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.

The hypothalamic-pituitary-adrenal and -thyroid axes activation lasting one year after an earthquake swarm: results from a big data analysis.

PURPOSE: To cope physical and/or psychological threats, the human body activates multiple processes, mediated by a close interconnection among brain, endocrine and inflammatory systems. The aim of the study was to assess the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes involvement after an acute stressful event (Emilia Romagna earthquake swarm) with a big data approach. METHODS: A retrospective, observational trial was performed, collecting all biochemical examinations regarding HPA and HPT axes performed in the same laboratory the year before and the year after the earthquake swarm (20-29 May 2012). RESULTS: Comparing 2576 pre-earthquake to 3021 post-earthquake measurements, a cortisol serum level increase was observed (p < 0.001). Similar increase was evident for urinary free cortisol (p = 0.016), but not for adrenocorticotropic hormone (p = 0.222). The biochemical hypercortisolism incidence increased from 7.6 to 10.3% after earthquakes (p = 0.001). Comparing 68,456 pre-earthquake to 116,521 post-earthquake measurements, a reduction in thyroid-stimulating hormone (TSH) levels was evident (p = 0.018), together with an increase in free triiodothyronine and free thyroxine levels (p < 0.001 and p < 0.001). Moreover, a significant increase in altered TSH after earthquakes was registered considering the epicenter-nearest measurements (p < 0.001). No clinically relevant alterations were observed considering thyroid-specific autoantibodies. CONCLUSION: A long-term HPA axis activation in the inhabitants of the earthquake-affected areas was highlighted for the first time. Moreover, an increased incidence of biochemical hypercortisolism emerged after earthquakes. We confirmed a recruitment of HPT axis after stressful events, together with increased incidence of altered TSH in the. Our big data study allowed to increase knowledge about the connection between external stressors and endocrine regulation.

Endogenous transient doping: physical exercise acutely increases testosterone levels-results from a meta-analysis.

PURPOSE: Although endogenous testosterone levels are demonstrated to be affected by both acute exercise and resistance training, the dynamic regulation of androgen production after physical activity is still a matter of debate. This meta-analysis was designed to assess whether physical exercise acutely affects testosterone levels in men. METHODS: The literature search was conducted to identify longitudinal trials evaluating the acute change of both total testosterone (TT) and free testosterone (fT) after physical activity in adult men. Sensitivity analyses were performed considering the sample collected (blood or saliva), the intensity of the physical exercise and the interval between the end of the exercise and the sample collection. RESULTS: Forty-eight studies were included in the analysis, accounting for 126 trials. A total of 569 patients were enrolled (mean age 29.7 ± 13.1 years). The physical activity increased acutely TT (standardized mean difference 0.74, 95%CI: 0.56, 0.91 nmol/L), considering both serum and saliva samples (p < 0.001). Testosterone increased after moderate (p < 0.001) and high-intensity (p < 0.001) exercises, but not after mild physical activity (p = 0.19). Moreover, the testosterone increase was evident when measured immediately at the end of the exercise and within 30 min (p < 0.001), but not after 30 min (p = 0.930). Similar significant results were obtained considering fT, while SHBG did not change after physical activity (p = 0.090). CONCLUSION: The comprehensive evaluation of the acute physical activity effect on testosterone levels identified a clear increase after exercise, irrespective of the sample collected. The main determinant of this fluctuation was the exercise intensity, with a mechanism that seems to be mostly SHBG independent. In particular, moderate/intense physical activity resulted able to increase endogenous androgenic production, albeit acutely and transitory. TRIAL REGISTRATION NUMBER: PROSPERO registration ID: 157348.

Hormonal profile of menopausal women receiving androgen replacement therapy: a meta-analysis.

