Chronic urticaria and thyroid autoimmunity: a meta-analysis of case-control studies.

PURPOSE: Autoimmunity has been implicated in some patients with idiopathic chronic urticaria (CU). Because of the frequency of autoimmune thyroid diseases, their association with CU deserves special attention. We tested both the existence and the extent of an association between thyroid autoimmunity and CU. METHODS: A thorough search of PubMed, Scopus, Web of Science, and Cochrane databases was performed. Studies reporting the positivity rate for anti-thyroperoxidase antibodies (TPOAbs) in people with (cases) and without CU (controls) were included. Quality of the studies was assessed by the Newcastle-Ottawa Scale. Between-study heterogeneity was assessed by Cochrane Q and I2 tests, and the odds ratio (OR) for TPOAbs positivity was combined using random-effects models. RESULTS: Nineteen studies provided information about TPOAbs positivity on 14,351 patients with CU and 12,404 controls. The pooled estimate indicated a more than fivefold increased risk of exhibiting TPOAbs positivity in the group with CU (pooled OR 5.18, 95% CI 3.27, 8.22; P < 0.00001). Correction for publication bias had a negligible effect on the overall estimate (pooled adjusted OR: 4.42, 95% CI 2.84, 6.87, P < 0.0001). Between­study heterogeneity was established (I2 = 62%, Pfor heterogeneity = 0.0002) and when, according to meta­regression models, a sensitivity analysis was restricted to the 16 studies with the highest quality scores, the OR for TPOAbs positivity rose to 6.72 (95% CI 4.56, 9.89; P < 0.00001) with no significant heterogeneity (I2 = 31%, Pfor heterogeneity = 0.11). CONCLUSIONS: Patients with CU have a five-to-nearly sevenfold higher risk of displaying TPOAbs positivity. All patients with CU may well be offered a screening for thyroid autoimmunity.

Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE).

PURPOSE: To provide the evidence-based recommendations on the role of testosterone (T) on age-related symptoms and signs remains. METHODS: The Italian Society of Andrology and Sexual Medicine (SIAMS) and the and the Italian Society of Endocrinology (SIE) commissioned an expert task force to provide an updated guideline on adult-onset male hypogonadism. Derived recommendations were based on Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS: Clinical diagnosis of adult-onset hypogonadism should be based on a combination of clinical and biochemical parameters. Testosterone replacement therapy (TRT) should be offered to all symptomatic subjects with hypogonadism after the exclusion of possible contraindications. T gels and the long-acting injectable T are currently available preparations showing the best efficacy/safety profile. TRT can improve all aspects of sexual function, although its effect is limited in more complicated patients. Body composition (reducing fat mass and increasing lean mass) is improved after TRT, either in subjects with or without metabolic syndrome or type 2 diabetes. Conversely, the role of TRT in improving glycometabolic control is more conflicting. TRT can result in increasing bone mineral density, particularly at lumbar site, but no information on fracture risk is available. Limited data support the use of TRT for improving other outcomes, including mood frailty and mobility. CONCLUSIONS: TRT can improve sexual function and body composition particularly in less complicated adult and in aging subjects with hypogonadism. When hypogonadism is adequately diagnosed, T appropriately prescribed and subjects correctly followed up, no short-term increased risk of adverse events is observed. Longer and larger studies are advisable to better clarify TRT long-term efficacy/safety profile.

Management of male factor infertility: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS) : Endorsing Organization: Italian Society of Embryology, Reproduction, and Research (SIERR).

PURPOSE: Infertility affects 15-20% of couples and male factors are present in about half of the cases. For many aspects related to the diagnostic and therapeutic approach of male factor infertility, there is no general consensus, and the clinical approach is not uniform. METHODS: In the present document by the Italian Society of Andrology and Sexual Medicine (SIAMS), endorsed by the Italian Society of Embryology, Reproduction, and Research (SIERR), we propose evidence-based recommendations for the diagnosis, treatment, and management of male factor infertility to improve patient and couple care. RESULTS: Components of the initial evaluation should include at minimum medical history, physical examination, and semen analysis. Semen microbiological examination, endocrine assessment, and imaging are suggested in most men and recommended when specific risk factors for infertility exist or first-step analyses showed abnormalities. Full examination including genetic tests, testicular cytology/histology, or additional tests on sperm is clinically oriented and based on the results of previous investigations. For treatment purposes, the identification of the specific cause and the pathogenetic mechanism is advisable. At least, distinguishing pre-testicular, testicular, and post-testicular forms is essential. Treatment should be couple-oriented, including lifestyle modifications, etiologic therapies, empirical treatments, and ART on the basis of best evidence and with a gradual approach. CONCLUSION: These Guidelines are based on two principal aspects: they are couple-oriented and place high value in assessing, preventing, and treating risk factors for infertility. These Guidelines also highlighted that male infertility and in particular testicular function might be a mirror of general health of a man.

