Noonan syndrome (NS) is a genetic disorder characterized by multiple congenital defects caused by mutations in the RAS/mitogen-activated protein kinase pathway. Male fertility has been reported to be impaired in NS, but only a few studies have focused on fertility status in NS patients and underlying mechanisms are still incompletely understood. We describe the case of a 35-year-old man who underwent an andrological evaluation due to erectile dysfunction and severe oligospermia. A syndromic facial appearance and reduced testis size were present on clinical examination. Hormonal evaluation showed normal total testosterone level, high FSH level, and low–normal AMH and inhibin B, compatible with primary Sertoli cell dysfunction. Genetic analysis demonstrated the pathogenetic heterozygous variant c.742G>A, p.(Gly248Arg) of the LZTR1 gene (NM_006767.3). This case report provides increased knowledge on primary gonadal dysfunction in men with NS and enriches the clinical spectrum of NS from a rare variant in the novel gene LZTR1.

ABSTRACT Background The integrity of the neural pathways that link genital sensitive areas to the brain and the correlation with subjective sensations in transgender women with gender dysphoria after gender affirming surgery (GAS) have not been explored in detail and remain controversial, so far. Aim To test with electrophysiology the integrity of the nervous paths after GAS, and to explore the relationship between genital sensitivity and self-perceived orgasmic intensity in transgender women after GAS. Methods Six patients who underwent GAS between 2016 and 2019 were enrolled in the study, and the evaluation of genital and pelvic neural pathways was performed. Outcomes Genital sensory thresholds (at clitoral, vaginal, and anal sites) investigated by Somatosensory Evoked Potentials (SEP) and the intensity of orgasm (measured by a psychometric tool, the Orgasmometer) were combined to obtain an objective and subjective evaluation. Results SSEPs confirmed the integrity of the large diameter, dorsal column-lemniscus pathway subserving the genital area after GAS. Perceptual Threshold (PT) values were much lower at the neoclitoris compared to neovagina and anal sites. There was no correlation between Orgasmometer and SEP at anal and neovaginal level, while a trend was found at clitoral level. Clinical Implication These findings could lead clinicians to a better understanding of postsurgical sexual life in transgender women in order to develop surgical techniques that could focus more on functional aspects of neovagina and neoclitoris. Strengths & Limitations Limitations: study very preliminary/exploratory; small number of patients; no long-term follow-up. Strengths: first assessment of sensory pelvic floor innervation in transgender women after GAS; use of objective methods; first attempt at correlating objectives findings to subjective experience of the sexual orgasm. Conclusions Our evaluation showed that SSEPs is a good indicator of neural sensitivity, especially in neoclitoris, and that these measurements were consistent with the analysis of self-perceived orgasmic intensity.

Introduction: Medullary thyroid cancer (MTC) is a rare endocrine tumor, which can be sporadic or familial, as a component of multiple endocrine neoplasia 2 (MEN2). Overall, 10% of MTC cases have already developed at presentation or will develop metastasis during follow-up. Testicular metastases are exceptional and only one case of unilateral testis involvement by metastatic MTC has been already reported in literature. We described the first known case of asymptomatic bilateral testicular MTC metastases, discovered incidentally at testicular ultrasound (US) performed for unrelated reasons. Case presentation: A Latin American 32-year-old man with MEN 2A syndrome and metastatic MTC underwent andrological and urological examination due to premature ejaculation. US imaging showed two symmetrical hypoechoic lesions involving both testes. Suspecting a bilateral testicular cancer, the patient underwent excision biopsy of both testicular lesions. Histopathology and immunohistochemical examinations documented metastatic MTC of both testicular lesions. Conclusion: Beyond its rarity, testis should be considered as a potential metastatic site of MTC, especially in patients with advanced disease.

