The measurement of circulating concentrations of growth hormone (GH) is an indispensable tool in the diagnosis of both GH deficiency and GH excess. GH is a heterogeneous protein composed of several molecular isoforms, but the physiological role of these different isoforms has not yet been fully understood. The 22KD GH (22 K-GH) is the main isoform in circulation, followed by 20KD GH (20 K-GH) and other rare isoforms. Studies have been performed to better understand the biological actions of the different isoforms as well as their importance in pathological conditions. Generally, the non-22 K- and 20 K-GH isoforms are secreted in parallel to 22 K-GH, and only very moderate changes in the ratio between isoforms have been described in some pituitary tumors or during exercise. Therefore, in a diagnostic approach, concentrations of 22 K-GH accurately reflect total GH secretion. On the other hand, the differential recognition of GH isoforms by different GH immunoassays used in clinical routine contributes to the known discrepancy in results from different GH assays. This makes the application of uniform decision limits problematic. Therefore, the worldwide efforts to standardize GH assays include the recommendation to use 22 K-GH specific GH assays calibrated against the pure 22 K-GH reference preparation 98/574. Adoption of this recommendation might lead to improvement in diagnosis and follow-up of pathological conditions, and facilitate the comparison of results from different laboratories.

Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (P < 0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues.

Introduction: Measurements of GH and IGF-I are considered gold standard for biochemical acromegaly diagnosis and follow-up, but have limitations. Novel laboratory tools would be of interest, especially when results for GH and IGF-I are discrepant. Soluble alpha-klotho (αKL) might have endocrine functions and few studies have investigated αKLs role in acromegaly. Methods: We measured αKL in treatment-naïve patients before surgery (A; n=29), after surgery (controlled, B; n=32; not controlled, C; n=15) in postoperative patients on SSA (controlled, D; n=22; not controlled, E; n=11), in patients with non-functioning pituitary adenomas (NFPA, F; n=20) and in healthy controls (HC, G; n=31). Control was defined by IGF-I≤1.3XULN. Random GH was also measured. Agreement between categorizations based on IGF-I ≤1.3XULN, GH <1.0ng/mL and normal αKL was investigated. ROC analysis was used to define cut-offs above which αKL indicates lack of control of acromegaly. Results: As expected, GH and IGF-I significantly dropped after surgery and with pharmacological control. αKL was markedly elevated in treatment-naïve patients before surgery, decreased after surgery and normalized with biochemical control (A vs. B, D; p<0.0001). It remained higher in uncontrolled patients after surgery as compared to controlled patients, NPFA and HC (C, E vs. B, D, F, G; p<0.05) and did not differ between controlled patients, NFPA and HC (B, D vs. F, G; p>0.05). αKL was correlated with IGF-I (r=0.8) and - to a lesser degree - with random GH (r=0.6; p<0.0001 for both). High GH concentrations (>10ng/mL) still correlated significantly with αKL (r=0.50; p=0.03), but no longer with IGF-I. Concentrations of αKL were not correlated to prolactin and markers of calcium metabolism. In contrast to IGF-I, αKL did not change with sex and age in acromegaly, NFPA and HC. In patients which were controlled based on normalized IGF-I, but not on GH, αKL was also normalized in >95% of the cases. Concentrations of αKL>1617pg/mL indicate lack of control (ROC; 98.1% sensitivity, 76.3% specificity). Conclusion: Similar to GH and IGF-I, circulating αKL reflects disease activity in acromegaly. It might be useful as a surrogate parameter at diagnosis and during follow up, particularly if GH and IGF-I are discrepant. αKL has potential advantages over IGF-I as it seems to be unaffected by age and sex, and remains correlated to GH hypersecretion at very high GH concentrations.

Mesmo entre os especialistas mais dedicados, a prática clínica da Neuroendocrinologia é conhecida por sua larga complexidade. Os temas e subtemas a partir dos quais se pode dividir a especialidade são inúmeros e precisam ser tratados com o devido cuidado, assegurando aos profissionais médicos referências confiáveis para as abordagens e aplicações mais adequadas em sua rotina. O Guia Prático em Neuroendocrinologia é o resultado da reunião dos principais nomes da área e uma iniciativa do Departamento de Neuroendocrinologia da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM). Em 28 capítulos escritos em uma linguagem acessível, o guia oferece uma literatura que, ao assimilar a complexidade da Neuroendocrinologia, enfoca as lacunas de conhecimento de endocrinologistas de todo o país, visando transformá-las em informações consistentes e atualizadas para o melhor atendimento dos pacientes.

