Canary in the Coal Mine? Male Infertility as a Marker of Overall Health.

Male factor infertility is a common problem. Evidence is emerging regarding the spectrum of systemic disease and illness harbored by infertile men who otherwise appear healthy. In this review, we present evidence that infertile men have poor overall health and increased morbidity and mortality, increased rates of both genitourinary and non-genitourinary malignancy, and greater risks of systemic disease. The review also highlights numerous genetic conditions associated with male infertility as well as emerging translational evidence of genitourinary birth defects and their impact on male infertility. Finally, parallels to the overall health of infertile women are presented. This review highlights the importance of a comprehensive health evaluation of men who present for an infertility assessment.

Male factor infertility and risk of death: a nationwide record-linkage study.

STUDY QUESTION: What is the risk of death among men with oligospermia, unspecified male factor and azoospermia in the years following fertility treatment? SUMMARY ANSWER: No significantly elevated risk was observed among men with oligospermia and unspecified male factor, while an increased risk was found among men with azoospermia. WHAT IS KNOWN ALREADY: Previous studies have shown associations between male factor infertility and risk of death, but these studies have relied on internal reference groups and the risk of death according to type of male infertility is not well characterized. STUDY DESIGN, SIZE, DURATION: In this prospective record-linkage cohort study, we identified men who had undergone medically assisted reproduction (MAR) between 1994 and 2015. Data was linked to the Danish causes of death register and sociodemographic registers through personal identification numbers assigned to all Danish citizens at birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men that had undergone MAR in Denmark (MAR Cohort; n = 64 563) were identified from the Danish IVF register, which includes data on whether infertility was due to male factor. For each man in the MAR cohort, five age-matched men who became fathers without fertility treatment were selected from the general population (non-MAR fathers; n = 322 108). Men that could not adequately be tracked in the Danish CPR register (n = 1259) and those that were censored prior to study entry (n = 993) were excluded, leaving a final population of 384 419 men. Risk of death was calculated by Cox regression analysis with age as an underlying timeline and adjustments for educational attainment, civil status and year of study entry. The risk of death was compared among men with and without male factor infertility identified from the IVF register (internal comparisons) as well as to the non-MAR fathers (external comparison). MAIN RESULTS AND THE ROLE OF CHANCE: The risk of death between the MAR cohort (all men, regardless of infertility) and the non-MAR fathers was comparable [hazard ratio (HR), 1.07; 95% CI, 0.98-1.15]. When the MAR cohort was limited to infertile men, these men were at increased risk of death [HR, 1.27; 95% CI, 1.12-1.44]. However, when stratified by type of male factor infertility, men with azoospermia had the highest risk of death, which persisted when in both the internal [HR, 2.30; 95% CI, 1.54-3.41] and external comparison [HR, 3.32; 95% CI, 2.02-5.40]. No significantly elevated risk of death was observed among men with oligospermia [HR, 1.14; 95% CI, 0.87-1.50] and unspecified male factor [HR, 1.10; 95% CI, 0.75-1.61] compared with the non-MAR fathers. The same trends were observed for the internal comparison. LIMITATIONS, REASONS FOR CAUTION: Duration of the follow-up was limited and there is limited generalizability to infertile men who do not seek fertility treatment. WIDER IMPLICATIONS OF THE FINDINGS: Using national health registers, we found an increased risk of death among azoospermic men while no increased risk was found among men with other types of infertility. For the azoospermic men, further insight into causal pathways is needed to identify options for monitoring and prevention. STUDY FUNDING/COMPETING INTEREST(S): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. C.G.'s research stay at Stanford was funded by grants from the University of Copenhagen, Kong Christian den Tiendes Fond, Torben og Alice Frimodt Fond and Julie Von Müllen Fond. M.E. is an advisor for Sandstone and Dadi. All other authors declare no conflict of interests. TRIAL REGISTRATION NUMBER: Not relevant.

Semen quality, infertility and mortality in the USA.