Clinical and seminal parameters associated with testicular microlithiasis and its severity in males from infertile couples.

STUDY QUESTION: Is there an association of testicular microlithiasis (TM) and its severity with testicular dysfunction in men from infertile couples? SUMMARY ANSWER: The presence of ≥5 testis microcalcifications per sonogram at the scrotal ultrasonography (US) of infertile males was associated with a more severe testicular dysfunction as compared to males with limited, or without, TM. WHAT IS KNOWN ALREADY: TM, representing an incidental finding in the scrotal US, is associated with male infertility and a higher risk for testicular cancer as compared to that in infertile males without TM. Still, there are unresolved questions on the relation between TM severity and testicular dysfunction in infertile men, as well as on the identification of risk factors for TM. STUDY DESIGN, SIZE, DURATION: This study was an observational, retrospective, case-control investigation involving males who underwent clinical evaluation, measurement of reproductive hormones, seminal analysis and scrotal US as part of diagnostic work-up for couple infertility at an andrology clinic, between January 2004 and December 2018. One hundred patients, out of the 2112 scored men, were found to have TM during the US evaluation. One hundred male partners from 100 infertile couples without TM, comprising the control group, were selected through a matched analysis by age and date of evaluation to reduce the confounding effect of both age and technique variability all along the long period of observation. PARTICIPANTS/MATERIALS, SETTING, METHODS: TM was defined as limited TM (LTM) or classical TM (CTM), when the maximum number of hyperecogenic spots per sonogram was <5 or ≥5, respectively. CTM, LTM and control groups were compared for clinical variables, serum levels of FSH, LH, and total testosterone, as well for semen parameters and scrotal US features. MAIN RESULTS AND THE ROLE OF CHANCE: After the exclusion of cases with testicular nodules to eliminate the possible confounding effect of testis cancer on testicular dysfunction, cases with CTM showed a lower mean testis volume (P = 0.03) and a lower sperm concentration (P = 0.03) as compared to the other two groups. A higher FSH level was observed in the CTM group compared to the LTM group (P = 0.02) and in controls (P = 0.009). The multiple logistic regression analysis showed that only a smaller testicle volume exhibited an independent significant association with a higher odds of detecting CTM (odds ratio = 0.84, 95% CI: 0.75-0.94; P = 0.02). No significant differences were observed between groups in the prevalence of risk factors for testicular cancer, or in the prevalence of conditions associated with TM. LIMITATIONS, REASONS FOR CAUTION: The retrospective design of the study did not allow conclusions to be drawn about the possible underlying links in the associations of TM with defective spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS: Males from infertile couples who exhibit a reduced testicular volume should undergo scrotal US, independent of sperm parameters, to exclude CTM and, eventually, testis cancer, although the association of CTM and current or future testis cancer risk is not yet clear. Evidence is provided here demonstrating that the presence of LTM has no clinical relevance in males from infertile couples. STUDY FUNDING/COMPETING INTEREST(S): Investigation was funded by Ministero dell'Università e della Ricerca, PRIN 2018, Italy. The authors have not declared any competing interests. TRIAL REGISTRATION NUMBER: N/A.

Relationship between natural and intrauterine insemination-assisted live births and the degree of sperm autoimmunisation.