PURPOSE: Ovarian and adrenal aging leads to a progressive decline in androgen levels and deleterious effects on the quality of life. Despite this, specific replacement is not routinely recommended in the management of women with a physiological or pathological decline in their production, mainly due to the lack of long-term follow-up safety data. The purpose of this paper was to meta-analyze and summarize the existing data about hormonal profile changes in menopausal women receiving androgen replacement treatments. Full-text articles published through May 30, 2018 were found via MEDLINE and Embase and selected according to the strict inclusion criteria. METHODS: Randomized clinical trials and case-control studies were enrolled. Studies not reporting steroid serum levels or not providing a control group were excluded from the analysis. Studies enrolling women with genetic defects or severe chronic systemic diseases were excluded. 113 papers fulfilled the inclusion criteria and 56 papers were included in the analysis. Desired data were compiled and extracted by independent observers. RESULTS: Androgen administration increases E1, E2, testosterone, DHEA and DHEAS serum levels, and reduces SHBG. However, the E1 and E2 increase is evident only when DHEA is administered. CONCLUSIONS: Whatever androgen formulation we choose in postmenopausal women, the end result is a rise in testosterone serum levels. However, DHEA regimen is also associated with an increased estrogenic availability. This might be crucial when choosing the best possible treatment for each patient individually taking into consideration if potential benefits outweigh the risks.

Impairment of sperm DNA methylation in male infertility: a meta-analytic study.

Considering the widespread use of assisted reproductive techniques (ART), DNA methylation of specific genes involved in spermatogenesis achieves increasingly clinical relevance, representing a possible explanation of increased incidence of syndromes related to genomic imprinting in medically assisted pregnancies. Several trials suggested a relationship between male sub-fertility and sperm DNA methylation, although its weight on seminal parameters alteration is still a matter of debate. To evaluate whether aberrant sperm DNA methylation of imprinted genes is associated with impaired sperm parameters. Meta-analysis of controlled clinical trials evaluating imprinted genes sperm DNA methylation comparing men with idiopathic infertility to fertile controls. Twenty-four studies were included, allowing a meta-analytic evaluation for H19, MEST, SNRPN, and LINE-1. When a high heterogeneity of the results was demonstrated, the random effect model was used. H19 methylation levels resulted significantly lower in 879 infertile compared with 562 fertile men (7.53%, 95% CI: 5.14-9.93%, p < 0.001), suggesting a 9.91-fold higher risk ratio to show aberrant sperm DNA methylation (95% CI: 5.55-17.70, p < 0.001, I2  = 19%) in infertile men. The mean MEST methylation level was significantly higher in 846 infertile compared with 353 fertile men (3.35%, 95% CI: 1.41-5.29%, p < 0.001), as well as for SNRPN comparing 301 infertile men with 124 controls (3.23%, 95% CI: 0.75-5.72%, p < 0.001). LINE-1 methylation levels did not differ between 291 infertile men and 198 controls (0.44%, 95% CI: -2.04-1.16%, p = 0.63). The meta-analytic approach demonstrated that male infertility is associated with altered sperm methylation at H19, MEST, and SNRPN. Although its role in infertility remains unclear, sperm DNA methylation could be associated with the epigenetic risk in ART. In this setting, before proposing this analysis in clinical practice, an accurate identification of the most representative genes and a cost-effectiveness evaluation should be assessed in ad hoc prospective studies.

NK cell-mediated lysis of autologous antigen-presenting cells is triggered by the engagement of the phosphatidylinositol 3-kinase upon ligation of the natural cytotoxicity receptors NKp30 and NKp46.

Interleukin-2 (IL-2)-activated polyclonal or clonal NK cells lysed autologous antigen presenting cells (APC) through the engagement of the natural cytotoxicity receptors (NCR) NKp30 and NKp46. NK cell-mediated cytolysis of APC correlated with the surface density of these NCR. Indeed, NK cell clones bearing low amounts of NKp30 and NKp46 did not lyse autologous APC, whereas NK cell clones with bright expression of these NCR efficiently killed autologous APC. Upon masking of NKp30 or NKp46 by specific monoclonal antibodies a strong reduction (by 50%) of APC lysis could be detected and the complete inhibition was achieved by the simultaneous masking of these NCR. Interestingly, NK cell-mediated APC lysis was impaired by the phosphatidylinositol 3-kinase (PI-3 K) inhibitors LY294002 or wortmannin. Similarly, these drugs strongly reduced NK cell activation triggered by NKp30 or NKp46 in a re-directed killing assay as well as the activation of Akt/PKB, substrate of PI-3 K, induced by the engagement of these receptors. Altogether, these findings strongly suggest that NCR are responsible for the killing of autologous APC through the activation of PI-3 K.

