (1.02–6.70), P = .045), and higher bodyweight (OR = 1.02, (1.01–1.04) kg, P = .0023) were associated with achieving partial response. Younger patients at diagnosis are more likely to achieve nonresponse (OR = 0.96, (0.94–0.99) year, P = .0070). Baseline IGF-1 and growth hormone concentration at diagnosis were associated with absolute IGF-1 reduction (β = 0.90, standard error (SE) = 0.02, P ≤ .0001 and β = 0.002, SE = 0.001, P = .014, respectively). Conclusion Baseline IGF-1 concentration was the best predictor of biochemical response to fg-SRL, followed by bodyweight, while younger patients were more likely to achieve nonresponse.

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.

Background: Previous studies indicate that PAS-LAR can achieve control of insulin-like growth factor I (IGF-I) levels and may reduce tumor size, however a subset of acromegaly patients responds poorly. T2-signal intensity, somatostatin receptor (SST) subtype 2 and 5 expression, and the response to first-generation somatostatin receptor ligands (SRLs) are recognized predictors of therapy response. Valid prediction of the response to PAS-LAR can alter treatment stratification. Aim: To analyze T2-signal intensity and SST receptor expression in relation to the hormone and tumor response during PAS-LAR treatment, and to determine to what extent this equals SRLs responsiveness. Methods: We included 45 patients initially receiving SRLs, followed by a combination therapy including pegvisomant, and finally treated with PAS-LAR. The hormone response to PAS-LAR was evaluated using IGF-I (x ULN) levels at 24 weeks. T2-weighted MRI signal intensity of the adenoma was visually assessed and quantified by region of interest measurement. A tumor volume change of ≥25% from baseline was considered significant. SST receptor expression in adenomas was evaluated in 13 out of 45 patients using a validated immunoreactivity score (IRS). The clinical characteristics and the hormone and tumor response to PAS-LAR were assessed using multivariable regressions. Results: Patients with the lowest percentage IGF-I (x ULN) reduction during SRLs also showed weak IGF-I (x ULN) control during PAS-LAR and, however, more significant tumor shrinkage (r=0.41, p=0.006; p=0.036). Lower IGF-I (x ULN) levels during PAS-LAR were associated with higher T2-signal intensity and less significant tumor shrinkage (ß=-0.29, p=0.045; ß=0.34, p=0.035). With regards to tumor response, adenoma volume at baseline was associated with higher random GH levels at diagnosis and greater absolute tumor shrinkage during PAS-LAR (ß=69, p=0.0018; ß=1.05, p=0.020). Significant tumor shrinkage was associated with female patients, higher IGF-I (x ULN) levels during PAS-LAR and borderline significant with non-hypointense adenomas at baseline (OR=6.35, 95% CI=1.42-36.4; OR=13.2, 95% CI=2.14-129.1; OR=5.97, 95% CI=0.91-65.5 respectively). Lower IGF-I (x ULN) levels after PAS-LAR correlated with higher (r=-0.68, p=0.011; r=-0.52, p=0.083), while significant tumor shrinkage correlated with lower SST2 levels as well as SST2/SST5 ratio expression (p=0.040; p=0.024). Conclusions: Patients not responding to somatostatin analogs with particularly large adenomas, low SST2 receptor expression and higher T2-signal intensity are more prone to show tumor shrinkage during PAS-LAR than patients with high SST2 receptor expression and T2-hypointense adenomas. Surprisingly, tumor shrinkage is not accompanied by lower IGF-I (x ULN) levels, which are associated with a high SST2 receptor expression and a higher T2-signal intensity. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Familial pituitary adenomas account for approximately 5–8% of all pituitary adenomas. Besides the adenomas occurring as part of syndromic entities that group several endocrine or nonendocrine disorders (multiple endocrine neoplasia type 1 or 4, Carney complex and McCune–Albright syndrome), 2–3% of familial pituitary adenomas fit into the familial isolated pituitary adenomas (FIPA) syndrome, an autosomal dominant condition with incomplete penetrance. About 20% of FIPA cases are due to mutations in the AIP gene and have distinct clinical characteristics. Recent findings have isolated a new non-AIP FIPA syndrome called X-linked acrogigantism, resulting from a microduplication that always includes the GPR101 gene. These new advances in the field of pituitary disease are opening up a new challenging domain to both clinicians and researchers. This review will focus on these recent findings and their contribution to the diagnosis and the management of familial pituitary adenomas.

