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
, 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;
< 0.001). The median delay from first symptoms to diagnosis was 2 years longer in females (
= 0.015). Ages at diagnosis and first symptoms increased significantly over time (
< 0.001). Tumors were larger in males than females (
< 0.001); tumor size and invasion were inversely related to patient age (
< 0.001). Random GH at diagnosis correlated with nadir GH levels during OGTT (
< 0.001). GH was inversely related to age in both sexes (
< 0.001). Diabetes mellitus was present in 27.5%, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%. Serious cardiovascular outcomes like stroke, heart failure and myocardial infarction were present in <5% at diagnosis. Erythrocyte levels were increased and correlated with IGF-1 values. Thyroid nodules were frequent (34.0%); 820 patients had colonoscopy at diagnosis and 13% had polyps. Osteoporosis was present at diagnosis in 12.3% and 0.6-4.4% had experienced a fracture. In conclusion, this study of >3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.
Iodine deficiency in Spain is a persisting public health problem and the prescription of potassium iodide is recommended during pregnancy. The purpose of this study was to develop an Artificial ...Neural Network (ANN) to predict the risk factors of iodine deficiency during pregnancy, and compare the results obtained with a logistic regression model. Two hundred forty-four healthy pregnant women were included in a descriptive and prospective study in their first trimester of pregnancy. The women enrolled were asked specifically about their use of supplements containing potassium iodide, iron, folic acid and/or multivitamins during pregnancy. The consumption of iodine-rich foods was assessed through a food frequency questionnaire. A median UIC of 57.4 μg/L (IQR 32.8-99.3) was obtained, with 89.3% < 150 μg/L, the minimum recommended ioduria level by the WHO. There was no correlation between urinary iodine concentrations and maternal age, BMI or gestation week at recruitment. The urinary iodine concentrations were significantly higher in women who reported taking iodized supplements and/or iodized salt than those who did not. Number of gestations, age, body mass index, and intake of iodized supplements and iodized salt were the most important predictors of iodine deficiency. Based on Receiver Operating Characteristic analysis, the diagnostic performance of the ANN model was superior to the logistic regression model. The ANN model, with variables on pregnancy and the intake of iodine rich foods, iodized supplement and iodized salt may be useful for predicting iodine deficiency in the early pregnancy.
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.
Pituitary adenomas in patients with germline AIP mutations have an aggressive clinical course.
Predicting which acromegaly patients could benefit from somatostatin receptor ligands (SRL) is a must for personalized medicine. Although many biomarkers linked to SRL response have been identified, ...there is no consensus criterion on how to assign this pharmacologic treatment according to biomarker levels. Our aim is to provide better predictive tools for an accurate acromegaly patient stratification regarding the ability to respond to SRL. We took advantage of a multicenter study of 71 acromegaly patients and we used advanced mathematical modelling to predict SRL response combining molecular and clinical information. Different models of patient stratification were obtained, with a much higher accuracy when the studied cohort is fragmented according to relevant clinical characteristics. Considering all the models, a patient stratification based on the extrasellar growth of the tumor, sex, age and the expression of E-cadherin, GHRL, IN1-GHRL, DRD2, SSTR5 and PEBP1 is proposed, with accuracies that stand between 71 to 95%. In conclusion, the use of data mining could be very useful for implementation of personalized medicine in acromegaly through an interdisciplinary work between computer science, mathematics, biology and medicine. This new methodology opens a door to more precise and personalized medicine for acromegaly patients.
Abstract Context Few data exist about the clinical course of acromegaly, surgical and medical outcomes in patients with GH- and prolactin cosecreting pituitary adenomas (GH&PRL-PAs). Nevertheless, ...some series described a more aggressive clinic-radiological behavior than in growth hormone–secreting pituitary adenomas (GH-PAs). Objective This work aims to evaluate differences in clinical presentation and in surgical outcomes between GH-PAs and GH&PRL-PAs. Methods A multicenter retrospective study was conducted of 604 patients with acromegaly who underwent pituitary surgery. Patients were classified into 2 groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal (ULN) and IHC for GH and PRL was positive or PRL levels were greater than 100 ng/dL and PRL IHC was not available (n = 130) and b) GH-PA patients who did not meet the previously mentioned criteria (n = 474). Results GH&PRL-PAs represented 21.5% (n = 130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P < .001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs 77.4%; P = .001) and tended to be more invasive (33.6% vs 24.7%; P = .057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (odds ratio 2.8; 95% CI, 1.83-4.38). Insulin-like growth factor ULN levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 interquartile range (IQR) 1.73-3.29 vs 2.7 IQR 1.91-3.67; P = .023). There were no differences in the immediate (41.1% vs 43.3%; P = .659) or long-term postsurgical acromegaly biochemical cure rate (53.5% vs 53.1%; P = .936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs 2.4%; P = .011) in GH&PRL-PA patients. Conclusion GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger, and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.
Context: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown.
Objective: The objective of the study was to ...assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA).
Design: This was a multicenter, international, collaborative study.
Setting: The study was conducted in 34 university endocrinology and genetics departments in nine countries.
Patients: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis.
Main Outcome Measures: Presence/absence and description of AIP gene mutations were the main outcome measures.
Intervention: There was no intervention.
Results: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations.
Conclusions: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.
Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of ...persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse.
This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas.
A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years' follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery.
Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P < .001).
This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas.
We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have ...prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) .
A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered
and those whose IGF1 was ≥3SDS, were considered
. The 2 hours GH value (GH
) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively.
In all, 30 patients were responders and 17 were non-responders. GH
was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH
= 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH
= 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH
than those with E-cadherin-negative tumors 0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01, and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01).
The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly.
Acromegaly is caused by excess growth hormone (GH) produced by a pituitary tumor. First-generation somatostatin receptor ligands (SRLs) are the first-line treatment. Several studies have linked ...E-cadherin loss and epithelial-mesenchymal transition (EMT) with resistance to SRLs. Our aim was to study EMT and its relationship with SRLs resistance in GH-producing tumors. We analyzed the expression of EMT-related genes by RT-qPCR in 57 tumors. The postsurgical response to SRLs was categorized as complete response, partial response, or nonresponse if IGF-1 was normal, had decreased more than 30% without normalization, or neither of those, respectively. Most tumors showed a hybrid and variable EMT expression profile not specifically associated with SRL response instead of a defined epithelial or mesenchymal phenotype. However, high
expression was related to invasive and SRL-nonresponsive tumors.
was overexpressed in tumors treated with SRLs before surgery, and this increased expression was more prominent in those cases that normalized postsurgical IGF-1 levels under SRL treatment. In conclusion, GH-producing tumors showed a heterogeneous expression pattern of EMT-related genes that would partly explain the heterogeneous response to SRLs.
and
may be useful to predict response to SRLs and help medical treatment decision making.
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