Cryptorchidism is the most frequent congenital birth defect in male children (2–4% in full-term male births), and it has the potential to impact the health of the human male. In fact, although it is often considered a mild malformation, it represents the best-characterized risk factor for reduced fertility and testicular cancer. Furthermore, some reports have highlighted a significant increase in the prevalence of cryptorchidism over the last few decades. Etiology of cryptorchidism remains for the most part unknown, and cryptorchidism itself might be considered a complex disease. Major regulators of testicular descent from intraabdominal location into the bottom of the scrotum are the Leydig-cell-derived hormones testosterone and insulin-like factor 3. Research on possible genetic causes of cryptorchidism has increased recently. Abundant animal evidence supports a genetic cause, whereas the genetic contribution to human cryptorchidism is being elucidated only recently. Mutations in the gene for insulin-like factor 3 and its receptor and in the androgen receptor gene have been recognized as causes of cryptorchidism in some cases, but some chromosomal alterations, above all the Klinefelter syndrome, are also frequently involved. Environmental factors acting as endocrine disruptors of testicular descent might also contribute to the etiology of cryptorchidism and its increased incidence in recent years. Furthermore, polymorphisms in different genes have recently been investigated as contributing risk factors for cryptorchidism, alone or by influencing susceptibility to endocrine disruptors. Obviously, the interaction of environmental and genetic factors is fundamental, and many aspects have been clarified only recently.

What are the effects of continuous sauna exposure on seminal parameters, sperm chromatin, sperm apoptosis and expression of genes involved in heat stress and hypoxia? Scrotal hyperthermia by exposure to sauna can induce a significant alteration of spermatogenesis. Several authors have evidenced that high temperature has dramatic effects on spermatogenesis. A longitudinal time-course study. Data from 10 subjects exposed to Finnish sauna were collected before sauna (T0), after3 months of sauna sessions (T1) and after 3 (T2) and 6 months (T3) from the end of sauna exposure. Ten normozoospermic volunteers underwent two sauna sessions per week for 3 months, at 80–90°C, each lasting 15 min. Sex hormones, sperm parameters, sperm chromatin structure, sperm apoptosis and expression of genes involved in heat stress and hypoxia were evaluated at the start, at the end of sauna exposure and after 3 and 6 months from sauna discontinuation. Student's t-test for paired data was used for statistical analysis. At the end of sauna exposure, we found a strong impairment of sperm count and motility (P < 0.001), while no significant change in sex hormones was present. Decreases in the percentage of sperm with normal histone-protamine substitution (78.7 ± 4.5 versus 69.0 ± 4.1), chromatin condensation (70.7 ± 4.7 versus 63.6 ± 3.3) and mitochondrial function (76.8 ± 4.9 versus 54.0 ± 6.1) were also evident at T1, and strong parallel up-regulation of genes involved in response to heat stress and hypoxia was found. All these effects were completely reversed at T3. Absence of subjects with abnormal sperm parameters was the major limitation of this study. Our data demonstrated for the first time that in normozoospermic subjects, sauna exposure induces a significant but reversible impairment of spermatogenesis, including alteration of sperm parameters, mitochondrial function and sperm DNA packaging. The large use of Finnish sauna in Nordic countries and its growing use in other parts of the world make it important to consider the impact of this lifestyle choice on men's fertility. No external funding was sought for this study and the authors have no conflict of interest to declare.

Background: Considerable attention has been paid to perfluoroalkyl compounds (PFCs) because of their worldwide presence in humans, wildlife, and environment. A wide variety of toxicological effects is well supported in animals, including testicular toxicity and male infertility. For these reasons, the understanding of epidemiological associations and of the molecular mechanisms involved in the endocrine-disrupting properties of PFCs on human reproductive health is a major concern.Objective: To investigate the relationship between PFC exposure and male reproductive health.Design: This study was performed within a screening protocol to evaluate male reproductive health in high schools.Patients: This is a cross-sectional study on 212 exposed males from the Veneto region, one of the four areas worldwide heavily polluted with PFCs, and 171 nonexposed controls.Main Outcome Measures: Anthropometrics, seminal parameters, and sex hormones were measured in young males from exposed areas compared with age-matched controls. We also performed biochemical studies in established experimental models.Results: We found that increased levels of PFCs in plasma and seminal fluid positively correlate with circulating testosterone (T) and with a reduction of semen quality, testicular volume, penile length, and anogenital distance. Experimental evidence points toward an antagonistic action of perfluorooctanoic acid on the binding of T to androgen receptor (AR) in a gene reporter assay, a competition assay on an AR-coated surface plasmon resonance chip, and an AR nuclear translocation assay.Discussion: This study documents that PFCs have a substantial impact on human health as they interfere with hormonal pathways, potentially leading to male infertility.

Background: Complete deletions of the AZFc region in distal Yq are the most frequent molecular genetic cause of severe male infertility. They are caused by intrachromosomal homologous recombination between amplicons—large, nearly identical repeats—and are found in 5–10% of cases of azoospermia and severe oligozoospermia. Homologous recombination may also generate different partial deletions of AZFc, but their contribution to spermatogenic impairment has not been confirmed. Methods: In this study we analysed the prevalence and characteristics of different partial AZFc deletions and their association with spermatogenic failure. We studied 337 infertile men with different spermatogenic impairment and 263 normozoospermic fertile men using AZFc specific sequence tagged site markers and DAZ specific single nucleotide variants. Results: We identified 18 cases of partial AZFc deletions in the infertile group (5.3%) and one case in the control group (0.4%). Seventeen deletions had the “gr/gr” pattern, one the “b2/b3” pattern, and one represented a novel deletion with breakpoints in b3 and b4 amplicons. Partial AZFc deletions were associated with different spermatogenic phenotypes ranging from complete azoospermia to only moderate oligozoospermia. Conclusions: Together with published data, our analysis of DAZ gene copy suggested that the contribution of the different deletions to male infertility varies: only partial AZFc deletions removing DAZ1/DAZ2 seem to be associated with spermatogenic impairment, whereas those removing DAZ3/DAZ4 may have no or little effect on fertility. These data show that, beside complete AZFc deletions, specific partial deletions represent a risk factor for male infertility, even if with different effect on spermatogenesis.

Insulin-like factor 3 (INSL3) is a member of the relaxin-insulin family, and it is expressed in pre- and postnatal Leydig cells of the testis. This peptide affects testicular descent during embryonic development, and mutations in INSL3 gene or its receptor LGR8 (leucine-rich repeat-containing G protein-coupled receptor 8)/GREAT (G protein-coupled receptor affecting testicular descent) cause cryptorchidism in humans. The expression of LGR8/GREAT in different tissues and the production of INSL3 also by adult-type Leydig cells suggest additional roles of this hormonal system in adulthood. In this preliminary report we performed the first analysis in humans of INSL3 using a novel RIA kit to measure INSL3 concentrations in serum of normal men and with different testicular pathologies. The results show that INSL3 is circulating in adult men, and it is almost exclusively of testicular origin. Subjects with severe testicular damage, such as men with severe infertility, produce low amount of INSL3, and the concentrations of this hormone seem to reflect the functional status of the Leydig cells. In particular, INSL3 concentrations may be an even more sensitive marker of Leydig cell function than testosterone itself. Analysis of men treated with different combinations of hormones of the hypothalamus-pituitary-testis axis suggests that the production of INSL3 is related to LH in a manner similar to that of the LH-testosterone axis.