STUDY QUESTION: What is the relationship between the degree of sperm autoimmunisation, as assessed by IgG-mixed antiglobulin reaction (MAR) test, and natural and intrauterine insemination (IUI)-assisted live births? SUMMARY ANSWER: Compared with a lower degree of positivity (50-99%), a 100%-positive MAR test was associated with a much lower occurrence of natural live births in infertile couples, who could be successfully treated with IUI, as first-line treatment. WHAT IS KNOWN ALREADY: The World Health Organization (WHO) has recommended screening for antisperm antibodies, through either the IgG-MAR test or an immunobead-binding test, as an integral part of semen analysis, with 50% antibody-coated motile spermatozoa considered to be the clinically relevant threshold. However, the predictive value of the degree of positivity of the MAR test above such a cut-off on the occurrence of natural pregnancies remains largely undetermined. Furthermore, the effectiveness of IUI in cases of strong sperm autoimmunisation is not yet well-established. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study on 108 men with a ≥50%-positive MAR test, where the couple had attended a university/hospital andrology/infertility clinic for the management of infertility from March 1994 to September 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: The IgG-MAR test was carried out as an integral part of semen analysis. The patients were divided into two groups: 100% and 50%-99%-positive MAR test. The post-coital test (PCT) was performed in all the couples, and IUI was offered as the first-line treatment. Laboratory and other clinical data were retrieved from a computerised database. Data on subsequent pregnancies were obtained by contacting patients over the telephone. MAIN RESULTS AND THE ROLE OF CHANGE: A total of 84 men (77.8%) were successfully contacted by telephone, and they agreed to participate. Of these, 44 men belonged to the group with a 100%-positive MAR test, while 40 showed lower MAR test positivity. The couples with a 100%-positive MAR test showed a natural live birth rate per couple (LBR) that was considerably lower than that observed with a lower degree of positivity (4.5% vs. 30.0%; P = 0.00001). Among the clinical variables, a significant difference between the two groups was observed only for the PCT outcome, which was poor in the 100%-positive MAR test group. Better PCT outcomes (categorised as negative, subnormal and good) were positively associated with the occurrence of natural live births (6.3, 21.7 and 46.2%, respectively; P = 0.0005 for trend), for which the sole independent negative predictor was the degree of sperm autoimmunisation. IUI was performed as the first-line treatment in 38 out of 44 couples with a 100%-positive MAR test, yielding 14 live births (36.8%). In couples with lower MAR test positivity, the LBR after IUI (26.9%) was similar to the natural LBR in this group (30.0%). LIMITATIONS, REASONS FOR CAUTION: Given the retrospective nature of the study, we cannot exclude uncontrolled variables that may have affected natural pregnancies during the follow up or a selection bias from the comparison of natural live births with those after IUI. WIDER IMPLICATIONS OF THE FINDINGS: The routine use of the IgG-MAR test in the basic fertility workup is justified as it influences decision making. A 100%-positive IgG-MAR test can represent the sole cause of a couple's infertility, which could be successfully treated with IUI. On the other hand, a lower degree of positivity may only represent a contributing factor to a couple's infertility, and so the decision to treat or wait also depends on the evaluation of conventional prognostic factors including the PCT outcome. STUDY FUNDING, COMPETING INTEREST(S): This study was supported by PRIN 2017, Ministero dell'Università e della Ricerca Scientifica (MIUR), Italy. On behalf of all authors, the corresponding author states that there is no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Thyroid autoimmunity and risk of post-partum depression: a systematic review and meta-analysis of longitudinal studies.

PURPOSE: The aim of this study was to systematically investigate whether, and to what extent, the detection of thyroid autoimmunity during pregnancy and in the weeks after childbirth is associated with an increased risk of developing post-partum depression (PPD), a condition associated with possible adverse outcomes for both mother and offspring. We performed a systematic review and meta-analysis of longitudinal studies, assessing the incidence of PPD in women with and without anti-thyroperoxidase antibody (TPOAb) positivity. METHODS: We searched MEDLINE, EMBASE, Web of Science, Cochrane Library, and CINAHL. Methodological quality of the studies was assessed by the Newcastle-Ottawa Scale. In the presence of even modest between-studies heterogeneity, assessed by Cochrane Q and I2 tests, risk ratios (RRs) for PPD were combined using a random effects model. Funnel plot and trim-and-fill analysis were used to assess publication bias. RESULTS: Five included studies provided information on 449 women with TPOAb-positive and 2483 TPOAb-negative women. Pooled RR indicated a significantly increased risk to develop PPD in TPOAb-positive group (RR 1.49, 95% CI 1.11-2.00; P = 0.008; I2 = 47%, Pfor heterogeneity = 0.11). Consistent with a possible publication bias, the trim-and-fill test detected two putative missing studies in the funnel plot. Nevertheless, the adjustment for publication bias produced a negligible effect on the pooled estimate (adjusted RR 1.41, 95% CI 1.18-1.68, P = 0.0002). CONCLUSIONS: Thyroid autoimmunity during pregnancy and in the weeks after childbirth is associated with an increased risk of developing PPD. Further well-designed studies are warranted to confirm this association and elucidate underlying pathophysiological mechanisms. PROSPERO REGISTRATION: CRD42019129643.

Testosterone, level of the lesion and age are independently associated with prostate volume in men with chronic spinal cord injury.

PURPOSE: Although men with spinal cord injury (SCI) exhibit a prostate volume significantly smaller compared to age-matched able-bodied men, the independent association of lower prostate volume with its putative determinants has never been analyzed in this population. This study was designed to identify variables independently associated with prostate volume in men with chronic SCI. METHODS: In this cross-sectional study, prostate volume of 138 men with chronic (> 1 years) SCI, aged 54.5 (25th-75th percentile: 36.0-66.0) years, was evaluated with trans-rectal ultrasonography. All patients underwent a complete neurological exam, as well as biochemical and hormonal assessment, including total testosterone (TT) levels. Free testosterone levels were calculated (cFT) by the Vermeulen formula. RESULTS: The median prostate volume was 23.4 mL. At the univariate analysis, a larger prostate volume was associated with higher TT (p = 0.00001) and cFT (p = 0.001), SCI level below T12 (p = 0.007), more advanced age (p = 0.04), lower body mass index (p = 0.04), higher functional independence score (p = 0.06), higher values of prostate-specific antigen (p = 0.12) and shorter duration of the injury (p = 0.21). However, at the multiple regression analyses, an independent and positive association only persisted between the prostate volume with either TT or cFT levels, and, to a lesser extent, with age and a level of spinal lesion below T12. A prostate volume below the median value was observed in 91.4% (32/35) of patients with both androgen deficiency (TT < 264 ng/dL) and spinal lesion level ≥ T12, but only in 16.5% (2/12) of patients with both normal androgen levels and spinal lesion level below T12 (p < 0.001). CONCLUSIONS: Our data indicate that lower testosterone levels and, to a lesser extent, a younger age and a spinal lesion level ≥ T12 represent the only variables exhibiting an independent association with a smaller prostate volume in men with SCI.

