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Background: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. Summary: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. Key Messages: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.

Background: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in a Disorder (or difference) of Sex Development (DSD), which may include abnormalities of the male reproductive tract including cryptorchidism, hypospadias, infertility and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a Testicular Dysgenesis Syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. Summary: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates, bisphenols), lifestyle factors (e.g. smoking) and pharmaceuticals (e.g. analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiological approaches, for a role of environmental factors in the development of specific male reproductive disorders including cryptorchidism, hypospadias and testicular germ cell cancer. Key Messages: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.

Background: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. Summary: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. Key Messages: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.

Background: Hypospadias affects around 1/200 newborn males. Intrauterine testicular dysfunction may underlie a subset of cases. The long-term endocrine and reproductive outcomes in these men remain largely unknown. Methods: Cross-sectional study in Ghent and Vienna University Hospitals to assess the endocrine and seminal parameters of young adult men (16–21 years) born with non-syndromic hypospadias (NSH) (n = 193) compared to healthy typical males (n = 50). Assessments included physical exam, semen analysis, hormone assays and exome-based gene panel analysis (474 genes). Findings: All participants had experienced a spontaneous puberty, in spite of higher LH and INSL3 levels than typical males. Oligo- or azoospermia was observed in 32/172 (18·6%; 99%-CI: 12·2–27·4%) of NSH men; but in 5/16 (31·3%; 99%-CI: 11·1;62·4%) of complex NSH men and in 13/22 (59·1%; 99%-CI: 33·2–80·7%) of those born small for gestational age (SGA). No (likely) pathogenic coding variants were found in the investigated genes. Suboptimal statural growth affected 8/23 (34·8%; 99%-CI: 15·4–61·0%) of men born SGA with NSH. Interpretation: Spermatogenesis is significantly compromised in NSH men, especially in those born SGA or those with complex NSH. Long-term andrological follow-up is recommended, including end-pubertal semen analysis. No clear monogenic causes could be demonstrated in our cohort even in proximal or complex NSH. Being born SGA with NSH is frequently associated with poor catch-up growth, requiring growth hormone therapy in some. Funding: Research grants from the European Society of Paediatric Endocrinology, the Belgian Society of Pediatrics, the Belgian Society of Pediatric Endocrinology and Diabetology and the Research Foundation Flanders (FWO).

Background: Hypospadias affects around 1/200 newborn males. Intrauterine testicular dysfunction may underlie a subset of cases. The long-term endocrine and reproductive outcomes in these men remain largely unknown. Methods: Cross-sectional study in Ghent and Vienna University Hospitals to assess the endocrine and seminal parameters of young adult men (16–21 years) born with non-syndromic hypospadias (NSH) (n = 193) compared to healthy typical males (n = 50). Assessments included physical exam, semen analysis, hormone assays and exome-based gene panel analysis (474 genes). Findings: All participants had experienced a spontaneous puberty, in spite of higher LH and INSL3 levels than typical males. Oligo- or azoospermia was observed in 32/172 (18·6%; 99%-CI: 12·2–27·4%) of NSH men; but in 5/16 (31·3%; 99%-CI: 11·1;62·4%) of complex NSH men and in 13/22 (59·1%; 99%-CI: 33·2–80·7%) of those born small for gestational age (SGA). No (likely) pathogenic coding variants were found in the investigated genes. Suboptimal statural growth affected 8/23 (34·8%; 99%-CI: 15·4–61·0%) of men born SGA with NSH. Interpretation: Spermatogenesis is significantly compromised in NSH men, especially in those born SGA or those with complex NSH. Long-term andrological follow-up is recommended, including end-pubertal semen analysis. No clear monogenic causes could be demonstrated in our cohort even in proximal or complex NSH. Being born SGA with NSH is frequently associated with poor catch-up growth, requiring growth hormone therapy in some. Funding: Research grants from the European Society of Paediatric Endocrinology, the Belgian Society of Pediatrics, the Belgian Society of Pediatric Endocrinology and Diabetology and the Research Foundation Flanders (FWO).