Introduction: Efficacy evaluation of a new treatment, improving the symptoms of Peyronie's disease (PD) in patients with a curvature deformity < 30 degrees and with an onset of symptoms of at least 6 months before the treatment. We investigated the effects of Transfer Capacitive Resistive Energy (TCARE) therapy accompanied by hydroelectrophoresis (HEP), a new electromotive system, for the transcutaneous delivery of Verapamil in men with PD. Materials and Methods: Sixty-one patients affected by PD were enrolled. They were randomly divided into two groups: Group 1 (n. 30 patients, median age 56, range 49-62 yrs) was assigned to receive only TCARE; Group 2 (n. 31 patients; median age 58, range 51-60 yrs) received both TCARE and HEP. Every patient underwent 16 treatment sessions, 2 sessions a week for each group. TCARE was performed with resistive energy and each treatment lasted 15 minutes. In Group 2 TCARE was also followed by HEP (with Hydro4and apparatus, Swiss4Med SA, Morbio Inferiore, Switzerland). HEP delivered 10 mg/4ml of Verapamil per session (2 ampoules of Verapamil 5mg/2ml each; Isoptin, BGP products, Rome, Italy) for a 20-minute lasting. The endpoints were: a pain increase in erection, the International Index of Erectile Function questionnaire (IIEF-15) scale score, and penile curvature (in degrees). They were evaluated at the beginning of the study, at the end and three months after the discontinuation of the treatment. The pain was measured by using the Numeric Rating Scale (NRS) for pain 1-10 and the erectile function by IIEF15. The penile curvature was measured instead by using photography, a personal paper protractor after injection of PGE1 10 mcg. Some side effects during or immediately after the treatment were recorded. Statistical analysis was performed using ANOVA for repeated measurements, corrected with Bonferroni. The side effects were compared between the two groups using the Chi-square Test (test chi 2). Results : The pain, the erectile function, and the penile curvature were all significantly improved with both treatments (p<0.001). In Group 2 (TCARE + HEP) the improvement was greater than Group 1 (p<0.001 for IIEF and curvature; p <0.05 for pain). The amelioration was maintained until three months after the end of treatment. No relevant side effects were observed or indicated by the patients. Conclusions: TCARE followed by Verapamil administration by HEP is an effective and safe treatment for PD.

To meet clinicians’ request for adequate results and reliable reference ranges for testosterone, this study was planned with the aims (i) to verify the reliability of the reference interval for total testosterone (TT) declared by immunoassay manufacturer and adopted by laboratory, (ii) to compare results for serum TT obtained by immunoassay and LC–MS/MS and (iii) to verify if the cutoff values for low TT and measured free testosterone (FT), defined by Endocrine Society Guidelines for diagnosis of hypogonadism, are applicable to our study group. Sera from anonymous young/middle-aged male blood donors were selected for the study. TT was measured by immunoassay and LC–MS/MS. SHBG was measured by immunoassay and used with albumin concentration to calculate FT according to Vermeulen’s formula. The reference interval declared by the manufacturer and adopted by the lab was validated. The two methods for TT evaluation correlated very well. TT and FT lower limits at 5th and 2.5th percentile are below the cutoffs reported in the literature for the diagnosis of hypogonadism. The immunoassay currently used in our lab can be considered an adequate tool for TT, but it’s essential that clinical data agree with the biochemical ones, particularly in the presence of TT values between the lower limit of reference range and the cutoff values recommended by scientific societies.

BACKGROUND: Proxelan® and antibiotics combined therapy was successfully previously used in the treatment of symptoms of patients with chronic prostatitis. Aim of the present study was to investigate the effects of Proxelan® monotherapy on pain symptoms of patients with chronic prostatitis (CP) or chronic pelvic pain syndrome (CPPS) in a prospective pilot study.METHODS: Thirty consecutive patients with CP/CPPS symptoms younger than 50, without urinary obstruction, total prostate-specific antigen (PSA) <4 ng/mL, negative microbiology testing on prostate fluid and urethral swab, naïve from other treatments during the previous three months were enrolled in a pilot study. IPSS and NIH-CPSI questionnaires were administered to all the patients. Patients could choose to be investigated regarding semen quality and IL6/IL8 seminal markers for inflammatory disease prior and after the therapy course. Proxelan® suppositories were prescribed for each patient for a month with a daily dosage of 1 suppository at bed-time. The primary endpoint of the study included at least a 30% reduction of pain symptoms because similar results can be obtained in each previously investigated placebo group. Effects on semen parameters such as leukocytospermia, spermatozoa concentration and motility, cytokine levels were considered as secondary endpoints.RESULTS: Subjective pain relief was obtained in all the patients with significant decrease of NIH-CPSI pain items (P=0.04). Urinary symptoms, investigated by IPSS questionnaire, decreased significantly (P=0.04) as well as quality of life items (P=0.04). Leukocytospermia was found in 5/15 patients available for further investigations. IL6 decreased by 11.55% one month after the treatment while sperm motility resulted increased by 17.3%.CONCLUSIONS: Proxelan® monotherapy may represents a promising valid alternative to combined treatment with antibiotics in patients with CP/CPPS symptoms although the results obtained should be investigated in randomized controlled trials.

