Glucose Abnormalities Associated to Prolactin Secreting Pituitary Adenomas

The pathogenesis of obesity and alterations in glucose profile have been linked to PRL excess, as it is reportedly associated with metabolic syndrome in thereabout one third of patients. In vitro exposure of pancreatic islet to PRL is known to stimulate insulin secretion and β-cell proliferation, and in turn overexpression of PRL in β-cells increases insulin release and β-cell replication. PRL excess has been found to worsen glucose profile because it reduces glucose tolerance and induces insulin resistance either in obese and non-obese patients. To note, pancreatic β-cells and adipocytes widely express dopamine receptors type 2, and dopamine has been hypothesized to play a key role as modulator of insulin and adipose functions. The dopamine agonists bromocriptine and cabergoline significantly improve abnormalities in glucose profile and reduce the prevalence of metabolic syndrome in a remarkable proportion of patients, regardless of whether body weight and PRL status may change. However, in men with hyperprolactinemia complicated by hypogonadism, testosterone replacement can ameliorate insulin resistance and abnormalities in glucose metabolism. Therefore, in patients with PRL-secreting pituitary adenomas control of PRL excess by dopamine agonists is mandatory to improve glucose and insulin abnormalities

The spectrum of cardiac abnormalities in patients with acromegaly: results from a case-control cardiac magnetic resonance study

Purpose: Cardiac abnormalities are common in patients with acromegaly, contributing to the increased morbidity and mortality. Cardiac magnetic resonance (CMR) is the gold standard for measuring cardiac morpho-functional changes. This study aims to detect cardiac alterations in acromegaly through CMR, even when the disease is adequately controlled. Methods: In this, multicentre, case-control study, we compared consecutive patients with acromegaly, cured after surgery or requiring medical treatment, with matched controls recruited among patients harbouring non-functioning adrenal incidentalomas. Results: We included 20 patients with acromegaly (7 females, mean age 50 years) and 17 controls. Indexed left ventricular-end-diastolic volume (LV-EDVi) and LV-end-systolic volume (LV-ESVi) were higher in patients than in controls (p < 0.001), as were left ventricular mass (LVMi) (p = 0.001) and LV-stroke volume (LV-SVi) (p = 0.028). Right ventricle (RV) EDVi and ESVi were higher, whereas RV-ejection fraction (RV-EF) was lower (p = 0.002) in patients than in controls (p < 0.001). No significant differences were observed in the prevalence of cardiometabolic comorbidities, including hypertension, glucose and lipid metabolism impairment, obstructive sleep apnoea syndrome, and obesity. IGF1 x upper limit of normal significantly predicted LVMi (b = 0.575; p = 0.008). Subgroup analysis showed higher LVMi (p = 0.025) and interventricular septum thickness (p = 0.003) in male than female patients, even after adjusting cardiac parameters for confounding factors. Conclusions: The CMR analysis reveals a cluster of biventricular structural and functional impairment in acromegaly, even when the biochemical control if achieved. These findings appear specifically triggered by the exposure to GH-IGF1 excess and show sex-related differences advocating a possible interaction with sex hormones in cardiac disease progression

Cardiac magnetic resonance reveals biventricular impairment in Cushing’s syndrome: a multicentre case-control study

Purpose: Cushing’s syndrome (CS) is associated with severe cardiovascular (CV) morbidity and mortality. Cardiac magnetic resonance (CMR) is the non-invasive gold standard for assessing cardiac structure and function; however, few CMR studies explore cardiac remodeling in patients exposed to chronic glucocorticoid (GC) excess. We aimed to describe the CMR features directly attributable to previous GC exposure in patients with cured or treated endogenous CS. Methods: This was a prospective, multicentre, case-control study enrolling consecutive patients with cured or treated CS and patients harboring non-functioning adrenal incidentalomas (NFAI), comparable in terms of sex, age, CV risk factors, and BMI. All patients were in stable condition and had a minimum 24-month follow-up. Results: Sixteen patients with CS and 15 NFAI were enrolled. Indexed left ventricle (LV) end-systolic volume and LV mass were higher in patients with CS (p = 0.027; p = 0.013); similarly, indexed right ventricle (RV) end-diastolic and end-systolic volumes were higher in patients with CS compared to NFAI (p = 0.035; p = 0.006). Morphological alterations also affected cardiac function, as LV and RV ejection fractions decreased in patients with CS (p = 0.056; p = 0.044). CMR features were independent of metabolic status or other CV risk factors, with fasting glucose significantly lower in CS remission than NFAI (p < 0.001) and no differences in lipid levels or blood pressure. Conclusion: CS is associated with biventricular cardiac structural and functional impairment at CMR, likely attributable to chronic exposure to cortisol excess independently of known traditional risk factors