STUDY QUESTION: Is anogenital distance (AGD) shorter in testicular cancer (TC) survivors than in men from the general population, and is AGD affected by testosterone replacement therapy in adulthood? SUMMARY ANSWER: AGD, measured as distance from anus to scrotum (AGDas), is shorter in TC survivors and does not change as a result of testosterone replacement therapy. WHAT IS KNOWN ALREADY: Animal studies have shown that AGD is a postnatal 'read-out' of foetal androgen action, and short AGD in male offspring is considered a sign of feminization caused by in utero disruption of the reproductive system. Likewise, measurement of AGD in human studies has suggested AGD to be part of the testicular dysgenesis syndrome hypothesis, which proposes that male reproductive disorders, such as hypospadias, cryptorchidism, some cases of impaired semen quality and TC, all share a common foetal origin. STUDY DESIGN, SIZE, DURATION: The aim was to assess AGD in men with a history of TC and controls, and furthermore to examine AGD during testosterone replacement therapy in adulthood. Study participants were TC survivors with a mild Leydig cell insufficiency who participated in a randomized double-blind study of testosterone replacement therapy versus placebo for 52 weeks (N = 69). Men from the general population were prospectively included from a study on testicular function as controls (N = 67). PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured two variants of AGD; as our primary outcome the anoscrotal distance (AGDas) measured from the centre of the anus to the posterior base of the scrotum, and secondarily the anopenile distance (AGDap) measured from the anus to the cephalad insertion of the penis. Using multiple regression analysis, the mean difference in AGD between TC survivors and men from the general population was assessed, adjusted for height, BMI and examiner. Next, AGD was measured before and after 52 weeks of treatment with testosterone or placebo, and with covariance an

Certain adverse trends in male reproductive health were noted by researchers in the late 1900s demonstrating declining semen quality. At the same time, the incidence of testis cancer, cryptorchidism, and hypospadias increased in the same geographic areas. Looking for a common underlying explanation, the theory of a testicular dysgenesis syndrome was coined, describing how a disturbance in the development of the male urogenital tract in fetal life, partly due to in utero exposure to endocrine disruptors, can have consequences including birth defects such as cryptorchidism and hypospadias and long-term clinical conditions such as testis cancer and male infertility. While the associations between these conditions have been established, the theory still has limitations. Much of the evidence gathered stems from animal studies and observational studies, and causation in humans with interventional studies exposing pregnant women to endocrine disruptors is, of course, impossible to perform. However, the sum of today’s evidence points to a detrimental role of exposure to endocrine disruptors possibly causing testicular dysgenesis with impact on men’s health.

The decline in semen quality has been the subject of an animated debate. A recent prospective study now irrefutably shows a decline in semen quality in men from Finland, a country that previously boasted good semen quality. Semen quality has, in some countries, reached a level where a considerable fraction of young men are at risk of fertility problems. Impaired semen quality, testicular cancer, cryptorchidism and hypospadias are risk factors for each other, and the testicular dysgenesis syndrome (TDS) has been put forward to explain the observations. This syndrome implies that the four disease entities share the same patho-physiological etiology caused by disturbed testicular development in early fetal life. It seems likely that the rapid rise in TDS-associated conditions can, at least partly, be explained by environmental factors. Animal studies provide strong evidence that manmade chemicals can disrupt the hormone dependent pathways responsible for fetal gonadal development, subsequently leading to TDS-like symptoms. In humans, fetal exposure to endocrine disrupting substances may play a role, although genetic factors are probably also involved. Recent studies indicate that exposure to endocrine disrupters also in adulthood may affect semen quality and reproductive hormones. Causal relationships are inherently difficult to establish in humans, and a clear connection between the disorders and specific toxicants has not been established. It seems likely that the cumulative effects of various low-dose exposures to endocrine disrupters in our environment are responsible for the adverse effects in the male reproductive system. Semen quality may be the most sensitive marker of adverse environmental exposures, and we suggest that standardized surveillance studies of semen quality are continued or initiated to monitor the combined effects of various preventive actions.