[Background] Pituitary adenomas have a high disease burden due to tumor growth/invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy., [Aims] We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center., [Methods] Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response., [Results] Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen., [Conclusions] Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients., This research was supported by a grant from the Fonds d’Investissement pour la Recherche (FIRS) of the CHU de Liège, the JABBS Foundation, United Kingdom (to A B) and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación co-funded with Fondos FEDER (PI13/02043 to A S-M and PI16/00175 to A S-M and D A C). A S-M and D A C were also supported by grants from the Andalusian Ministry of Health (A-0003-2016, A-0006-2015, C-0015-2014 and RC-0006-2018).

In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.

Background Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. Objective To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). Design Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. Results For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week). Conclusion In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient’s weight was associated with the IGF-I normalization PEGV dosage.

Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly characteristics over time. The Liège Acromegaly Survey (LAS) Database, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years; P P = 0.015). Ages at diagnosis and first symptoms increased significantly over time (P P P P P 3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.

Since the 1990's cabergoline has been the treatment of choice in prolactinoma, as it permits rapid and effective hormonal and tumor control in most cases. Evidence of cardiac valvulopathy was demonstrated in Parkinson's disease patients treated with dopamine agonists. Retrospective studies in prolactinoma patients treated with cabergoline at lower doses did not show such an effect. However, few prospective data with long-term follow-up are available. The aim of this study was to assess the safety of cabergoline regarding cardiac valvular status during prospective follow-up in patients treated for prolactinoma or idiopathic hyperprolactinemia. We report here a series of 100 patients (71F; median age at diagnosis: 41.5 years) treated with cabergoline for endocrine diseases (prolactinoma n = 89, idiopathic hyperprolactinemia n = 11). All patients underwent complete transthoracic echocardiographic studies at baseline and during long-term prospective surveillance using the same equipment and performed by the same technicians. The median interval between baseline and last follow-up echocardiographic studies while on cabergoline was 62.5 months (interquartile range: 34.75-77.0). The median total duration of cabergoline treatment was 124.5 months (interquartile range: 80.75-188.75) and the median cumulative total dose of cabergoline was 277.8 mg (interquartile range : 121.4-437.8 mg) at last follow-up. We found no clinically relevant alterations in cardiac valve function or valvular calcifications with cabergoline treatment. Our data suggest that findings from retrospective analyses are correct and that cabergoline is a safe chronic treatment at the doses used typically in endocrinology.

Context Acromegaly is a rare disease associated with chronic multisystem complications. National registries have been created in several countries. Design The French Registry contains data on acromegaly epidemiology, management and comorbidities recorded over more than three decades, retrospectively until 1999 and prospectively from 1999 to 2012. Results Data could be analyzed for 999 of the 1034 patients included in the registry (46% males). Disease control, defined as IGF-I normalization (adjusted for age and sex), was achieved in 75% of patients at the last follow-up visit. Half the patients with uncontrolled disease had IGF-I levels below 1.5 times the upper limit of normal (ULN). The proportion of patients with surgically cured disease did not change markedly over time, whereas the proportion of patients with uncontrolled disease fell and the proportion of patients with medically controlled disease rose. Cardiovascular, metabolic, respiratory and rheumatologic comorbidities and their outcomes were recorded for most patients, and no noteworthy overall deterioration was noted over time. Cancer occurred in 10% of patients, for a standardized incidence ratio of 1.34 (95% CI: 0.94–1.87) in men and 1.24 (0.77–1.73) in women. Forty-one patients died during follow-up, for a standardized mortality ratio of 1.05 (0.70–1.42). Most deaths were due to cancer. Conclusions The majority of patients with acromegaly now have successful disease control thanks to the multistep management. The incidence of comorbidities following diagnosis of acromegaly is very low. Life expectancy is now close to that of the general population, probably owing to better management of the GH/IGF-I excess and comorbidities.

Background Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood. Design and methods A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly. Results Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CABmax/w) was 3.5 mg (2.0–10.5). Despite a higher CABmax/w in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CABmax/w (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CABmax/w or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%). Conclusion CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.