Metabolic syndrome is the key determinant of impaired vaginal lubrication in women with chronic spinal cord injury.

PURPOSE: Spinal cord injury (SCI) affects sexual health of both male and female, but little attention has been given to sexuality of SCI women. Similar to penile erection, vaginal lubrication represents a neurovascular event and then both denervation and vascular damage might contribute to its impairment. Nevertheless, the relative weight of lesion location/degree and vascular risk factors in determining hypolubrication in women with SCI has not yet been investigated. The aim of this study was to recognize among putative determinants of poor sexual arousal in women with SCI, neurogenic and vascular/metabolic independent predictors of vaginal hypolubrication. METHODS: Twenty-eight consecutive female patients admitted to a rehabilitation program because of chronic SCI (≥ 1 year) underwent clinical and biochemical evaluations, including assessment of vaginal lubrication by the Female Sexual Function Index (FSFI). As, in people with SCI, waist circumference overestimates visceral fat mass due to abdominal muscle paralysis, metabolic syndrome (MetS) was defined according to specific criteria proposed for SCI population: BMI ≥ 22 kg/m2 and two or more of the following: triglycerides ≥ 150 mg/dL (or actual treatment), HDL < 50 mg/dL, hypertension (or actual treatment), fasting glucose ≥ 100 mg/dL or diabetes mellitus type 2. RESULTS: A FSFI lubrication sub-score < 3.6, suggestive for impaired vaginal lubrication, was exhibited by 53.7% of the study population. When compared to the group with normal lubrication, a significantly higher proportion of these women had paraplegia (93.3% vs 38.5%, p = 0.003) and met the SCI-specific criteria for MetS (73.4% vs 7.6%, p = 0.0006), whereas, no significant differences were found between the two groups in the proportion of women exhibiting the single components of MetS. At the multiple logistic regression analysis, only the presence of MetS exhibited a significant independent association with impaired vaginal lubrication (OR = 3.1, 95% CI 1.2, 5.8, p = 0.01). CONCLUSIONS: In women with SCI, a clustering of modifiable vascular/metabolic risk factors, constituting the MetS, could contribute to sexual dysfunctions by affecting the vaginal lubrication, independently of the level of the spinal cord lesion.

Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis.

PURPOSE: Low testosterone (T) in Klinefelter's syndrome (KS) can contribute to typical features of the syndrome such as reduced bone mineral density, obesity, metabolic disturbances and increased cardiovascular risk. The aim of the present study is to review and meta-analyze all available information regarding possible differences in metabolic and bone homeostasis profile between T treated (TRT) or untreated KS and age-matched controls. METHODS: We conducted a random effect meta-analysis considering all the available data from observational or randomized controlled studies comparing TRT-treated and untreated KS and age-matched controls. Data were derived from an extensive MEDLINE, Embase, and Cochrane search. RESULTS: Out of 799 retrieved articles, 21 observational and 22 interventional studies were included in the study. Retrieved trials included 1144 KS subjects and 1284 healthy controls. Not-treated KS patients showed worse metabolic profiles (including higher fasting glycemia and HOMA index as well as reduced HDL-cholesterol and higher LDL-cholesterol) and body composition (higher body mass index and waist circumference) and reduced bone mineral density (BMD) when compared to age-matched controls. TRT in hypogonadal KS subjects was able to improve body composition and BMD at spinal levels but it was ineffective in ameliorating lipid and glycemic profile. Accordingly, TRT-treated KS subjects still present worse metabolic parameters when compared to age-matched controls. CONCLUSION: TRT outcomes observed in KS regarding BMD, body composition and glyco-metabolic control, are similar to those observed in male with hypogonadism not related to KS. Moreover, body composition and BMD are better in treated than untreated hypogonadal KS. Larger and longer randomized placebo-controlled trials are advisable to better confirm the present data, mainly derived from observational studies.

Prevalence of anti-sperm antibodies and relationship of degree of sperm auto-immunization to semen parameters and post-coital test outcome: a retrospective analysis of over 10 000 men.

