Over the past two decades, public health has focused on the identification of environmental chemical factors that are able to adversely affect hormonal function, known as endocrine disruptors (EDs). ...EDs mimic naturally occurring hormones like estrogens and androgens which can in turn interfere with the endocrine system. As a consequence, EDs affect human reproduction as well as post and pre-natal development. In fact, infants can be affected already at prenatal level due to maternal exposure to EDs. In particular, great attention has been given to those chemicals, or their metabolites, that have estrogenic properties or antagonistic effects on the activity of androgen or even inhibiting their production. These compounds have therefore the potential of interfering with important physiological processes, such as masculinization, morphological development of the urogenital system and secondary sexual traits. Animal and in vitro studies have supported the conclusion that endocrine-disrupting chemicals affect the hormone-dependent pathways responsible for male gonadal development, either through direct interaction with hormone receptors or via epigenetic and cell-cycle regulatory modes of action. In human populations, epidemiological studies have reported an overall decline of male fertility and an increased incidence of diseases or congenital malformations of the male reproductive system. The majority of studies point towards an association between exposure to EDs and male and/or female reproductive system disorders, such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality and/or function. Despite promising discoveries, a causal relationship between the reproductive disorders and exposure to specific toxicants has yet to be established, due to the complexity of the clinical protocols used, the degree of occupational or environmental exposure, the determination of the variables measured and the sample size of the subjects examined. Despite the lack of consistency in the results of so many studies investigating endocrine-disrupting properties of many different classes of chemicals, the overall conclusion points toward a positive association between exposure to EDs and reproductive system. Future studies should focus on a uniform systems to examine human populations with regard to the exposure to specific EDs and the direct effect on the reproductive system.
To study the role of NR5A1 in cryptorchidism and male factor infertility. Mutations in NR5A1 have been initially associated with primary adrenal insufficiency and 46,XY gonadal dysgenesis and more ...recently with less severe phenotypes, including preliminary descriptions in severe forms of male factor infertility. Far less clear is the possible involvement of NR5A1 mutations in cryptorchidism.
Retrospective cross-sectional cohort study and functional analysis of mutant proteins.
University department.
Nine hundred fifty-nine subjects, including children with cryptorchidism and adults with different semen phenotypes associated or not associated with a history of cryptorchidism.
None.
Mutation screening of NR5A1 by sequencing all exons. Functional analysis of mutant proteins by transactivation assays of CYP11A1 and CYP17A1 promoters.
We identified seven undescribed and one previously described missense mutation in subjects with severe spermatogenic impairment, without (4/236, 1.7%) and with (3/85, 3.5%) a history of cryptorchidism. Newborns with cryptorchidism carry NR5A1 mutations at low frequency (0.7%), whereas no mutations were found in milder forms of infertility and normozoospermia, irrespective of the presence of cryptorchidism. The mutant proteins showed impaired transactivation of gonadal promoters. A single nucleotide polymorphism (rs1110061; c.437 G→C; p.Gly146Ala) was also associated with more severe forms of spermatogenic impairment with cryptorchidism.
This study, combined with what is already known about NR5A1-associated phenotypes, suggests considering mutations in this gene as a novel genetic cause of more severe forms of male factor infertility, especially when associated with a history of cryptorchidism.
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Perfluoroalkyl substances (PFASs) are synthetic chemicals widely used in industrial and consumer products. The environmental spreading of PFASs raises concerns for their impact on ...human health. In particular, the bioaccumulation in humans due to environmental exposure has been reported also in total brain samples and PFAS exposure has been associated with neurodevelopmental disorders. In this study we aimed to investigate the specific PFAS bioaccumulation in different brain areas. Our data reported major accumulation in the brainstem region, which is richly populated by dopaminergic neurons (DNs), in brain autopsy samples from people resident in a PFAS-polluted area of Italy.