Acromegaly is a chronic rare disease associated with negative pathological effects on multiple systems and organs. We designed a new informatics tool to study data from patients with acromegaly, the Liege Acromegaly Survey (LAS). This relational database permits the inclusion of anonymous historical and prospective data on patients and includes pathophysiology, clinical features, responses to therapy and long term outcomes of acromegaly. We deployed the LAS in a validation study at a single center in order to study the characteristics of patients with acromegaly diagnosed at our center from 1970-2011. A total of 290 patients with acromegaly were included (147 males and 143 females). There was a linear relationship between age at diagnosis and the date of diagnosis, indicating that older patients are being diagnosed with acromegaly more frequently. A majority presented with macroadenomas (77.5%) and the median diameter was 14 mm. Patients with macroadenomas were significantly younger than patients with microadenomas (P=0.01). GH values at diagnosis decreased with the age of the patients (P=0.01) and there was a correlation between GH values and tumor size at diagnosis (P=0.02). No correlation existed between insulin-like growth factor 1 (IGF-1) levels and tumor characteristics. The prevalence of diabetes was 21.4% in this population and 41.0% had hypertension. The presence of hypertension and diabetes were significantly associated with one another (P

Objective: To summarize current knowledge on the clinical and genetic characteristics of familial pituitary tumor syndromes. Methods: This review is based on a comprehensive search through the English-language literature with use of the following terms: “familial,” “pituitary,” “adenomas,” and “tumors.” Results: Familial pituitary tumors are rare and constitute approximately 5% of all pituitary adenomas. Currently, there are 4 recognized inherited syndromes that involve pituitary tumorigenesis—multiple endocrine neoplasia type 1 (MEN 1), multiple endocrine neoplasia type 4 (MEN 4), Carney complex (CNC), and familial isolated pituitary adenomas (FIPA). MEN 1 and CNC have been known for several decades, and their clinical and molecular characteristics have been comprehensively studied. Many familial cases of pituitary adenomas can be attributed to mutations in MEN1 and PRKAR1A genes. The recently defined MEN 4 is extremely rare. Familial pituitary tumors that are not associated with MEN 1 and CNC have been united under a new term introduced in the 1990s—FIPA. About 15% to 25% of patients with FIPA harbor mutations in the AIP gene. Conclusion: Although rare, familial pituitary tumors present an opportunity to study inherited molecular and genetic mechanisms of pituitary tumorigenesis. A comprehensive understanding of their characteristics may provide a basis for early diagnosis and better management of affected patients. (Endocr Pract. 2011;17[Suppl 3]:41-46) Abbreviations: AhR = aryl hydrocarbon receptor; AIP = aryl hydrocarbon receptor interacting protein; CNC = Carney complex; FIPA = familial isolated pituitary adenomas; GH = growth hormone; MEN 1 = multiple endocrine neoplasia type 1; MEN 4 = multiple endocrine neoplasia type 4

Pituitary adenomas usually present sporadically, with a multifactorial pathogenesis including somatic mutational events in cancer-related genes. Genetic predisposition implies the presence of germline DNA alterations with a range of impacts on pituitary cell biology, translating into a variable penetrance of the disease. Genetic causes must be considered in the presence of specific clinical settings, such as familial occurrence of pituitary adenoma, with or without extrapituitary diseases, and may also be suspected in young patients (

Dopamine (DA) is a catecholamine with a wide range of functions and whose five subtype receptors are found in different organs where they exert a mainly inhibitory action. Since this action may also appear in a number of secretory tumors in various locations, DA agonists have elicited some interest as a medical treatment for hypercorticism. Non-iatrogenic Cushing’s syndromes are due in 70% of the cases to a pituitary adrenocorticotropic hormone (ACTH)-producing adenoma, and, less frequently, to an adrenal adenoma or an ectopic ACTH secretion by a neuroendocrine tumor. First-line treatment in Cushing’s syndrome consists of the surgical removal of the secreting tumor. However, surgery may not achieve a complete cure in a number of cases, hence emphasizing the potential benefit of a medical complementary treatment, which could also benefit patients as an alternative approach, either when waiting for, or when the patient is not eligible for surgery. Studies of corticotropic adenomas have shown that 80% of these tumors express D2 receptors. Clinical trials of DA agonists in Cushing’s disease have shown an inhibitory effect of these drugs with an inhibition of ACTH secretion and/or a decrease of tumor size. There are only a few cases of documented use of DA agonists in ectopic ACTH secretion, but when the tumor expresses DA receptors, DA agonists may represent a useful complementary treatment. DA receptors are also expressed in normal and tumoral adrenals, suggesting a potential use of DA agonists in Cushing’s syndrome secondary to adrenal tumors. However, clinical data regarding this specific situation are very scarce, maybe due to the relatively high rate of surgical cure of adrenal adenomas. In conclusion, DA agonists represent a potential preparatory or complementary treatment for endogenous Cushing’s syndrome, especially in Cushing’s disease. These compounds may be underused as suggested by the scarce number of publication and case reports in the literature. In the future, association of these drugs with somatostatin analogs may also prove beneficial.