STUDY QUESTION: What is the prevalence and the relationship of anti-sperm antibodies (ASA), screened by means of IgG-mixed anti-globulin reaction (MAR) test, to semen quality and post-coital test (PCT) outcome? SUMMARY ANSWER: A 100% positive IgG-MAR test, detected in 2% of the study population, was associated with lower sperm output and progressive motility, and was the sole determinant of higher prevalence of a negative PCT outcome. WHAT IS KNOWN ALREADY: Although ASA may affect sperm fertilizing ability and the IgG-MAR test is recommended by the World Health Organization (WHO) as an integral part of semen analysis for screening the occurrence of ASA, the prevalence and clinical relevance of positive MAR test results remain controversial. STUDY DESIGN, SIZE, DURATION: A retrospective analysis of 12 296 consecutive men who attended a university/hospital andrology clinic for the evaluation of fertility potential was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunological screening with the IgG-MAR test was performed on all ejaculates as an integral part of semen analysis. Positive samples (≥10%) were further tested for IgA-ASA. The prevalence of positive IgG-MAR tests results, along with the relationship of the degree of sperm auto-immunization to semen parameters and PCT outcome, were analyzed. MAIN RESULTS AND THE ROLE OF CHANCE: After excluding semen samples showing azoospermia or severe oligo-asthenozoospermia, the prevalence of a positive IgG-MAR test in the remaining 10 025 men was 4%, 3.4% and 2%, with 10%, 50% and 100% thresholds, respectively. The 100%-positive MAR tests exhibited significantly higher consistency over time, and were significantly associated with higher prevalence of a mixed pattern (i.e. when the majority of sperm exhibited beads attached on both the head and along the tail) of positivity as well as with the concomitant occurrence of IgA-ASA. Additionally, the 100%-positive MAR tests were significantly associated with a lower median value of the total number of spermatozoa and progressive motility, compared to samples with a lower degree of positivity or negative samples. In the PCT performed in 120 couples, where ASA were detected in the male partner, the 100%-positive MAR tests were significantly associated with a higher prevalence of negative PCT outcome, in comparison to the lower degree of positivity, independent of, and without any significant contribution from, other determinants (semen and cervical mucus quality). LIMITATIONS, REASONS FOR CAUTION: Only surrogate infertility-related end-points were analyzed in the present study. However, since the impairment of sperm penetration through the cervical mucus represents the primary mechanism of ASA-interference with fertility, PCT outcome may represent a suitable clinical end-point. WIDER IMPLICATIONS OF THE FINDINGS: The present study, being the largest reported to date, provides a reliable estimate of ASA prevalence. Moreover, it indicates that a 50%-positive MAR test, which is suggested by WHO as the clinically-relevant threshold, also includes patients with a degree of sperm auto-immunization that contributes to couple infertility only in the presence of other causal factors; conversely, the 100%-positive MAR test can represent the sole determinant of couple infertility, as it was the sole significant predictor of the highly prevalent negative PCT outcome. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the University of L'Aquila, Italy. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Can the positive association of osteocalcin with testosterone be unmasked when the preeminent hypothalamic-pituitary regulation of testosterone production is impaired? The model of spinal cord injury.

PURPOSE: Osteocalcin (OCN), released from the bone matrix during the resorption phase, in its undercarboxylated form, stimulates testosterone (T) biosynthesis in mouse and a loss-of-function mutation of its receptor was associated with hypergonadotropic hypogonadism in humans. Nevertheless, when population-based studies have explored the OCN-T association, conflicting results have been reported. Hypothesizing that the evidence of a positive association between OCN and T could have been hindered by the preeminent role of a well-functioning hypothalamus-pituitary axis in promoting T biosynthesis, we explored this association in men with chronic spinal cord injury (SCI), exhibiting high prevalence of non-hypergonadotropic androgen deficiency. METHODS: Fifty-five consecutive men with chronic SCI underwent clinical/biochemical evaluations, including measurements of total T (TT), OCN and 25(OH)D levels. Free T (FT) levels were calculated by the Vermeulen formula. Comorbidity was scored by Charlson comorbidity index (CCI). RESULTS: A biochemical androgen deficiency (TT < 300 ng/dL) was observed in 15 patients (27.3%). TT was positively correlated with OCN, 25(OH)D and leisure time physical activity and negatively correlated with age, BMI and CCI. OCN was also positively correlated with calculated FT and negatively correlated with BMI and HOMA-IR. At the multiple linear regression analyses, a positive association of OCN with TT and calculated FT persisted after adjustment for confounders. CONCLUSIONS: The positive association here found between OCN and T levels in men with chronic SCI reinforces the notion that a bone-testis axis is also functioning in humans and suggests that it can be unmasked when the preeminent hypothalamic-pituitary regulation of T production is impaired.

Left spermatic vein reflux after varicocele repair predicts pregnancies and live births in subfertile couples.