Clinical and Molecular Characteristics of Gonadotroph Pituitary Tumors According to the WHO Classification

: Since 2017, hormone-negative pituitary neuroendocrine tumors expressing the steroidogenic factor SF1 have been recognized as gonadotroph tumors (GnPT) but have been poorly studied. To further characterize their bio-clinical spectrum, 54 GnPT defined by immunostaining for FSH and/or LH (group 1, n = 41) or SF1 only (group 2, n = 13) were compared and studied for SF1, βFSH, βLH, CCNA2, CCNB1, CCND1, caspase 3, D2R, and AIP gene expression by qRT-PCR. Immunohistochemistry for AIP and/or D2R was performed in representative cases. Overall, patients were significantly younger in group 1 (P = 0.040 vs group 2), with a similar trend excluding recurrent cases (P = 0.078), and no significant difference in gender, tumor size, invasion or Ki67. SF1 expression was similar in both groups but negatively correlated with the patient's age (P = 0.013) and positively correlated with βLH (P &lt; 0.001) expression. Beta-FSH and AIP were significantly higher in group 1 (P = 0.042 and P = 0.024, respectively). Ki67 was unrelated to gonadotroph markers but positively correlated with CCNB1 (P = 0.001) and negatively correlated with CCND1 (P = 0.008). D2R and AIP were strongly correlated with each other (P &lt; 0.001), and both positively correlated with SF1, βFSH, βLH, and CCND1. AIP immunopositivity was frequently observed in both groups, with a similar median score, and unrelated to Ki67. D2R immunostaining was best detected with a polyclonal antibody and mostly cytoplasmic. This study indicates that hormone-negative GnPT tend to occur in older patients but do not significantly differ from other GnPT in terms of invasion or proliferation. It also points out the current limits of D2R immunostaining in such tumors

Pituitary adenoma consistency affects postoperative hormone function: a retrospective study

Background: Tumor consistency recently emerged as a key factor in surgical planning for pituitary adenomas, but its impact on postoperative endocrine function is still unclear. Our study aimed to evaluate the impact of tumor consistency on the development of postoperative pituitary deficiencies. Methods: Single-center, retrospective analysis of consecutive pituitary surgeries performed between January 2017 and January 2021 at Policlinico Umberto I in Rome. All patients underwent radiological and biochemical evaluations at baseline, and hormone assessments 3 and 6&nbsp;months after pituitary surgery. Postoperative MRI studies were used to determine resection rates following surgery. Data on tumor consistency, macroscopic appearance, neurosurgical approach, and intraoperative complications were collected. Results: Fifty patients [24 women, mean age 57 ± 13&nbsp;years, median tumor volume 4800 mm3 [95% CI 620-8828], were included. Greater tumor volume (χ2 = 14.621, p = 0.006) and male sex (χ2 = 12.178, p &lt; 0.001) were associated with worse preoperative endocrine function. All patients underwent transsphenoidal adenomectomy. Fibrous consistency was observed in 10% of patients and was associated with a Ki-67 greater than 3% (χ2 = 8.154, p = 0.04), greater risk of developing postoperative hormone deficiencies (χ2 = 4.485, p = 0.05, OR = 8.571; 95% CI: 0.876-83.908), and lower resection rates (χ2 = 8.148, p = 0.004; OR 1.385, 95% CI; 1.040-1.844). Similarly, worse resection rates were observed in tumors with suprasellar extension (χ2 = 5.048, p = 0.02; OR = 6.000, 95% CI; 1.129-31.880) and CSI (χ2 = 4.000, p = 0.04; OR = 3.857, 95% CI; 0.997-14.916). Conclusions: Tumor consistency might provide useful information about postoperative pituitary function, likely due to its impact on surgical procedures. Further prospective studies with larger cohorts are needed to confirm our preliminary findings

Testicular adrenal rest tumours: fisiopatologia, diagnosi e trattamento

I testicular adrenal rest tumors (TARTs) costituiscono una causa comune di disfunzione gonadica e infertilità in pazienti affetti da iperplasia surrenalica congenita (Congenital Adrenal Hyperplasia, CAH), con una prevalenza che varia dal 14 all’86%. Dal punto di vista biochimico, istologico e molecolare, i TARTs mostrano caratteristiche tipiche delle cellule surrenaliche e per questo si è ipotizzato che derivino da una proliferazione di cellule della corteccia surrenalica in sede testicolare. Studi recenti riconducono però l’origine dei TARTs a una popolazione di cellule staminali pluripotenti adrenal-like, derivanti dalla cresta urogenitale, già presenti in sede gonadica durante l’embriogenesi, che vanno incontro a differenziazione surrenalica e ad aumentata proliferazione se sottoposti a elevati livelli di ormone adrenocorticotropo (ACTH). La loro crescita può determinare un’alterazione della funzione gonadica per compressione diretta sui tubuli seminiferi e per l’influenza sull’ambiente ormonale intratesticolare per via paracrina, risultando spesso in un quadro di azoospermia di tipo ostruttivo. La diagnosi di TARTs si avvale principalmente dell’eco Color-Doppler testicolare, ma richiede una puntuale diagnosi differenziale con lesioni morfologicamente simili, quali i tumori germinali e i tumori a cellule del Leydig, in quanto la gestione terapeutica è differente. La terapia classica si basa sull’impiego di glucocorticoidi ad alte dosi, che in alcuni casi possono condurre a una regressione delle dimensioni della massa. La gestione della CAH nei soggetti che presentano TARTs richiede un approccio personalizzato con screening ecografico da adottare già a partire dall’infanzia e si avvale altresì di counseling andrologico in merito alla possibilità di preservare la fertilità tramite crioconservazione