UNLABELLED Multicentric registers such as The French Acromegaly Register provide data on rare disorders that are otherwise difficult to obtain, so avoiding extrapolation from limited data sets. This study focuses on clinical, hormonal and therapy characteristics of acromegaly in people over 70 years old. The objective was to compare this population with the youngest to disclose if the medical management was similar. PATIENTS AND METHODS The data were obtained from the 30 centres that have registered patients in the Acromegaly Register since 1999. RESULTS The register listed 644 acromegaly patients on 1st January 2005, of whom 68 (22 men and 46 women) were over 70 years old, independently of the diagnosis date of their disease. Their average age was 76.8 + or - 5 years (range: 70-95) and they had suffered from acromegaly for 11 + or - 6 years (compared to 7 years in those aged less than 70). Their BMI were similar. Diabetes and hypertension were more frequent than in younger acromegalic patients and in the general French population matched for age. Circulating GH and IGF-1 concentrations were lower than in the younger acromegalic patients on inclusion and 1 year after treatment. There was no significant difference in the tumor size. Only 44% of the patients over 70 underwent surgery, against 90% of patients under 70 years. However, the fractions of young and elderly patients with a controlled disease 1 year after inclusion were the same (51%). CONCLUSION In the limits of the use of register, these data reveal a high prevalence of diabetes and hypertension in the eldest acromegalic patients. Despite much less frequent surgical intervention, patients' disease under control is equivalent to the younger population 1 year after the initial interview, confirming the effectiveness of the choices of treatment.

Somatostatin analogs (SSA) with their potent antise cretory and antiproliferative effects are the main medical treatment option for patients with neuroendocrine t umors, such as gastroenteropancreatic and acromegalyassociated growth hormone secreting pituitary tumor s. Although a good portion of acromegalic patients gets normalized after SSA treatment, strict hormonal con trol is not achieved in a sizeable proportion of th ese patients. The reasons for this incomplete response to SSA trea tment are unclear. We have found that the tumor sup pressor ZAC1 (LOT1/PLAGL1) is essential for the antiproliferative effect of SSA in pituitary tumor cells. The aim of the present retrospective cohort study was to deter mine whether ZAC1 immunoreactivity in archival somatotrophinoma tissue derived from 45 patients with acromegaly routinely pretreated with SSA before surgery, was associated with response to SSA (normalization of GH, IGF-I and presence of tumor shrinka ge). All tumors displayed ZAC1 immunoreactivity [weak (+ ; n = 15), moderate (+ + ; n = 16) and strong (+ + + ; n = 14)]. A significant positive correlation was found between strong ZAC1 immunoreactivity and IGF-I normalization and presence of tumor shrinkage after SSA treatment, which was not affected by age at di agnosis, gender or duration of SSA treatment. These in vivo data combined with the antiproliferative properties of ZAC1/Zac1 provide evidence of a mechanistic role for this transcription factor on SSA induced tumor shri nkage and hormone normalization.

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P P P r = 0.22), IGF-1 (P r = 0.14) and adenoma volume (P r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.

