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Purpose: Information on the general health of transgender and gender diverse (TGD) individuals continues to be lacking. To bridge this gap, the National Institute of Health in Italy together with the National Office against Racial Discriminations, clinical centres, and TGD organizations carried out a cross-sectional study to define the sociodemographic profile, health-related behaviours, and experiences of healthcare access in Italian TGD adult population. Methods: A national survey was conducted by Computer-Assisted Web Interviewing (CAWI) technique. Collected data were compared within the TGD subgroups and between TGD people and the Italian general population (IGP). Results: TGD respondents were 959: 65% assigned female at birth (AFAB) and 35% assigned male at birth (AMAB). 91.8% and 8.2% were binary and non-binary TGD respondents, respectively. More than 20% of the TGD population reported to be unemployed with the highest rate detectable in AMAB and non-binary people. Cigarette smoking and binge drinking were higher in the TGD population compared with IGP (p< 0.05), affecting TGD subgroups differently. A significant lower percentage of AFAB TGD people reported having had screening for cervical and breast cancer in comparison with AFAB IGP (p< 0.0001, in both cases). Over 40% was the percentage of AFAB and non-binary TGD people accessing healthcare who felt discriminated against because of their gender identity. Conclusions: Our results are a first step towards a better understanding of the health needs of TGD people in Italy in order to plan the best policy choices for a more inclusive public health.

Objective: Aim of this study is to report on basal clinical phenotype and follow up after diagnosis, of patients with 17β-hydroxysteroid-dehydrogenase type 3 (17β-HSD3) deficiency in Italy. Setting: Pediatric Endocrine Departments, University Hospitals. Patients: The cases of 5 Italian subjects affected by 17β-HSD3 deficiency are presented in this study. Interventions: Laboratory and genetic assessment. Gonadectomy and female sex assignment (4 patients) or GnRH analog therapy to regress puberty and gender identity disorder (1 patient). Results: Presentation lasted from pregnancy (pre-natal diagnosis of a 46,XY fetus with female external genitalia) to infancy (inguinal hernia containing testes/clitoromegaly) and adolescence (virilisation). All subjects but one (subject 1, Central-Northern Italy) were from small areas of Southern Italy. Endocrine data (baseline and/or stimulated testosterone/A4-androstenedione ratio) were informative. Two girls were homozygous for 17β-HSD3 gene mutations (G289S/G289S; R80W/R80W), while the others were compound heterozygous (IVS325+4 A>T/A203V; L212Q/M235V; R80W/A235E). Four patients were confirmed as females and were well-adjusted with assigned sex; gender identity disorder improved during treatment with GnRH analog in the last subject. Conclusions: 17βHSD3 deficiency may present from pregnancy to puberty for different clinical issues. Albeit testosterone/A4-androstenedione ratio represents the most accurate endocrine marker to diagnose the disorder, hCG-stimulation is mandatory in pre-puberty. Molecular analysis of 17β-HSD3 gene should be performed to confirm the diagnosis. Temporary GnRH analog treatment may regress gender identity disorder and provide time to confirm or change the birth sex assignment. Female individuals seems to be compliant with their sex, providing that virilisation does not occur. In Italy, the disorder seems to be more prevalent in the Southern regions and shows genetic heterogeneity.

CpG ODN drives B cells to differentiate into plasma cells; IFN‐α amplifies the inductive effect of CpG ODN on B cells. TLRs are a family of molecules that function as sensors for the detection of pathogens. TLR‐9, expressed on B cells and pDCs, recognizes CpG motifs of unmethylated bacterial DNA and plays a role in the development of autoimmunity. The present study was designed to investigate the effects of IFN‐α in combination with CpG ODN on the activation of CD27–naïve B cells and on Ig production. We provide evidence that CpG ODN not only induces a total and T‐dependent, specific IgM response by naïve B cells but also their phenotypic differentiation in plasma cells, as demonstrated by the up‐regulation of CD38 expression. We found that TLR‐9 stimulation with CpG ODN induces IL‐1β, TNF‐α, IL‐10, and IL‐6 production. Interestingly, we also found that CpG ODN induces naïve B cell maturation into memory cells, as demonstrated by the induction of CD27, AID mRNA expression, and IgG production. More importantly, our results demonstrate that IFN‐α amplifies the inductive effect of CpG ODN on naïve B activation and on Ig production through a mechanism involving TLR‐9/MyD88‐dependent signaling. Moreover, we found that IFN‐α enhances the frequency of CpG ODN‐induced memory B cells. Our results may contribute to clarify the events promoting IFN‐α‐induced amplification of naïve B cell activation via TLR‐9 for a better understanding of the pathogenesis of autoimmune disorders and may guide treatments targeting this pathway within B cells.

The 17β-hydroxysteroid dehydrogenases (17βHSD) gene family comprises different enzymes involved in the biosynthesis of active steroid hormones. The 17βHSD type 3 (17βHSD3) isoenzyme catalyzes the reductive conversion of the inactive C19-steroid, Δ4-androstenedione (Δ4- A), into the biologically active androgen, testosterone (T), in the Leydig cells of the testis. It is encoded by the 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) gene, which maps to chromosome 9q22. Mutations in the HSD17B3 gene are associated with a rare form of 46,XY disorder of sex development referred to as 17βHSD3 deficiency (or as 17-ketosteroid reductase deficiency), due to impaired testicular conversion of Δ4-A into T. 46,XY patients with 17βHSD3 deficiency are usually classified as female at birth, raised as such, but develop secondary male features at puberty. Diagnosis, and consequently early treatment, is difficult because clinical signs from birth until puberty may be mild or absent. Biochemical diagnosis of 17βHSD3 deficiency requires measurement of serum T/Δ4-A ratio after hCG stimulation test in pre-pubertal subjects, while baseline values seem to be informative in early infancy and adolescence. However, low basal T/Δ4-A ratio is not specific for 17βHSD3 deficiency, being sometimes also found in patients with other defects in T synthesis or with Leydig cells hypoplasia. Mutational analysis of the 17HSDB3 gene is useful in confirming the clinical diagnosis of 17βHSD3 deficiency. This review describes clinical findings, diagnosis, and molecular basis of this rare disease.