The decline in semen quality has been the subject of an animated debate. A recent prospective study now irrefutably shows a decline in semen quality in men from Finland, a country that previously boasted good semen quality. Semen quality has, in some countries, reached a level where a considerable fraction of young men are at risk of fertility problems. Impaired semen quality, testicular cancer, cryptorchidism and hypospadias are risk factors for each other, and the testicular dysgenesis syndrome (TDS) has been put forward to explain the observations. This syndrome implies that the four disease entities share the same patho-physiological etiology caused by disturbed testicular development in early fetal life. It seems likely that the rapid rise in TDS-associated conditions can, at least partly, be explained by environmental factors. Animal studies provide strong evidence that manmade chemicals can disrupt the hormone dependent pathways responsible for fetal gonadal development, subsequently leading to TDS-like symptoms. In humans, fetal exposure to endocrine disrupting substances may play a role, although genetic factors are probably also involved. Recent studies indicate that exposure to endocrine disrupters also in adulthood may affect semen quality and reproductive hormones. Causal relationships are inherently difficult to establish in humans, and a clear connection between the disorders and specific toxicants has not been established. It seems likely that the cumulative effects of various low-dose exposures to endocrine disrupters in our environment are responsible for the adverse effects in the male reproductive system. Semen quality may be the most sensitive marker of adverse environmental exposures, and we suggest that standardized surveillance studies of semen quality are continued or initiated to monitor the combined effects of various preventive actions.

Testicular dysgenesis syndrome (TDS) comprises a series of disorders, which are linked by an aberrant development of the testis, including abnormal differentiation of somatic cells and delayed maturation of germ cells. Environmental factors (including endocrine disrupters) are thought to impair development of the testis. It is likewise though that epigenetic patterns can be regulated by environmental stimuli and we here review the current knowledge on epigenetic patterns in testicular dysgenesis, which to a large extend is limited to testicular cancer. Testicular Germ Cell Tumors (TGCTs) of young adults originate from a precursor cell, carcinoma in situ testis, which has features of arrested and transformed gonocytes, including high expression of embryonic pluripotency genes and low genome methylation. Overt TGCTs are capable of a marked re-programming with loss of germinal phenotype and increased somatic differentiation. These features suggest a role for epigenetic changes in the pathogenesis and progression of TGCT. In addition to chromatin modifications and gene imprinting, other regulatory mechanisms have been emerging, i.e., miRNAs, which are instrumental in the regulation of gene transcription. It is possible that epigenetic reprogramming during early development may also be a cause of genital malformations and reduced spermatogenesis, but more research is needed to identify the causative environmental factors, their precise targets and affected pathways.

Testicular dysgenesis syndrome (TDS) comprises a series of disorders, which are linked by an aberrant development of the testis, including abnormal differentiation of somatic cells and delayed maturation of germ cells. Environmental factors (including endocrine disrupters) are thought to impair development of the testis. It is likewise though that epigenetic patterns can be regulated by environmental stimuli and we here review the current knowledge on epigenetic patterns in testicular dysgenesis, which to a large extend is limited to testicular cancer. Testicular Germ Cell Tumors (TGCTs) of young adults originate from a precursor cell, carcinoma in situ testis, which has features of arrested and transformed gonocytes, including high expression of embryonic pluripotency genes and low genome methylation. Overt TGCTs are capable of a marked re-programming with loss of germinal phenotype and increased somatic differentiation. These features suggest a role for epigenetic changes in the pathogenesis and progression of TGCT. In addition to chromatin modifications and gene imprinting, other regulatory mechanisms have been emerging, i.e., miRNAs, which are instrumental in the regulation of gene transcription. It is possible that epigenetic reprogramming during early development may also be a cause of genital malformations and reduced spermatogenesis, but more research is needed to identify the causative environmental factors, their precise targets and affected pathways.

Testicular dysgenesis syndrome (TDS) comprises a series of disorders, which are linked by an aberrant development of the testis, including abnormal differentiation of somatic cells and delayed maturation of germ cells. Environmental factors (including endocrine disrupters) are thought to impair development of the testis. It is likewise though that epigenetic patterns can be regulated by environmental stimuli and we here review the current knowledge on epigenetic patterns in testicular dysgenesis, which to a large extend is limited to testicular cancer. Testicular Germ Cell Tumors (TGCTs) of young adults originate from a precursor cell, carcinoma in situ testis, which has features of arrested and transformed gonocytes, including high expression of embryonic pluripotency genes and low genome methylation. Overt TGCTs are capable of a marked re-programming with loss of germinal phenotype and increased somatic differentiation. These features suggest a role for epigenetic changes in the pathogenesis and progression of TGCT. In addition to chromatin modifications and gene imprinting, other regulatory mechanisms have been emerging, i.e., miRNAs, which are instrumental in the regulation of gene transcription. It is possible that epigenetic reprogramming during early development may also be a cause of genital malformations and reduced spermatogenesis, but more research is needed to identify the causative environmental factors, their precise targets and affected pathways.