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BACKGROUND: Transsphenoidal surgery is the cornerstone of acromegaly treatment. However, cure is obtained in only ~50% of the cases. Until today, no biochemical marker has been identified to preoperatively predict surgical outcome and long-term remission. Recently, soluble alpha klotho (αKL) was proposed as new biomarker for diagnosis and follow-up of acromegaly. Therefore, we aimed to evaluate the potential of pre-surgery αKL concentrations as a prognostic factor to predict remission by surgery alone. Methods: We measured αKL concentrations (IBL-ELISA) and classical biomarkers (IGF-I and GHrandom, both by IDS-iSYS, GHnadir measured by IDS-iSYS (n=13) or DiaSorin-Liaison® (n=7)) in samples from a prospective study in treatment-naïve patients with acromegaly (total n=25). Patients were then followed for at least 6 months after surgery (median (range) 30.1 (6–142) months). Outcome was evaluated and classified as non-remission (NR: IGF-I&gt;1.2xULN (n=2) or continued need for medical treatment with somatostatin analogues (n=10)) or remission (R: improvement on clinical signs and symptoms and IGF-I&lt;1.2xULN without medical treatment, n=13). Results: Before surgery, all patients had elevated IGF-I (&gt;1.2xULN), GHnadir (&gt;0.4 ng/mL) and GHrandom (&gt;1.0 ng/mL). As expected, αKL (pg/mL) was also high (&gt;1.2xULN) in 92% patients. Before surgery, αKL was significantly higher in NR compared to R [6648 (4408–13951) vs. 3389 (2132–6837); p&lt;0.05), as was IGF-I (ng/mL) [NR: 879.7 (771.8–961.5) vs. R: 640.2 (448.6–862.6); p&lt;0.05). There was no difference in GHnadir and GHrandom (ng/mL) [10.42 (6.35–16.40) vs. 5.19 (1.19–10.70) and 12.39 (8.24–24.87) vs. 8.94 (4.24–15.55); p&gt;0.05 for both comparisons). ROC analysis indicated that concentrations of αKL&gt;4470pg/mL (~3.5xULN) (75% specificity, 62% sensitivity, AUC=0.72) and IGF-I&gt;3.8xULN (67% specificity, 85% sensitivity, AUC=0.79) indicate lack of long-term remission. Conclusion: High αKL (&gt;4470pg/mL, ~3.5xULN) and IGF-I (&gt;3.8xULN) concentrations before surgery are significantly associated with persistent disease activity after surgery. However, both biomarkers alone or in combination have insufficient specificity (though acceptable sensitivity) as predictors of surgical outcome.

Background: The impact of estrogens (E2) on the growth hormone (GH)/IGF-I axis is known to depend on route of administration: While oral E2 increases GH and decreases IGF-I, transdermal E2 has only limited or no effect. However, data concerning the impact of E2 on IGF binding protein 3 (IGFBP 3) and ALS are less clear. One study in girls demonstrated higher ALS with oral E2, while the opposite was suggested for postmenopausal women. No data are available for healthy premenopausal women.Methods: We measured IGF-I, IGFBP 3 and ALS in fasted healthy adults (93 males (M), 35 premenopausal women without E2-containing oral contraception (FPRE), 37 premenopausal women with E2-containing oral contraception (FPREOC) and 34 postmenopausal women (FPOST)). IGF-I and IGFBP 3 were measured using the IDS-iSYS chemiluminescence immunoassay, and ALS by an in-house immunofluorometric assay (limit of quantification (LoQ) &lt; 50 mU/ml, range 50 - 4000 mU/mL).Results: Median age (range) was 33 (20 - 76), 28 (20 - 44), 24 (21 - 36) and 56 (49 - 70) years for M, FPRE, FPREOC and FPOST, respectively. As expected, IGF-I was lower in FPREOC compared to FPRE (median IGF-I xULN (IQR) 0.56 (0.45 - 0.73) and 0.72 (0.63 – 0.80), P = 0.0017, Kruskal-Wallis). ALS was significantly higher in FPREOC compared to all other groups (mean ALS in M, FPRE, FPREOC and FPOST: 636, 708, 861 and 648 mU/mL, respectively, ANOVA P &lt; 0.0001, Dunnett’s post-hoc test: M vs FPREOC: P &lt; 0.0001, FPRE vs FPREOC: P = 0.0007, FPOST vs FPREOC: P &lt; 0.0001). IGFBP 3 was not different in females with and without oral E2 (median IGFBP 3 xULN (IQR) FPREOC vs FPRE: 0.62 (0.54 - 0.67) vs 0.60 (0.49 – 0.76), Kruskal-Wallis P = 0.295, Dunn’s post-hoc test: P &gt; 0.9999). This was also true between all other groups (Dunn’s post-hoc test: P ≥ 0.4). In our adult cohort, ALS exhibited negative correlation with age (Pearson r = -0.282, P = 0.0003), similar to IGF-I and IGFBP 3. While IGF-I exhibited a moderate negative correlation to BMI (Pearson r = -0.25, P = 0.0013), IGFBP 3 and ALS were not significantly related to BMI.Conclusion: While IGF-I, IGFBP 3 and ALS all are known to be secreted in response to GH, and IGF-I and ALS are assumed to be produced by the same cells in the liver (hepatocytes), the three GH dependent biomarkers appear to be differently regulated by metabolic factors and oral E2. Only IGF-I has some modest association with BMI. Oral E2 is associated with reduced IGF-I, unchanged IGFBP 3 but increased ALS. While the mechanism behind the differential regulation remains to be uncovered, E2 therapy must be taken into account when interpreting IGF-I and ALS concentrations.

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