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Context: Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparisons with traditional biomarkers in acromegaly are lacking., Objective: To evaluate the potential of sαKL to aid classification of disease activity., Methods: This retrospective study at 2 academic centers included acromegaly patients before surgery (A, n = 29); after surgery (controlled, discordant, or uncontrolled) without (B1, B2, B3, n = 28, 11, 8); or with somatostatin analogue treatment (C1, C2, C3, n = 17, 11, 5); nonfunctioning pituitary adenomas (n = 20); and healthy controls (n = 31). sαKL was measured by immunoassay and compared with traditional biomarkers (random and nadir GH, insulin-like growth factor I [IGF-I], IGF binding protein 3). Associations with disease activity were assessed., Results: sαKL was correlated to traditional biomarkers, particularly IGF-I (rs=0.80, P <0.0001). High concentrations before treatment (A, median, interquartile range: 4.04 × upper limit of normal [2.26-8.08]) dropped to normal after treatment in controlled and in most discordant patients. A cutoff of 1548 pg/mL for sαKL discriminated controlled (B1, C1) and uncontrolled (B3, C3) patients with 97.8% (88.4%-99.9%) sensitivity and 100% (77.1%-100%) specificity. sαKL was below the cutoff in 84% of the discordant subjects. In the remaining 16%, elevated sαKL and IGF-I persisted, despite normal random GH. Sex, age, body mass index, and markers of bone and calcium metabolism did not significantly affect sαKL concentrations., Conclusion: Our data support sαKL as a biomarker to assess disease activity in acromegaly. sαKL exhibits close association with GH secretory status, large dynamic range, and robustness toward biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

PDE4 cyclic nucleotide phosphodiesterases regulate cAMP abundance in cells and therefore regulate numerous processes, including cell growth and differentiation. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein (also called XAP2 or ARA-9). Germline mutations in AIP occur in approximately 20% of patients with Familial Isolated Pituitary Adenoma (FIPA) and 20% of childhood-onset simplex somatotroph adenomas. We therefore examined the protein expression of PDE4A4 and the closely related isoform PDE4A8 in normal human pituitary tissue and in pituitary adenomas. PDE4A4 had low expression in normal pituitary but was significantly overexpressed in somatotroph, lactotroph, corticotroph and clinically nonfunctioning gonadotroph adenomas (P<0.0001 for all subtypes). Likewise, PDE4A8 was expressed in normal pituitary and was also significantly overexpressed in the adenoma subtypes (P<0.0001 for all). Among the different adenoma subtypes, corticotroph and lactotroph adenomas were the highest and lowest expressed for PDE4A4, respectively, whereas the opposite was observed for PDE4A8. Naturally occurring oncogenic variants in AIP were shown by a two-hybrid assay to disrupt the ability of AIP to interact with PDE4A5. A reverse two-hybrid screen identified numerous additional variants in the tetratricopeptide repeat (TPR) region of AIP that also disrupted its ability to interact with PDE4A5. The expression of PDE4A4 and PDE4A8 in normal pituitary, their increased expression in adenomatous pituitary cells where AIP is meant to participate, and the disruption of the PDE4A4-AIP interaction by AIP mutants may play a role in pituitary tumorigenesis., (© 2016 Society for Endocrinology.)

Prolactinomas are prolactin-secreting neoplasias accounting for 40% of the pituitary adenomas. Much is known about the effects of prolactinomas on the reproductive system, but few data are yet available regarding their induced changes on metabolism. This study was aimed at evaluating patients with prolactinomas for insulin resistance and adiponectinemia. Forty patients with prolactinoma were allocated to 2 different groups according to disease control: 20 with uncontrolled disease (UPRL) and 20 with controlled disease in the last 6 months (CPRL). Forty healthy individuals (CG) matched for age, sex, and body mass index were taken as controls. Patients with prolactinoma were compared both as a one group and according to disease control with CG. All subjects were evaluated for waist/hip ratio (WHR), blood pressure, lipid profile, fasting glucose, homeostasis assessment model of insulin resistance (HOMAIR), and adiponectin. Patients with prolactinomas (UPRL+CPRL) showed higher insulin (p<0.05) and HOMAIR (p<0.05), alongside with lower adiponectin levels (p<0.01) than matched controls. When UPRL was compared to CPRL and CG, UPRL was disclosed as a subgroup of significant altered metabolic profile as related to WHR (p<0.01 for comparisons), high-density lipoprotein cholesterol (p<0.05 for comparisons), triglycerides (p<0.05 for comparisons), HOMAIR (p<0.05 and p<0.01, respectively), and adiponectin (p<0.01 for comparisons). All these metabolic abnormalities, except hypoadiponectinemia (p<0.01), were not observed in CPRL. These data suggest that prolactinomas are associated with hypoadiponectinemia, which is further exacerbated in uncontrolled patients when insulin resistance is also prominent., (© Georg Thieme Verlag KG Stuttgart · New York.)