Since DNs are the main source of dopamine (DA) in the mammalian central nervous system (CNS), we evaluated the possible functional consequences of perfluoro-octanoic acid (PFOA) exposure in a human model of DNs obtained by differentiation of human induced pluripotent stem cells (hiPSCs). Particularly, we analyzed the specific effect of the exposure to PFOA for 24 h, at the concentration of 10 ng/ml, at 3 different steps of dopaminergic differentiation: the neuronal commitment phase (DP1), the neuronal precursor phase (DP2) and the mature dopaminergic differentiation phase (DP3). Interestingly, compared to untreated cells, exposure to PFOA was associated with a reduced expression of Tyrosine Hydroxylase (TH) and Neurofilament Heavy (NFH), both markers of dopaminergic maturation at DP2 phase. In addition, cells at DP3 phase exposed to PFOA showed a severe reduction in the expression of the Dopamine Transporter (DAT), functionally involved in pre-synaptic dopamine reuptake.
In this proof-of-concept study we show a significant impact of PFOA exposure, mainly on the most sensitive stage of neural dopaminergic differentiation, prompting the way for further investigations more directly relevant to risk assessment of these chemicals.
Specific factors underlying successful surgical sperm retrieval rates (SRR) or pregnancy rates (PR) after testicular sperm extraction (TESE) in adult patients with Klinefelter syndrome (KS) have not ...been completely clarified.
The aim of this review was to meta-analyse the currently available data from subjects with KS regarding SRRs as the primary outcome. In addition, when available, PRs and live birth rates (LBRs) after the ICSI technique were also investigated as secondary outcomes.
An extensive Medline, Embase and Cochrane search was performed. All trials reporting SRR for conventional-TESE (cTESE) or micro-TESE (mTESE) and its specific determinants without any arbitrary restriction were included.
Out of 139 studies, 37 trials were included in the study, enrolling a total of 1248 patients with a mean age of 30.9 ± 5.6 years. The majority of the studies (n = 18) applied mTESE, 13 applied cTESE and in one case testicular sperm aspiration (TESA) was used. Additionally, four studies used a mixed approach and in one study, the method applied for sperm retrieval was not specified. Overall, a SRR per TESE cycle of 4439;48% was detected. Similar results were observed when mTESE was compared to cTESE (SRR 4335;50% vs 4538;52% for cTESE vs micro-TESE, respectively; Q = 0.20, P = 0.65). Meta-regression analysis showed that none of the parameters tested, including age, testis volume and FSH, LH and testosterone (T) levels at enrollment, affected the final SRR. Similarly, no difference was observed when a bilateral procedure was compared to a unilateral approach. No sufficient data were available to evaluate the effect of previous T treatment on SRR. Information on fertility outcome after ICSI was available for 29 studies. Overall a total of 218 biochemical pregnancies after 410 ICSI cycles were observed (PR = 4336;50%). Similar results were observed when LBR was analyzed (LBR = 4334;53%). Similar to what was observed for SRR, no influence of KS age, mean testis volume, LH, FSH or total T levels on either PR and LBR was observed. No sufficient data were available to test the effect of the women's age or other female fertility problems on PR and LBR. Finally, no difference in PR or LBR was observed when the use of fresh sperm was compared to the utilization of cryopreserved sperm.
The present data suggest that performing TESE/micro-TESE in subjects with KS results in SRRs of close to 50%, and then PRs and LBRs of close to 50%, with the results being independent of any clinical or biochemical parameters tested.
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.
Skeletal muscles and bones form a joined functional unit sharing a complex mechanical, biochemical and hormonal crosstalk. A number of factors, including sex hormones, physiologically regulate the ...musculoskeletal system. Striking gender differences in muscle and bone mass, and function are mainly caused by distinct actions exerted by oestrogens and androgens. However, relaxin and relaxin‐related peptides, such as insulin‐like peptide 3 (INSL3), might contribute to these sex‐associated differences in physiological and pathological conditions (such as osteoporosis and sarcopenia). Relaxin is a ‘pregnancy’ hormone, but it is also produced from the prostate gland, and has recently attracted attention as a potential drug for cardiovascular disorders and fibrosis. In contrast, INSL3 is a male‐specific hormone produced by the Leydig cells of the testis with a fundamental role in testicular descent during fetal life. Recent evidence suggests that both hormones have interesting roles in the musculoskeletal system. Relaxin and INSL3, by finely tuning bone formation and resorption, are involved in bone remodelling processes, and relaxin contributes to the healing of injured ligaments and promotes skeletal muscle regeneration. Here, we review the most recent findings on the effects of relaxin and INSL3 on skeletal muscle and the cell components of bone. In the light of the experimental evidence available and animal models, their clinical implications are also discussed.
