Gender-affirming hormone treatment: friend or foe? Long-term follow-up of 755 transgender people.

PURPOSE: Gender-affirming hormone treatment (GAHT) is one of the main demands of transgender and gender diverse (TGD) people, who are usually categorised as transgender assigned-male-at birth (AMAB) and assigned-female-at birth (AFAB). The aim of the study is to investigate the long-term therapeutic management of GAHT, considering hormonal targets, treatment adjustments and GAHT safety. METHODS: A retrospective, longitudinal, observational, multicentre clinical study was carried out. Transgender people, both AMAB and AFAB, were recruited from two Endocrinology Units in Italy (Turin and Modena) between 2005 and 2022. Each subject was managed with specific and personalized follow-up depending on the clinical practice of the Centre. All clinical data routinely collected were extracted, including anthropometric and biochemical parameters, lifestyle habits, GAHT regime, and cardiovascular events. RESULTS: Three-hundred and two transgender AFAB and 453 transgender AMAB were included. Similar follow-up duration (p = 0.974) and visits' number (p = 0.384) were detected between groups. The transgender AFAB group reached therapeutic goals in less time (p = 0.002), fewer visits (p = 0.006) and fewer adjustments of GAHT scheme (p = 0.024). Accordingly, transgender AFAB showed a higher adherence to medical prescriptions compared to transgender AMAB people (p < 0.001). No significantly increased rate of cardiovascular events was detected in both groups. CONCLUSION: Our real-world clinical study shows that transgender AFAB achieve hormone target earlier and more frequently in comparison to transgender AMAB individuals. Therefore, transgender AMAB people may require more frequent check-ups in order to tailor feminizing GAHT and increase therapeutic adherence.

Risk behaviours and alcohol in adolescence are negatively associated with testicular volume: results from the Amico-Andrologo survey.

BACKGROUND: Risk factors established during adolescence affect health outcomes in adulthood, although little is known about how adolescent health risk behaviours (HRBs) affect testicular development and reproductive health. OBJECTIVES: To assess prevalence of HRBs among last year high school students; to describe the most prevalent andrological disorders in this cohort; to explore HRBs associated with andrological disorders and investigate factors possibly associated with impaired testicular development in puberty. MATERIALS AND METHODS: The Amico-Andrologo Survey is a permanent nationwide surveillance programme conducted by the Italian Society of Andrology and Sexual Medicine and supported by the Ministry of Health. A nationally representative survey of final-year male high school students was conducted using a validated structured interview (n = 10124) and medical examination (n = 3816). RESULTS: Smoking (32.6%), drinking (80.6%) and use of illegal drugs (46.5%) are common in adolescence. 16.6% of subjects were overweight, 3.1% were underweight and 2.3% were obese. Among sexually active students (60.3%), unprotected sex was very common (48.3%). Only 11.6% had been treated for andrological disorders, despite an abnormal clinical examination in 34.6%. Bilateral testicular hypotrophy (14.0%), varicocoele (27.1%) and phimosis (7.1%) were the most prevalent disorders; 5.1% complained of premature ejaculation and 4.7% had an STI. Underweight and heavy alcohol or drug use were associated with testicular hypotrophy. HRBs emerged as significant predictors of testicular hypotrophy, explaining up to 9.6% of its variance. Limitations include risk of selection bias for voluntary physical examination and recall bias for the self-compiled questionnaire. DISCUSSION: There is an emerging global adverse trend of HRBs in male high school students. A significant proportion of adolescent males with unsuspected andrological disorders engage in behaviours that could impair testicular development. CONCLUSION: Greater attention to the prevention of andrological health in adolescence is needed.

[CAR-T cells: Lymphocytes that express a chimeric antigen receptor]. / CAR-T cells : lymphocytes exprimant un récepteur chimérique à l'antigène.