Dendritic cells efficiently cross-prime HLA class I-restricted cytolytic T lymphocytes when pulsed with both apoptotic and necrotic cells but not with soluble cell-derived lysates.

Dendritic cells (DC) have been shown to efficiently present antigen to CD8(+) cytolytic T cells (CTL) when pulsed with apoptotic cells as a source of cell-derived antigen. Such cross-priming could not be detected by the use of necrotic cells, while conflicting results have been reported for cell-derived soluble lysates. In this study, we reinvestigated this issue by using autologous Epstein-Barr virus-transformed lymphoblastoid cell lines (LCL) as a source of antigen to pulse monocyte-derived DC. Both autologous and HLA-mismatched allogeneic LCL have been used either in the form of apoptotic or of necrotic cells or of soluble cell lysates. At day 7, DC were co-cultured with the autologous CD8(+) lymphocyte fraction for an additional 9 days, in the presence of exogenous IL-2 (added after 48 h). At the end of the culture period, CD8(+) CTL efficiently lysed autologous LCL only when they had been co-cultured with DC pulsed with necrotic or apoptotic cells. That an efficient cross-priming of autologous CD8(+) cells could be induced by DC pulsed with apoptotic or necrotic LCL but not with cell lysates was further demonstrated in assays of IFN-gamma production in response to short-term re-stimulation of CD8(+) cells with LCL. In addition, LCL-specific CD8(+) cells could specifically lyse autologous DC that had been pulsed with LCL-derived antigens, further suggesting that DC presented exogenous antigens on HLA class I molecules.

Engagement of CD33 surface molecules prevents the generation of dendritic cells from both monocytes and CD34+ myeloid precursors.

Although CD33 represents an important marker of myeloid cell differentiation, its function remains poorly defined. In view of its homology with p75/AIRM1, a recently identified surface molecule which exerts a potent inhibition on NK cell function, we re-evaluated the effect of CD33 engagement in defined myeloid cell functions. Addition of anti-CD33 mAb to cultures of CD14+ monocytes supplemented with granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4 and TNF-alpha, prevented the generation of dendritic cells. In these cultured cells, engagement of CD33 resulted in an increased surface binding of annexin-V, followed by cell death. Mature dendritic cells were resistant to the CD33-mediated effect. Also in CD34+ precursors, cultured in the presence of flt3-ligand, c-Kit-ligand, GM-CSF, IL-4 and TNF-alpha, addition of anti-CD33 mAb prevented the recovery of mature dendritic cells. These data suggest a regulatory role of CD33 in the myeloid cell maturation and may offer a tool to interfere with the monocyte/macrophage cell function as well as with the development of dendritic cells.

Training in colposcopy: experience with a videocolposcopy test.

The authors evaluate the results of a videocolposcopy test (330 total cases, 12 cases of histologically confirmed CIN2 or more severe lesions) taken by 9 accredited and 17 unaccredited colposcopists during 1995. Seven of 9 accredited and 4 of 13 unaccredited colposcopists reached the requested standard (sensitivity > 90%, biopsy rate < 60%). Performance was definitely better when the test was not blind to the cytologic report (4 of 13 reached the requested standard) with respect to blind reading (none of 17). The study confirmed that colposcopy at unaccredited practices is poorly accurate. Colposcopic assessment of patients with abnormal smears should be centralized in accredited practices, which should undergo periodic quality control to guarantee screening efficacy. Tape-recorded videocolposcopy tests are a good, simple, practical and inexpensive method for interobserver quality control of colposcopic performance.