STUDY QUESTION: What is the relationship between semen parameters and mortality in men evaluated for infertility? SUMMARY ANSWER: Among men undergoing an infertility evaluation, those with abnormal semen parameters have a higher risk of death, suggesting a possible common etiology between infertility and mortality. WHAT IS KNOWN ALREADY: Conflicting data exist that suggest either an inverse relationship or no relationship between semen quality and mortality. STUDY DESIGN, SIZE, DURATION: A study cohort was identified from two centers, each specializing in infertility care. In California, we identified men with data from 1994 to 2011 in the Stanford Reproductive Endocrinology and Infertility semen database. In Texas, we identified men with data from 1989 to 2009 contained in the andrology database at the Baylor College of Medicine Special Procedures Laboratory who were evaluated for infertility. Mortality was determined by data linkage to the National Death Index or Social Security Death Index. Comorbidity was estimated based on calculation of the Charlson Comorbidity Index or Centers for Medicare & Medicaid Services-Hierarchical Condition Categories Model. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all, 11,935 men were evaluated for infertility from 1989 to 2011. During 92 104 person years of follow-up, 69 of 11,935 men died (0.58%). The mean age at infertility evaluation was 36.6 years with a mean follow-up of 7.7 years. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with the general population, men evaluated for infertility had a lower risk of death with 69 deaths observed compared with 176.7 expected (Standardized mortality rate 0.39, 95% CI 0.30-0.49). When stratified by semen parameters, however, men with impaired semen parameters (i.e. male factor infertility) had significantly higher mortality rates compared with men with normal parameters (i.e. no male factor infertility). Low semen volume, sperm concentration, sperm motility, total sperm count and total motile sperm count were all associated with higher risk of death. In contrast, abnormal sperm morphology was not associated with mortality. While adjusting for current health status attenuated the association between semen parameters and mortality, men with two or more abnormal semen parameters still had a 2.3-fold higher risk of death compared with men with normal semen (95% CI 1.12-4.65). LIMITATIONS, REASONS FOR CAUTION: Our cohort represents infertile men, which may limit generalizability. As comorbidity relied on administrative data, granular information on each man regarding infertility diagnosis and lifestyle factors was unavailable. WIDER IMPLICATIONS OF THE FINDINGS: Men with impaired semen parameters have an increased mortality rate in the years following an infertility evaluation suggesting semen quality may provide a marker of health. STUDY FUNDING/COMPETING INTEREST(S): This study is supported in part by P01HD36289 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health (to D.J.L. and L.I.L.). The project was also partially supported by an NIH CTSA award number UL1 RR025744. None of the authors has any conflict of interest to declare.

Increased risk for prostate cancer related mortality among childless men in a population-based cohort followed for up to 40 years.

Based on a nationwide register data we recently reported a link between male infertility and increased risk of early onset prostate cancer. However, mortality due to prostate cancer, which can be regarded as the ultimate proxy for its clinical significance, especially in the context of over-diagnosis and over-treatment, could not be explored in the previous study, since the follow-up period in most cases was too short. Data therefore must be retrieved from other cohorts, with longer follow-up. We sourced data from a population-based prospective cohort including 11,343 men aged over 45 years, enrolled in the 1970s. The results showed that childless men have higher risk for prostate cancer related mortality (HR: 1.49, 95% CI: 1.09-2.03, p = 0.01) compared to men with children, in particular when only married men, who most probably are involuntary childless, were considered (HR 1.54, 95% CI 1.13 - 2.10, p = 0.006). However, the prostate cancer incidence did not differ (HR = 1.04, 95% CI: 0.88-1.24). In conclusion, our results show that childless men are at higher risk for dying from prostate cancer, probably due to a more aggressive form of the disease.

Good semen quality and life expectancy: a cohort study of 43,277 men.

Fertility status may predict later mortality, but no studies have examined the effect of semen quality on subsequent mortality. Men referred to the Copenhagen Sperm Analysis Laboratory by general practitioners and urologists from 1963 to 2001 were, through a unique personal identification number, linked to the Danish central registers that hold information on all cases of cancer, causes of death, and number of children in the Danish population. The men were followed until December 31, 2001, death, or censoring, whichever occurred first, and the total mortality and cause-specific mortality of the cohort were compared with those of all age-standardized Danish men or according to semen characteristics. Among 43,277 men without azospermia referred for infertility problems, mortality decreased as the sperm concentration increased up to a threshold of 40 million/mL. As the percentages of motile and morphologically normal spermatozoa and semen volume increased, mortality decreased in a dose-response manner (P(trend) < 0.05). The decrease in mortality among men with good semen quality was due to a decrease in a wide range of diseases and was found among men both with and without children; therefore, the decrease in mortality could not be attributed solely to lifestyle and/or social factors. Semen quality may therefore be a fundamental biomarker of overall male health.

Neonatal outcomes after early rescue intracytoplasmic sperm injection: an analysis of a 5-year period.