PURPOSE: Varicocele repair (VR) is proposed to improve fertility in subfertile couples with a poor semen quality. We explored whether the disappearance of a left continuous spermatic venous reflux (SVR) at scrotal colour-Doppler ultrasound (CDUS), an objective evidence for a VR, is predictive for improved fertility outcome in subfertile couples. METHODS: VR was performed by left internal spermatic vein sclero-embolisation in 88 males seeking a consultation for subfertility. Semen analysis and scrotal CDUS were evaluated before and 6 months after VR. Serum levels of FSH and total testosterone (TT) were obtained at baseline. Telephone interview was used to obtain information about fertility outcome. Significant predictors of pregnancy and live births, selected by univariate analyses, were included into multiple logistic regression models to assess independent associations. RESULTS: At the adjusted model, independent significant predictors of pregnancy after VR were a disappeared SVR at CDUS (OR = 5.5, 97.5% CI 2.01-15.4; p = 0.0009) and an improved sperm total motile count (TMC) (OR = 5.5, 97.5% CI 1.4-27.9; p = 0.02). Even live births were independently associated with both disappeared left SVR at CDUS (OR = 4.3, 97.5% CI = 1.6-11.8; p = 0.003) and improved TMC after VR (OR = 4.8, 97.5% CI 1.3-24.2; p = 0.02). CONCLUSION: The still controversial effect of varicocele repair on fertility in subfertile couples may reside on the undefined objective methods to document a successful VR and its effect on couple fertility. The disappearance of a continuous left SVR at CDUS after VR was the objective best predictor for subsequent improved fertility in subfertile couples.

Determination of spermatic vein reflux after varicocele repair helps to define the efficacy of treatment in improving sperm parameters of subfertile men.

PURPOSE: A continuous spermatic venous reflux (SVR) at colour Doppler ultrasound (CDU) is an evidence for varicocele, a frequent correlate for male subfertility. We explored whether SVR after left varicocele repair is predictive for changes in semen quality in subfertile men. METHODS: Blood hormones (FSH, LH, and total testosterone) and scrotal CDU were obtained in subfertile patients with left grade II or grade III varicocele on physical evaluation and a poor sperm quality. Semen analysis and CDU were re-evaluated 6 months after a retrograde internal spermatic vein scleroembolisation. RESULTS: The retrospective study included 100 men with a baseline SVR >3 cm/s; 60 men showed a disappearance (group 1) and 40 men (group 2) showed a reduced SVR after varicocele repair. Total motile sperm count (TMC) was markedly increased after treatment (p < 0.0001; F = 35.79) and the increase was more relevant in group 1 compared to group 2 (p = 0.04; F = 4.20). TMC and left SVR values after varicocele repair were negatively correlated (R = -0.218; p = 0.035). Multivariate analysis showed that adjusted SVR after repair negatively predicted TMC change (TMC after repair minus baseline TMC) (ß = -2.56; p = 0.022). Disappearance of a continuous left SVR at CDU after varicocele repair was associated to a better improvement of semen parameters in subfertile men. CONCLUSION: Recording of a continuous left spermatic vein reflux is an objective method to assess a successful varicocele repair aimed to improve sperm parameters in subfertile men.

Sperm forward motility is negatively affected by short-term exposure to altitude hypoxia.

Human exposure to altitude is a model to study the role of oxygen in different areas of physiology and pathophysiology. The aim of this study was to evaluate whether a short exposure to hypoxia (5 days) combined with exercise, at altitude ranging from 900 m above sea level to 5895 m above sea level (Kilimanjaro Expedition) can modify seminal and reproductive hormonal parameter levels in human beings. During the ascent, blood oxygen saturation at 3.848 m above sea level was found to be decreased when compared to sea level (P < 0.02). The sperm forward motility at sea level after the expedition showed a significant reduction ​​(P < 0.02). There were no changes in other seminal parameters among those compared. Determination of the hormonal plasma concentrations showed that baseline values of follicle-stimulating hormone, total testosterone, prolactin and oestradiol were unchanged at sea level after the hypoxic experience, with respect to baseline values at sea level. On the other hand, luteinising hormone levels after altitudes trekking significantly increased compared to levels before the expedition (P < 0.05). Because of the short-term exposure, we can assume that the reduced forward motility described here may result from the effects of the acute altitude hypoxia on spermatozoa during the epididymal transit where they mature acquiring their motility.

Outcomes of androgen replacement therapy in adult male hypogonadism: recommendations from the Italian society of endocrinology.

OBJECTIVE: We developed clinical practice guidelines to assess the individual risk-benefit profile of androgen replacement therapy in adult male hypogonadism (HG), defined by the presence of specific signs and symptoms and serum testosterone (T) below 12 nmol/L. PARTICIPANTS: The task force consisted of eight clinicians experienced in treating HG, selected by the Italian Society of Endocrinology (SIE). The authors received no corporate funding or remuneration. CONSENSUS PROCESS: Consensus was guided by a systematic review of controlled trials conducted on men with a mean T < 12 nmol/L and by interactive discussions. The guidelines were reviewed and sequentially approved by the SIE Guidelines Commission and Executive Committee. CONCLUSIONS: We recommend T supplementation (TS) for adult men with severely reduced T levels (T < 8 nmol/L) to improve body composition and sexual function. We suggest that TS be offered to subjects with T < 12 nmol/L to improve glycaemic control, lipid profile, sexual function, bone mineral density, muscle mass and depressive symptoms, once major contraindications have been ruled out. We suggest that lifestyle changes and other available interventions (e.g. for erectile dysfunction) be suggested prior to TS. We suggest that TS should be combined with currently available treatments for individuals at high risk for complications, such as those with osteoporosis and/or metabolic disorders. We recommend against using TS to improve cardiac outcome and limited mobility. We recommend against using TS in men with prostate cancer, unstable cardiovascular conditions or elevated haematocrit. The task force places a high value on the timely treatment of younger and middle-aged subjects to prevent the long-term consequences of hypoandrogenism.