The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccessibility. We have used a large national biobank of amniotic fluid samples collected at routine amniocentesis to determine the impacts of exogenous endocrine disruptor load on specific fetal biomarkers at this critical time. While adrenal and testicular steroids are highly correlated, they are also mostly positively influenced by increasing phthalate load, represented by the metabolites 7cx-MMeHP and 5cx-MEPP, by PFOS exposure, and by smoking, suggesting an adrenal stress response. In contrast, the testis specific biomarkers INSL3 and androstenedione are negatively impacted by the phthalate endocrine disruptors. Using a case-control design, we show that cryptorchidism and hypospadias are both significantly associated with increased amniotic concentration of INSL3 during gestational weeks 13 to 16, and some, though not all steroid biomarkers. Cases are also linked to a specifically increased variance in the Leydig cell biomarker INSL3 compared to controls, an effect exacerbated by maternal smoking. No influence of phthalate metabolites or PFOS was evident on the distribution of cases and controls. Considering that several animal and human studies have shown a negative impact of phthalate load on fetal and cord blood INSL3, respectively, the present results suggest that such endocrine disruptors may rather be altering the relative dynamics of testicular development and consequent hormone production, leading to a desynchronization of tissue organization during fetal development. Being born small for gestational age appears not to impact on the testicular biomarker INSL3 in second trimester amniotic fluid.

The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccessibility. We have used a large national biobank of amniotic fluid samples collected at routine amniocentesis to determine the impacts of exogenous endocrine disruptor load on specific fetal biomarkers at this critical time. While adrenal and testicular steroids are highly correlated, they are also mostly positively influenced by increasing phthalate load, represented by the metabolites 7cx-MMeHP and 5cx-MEPP, by PFOS exposure, and by smoking, suggesting an adrenal stress response. In contrast, the testis specific biomarkers INSL3 and androstenedione are negatively impacted by the phthalate endocrine disruptors. Using a case-control design, we show that cryptorchidism and hypospadias are both significantly associated with increased amniotic concentration of INSL3 during gestational weeks 13 to 16, and some, though not all steroid biomarkers. Cases are also linked to a specifically increased variance in the Leydig cell biomarker INSL3 compared to controls, an effect exacerbated by maternal smoking. No influence of phthalate metabolites or PFOS was evident on the distribution of cases and controls. Considering that several animal and human studies have shown a negative impact of phthalate load on fetal and cord blood INSL3, respectively, the present results suggest that such endocrine disruptors may rather be altering the relative dynamics of testicular development and consequent hormone production, leading to a desynchronization of tissue organization during fetal development. Being born small for gestational age appears not to impact on the testicular biomarker INSL3 in second trimester amniotic fluid.

The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccessibility. We have used a large national biobank of amniotic fluid samples collected at routine amniocentesis to determine the impacts of exogenous endocrine disruptor load on specific fetal biomarkers at this critical time. While adrenal and testicular steroids are highly correlated, they are also mostly positively influenced by increasing phthalate load, represented by the metabolites 7cx-MMeHP and 5cx-MEPP, by PFOS exposure, and by smoking, suggesting an adrenal stress response. In contrast, the testis specific biomarkers INSL3 and androstenedione are negatively impacted by the phthalate endocrine disruptors. Using a case-control design, we show that cryptorchidism and hypospadias are both significantly associated with increased amniotic concentration of INSL3 during gestational weeks 13 to 16, and some, though not all steroid biomarkers. Cases are also linked to a specifically increased variance in the Leydig cell biomarker INSL3 compared to controls, an effect exacerbated by maternal smoking. No influence of phthalate metabolites or PFOS was evident on the distribution of cases and controls. Considering that several animal and human studies have shown a negative impact of phthalate load on fetal and cord blood INSL3, respectively, the present results suggest that such endocrine disruptors may rather be altering the relative dynamics of testicular development and consequent hormone production, leading to a desynchronization of tissue organization during fetal development. Being born small for gestational age appears not to impact on the testicular biomarker INSL3 in second trimester amniotic fluid.