Daily Endocrinology Research Analysis

BACKGROUND: Testicular disorders, including male infertility and hypogonadism, are increasingly prevalent and current diagnostic tools have important limitations. The testicular microcirculation underpins testicular function. Ultrasound localisation microscopy (ULM) enables super-resolution mapping of microvascular structure and flow at clinically relevant organ depth. METHODS: Prospective case-control study of ULM-assessed testicular activity in men and rodents using clinical and research ultrasound systems. Study 1 compared healthy men (n = 10) with hypogonadotrophic hypogonadism (HH) (n = 9). Study 2 included men with HH receiving testosterone (n = 11), gonadotrophins (n = 9), or no treatment (n = 12). Study 3 assessed 12-month fertility treatment response in HH (n = 7). A rodent pubertal-blockade model was also studied (n = 5). FINDINGS: ULM markers discriminated HH from controls (vessel density p < 0.01; diameter p = 0.01; tortuosity p < 0.01) and correlated with testosterone (r = 0.53-0.67, p < 0.05) and inhibin B (r = -0.61, p < 0.01). Vessel density, diameter, area and flow-related index were reduced in azoospermia (p < 0.01). ULM distinguished HH treatment groups (vessel density p < 0.001; diameter p < 0.05), with density and diameter correlating with testosterone (r = 0.69, 0.62; p < 0.001) and inhibin B (r = 0.64, 0.65; p < 0.001). Vessel density (p < 0.001) and diameter (p < 0.01) were reduced in azoospermia irrespective of treatment. During fertility therapy, ULM parameters increased (p < 0.05) and detected testicular activation earlier than volume or inhibin B. In rodents, pubertal development showed dynamic microvascular remodelling driven by testis growth. INTERPRETATION: ULM provides a treatment-responsive, biologically grounded biomarker of testicular function enabling patient stratification, early detection of therapeutic response, and potential for both refinement of clinical decision-making in HH, and application within other testicular disorders. FUNDING: MRC, NIHR Biomedical Research Centre Funding Scheme and the NIHR/Imperial Clinical Research Facility, Diabetes UK, BBSRC, MRC, Imperial Private Healthcare Clinical Research Fellowship Scheme, NWLP Research Grant.

Somatic mutations in the gene encoding splicing factor 3B subunit 1 (SF3B1), a key component of the splicing machinery, have been described in patients with PRL-secreting pituitary neuroendocrine tumors (PRL-PitNET) and associated with aggressiveness and resistance to pharmacological therapy with dopamine agonists (DAs). Dopamine receptor type 2 (DRD2) represents the main target for PRL-PitNETs treatment with DAs, even if about 10% of patients is resistant. Aims of the study were to: 1) test the effects of SF3B1 inhibitor pladienolide B in tumoral lactotroph cells expressing wild-type or mutated SF3B1R625H; 2) investigate SF3B1 impact on tumoral cells responsiveness to DRD2 agonist cabergoline. Pladienolide B treatment reduced cell proliferation (-45.1(15.3)%,p<0.001), PRL secretion (-19.25(35.1)%,p<0.05) and increased apoptosis (+2.4(2.5)-fold,p<0.05) in rat tumoral MMQ cells. Pladienolide B antimitotic, proapoptotic and antisecretory effects were maintained in primary cultured cells from both resistant and responsive PRL-PitNETs. SF3B1R625H overexpression increased tumoral lactotrophs proliferation and migration. Moreover, the antimitotic efficacy of pladienolide B, but not of cabergoline, was maintained in MMQ cells transfected with SF3B1R625H. Cabergoline effects on cell proliferation, AKT activation, cyclin D3 and p27 were abolished in MMQ cells silenced for SF3B1. Accordingly, SF3B1R625H overexpression and SF3B1 silencing reduced DRD2 expression at both protein and transcript level, an effect reverted by nonsense-mediated decay inhibitor NMDI14. In conclusion, we demonstrated a relevant role of SF3B1 in PRL-PitNET. Indeed, SF3B1 inhibitor pladienolide B exerted antitumoral actions in PRL-PitNET cells bearing wild-type or mutated SF3B1. Moreover, both SF3B1R625H overexpression and SF3B1 genetic silencing reduced DRD2 expression and signaling.

FRAX is poorly validated in Black and Hispanic people in the United States. We recently demonstrated that FRAX underestimated fractures in Black and Hispanic patients with diabetes (DM), but it is not known if this is a diabetes-specific issue. We sought to compare the performance of the original FRAX (oFRAX) without BMD and a hypothetical race-neutral FRAX (rn-FRAX) in a retrospective multiethnic cohort of patients with DM and control patients with hypertension (HTN). We specifically sought to compare performance across race. Patients were included if they were followed for DM or HTN in the health system and averaged at least 1 visit per year. Incident major osteoporotic fractures (MOFs) and FRAX inputs were collected using diagnosis codes or medication data. A rn-FRAX was created using U.S. census data. Performance was compared using measures of discrimination (area under the curve, AUC) and calibration (observed-to-predicted ratios, O/P). There were 17,400 Black (45.4% DM), 9,865 White (35.3% DM), and 1,196 Hispanic (57.9% DM) patients included. Discrimination was similar for oFRAX and rn-FRAX (AUC 0.72-0.73). In DM patients, the O/P was 1.4 for oFRAX and 1.0 for rn-FRAX. By race, we found good performance for both calculators in White patients (O/P 0.8-1.2). In Black patients, oFRAX underestimated risk (O/P 1.3-2.3). Conversely, rn-FRAX overestimated risk in Black women (O/P 0.7-0.8) but performed well in Black men (O/P 0.9-1.1). In Hispanic patients, oFRAX substantially underestimated fractures (O/P 1.8-2.4), and this was only partially alleviated by rn-FRAX (O/P 1.2-1.6). In conclusion, we found that the current FRAX without BMD significantly underestimated major osteoporotic fractures in Black and Hispanic patients, while a hypothetical race-neutral FRAX improved performance overall. Our findings suggest the current adjustments for race in U.S. FRAX may not be necessary or, if maintained, need to be updated. The U.S. Fracture Risk Assessment Tool (FRAX) includes adjustments for race that lower the predicted risk of fracture. We previously found that Black and Hispanic people with diabetes fracture at much higher rates than predicted. To test if a race-neutral version of FRAX would perform better, we examined 12,067 patients with diabetes and 16,394 control patients with hypertension. We found that the original FRAX without BMD substantially underestimated fractures in Black and Hispanic patients. A race-neutral FRAX performed better overall, especially in Black men and Hispanic patients. Our study suggests that the adjustments for race in FRAX may not be needed or require an update.