INTRODUCTION:Loss of function mutations of CYP24A1 gene, which is involved in vitamin D catabolism, cause vitamin D-mediated PTH-independent hypercalcemia. The phenotype varies from life-threatening forms in the infancy to milder forms in the adulthood.CASE PRESENTATION:We report a case of a 17-year-old woman with a history of nephrolithiasis, mild PTH-independent hypercalcemia (10,5mg/dL), and high serum 1,25(OH)2D concentrations (107pg/mL). Other causes of hypercalcemia associated with the above biochemical signature were excluded. Family history revealed nephrolithiasis in the sister. Blood testing in first-degree relatives showed serum PTH in the low-normal range and 1,25(OH)2D at the upper normal limit or slightly elevated. The CYP24A1 gene analysis revealed a known homozygous loss-of-function pathogenic variant (c.428_430delAAG, rs777676129, p.Glu143del). The panel of vitamin D metabolites evaluated by liquid chromatography showed the typical profile of CYP24A1 mutations, namely, low 24,25(OH)2D3, elevated 25(OH)D3:24,25(OH)2D3 ratio, and undetectable 1,24,25(OH)3D3. The parents and both the siblings harbored the same variant in heterozygosis. We decided for a watchful waiting approach and the patient remained clinically and biochemically stable over a 24-month followup.CONCLUSION:CYP24A1 gene mutations should be considered in cases of PTH-independent hypercalcemia, once that more common causes (hypercalcemia of malignancy, granulomatous diseases, and vitamin D intoxication) have been ruled out.

NR5A1 (nuclear receptor subfamily 5 group A member 1) is a transcriptional regulator of adrenal and gonadal development and function. Heterozygous and homozygous NR5A1 mutations have been described in people with 46,XY disorders of sex development (DSD). The clinical, endocrine, and genetic features of four 46,XY subjects with NR5A1 genetic variants (2 sisters, 2 boys) from 3 unrelated families are reported. All subjects presented with hypergonadotropic hypogonadism and abnormal pubertal progression. Markers of Sertoli cell function were more affected than those of Leydig cell function. Genetic investigation demonstrated the presence of different heterozygous NR5A1 genetic variants. In the boys, pathogenetic NR5A1 gene variants were found that had been previously reported. The 2 sisters carried a new genetic variant in exon 4, and in silico analysis and ACMG classification indicated its pathogenicity. The data confirmed that NR5A1 gene mutations may present with variable genital phenotypes. Anyway, reproductive function was always impaired. Any clinical or endocrine data seem to be unable to differentiate these patients from other 46,XY DSD cases, suggesting that molecular analysis must be warranted. In subjects with NR5A1 mutations, different decisions in sex assignment may permit satisfying somatic and psychological outcome, but any option requires hormonal substitutive therapy from adolescence onward.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Vitamin D deficiency following malabsorptive bariatric surgery can lead to osteomalacia. We report a patient with severe vitamin D deficiency following malabsorptive bariatric surgery successfully treated with calcifediol but not cholecalciferol. A 40-year-old woman, submitted to biliopancreatic diversion 20 years before and chronically treated with 50,000 IU cholecalciferol weekly, was admitted to our Endocrine Unit because of severe lower back pain, muscle weakness, and generalized muscular hypotrophy, associated with hypocalcemia and elevated PTH levels. Initial evaluation revealed low serum albumin, low albumin-corrected serum calcium (7.36 mg/dL), high serum PTH (240 pg/mL), bone-specific alkaline phosphatase (125 μg/L) and 1,25-dihydroxyvitamin D (112 pg/mL) concentrations, undetectable serum 25-hydroxyvitamin D (<7 ng/mL), and evidence of reduced liver function. Bone mineral density was markedly low. Normocalcemia was initially restored with intravenous albumin and calcium gluconate. Treatment with calcitriol (0.5 μg three times daily) and oral calcium carbonate (1000 mg daily) was simultaneously started and cholecalciferol was replaced with calcifediol [125 μg (5000 IU) daily)]. During follow-up the calcifediol dose was progressively tapered to 25 μg (1000 IU) daily and the calcitriol dose was progressively reduced and finally withdrawn. Serum albumin and other biochemical parameters normalized, bone mineral density significantly increased, and the patient's clinical conditions progressively improved, with a substantial recovery of autonomy. Serum vitamin D binding protein at the last observation was in the normal range. Our data suggest that calcifediol might be more efficacious than cholecalciferol for prevention and treatment of vitamin D deficiency in patients treated by malabsorptive bariatric surgery.

Management of late onset hypogonadism (LOH) is not homogenous. The aim of the study is to observe the management of patients with low testosterone (T) in highly specialized Italian centres.