CAR-T cells are genetically modified human lymphocytes and gene therapy medicinal products. They are developed to treat cancers that express a membrane antigen targeted by the CAR. The FDA approved the two first-in-class medicinal products in 2017 and EMA in August 2018; both are autologous CAR-T cells targeting CD19 that is expressed at the surface of normal B-cells throughout their differentiation, and on B-cell lymphoid malignancies. Clinical efficacy was demonstrated for B-cell acute lymphoblastic leukemias, non-Hodgkin's lymphoma and chronic lymphocytic leukemia, although the marketing authorizations are less liberal in terms of indications. Manufacturing of these personalized treatments necessitates that a novel organization and supply chain be set in place, to ensure product preservation, patient safety and compliance with complex regulatory requirements. Side effects are commensurate with clinical efficacy and can be life-threatening: proper management imposes tight coordination between various specialists, particularly between hematologists and intensive care practitioners. High pricing for these treatments is part of a long-term trend for increasing costs of innovations in hematology and oncology; it questions the ability of healthcare systems to sustain their reimbursement.

Corrigendum: Disease status is a more reliable predictive factor than histology in lymphoma patients after reduced-intensity conditioning regimen and allo-SCT.

This corrects the article DOI: 10.1038/bmt.2012.225.

The steroid response to human chorionic gonadotropin (hCG) stimulation in men with Klinefelter syndrome does not change using immunoassay or mass spectrometry.

PURPOSE: Liquid-chromatography tandem mass-spectrometry (LC-MS/MS) was developed in parallel to Immunoassays (IAs) and today is proposed as the "gold standard" for steroid assays. Leydig cells of men with Klinefelter syndrome (KS) are able to respond to human chorionic gonadotropin (hCG) stimulation, even if testosterone (T) production was impaired. The aim was to evaluate how results obtained by IAs and LC-MS/MS can differently impact on the outcome of a clinical research on gonadal steroidogenesis after hCG stimulation. METHODS: A longitudinal, prospective, case-control clinical trial. (clinicaltrial.gov NCT02788136) was carried out, enrolling KS men and healthy age-matched controls, stimulated by hCG administration. Serum steroids were evaluated at baseline and for 5 days after intramuscular injection of 5000 IU hCG using both IAs and LC-MS/MS. RESULTS: 13 KS patients (36 ± 9 years) not receiving T replacement therapy and 14 controls (32 ± 8 years) were enrolled. T, progesterone, cortisol, 17-hydroxy-progesterone (17OHP) and androstenedione, were significantly higher using IAs than LC-MS/MS. IAs and LC-MS/MS showed direct correlation for all five steroids, although the constant overestimation detected by IAs. Either methodology found the same 17OHP and T increasing profile after hCG stimulation, with equal areas under the curves (AUCs). CONCLUSIONS: Although a linearity between IA and LC-MS/MS is demonstrated, LC-MS/MS is more sensitive and accurate, whereas IA shows a constant overestimation of sex steroid levels. This result suggests the need of reference intervals built on the specific assay. This fundamental difference between these two methodologies opens a deep reconsideration of what is needed to improve the accuracy of steroid hormone assays.

Haploidentical transplantation with post-infusion cyclophosphamide in advanced Hodgkin lymphoma.

We investigated the use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of advanced Hodgkin lymphoma (HL). Sixty-two consecutive HL patients underwent haplo-HSCT. Unmanipulated stem cells and post-transplant cyclophosphamide were given to all patients as GVHD prophylaxis. At 100 days, the cumulative incidence of grades 2-3 and grades 3-4 acute GVHD was 23% and 4%, respectively. The chronic GVHD (cGVHD) cumulative incidence was 16%, with one patient experiencing severe cGVHD. The 3-year OS, PFS, relapse rates and 1-year non-relapse mortality (NRM) were 63%, 59%, 21% and 20%, respectively. Uncontrolled disease status and high hematopoietic cell transplantation comorbidity index (HCT-CI) were associated with lower OS, whereas PBSC was an independent protective factor. Uncontrolled disease and HCT-CI >2 was predictive for NRM. Finally, disease status other than CR was predictive of relapse. In conclusion, haplo-HSCT is a valid treatment in advanced HL, offering excellent rates of survival and acceptable toxicities.