Inhibition of activin signalling reduces the growth of LβT2 gonadotroph pituitary tumours in mouse

Pituitary tumours are benign neoplasms that derive from hormone-producing cells of the pituitary gland. While medical treatments have emerged for most subtypes, gonadotroph tumours that express follicle-stimulating hormone (FSH) and/or luteinizing hormone still lack therapeutic options apart from surgery and radiotherapy. Activin ligands are physiological regulators of production and secretion of FSH by gonadotroph cells, but their role in gonadotroph tumourigenesis remains little explored. Using the LβT2 mouse gonadotroph cell line which produces FSH under activin stimulation, we first tested whether subcutaneous xenografts of LβT2 cells resulted in tumour formation in Rag2KO mice. Histological analysis confirmed the presence of LβT2 tumours with endothelial cells and macrophages in their microenvironment. FSH expression was found in a subset of clusters of LβT2 cells in the tumours. We subsequently addressed the consequences of targeting activin signalling via injection of a soluble activin decoy receptor (sActRIIB-Fc). sActRIIB-Fc treatment resulted in significantly decreased LβT2 tumour volume. Reduced Smad2 phosphorylation as well as inhibition of tumour-induced FSH production confirmed the efficient targeting of activin-downstream signalling in treated tumours. More interestingly, treated tumours showed significantly fewer endothelial cells associated with reduced Vegfa expression. In vitro treatment of LβT2 cells with sActRIIB-Fc had no effect on cell proliferation or apoptosis, but Vegfa expression was inhibited, pointing to a likely paracrine effect of LβT2 cells on endothelial cells through activin-mediated Vegfa regulation. Further in vitro and in vivo studies are now needed to pinpoint the exact roles of activin signalling in these processes prior to translating these observations to the clinic

Prolactin and prostate: an observational case-control study in men with prolactinoma under cabergoline treatment

Prolactin (PRL) exerts independent hypertrophic effects on prostate in in vivo and in vitro experimental models, and prostatic PRL receptors are known to activate cell proliferation pathways such as MAPK and STAT. Nevertheless, in men with hyperprolactinemia the risk of prostate cancer has been found reduced suggesting a role of concomitant hypogonadism. Chronic cabergoline treatment generally normalizes PRL treatment and improves gonadal function. The current study aimed at investigating prostate morphology in patients with prolactinoma under cabergoline treatment as compared to healthy control subjects. Twenty men with prolactinoma on chronic cabergoline treatment (CAB, 6–12 months, median dose 0.5 mg/week), including 6 (30%) on testosterone replacement therapy (TR, 6 months, median dose 30 mg/day) and 20 healthy age-matched controls entered the study. In patients and controls, hormonal levels (PRL, FSH, LH, testosterone) were evaluated and transrectal prostate ultrasound was performed. In patients, LH (P=0.04) and testosterone (P=0.026) levels were significantly lower than in controls, with no significant difference in PRL levels. Prostate volume was slightly but not significantly lower in patients than in controls. Prevalence of normal prostate morphology was significantly higher (P=0.05) in controls as compared to patients, whereas ultrasound signs of prostatitis resulted significantly more frequent in patients (P=0.027) as compared to controls. Prevalence of prostate adenoma and carcinoma was similar in patients and controls, with two cases being recorded in each group. PRL levels (r=−0.44, P=0.05), but not testosterone levels and CAB or TR dose, significantly and inversely correlated with prostate volume. In conclusion, in men with prolactinoma on chronic CAB treatment the risk of prostate hypertrophy is lower compared to healthy subjects, whereas prostatitis is more prevalent in patients than in controls. Concomitant testosterone deficiency, together with the known action of PRL as regulator of inflammation and autoimmune pathology, might represent potential mechanisms responsible for these findings. Further studies are required to better elucidate the burden and the role of PRL, hypogonadism, CAB and TR on prostate morphology in prolactinomas