Embolization of left spermatic vein in non-obstructive azoospermic men with varicocele: role of FSH to predict the appearance of ejaculated spermatozoa after treatment.

PURPOSE: Varicocele repair in non-obstructive azoospermia (NOA) was occasionally associated to ejaculated spermatozoa independently from clinical and laboratory measures. We performed a prospective study in infertile men affected by NOA and left side varicocele to find whether or not the appearance of ejaculated spermatozoa after varicocele repair is predicted by baseline measures. METHODS: Patients with NOA and grade II, or grade III left side varicocele were submitted to hormone analysis and to scrotal color Doppler ultrasound (CDU). Azoospermia was confirmed in 23 patients aged 25-47 years who were than submitted to varicocele repair through a retrograde internal spermatic vein embolization. Patients were re-evaluated after 6 months. RESULTS: Six months after varicocele repair 12 patients (52.2 %) were still azoospermic (Group 1) while 11 patients (47.8 %) reported ejaculated spermatozoa (Group 2) [sperm count: 1.3 × 10(6)/mL; 0.5 × 10(6)/mL-1.6 × 10(6)/mL (median 25th-75th centiles)]. Serum baseline FSH was lower in Group 2 compared to Group 1 (p = 0.012), while no differences between groups were revealed for all other clinical and laboratory parameters. ROC analysis indicated that baseline FSH level predicted the appearance of ejaculated spermatozoa after treatment [AUC = 0.811; 95 % Confidence Interval (CI) 0.6-0.9; p = 0.0029]. A cut-off level of FSH <10.06 mIU/mL identified 82.0 % of cases with ejaculated spermatozoa with a specificity of 81.8 % and a sensitivity of 83.3 %. CONCLUSION: Selected patients with NOA may show ejaculated spermatozoa after a non-invasive repair of a left side varicocele, therefore avoiding testicular sperm extraction. Baseline serum FSH was a valuable predictor for ejaculated spermatozoa after treatment.

Ultrasonographic caput epididymis diameter is reduced in non-obstructive azoospermia compared with normozoospermia but is not predictive for successful sperm retrieval after TESE.

STUDY QUESTION: Is the ultrasonographic determination of the caput epididymis diameter predictive for sperm retrieval after testicular sperm extraction (TESE) in non-obstructive azoospermia (NOA)? SUMMARY ANSWER: Ultrasonographic determination of the caput epididymis diameter did not give any relevant clinical information in NOA and was not predictive for positive sperm retrieval after TESE. WHAT IS KNOWN ALREADY: The diameter of the caput epididymis in ultrasonography (US) has a diagnostic relevance in azoospermic men to correctly identify obstructive azoospermia; however, its clinical value in NOA is not yet determined. STUDY DESIGN, SIZE, DURATION: We performed a retrospective study of 100 azoospermic and 160 normozoospermic men attending a university infertility clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were submitted to scrotal US to determine the mean value of bilateral testicular volumes (ml), the bilateral longitudinal caput diameter (mm) and the antero-posterior diameter of the corpus (mm) epididymis. The number of spermatozoa retrieved after TESE and the testicular histology of azoospermic men was obtained and the percentage of seminiferous tubules with elongated spermatids (%T) was used to classify cases with normal spermatogenesis (obstructive azoospermia) (OA) (n = 20; %T ≥ 80) or with NOA (n = 80; %T < 70). MAIN RESULTS AND THE ROLE OF CHANCE: The US testes volumes and caput diameters were reduced (P < 0.05) in NOA compared with OA and with normozoospermia, but the corpus values were not different. The caput diameter in the side submitted to biopsy was significantly reduced when germinal epithelium was absent (Sertoli cell only) (P < 0.05) and the lowest value of caput diameter was observed when the seminiferous epithelium and tubule lumen were absent (testicular hyalinosis). On the contrary, a total arrest of spermatogenesis at the first meiosis level, or a defect of spermiogenesis resulting in scattered elongated spermatids in each tubule, did not show a reduced diameter of caput epididymis compared with normozoospermia. The caput diameter did not show any difference between NOA patients with or without successful sperm retrieval at TESE. On the contrary testicular volume was significantly reduced in NOA patients with no sperm retrieval (P = 0.0037). The caput diameter was not correlated with the number of retrieved sperm, the serum level of follicle stimulating hormone, or with the percentage of tubules with elongated spermatids at histological analysis. LIMITATIONS, REASONS FOR CAUTION: The aetiology of NOA was not included in the statistical analysis due to the low rate of cases with a specific aetiology for a testicular failure. Larger studies should exclude the possibility that besides testicular histology, aetiology of NOA might influence the diameter of caput epididymis. Moreover, whether a reduced diameter of caput epididymis is only a result of a testicular pathologic phenotype or whether it may underscore a primitive dysfunction influencing the number of ejaculated spermatozoa is not yet determined. WIDER IMPLICATIONS OF THE FINDINGS: We reported that US diameter of the caput epididymis is reduced in cases of NOA but, in contrast with the testicular volume, it is independent of the completion of spermatogenesis and subsequent presence of spermatozoa in the epididymis. Therefore ultrasonographic determination of caput epididymis diameter is not predictive for positive sperm retrieval after TESE in cases of a primitive testicular failure. Our novel findings may help to define which reproducible parameters of scrotal US should be assessed in the work-up of male infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Ministero dell'Università e Ricerca (I) PRIN 2009. The authors declare no competing interest.