Linked Articles
This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc
OBJECTIVE: To evaluate prevalence, association, and clearance of human papillomavirus (HPV) and antisperm antibodies (ASAs) in infected semen samples from infertile patients. DESIGN: Cross-sectional ...clinical study. SETTING: Andrology and microbiology sections at a university hospital. PATIENT(S): Three groups of subjects: 61 infertile patients with HPV semen infection, 104 noninfected infertile subjects, and 92 control subjects. INTERVENTION(S): Semen analysis, spermMar test, fluorescence in situ hybridization for sperm aneuploidy and for HPV, and immunofluorescence for HPV 16-L1 and immunoglobulins (IgA, IgG, and IgM) determination. MAIN OUTCOME MEASURE(S): Association of sperm procedures, HPV sperm infection, sperm aneuploidies, and sperm ASAs. RESULT(S): Infertile patients with HPV semen infection showed high percentages of ASAs. In these patients HPV sperm infection was associated with lower sperm motility, which was worse in subjects with ASAs. No alterations of sperm chromosomes were observed. To obtain a significant clearance of both HPV sperm infection and ASAs at least 24 months of follow-up were needed. CONCLUSION(S): Human papillomavirus has been recently suggested to have an important role in male infertility. This study demonstrated that HPV sperm infection can be long lasting and frequently associated with ASAs that may further reduce male fertility. Infertile patients with positive spermMar test results should be considered for investigation for HPV, especially if they are candidates for assisted reproduction.
About one-fifth of couples has fertility problems in Western countries. Male factors are present in about half of them, either alone or in combination with female causes. Therefore, both partners ...should be evaluated simultaneously. The fertility status and/or specific conditions of each partner influence the clinical and treatment approach. This article summarizes in a practical way when, how, and why the male partner of an infertile couple should be investigated. The available evidence and international guidelines were used, interpreting, discussing, and expanding them from personal decades-long experience in this field. The aim is to delineate the most appropriate clinical approach for the male partner of infertile couples, considering traditional and emerging technologies and laboratory analyses in the context of their clinical significance. Components of the initial evaluation in men without known risk factors for infertility should include at minimum medical history, physical examination, and semen analysis. Semen microbiological examination, endocrine assessment, scrotal ultrasound, and transrectal ultrasound are suggested in most men and are mandatory when specific risk factors for male infertility are known to be present or when the initial screening demonstrated abnormalities. Full examination, including genetic tests, testicular histology, or additional tests on sperm, is clinically oriented and/or suggested after the results of initial investigations.
Abstract Chronic viral infections can infect sperm and are considered a risk factor in male infertility. Recent studies have shown that the presence of HIV, HBV or HCV in semen impairs sperm ...parameters, DNA integrity, and in particular reduces forward motility. In contrast, very little is known about semen infection with human papillomaviruses (HPV), herpesviruses (HSV), cytomegalovirus (HCMV), and adeno-associated virus (AAV). At present, EU directives for the viral screening of couples undergoing assisted reproduction techniques require only the evaluation of HIV, HBV, and HCV. However, growing evidence suggests that HPV, HSV, and HCMV might play a major role in male infertility and it has been demonstrated that HPV semen infection has a negative influence on sperm parameters, fertilization, and the abortion rate. Besides the risk of horizontal or vertical transmission, the negative impact of any viral sperm infection on male reproductive function seems to be dramatic. In addition, treatment with antiviral and antiretroviral therapies may further affect sperm parameters. In this review we attempted to focus on the interactions between defined sperm viral infections and their association with male fertility disorders. All viruses considered in this article have a potentially negative effect on male reproductive function and dangerous infections can be transmitted to partners and newborns. In light of this evidence, we suggest performing targeted sperm washing procedures for each sperm infection and to strongly consider screening male patients seeking fertility for HPV, HSV, and HCMV, both to avoid viral transmission and to improve assisted or even spontaneous fertility outcome.
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