The benefits of spa therapy on different medical diseases are known since ancient times, as well its positive effects on some psychiatric symptoms. In the last decades different studies have been carried out in order to elucidate some of the possible biological mechanisms underlying spa treatment effectiveness, which include thermal, mechanical, immunomodulatory and chemical effects. It is still an open question whether or not spa waters may or not modify thyroid functions. Therefore, the aim of this study was to explore the possible influence of alkaline saline-sulfate spa waters on thyroid functions, as assessed by the FT3, FT4 and TSH levels, in a group of 12 healthy women. Al subjects were recruited amongst administrative and nursing staff at the Montecatini spa (Italy), on the basis of absence of hormonal dysfunctions, medical illness and psychiatric disorders. The thyroid hormones were measured by common chemiluminescent immunoassays before (t0) and 24 hours after (t1) inhalation therapy with alkaline saline-sulfate spa waters (Leopoldina water of Montecatini Terme Spa, Italy). The results, while showing a stability of thyroid hormone levels at to and t1, suggest that treatment with alkaline saline-sulfate spa waters may be safely used in patients with different thyroid disturbances.

Summary Objective To evaluate the effects of radioactive iodine ( RAI ) treatment for differentiated thyroid cancer ( DTC ) on testis function. Design A prospective longitudinal single‐centre study was performed. A comprehensive andrological evaluation including hormonal assessment, semen analysis and scrotal ultrasound was undertaken in male patients undergoing RAI treatment for DTC . Methods Hormonal assessment of FSH , LH , testosterone (T), sperm concentration and motility and testis volume were determined in 20 patients in basal conditions, 6 and 12 months after RAI . Results were analysed in the whole group of patients and then separately in those who received one single ablative treatment (‘Single’ group, n = 10) and those who received multiple treatments (‘Multiple’ group, n = 10). Results In basal conditions, 3 of 20 (15%) patients had a reduced sperm count and belonged to the ‘Multiple’ group. After RAI , an increase of FSH (8·8 ± 1·2 UI/l vs 5·2 ± 1·2, P < 0·005) and a decrease in sperm concentration (28·8 ± 7·7 millions/ml vs 54·5 ± 7·1, P < 0·005) and testis volume (15·2 ± 3·1 vs 13·7 ± 0·8 ml, P < 0·005) occurred at 6 months in the whole group. One year after RAI , seven patients had oligozoospermia (five from the ‘Multiple’ group and two from the ‘Single’ group). Permanent impairment of one or more testis function parameters was observed in patients who underwent multiple RAI treatments: 50% for sperm count, 40% for FSH levels and testis volume and, respectively, in 20 and 10% of those who received one single RAI treatment. Conclusions The single ablative RAI treatment in cancer patients is better tolerated respect multiple RAI treatments regard testis function. Multiple treatments for recurrent or metastatic disease may cause a permanent impairment of one or more parameters related to the reproductive potential of male patients.

Purpose: We evaluated the ability of the phosphodiesterase-5 inhibitor vardenafil to increase prostate microcirculation during power Doppler ultrasound. We also evaluated the results of contrast and vardenafil enhanced targeted biopsies compared to those of standard 12-core random biopsies to detect cancer.Materials and Methods: Between May 2008 and January 2010, 150 consecutive patients with prostate specific antigen more than 4 ng/ml at first diagnosis with negative digital rectal examination and transrectal ultrasound, and no clinical history of prostatitis underwent contrast enhanced power Doppler ultrasound (bolus injection of 2.4 ml SonoVue (R) contrast agent), followed by vardenafil enhanced power Doppler ultrasound (1 hour after oral administration of vardenafil 20 mg). All patients underwent standard 12-core transrectal ultrasound guided random prostate biopsy plus 1 further sampling from each suspected hypervascular lesion detected by contrast and vardenafil enhanced power Doppler ultrasound.Results: Prostate cancer was detected in 44 patients (29.3%). Contrast and vardenafil enhanced power Doppler ultrasound detected suspicious, contrast enhanced and vardenafil enhanced areas in 112 (74.6%) and 110 patients (73.3%), and was diagnostic for cancer in 32 (28.5%) and 42 (38%), respectively. Analysis of standard technique, and contrast and vardenafil enhanced power Doppler ultrasound findings by biopsy core showed significantly higher detection using vardenafil vs contrast enhanced power Doppler ultrasound and standard technique (41.2% vs 22.7% and 8.1%, p < 0.005 and <0.001, respectively). The detection rate of standard plus contrast or vardenafil enhanced power Doppler ultrasound was 10% and 11.7% (p not significant).Conclusions: Vardenafil enhanced power Doppler ultrasound enables excellent visualization of the microvasculature associated with cancer and can improve the detection rate compared to contrast enhanced power Doppler ultrasound and the random technique.