Human chorionic gonadotropin stimulation gives evidence of differences in testicular steroidogenesis in Klinefelter syndrome, as assessed by liquid chromatography-tandem mass spectrometry.

BACKGROUND: Men with Klinefelter syndrome (KS) show hypergonadotropic hypogonadism, but the pathogenesis of hypotestosteronemia remains unclear. Testicular steroidogenesis in KS men was evaluated over three decades ago after human chorionic gonadotropin (hCG) stimulation, but inconclusive results were obtained. Intriguingly, some recent studies show increased intratesticular testosterone concentrations in men with KS. OBJECTIVE: To analyze serum steroid profile, as a proxy of testicular steroidogenesis, after hCG stimulation in KS compared with control men. DESIGN: A prospective, longitudinal, case-control, clinical trial. METHODS: Thirteen KS patients (36±9 years) not receiving testosterone (TS) replacement therapy and 12 eugonadic controls (32±8 years) were enrolled. Serum steroids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at baseline and for five consecutive days after intramuscular injection of 5000IU hCG. RESULTS: Progesterone (P), 17-hydroxyprogesterone (17OHP), TS, and estradiol (E2) showed a significant increase (P<0.001) after hCG stimulation in both groups. On the contrary, androstenedione (AS) and dehydroepiandrosterone did not increase after hCG stimulation. The 17OHP/P ratio increased in both groups (P<0.001), the TS/AS ratio (17ß-hydroxysteroid dehydrogenase type 3 (17ßHSD3) activity) did not increase after hCG in any group, and the E2/TS ratio (aromatase activity) increased significantly in both groups (P=0.009 in KS and P<0.001 in controls). Luteinizing hormone decreased after hCG in both groups (P=0.014 in KS and P<0.001 in controls), whereas follicle-stimulating hormone decreased only in control men (P<0.001). CONCLUSION: This study demonstrates for the first time using LC-MS/MS that Leydig cells of KS men are able to respond to hCG stimulation and that the first steps of steroidogenesis are fully functional. However, the TS production in KS men is impaired, possibly related to reduced hydroxysteroid deydrogenase activity due to an unfavorable intratesticular metabolic state.

T-replete haploidentical allogeneic transplantation using post-transplantation cyclophosphamide in advanced AML and myelodysplastic syndromes.

Unmanipulated haploidentical transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy) represents an alternative for patients with high-risk diseases lacking HLA-identical donor. Although it provides low incidences of GVHD, the efficacy of Haplo-SCT is still questioned, especially for patients with myeloid malignancies. Thus, we analyzed 60 consecutive patients with refractory (n=30) or high-risk CR (n=30) AML or myelodysplastic syndromes (MDSs) who underwent PT-Cy Haplo-SCT. The median age was 57 years (22-73 years), hematopoietic cell transplantation comorbidity index was ⩾3 in 38 patients (63%) and Haplo-SCT was the second allogeneic transplantation for 10 patients (17%). Although most of patients received PBSC as graft source (n=48, 80%), we found low incidences of grade 3-4 acute (2%) and severe chronic GVHD (4%). Among patients with high-risk CR diseases, 1-year non-relapse mortality, cumulative incidence of relapse, progression-free and overall survivals were 20%, 32%, 47% and 62%, respectively. In patients with refractory disease, corresponding results were 34%, 35%, 32% and 37%, respectively. We conclude that PT-Cy Haplo-SCT could provide promising anti-leukemic effect even in the setting of very advanced diseases. Thus, it represents a viable alternative for high-risk AML/MDS patients without HLA-identical donor.

FSH treatment of male idiopathic infertility improves pregnancy rate: a meta-analysis.