Serum from patients with erectile dysfunction inhibits circulating angiogenic cells from healthy men: relationship with cardiovascular risk, endothelial damage and circulating angiogenic modulators.

Erectile dysfunction (ED) is an early manifestation of arteriosclerosis associated with endothelial damage/dysfunction and to a blunted ability of cultured mononuclear circulating cells (MNCs) to differentiate circulating angiogenic cells (CACs), putatively involved in endothelial damage repair. Here we explored effects of human serum (HS) from patients with ED and cardiovascular risk factors (VRFs) but no clinical atherosclerosis, on cultured MNCs of healthy men to differentiate CACs and to form colonies. Effect of HS on number of CACS and of colony forming units (CFUs) was correlated with circulating markers of endothelial damage and with angiogenic modulators. MNCs from healthy men were cultured in standard conditions or with 20% HS from 35 patients with ED and from 10 healthy men. CACs were identified after 7 days of culture by uptake of acetylated low-density lipoprotein with concomitant binding of Ulex europaeus agglutinin I. CFUs were counted after 5 days of culture. Enzyme-linked immunosorbent assays assessed plasmatic soluble (s) form of E-selectin, Endothelin (ET)-1, tissue type plasminogen activator (tPA), vascular endothelial growth factor (VEGF)(165) and sVEGF receptor (R)-1. The number of CACs and of CFUs from healthy men was reduced after culturing MNCs with HS compared to standard medium. The inhibitory effect was significantly higher with HS from ED patients with higher or lower VRF exposure compared to healthy men. Inhibition was positively correlated with VRFs exposure, with ED severity, with common carotid artery intima media thickness measured using B-mode ultrasound, and to a lesser extent with plasmatic sE-Selectin, sET-1 and sVEGFR-1. Dysfunction of cells involved in vascular homoeostasis is induced by soluble factors still unknown and already present in a very initial systemic vascular disease in men with ED and VRFs.

Relationship of Vitamin D status with testosterone levels: a systematic review and meta-analysis.

PURPOSE: Despite a biological plausibility of a direct link between low vitamin D and androgen deficiency, the association remains inconclusive in epidemiological studies. Therefore, this systematic review and meta-analysis of case-control studies aim to assess whether and in what populations such an association can be demonstrated. METHODS: A systematic search was performed in PubMed, EMBASE, Cochrane Library, Web of science, Science Direct, and CINAHL. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) in total testosterone (TT) levels between men with 25-hydroxyvitamin D (25(OH)D) <20 and ≥20 ng/mL were combined using random-effects models. Funnel plot and trim-and-fill analysis were used to assess publication bias. Heterogeneity source was explored by a sub-group analysis according to health-related characteristics of the study populations. RESULTS: Eighteen included studies collectively gave information on 9892 men with vitamin D deficiency and 10,675 controls. The pooled SMD revealed a slight, albeit just significant, positive association between 25(OH)D and TT (pooled SMD: -0.23, 95% CI: -0.45 to -0.01; P = 0.04) with a large between-study heterogeneity (I2 = 98%, Pfor heterogeneity < 0.00001). At the sub-group analysis, a significant positive association, along with noticeable decrease in heterogeneity, could only be demonstrated in studies of patients with frailty states (pooled SMD: -0.19; 95% CI: -0.27, -0.10, P < 0.0001; I2 = 51%, Pfor heterogeneity = 0.06). A sensitivity analysis revealed a high stability of the result and the trim-and-fill adjustment for publication bias did not affect pooled estimate. CONCLUSIONS: Both hypovitaminosis D and androgen deficiency should be regarded as markers of a poor health status, sharing common underlying aetiologies and risk factors.