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The aim of this observational study was to develop a new quantitative liquid chromatography-mass spectrometry (LC-MS/MS) method for Therapeutic-Drug-Monitoring (TDM) of psychotropic drugs in seminal fluid to investigate potential gonadotoxic effects in patients with reduced fertility. After the validation of the LC-MS/MS method for psychotropics' levels determination in seminal fluid, we included 20 male partners of infertile couples with idiopathic and/or unexplained male infertility, treated with psychotropic medications for more than 3 months and 10 untreated fertile controls. General and andrological clinical examination, semen analysis and seminal drugs, and metabolites levels determination were performed for each subject. Of the 20 patients included, 6 were treated with antidepressants; 4 with benzodiazepines and 10 with antipsychotics. Seminal drugs and metabolites levels were detectable in all samples. In particular, alprazolam, olanzapine, and levetiracetam showed seminal and serum similar concentrations, while fluoxetine, quetiapine, and aripiprazole were detectable, but seminal levels were significantly lower than the serum therapeutic range. Sperm progressive motility was significantly reduced in subjects treated with psychotropic drugs compared to the untreated controls (p = 0.03). Sperm concentration and progressive motility were significantly reduced in subjects treated with antipsychotics compared to the untreated controls and to the other classes of psychotropics (p < 0.05). In conclusion, this study reports a validated LC-MS/MS method for the detection of seminal psychotropic levels and preliminary data suggesting a potential correlation of seminal psychotropics with alterations of sperm concentration and motility. Pending larger studies, semen TDM might represent a new pivotal tool in the clinical management of reduced fertility in males treated with psychotropic medications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mazzilli, Curto, De Bernardini, Olana, Capi, Salerno, Cipolla, Zamponi, Santi, Mazzilli, Simmaco and Lionetto.)

Introduction: The aims of this study were to determine the prevalence of testicular-adrenal rest tumors (T-ARTs) in patients with congenital adrenal hyperplasia (CAH) and to evaluate the related ultrasound (US) features, hormonal profiles, and semen parameters. Therefore, we attempted to understand the potential impact of adrenocorticotropic hormone (ACTH) on the persistence or disappearance of T-ART. Methods: We conducted a longitudinal cohort study including patients with CAH who were undergoing treatment with cortisone and, when indicated, fludrocortisone replacement therapy. We performed andrological examinations, US of the testis, hormone profiling, and semen analysis. Results: Of the 25 patients (mean ± SD age, 32.2 ± 7.5 years), T-ARTs were detected by US in 14 (56.0%) patients. The mean ± SD diameter of the lesions was 13.2 ± 6.8 mm. Among 3 (21.4%) patients, the lesions were observed in one testis, whereas both testes were affected in the remaining 11 (78.6%) patients. The lesions were hypoechoic in 12 (85.7%) patients and hyperechoic in 2 (14.3%). Plasma ACTH and 17-hydroxyprogesterone (17-OHP) levels were significantly higher in patients with T-ART than in patients without lesions (319.4 ± 307.0 pg/ml and 12.4 ± 2.7 ng/ml vs. 33.5 ± 10.7 pg/ml and 8.2 ± 1.8 ng/ml, respectively; p < 0.01). The mean values of sperm concentration and motility were significantly lower in patients with T-ART than in patients without lesions (12.1 ± 12.4 × 10 6 cells/ml and 18.4 ± 11.1% vs. 41.5 ± 23.2 × 10 6 cells/ml and 30.8 ± 15.4%, respectively; p < 0.05). Logistic regression analysis showed ACTH level as a significant predictor of T-ART ( p < 0.05). In patients with T-ART, the dose of hydrocortisone was increased by ~25-30%, while the fludrocortisone treatment remained unchanged. After 6 months of steroid treatment, patients underwent US and hormonal evaluation. Disappearance and a reduction in T-ART were observed in 6 (42.9%) and 5 (35.7%) patients, respectively; a reduction in ACTH levels (from 319.4 ± 307.0 to 48.1 ± 5.1 pg/ml; p < 0.01) was reported. A significant correlation between ACTH level reduction and T-ART diameter reduction was observed ( p < 0.5; r = 0.55). Conclusions: T-ARTs were detected in 56% of patients with CAH and were associated with impaired semen parameters. However, these lesions are potentially reversible, as demonstrated by the disappearance/reduction after adjustment of cortisone therapy and by the reduction in plasma ACTH level. Our study supports the importance of periodic US evaluation and maintenance of plasma ACTH levels within the normal range in men with CAH.