Background Prolactin has been shown to exert potent immunomodulatory activities. Design Retrospective cross-sectional study examining the prevalence of autoimmune thyroid diseases (AITD) in patients with prolactinomas. The medical files of 462 patients (367 women and 95 men) followed up at a single tertiary referral centre were analyzed. Results The prevalence of AITD among prolactinoma patients was estimated at 21.0% (23.2% in females and 12.6% in males). In 51.5% of the patients, diagnosis of prolactinoma preceded the development of AITD; in 37.2%, both diseases were simultaneously diagnosed and 11.3% of patients were diagnosed first with AITD. Hyperthyroidism was observed in 1.24% of the investigated subjects. Primary hypothyroidism was detected in 15.6% of all patients (16.4% in women; 10.7% in men) with a mean incidence of 24 cases/1000/year. Conclusions Our results demonstrate the high frequency of AITD in patients with prolactinomas. The prevalence rate of hyperthyroidism is comparable with the literature data from community-based studies. In contrast, the prevalence of the spontaneous hypothyroidism due to autoimmune thyroiditis is significantly higher in female and male subgroups of patients with prolactinomas in comparison with the general population. A possible role of supraphysiologically increased prolactin levels in the pathogenesis and the clinical course of AITD in patients with prolactinomas can be suggested. Based on these findings we recommend routine screening for AITD with simple thyroid tests (TSH, TPO-Abs and ultrasound examination) in all patients diagnosed with prolactinoma.

Responses of GH-secreting adenomas to multimodal management of acromegaly vary widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying factors predictive of their evolution is a research priority. The aim of this study was to clarify the relationship between the T2-weighted adenoma signal on diagnostic magnetic resonance imaging (MRI) in acromegaly and clinical and biological features at diagnosis. An international, multicenter, retrospective analysis was performed using a large population of 297 acromegalic patients recently diagnosed with available diagnostic MRI evaluations. The study was conducted at ten endocrine tertiary referral centers. Clinical and biochemical characteristics, and MRI signal findings were evaluated. T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyperintense and isointense counterparts (PP=0.0001), invaded the cavernous sinus less frequently (P=0.0002), and rarely caused optic chiasm compression (PP=0.067) and presented higher IGF1 values (P=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (PP=0.0067). Most adenomas (45.1%) measured between 11 and 20 mm in maximal diameter and bigger adenomas were diagnosed at younger ages (P=0.0001). The T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether the T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies.

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the geneGPR101, 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.

McCune Albright syndrome (MAS) is a clinical association of endocrine and nonendocrine anomalies caused by postzygotic mutation of the GNAS1 gene, leading to somatic activation of the stimulatory α-subunit of G protein (Gsα). Important advances have been made recently in describing pathological characteristics of many MAS-affected tissues, particularly pituitary, testicular, and adrenal disease. Other rarer disease related features are emerging.The objective of the investigation was to study the pathological and genetic findings of MAS on a tissue-by-tissue basis in classically and nonclassically affected tissues.This was a comprehensive autopsy and genetic analysis.The study was conducted at a tertiary referral university hospital.An adult male patient with MAS and severe disease burden including gigantism was the subject of the study.Interventions included clinical, hormonal, and radiographic studies and gross and microscopic pathology analyses, conventional PCR, and droplet digital PCR analyses of affected and nonaffected tissues.Pathological findings and the presence of GNAS1 mutations were measured.The patient was diagnosed with MAS syndrome at 6 years of age based on the association of café-au-lait spots and radiological signs of polyostotic fibrous dysplasia. Gigantism developed and hyperprolactinemia, hypogonadotropic hypogonadism, and hyperparathyroidism were diagnosed throughout the adult period. The patient died at the age of 39 years from a pulmonary embolism. A detailed study revealed mosaiscism for the p.R201C GNAS1 mutation distributed across many endocrine and nonendocrine tissues. These genetically implicated tissues included rare or previously undescribed disease associations including primary hyperparathyroidism and hyperplasia of the thymus and endocrine pancreas.This comprehensive pathological study of a single patient highlights the complex clinical profile of MAS and illustrates important advances in understanding the characteristics of somatic GNAS1-related pathology across a wide range of affected organs.

A 40-yr-old female presented with an extensive lesion of the sellar area and the sphenoid sinus, spreading to the optic nerves and associated with pachymeningitis. Histological findings were consistent with an inflammatory pseudotumor, and steroid treatment allowed the disappearance of all the lesions. Inflammatory pseudotumors of the pituitary are very rare. This case appears unique with regard to the extension of the lesions and the dramatic response to medical treatment. The differential diagnosis of inflammatory lesions of the pituitary is difficult. It relies mainly on histological analysis and includes sarcoidosis, Wegener's granulomatosis, histiocytosis (Langerhans, Rosai-Dorfman, and Erdheim-Chester diseases) and lymphocytic hypophysitis.