OBJECTIVE: To evaluate the safety and efficacy of early rescue intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective cohort study. SETTING: Teaching hospital. PATIENT(S): There were 13,232 ovarian stimulation cycles (IVF, n = 9,631; ICSI, n = 2,871; early rescue ICSI, n = 730) that resulted in the delivery of 5,001 babies (IVF, n = 3,670; ICSI, n = 1,095; early rescue ICSI, n = 246) from August 2008 to August 2013. INTERVENTION(S): Early rescue ICSI. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates, neonatal outcomes, and congenital birth defects were analyzed. RESULT(S): The early rescue ICSI cycles did not seem to have a negative effect on the clinical pregnancy rate (43.42%) when IVF cycles (45.33%) were compared with ICSI cycles (44.39%). In the early rescue ICSI group, a total of 254 clinical pregnancies were achieved: 197 (33.67%) live births, 38 (6.49%) miscarriages, 2 (0.79%) induced abortions, 3 (1.18%) fetal deaths, and 4 pregnancies (1.57%) without completion at follow-up. Overall, the multiple gestations, the delivery method, mean gestational age, preterm deliveries, mean birth weight, and rate of congenital birth defects of the early rescue ICSI group were similar to those in the conventional IVF and ICSI groups. CONCLUSION(S): Early rescue ICSI had similar clinical pregnancy rates when compared with conventional IVF and ICSI, in addition to the delivery of healthy children. The clinical evidence from the early rescue ICSI group did not show an elevated rate of malformations. Early rescue ICSI seems to be a safe alternative method for individuals with total fertilization failure or near total fertilization failure when compared with conventional IVF treatment.

Prognostic parameters in adult impalpable ultrasonographic lesions of the testicle.

PURPOSE: Through an analysis of individual published data we assessed whether prognostic criteria exist for adult impalpable testicular sonographic lesions. MATERIALS AND METHODS: We performed a bibliographic search on PubMed, MEDLINE, EMBASE online databases from 1990 to May 2004 using search words such as sonographic lesions of the testicle, impalpable tumors of the testicle and impalpable testicular lesions. Six articles were found that presented a description of the histological characteristics, patient age, lesion dimensions, presence of cryptorchidism and association with tumors in other parts of the body. A multivariate analysis was performed comparing the characteristics that appeared more interesting from a univariate analysis. RESULTS: The characteristics of the 48 impalpable sonographic lesions were examined. Histologically 15 of the lesions were Leydig cell tumors (31%), 12 (25%) seminomas, 7 (14.5%) nonseminomatous germ cell tumors, 2 (4.5%) Sertoli cell tumors, 12 (25%) benign forms (fibrosis, infarct, lipoma, mesothelial hyperplasia, adenomatoid tumor). The average age was 37.5, average dimension was 10.11 mm. The lesions were hypoechoic in 85% of the cases. Of the patients 31% were infertile. Multivariate analysis showed that histological data were correlated with lesion dimensions and presence of infertility. Dimension was particularly related to germ cell tumors (for dimensions between 16 and 32 mm relative risk ratio [RRR] = 13.97, p=0.0449). Infertility proved significant in defining stromal tumors (RRR = 9,681, p=0.022) CONCLUSIONS: Although with the limits of a retrospective study consisting in an analysis of individual data, interesting correlations between malignant pathologies and the initial characteristics of impalpable sonographic lesions were revealed. In particular an interesting correlation was found between the dimensions of the lesion and the malignant pathology and between Leydig cell tumor and infertility.

Autocrine deactivation of macrophages in transgenic mice constitutively overexpressing IL-10 under control of the human CD68 promoter.

IL-10 plays an essential role in blocking cytokine production by activated macrophages. To analyze the consequences of enforced expression of IL-10 by macrophages on innate and adaptive immune responses, we generated transgenic mice (macIL-10tg mice) expressing an epitope-tagged IL-10 (Flag-IL-10) under control of the human CD68 promoter. Expression of Flag-IL-10 was constitutive and restricted to macrophages, as shown by sorting splenocyte cell populations and intracellular staining for IL-10. Transgenic macrophages displayed suppressed production of TNF-alpha and IL-12 upon stimulation with LPS. When macIL-10tg mice were challenged with LPS, serum levels of proinflammatory cytokines were attenuated compared with controls. Infection with Mycobacterium bovis bacille Calmette-Guérin resulted in approximately 10-fold-higher bacterial loads than in wild-type mice. Normal T and B cell responses were observed in macIL-10tg mice, suggesting that macrophage-specific overexpression of IL-10 predominantly acts in an autocrine/paracrine manner, resulting in chronically deactivated macrophages that manifest an impaired ability to control pathogens.