INTRODUCTION: The aim of this study is to comprehensively evaluate whether FSH administration to the male partner of infertile couples improves pregnancy rate, spontaneously and/or after assisted reproductive techniques (ART). METHODS: Meta-analysis of controlled clinical trials in which FSH was administered for male idiopathic infertility, compared with placebo or no treatment. Randomization was not considered as an inclusion criterion. RESULTS: We found 15 controlled clinical studies (614 men treated with FSH and 661 treated with placebo or untreated). Concerning the type of FSH, eight studies used recombinant FSH, whereas seven studies used purified FSH. Nine studies evaluated spontaneous pregnancy rate, resulting in an overall odds ratio (OR) of about 4.5 (CI: 2.17-9.33). Eight studies evaluated pregnancy rate after ART, showing a significant OR of 1.60 (CI: 1.08-2.37). Sub-dividing studies according to the FSH preparations (purified/recombinant), pregnancy rate improvement remained significant for each preparation. Eleven studies considered sperm quality after FSH treatment, finding a significant improvement of sperm concentration (2.66×10(6)/ml, CI: 0.47-4.84), but not of concentration of sperm with progressive motility (1.22×10(6)/ml, CI: -0.07 to 2.52). Three trials evaluated testicular volume, showing a non-significant increase in men treated (1.35 ml, CI: -0.44 to 3.14). CONCLUSION: The results of controlled clinical trials available in the literature indicate an improvement of pregnancy rate after FSH administration to the male partner of infertile couples, both spontaneously and after ART. However, the heterogeneity of studies, the high risk of bias and the lack of precise criteria to guide FSH administration limit the strength of these results. Future studies should be designed to identify the markers of FSH response which are helpful in the decision-making process. Meanwhile, the use of FSH in the treatment of male infertility should be cautious.

Sodium-glucose linked transporter-2 inhibitors in chronic kidney disease.

SGLT2 inhibitors are new antihyperglycaemic agents whose ability to lower glucose is directly proportional to GFR. Therefore, in chronic kidney disease (CKD) the blood glucose lowering effect is reduced. Unlike many current therapies, the mechanism of action of SGLT2 inhibitors is independent of insulin action or beta-cell function. In addition, the mechanism of action of SGLT2 inhibitors is complementary and not alternative to other antidiabetic agents. SGLT2 inhibitors could be potentially effective in attenuating renal hyperfiltration and, consequently, the progression of CKD. Moreover, the reductions in intraglomerular pressure, systemic blood pressure, and uric acid levels induced by SGLT inhibition may potentially be of benefit in CKD subjects without diabetes. However, at present, only few clinical studies were designed to evaluate the effects of SGLT2 inhibitors in CKD. Consequently, safety and potential efficacy beyond blood glucose lowering should be better clarified in CKD. In this paper we provide an updated review of the use of SGLT2 inhibitors in clinical practice, with particular attention on subjects with CKD.

[Phosphorus: a new cardiovascular risk factor?]. / Il Fosforo: nuovo fattore di rischio cardiovascolare?

Phosphorus is an essential mineral in the regulation of many metabolic processes. However, is known as alterations in serum phosphate levels, compared to the normal range, have clinical relevance: many studies about phosphorus and cardiovascular risk have shown that high serum phosphate levels are associated with clinical and subclinical cardiovascular disease, in CKD and non-CKD patients. In recent years, serum phosphate level within the upper limits of normal range is also identified as a "stealthier killer", and has emerged as a risk factor of cardiovascular mortality and progression of CKD. This mounting evidence suggests the possibility that lowering serum phosphate levels may be a future target of cardiovascular disease management, also through the use of early biomarkers of phosphate overload, such as FGF23, Klotho or the urinary fractional excretion of phosphate. The goal must be an early diagnosis and treatment of disordered phosphorus metabolism, before end-organ damage occurs. Since the western diet is rich in phosphate, a dietary restriction associated with the use of phosphate binders, as well as the use of intervention such as calcitriol supplementation, certainly will have a positive influence on the phosphate-regulatory axis.