OBJECTIVES: The authors present a case report that proposes the use of cabergoline treatment in silent ACTH adenoma, an unusual member of the heterogeneous group of the so-called clinically non-functioning pituitary adenomas. DESIGN: Following the clinical and radiological improvement of a recurrent silent ACTH adenoma in a 77-year-old patient treated with cabergoline (0.5 mg every 2 days for 2 years), in vitro studies of the original tumor were performed. METHODS: The original tumor from the patient was studied by in situ hybridization and dopamine D2 receptor autoradiography. It was compared with four macroprolactinomas and two macroadenomas from patients with Cushing's disease. RESULTS: The D2 receptor mRNA signal of the reported case was intense and of the same order of magnitude as that observed in control prolactinomas. Dopamine D2 receptor autoradiography was twice that of control corticotroph adenomas and was close to that observed in prolactinomas. CONCLUSIONS: This is the first description of an in vivo shrinkage of an ACTH silent adenoma under cabergoline. We demonstrate in vitro, the presence of D2 receptors in the primitive tumor in concentrations similar to those found in control prolactinomas. These results suggest that therapeutic trials with cabergoline might be undertaken in recurring cases of ACTH silent tumors and more generally, non-functioning pituitary adenomas.

Familial acromegaly is an exceptional clinical entity when not associated with features of multiple endocrine neoplasia type 1 (MEN1). We report here 3 pedigrees in each of which 2 patients have been shown to develop acromegaly. In 5/6 patients, clinical follow-up, and biological screening allowed to confidently exclude MEN1. Absence of mutation in the MEN1 gene after direct DNA analysis in 2 pedigrees reinforces the conviction that the families do not have MEN1. In families 1 and 2, diagnosis

BackgroundAryl hydrocarbon receptor interacting protein (AIP) mutations (AIPmut) cause aggressive pituitary adenomas in young patients, usually in the setting of familial isolated pituitary adenomas. The prevalence of AIPmut among sporadic pituitary adenoma patients appears to be low; studies have not addressed prevalence in the most clinically relevant population. Hence, we undertook an international, multicenter, prospective genetic, and clinical analysis at 21 tertiary referral endocrine departments.MethodsWe included 163 sporadic pituitary macroadenoma patients irrespective of clinical phenotype diagnosed at ResultsOverall, 19/163 (11.7%) patients had germline AIPmut; a further nine patients had sequence changes of uncertain significance or polymorphisms. AIPmut were identified in 8/39 (20.5%) pediatric patients. Ten AIPmut were identified in 11/83 (13.3%) sporadic somatotropinoma patients, in 7/61 (11.5%) prolactinoma patients, and in 1/16 non-functioning pituitary adenoma patients. Large genetic deletions were not seen using multiplex ligation-dependent probe amplification. Familial screening was possible in the relatives of seven patients with AIPmut and carriers were found in six of the seven families. In total, pituitary adenomas were diagnosed in 2/21 AIPmut-screened carriers; both had asymptomatic microadenomas.ConclusionGermline AIPmut occur in 11.7% of patients AIPmut mutation testing in this population should be considered in order to optimize clinical genetic investigation and management.

ObjectivesThe French Acromegaly Registry records data of acromegalic patients' since 1992 in French, Belgian (Liège), and Swiss (Lausanne) centers. We studied the prevalence of diabetes in this population looking for risk factors. Patients from one of the centers (Reims) were then analyzed more thoroughly.MethodsThis study has been conducted on all the patients recorded from 1999 until 2004 (519 patients). Evolution of cohorts' was reassessed in 2009. Of the different variables recorded in the registry: age, sex, body mass index (BMI), duration of acromegaly, GH, IGF1 and prolactin levels, pituitary tumor size, hormonal deficiencies, presence, duration and treatment of diabetes, hypertension, and rheumatological disease were analyzed.ResultsThe prevalence of diabetes in the registry was 22.3%. Diabetic patients were older and had a higher BMI. Compared with the data of the French Social Security, acromegalic patients showed a more precocious apparition of diabetes and prevalence was higher in each age group.Compared with non-diabetic acromegalic subjects, diabetic patients had a more prolonged evolution of acromegaly before diagnosis. The levels of GH and IGF1 were not significantly different between the two groups. Only hypertension was significantly more frequent in diabetic patients.ConclusionsIn our population, the prevalence of diabetes was estimated to be 22.3%. The GH and IGF1 levels did not appear as predictive factors for the presence of diabetes. On the contrary, age, BMI, and hypertension were significant risk factors as in the general population of type 2 diabetics.

Context: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. Objective: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. Design: This study was an international, multicenter, retrospective case collection/database analysis. Setting: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. Patients: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. Results: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. Conclusions: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility. (J Clin Endocrinol Metab 95: E373-E383, 2010)

Twenty-nine patients with macroprolactinomas were treated by monthly intramuscular injections of the long-acting and repeatable form of bromocriptine (Parlodel-LAR) in doses ranging from 50-150 mg. They were divided into two groups: group I consisted of 22 patients who received Parlodel LAR before transsphenoidal adenomectomy; group II was composed of 7 patients with earlier neurosurgery and of 2 patients from group I not cured by transsphenoidal adenomectomy. Duration of therapy varied from 1-12 months, and a total of 104 injections was given. At nadir day, serum PRL levels were situated between less than 1% and 43% of pretreatment values. At day 28 after the first injection, serum PRL levels varied between less than 1% to 139% of initial values. No difference could be detected between the two groups regarding the percent of PRL inhibition. Long-term treatment with Parlodel-LAR resulted in a sustained inhibition of PRL secretion, except for 1 case. Resumption of menstrual cycles occurred in 4 out of 15 women and correction of hypogonadism in 4 out of 14 men. Amelioration of disturbed visual fields was recorded in 3 out of 8 patients. Diminution of the adenoma volume was radiologically documented in 14 out of 22 cases. Only few and mild side effects were recorded. One patient with partial adrenal deficiency suffered from a syncope, but this was prevented by hydrocortisone supplementation during the subsequent Parlodel-LAR administration. In conclusion, Parlodel-LAR proved effective in the treatment of macroprolactinomas, achieving rapid inhibition of PRL secretion, and in some patients amelioration of hypopituitarism, reduction in tumor size, and improvement in visual fields, and caused no serious side effects. It is a valuable preparation to surgery and can also be used in long-term medical therapy.

Context Pegvisomant (Somavert, Pfizer Inc.) is the first and only available GH receptor antagonist. ACROSTUDY is an international surveillance study that offers inclusion in a web-based registry to all patients with acromegaly treated with pegvisomant; it aims at monitoring long-term safety and efficacy of this compound. Patients and methods This report summarizes the main baseline characteristics of this particular population of patients. In February 2009, over 300 centres in 10 countries had contributed 792 patients. A gradual increase in cumulative patient recruitment was observed since the launching of ACROSTUDY in 2004: from 116 patients in 2005, it steeply increased to 792 at the latest data freeze in February 2009. At the time of enrolment, 91.8% of patients were already treated with pegvisomant but baseline was considered at the time of pegvisomant start. IGF1 concentrations were measured at local laboratories. Results Of all patients, 80% were reported to have had surgery and 33% to have received radiation therapy. Of the 792 patients, 14% had received no prior medical treatment before pegvisomant start, 65.9% had received somatostatin analogues and 18.6% dopamine agonists. Interestingly, 66.7% had received only pegvisomant at study start, while it was taken in association with dopamine agonists in 5.7%, with somatostatin analogues in 23.4% and with both types of agents in 3.8%. Mean IGF1 at baseline was 522 ng/ml. Conclusion Analysis of the baseline features of these patients treated with pegvisomant and reported in the ACROSTUDY database underscores the severity of the disease in this subset of the population of patients with acromegaly previously unresponsive to several medical, surgical or radiation treatment approaches.

Malignant prolactinomas are extremely rare (1, 2). The diagnosis of these carcinomas is mainly based on the patient’s medical history and the detection of metastases. Nuclear medicine offers new imaging modalities for the detection of metastases of pituitary carcinomas. These techniques may have serious consequences for subsequent investigations and therapy. The case presented here shows the clinical behavior of a malignant prolactinoma. The usefulness of dopamine D2 receptor scintigraphy for establishing the diagnosis and subsequently directing the therapeutic approach is illustrated.