A cross-sectional study of cryptorchidism in children: testicular volume and hormonal function at 18 years of age

PubMed Central

Varela-Cives, R.; Méndez-Gallart, R.; Estevez-Martínez, E.; Rodríguez-Barca, P.; Bautista-Casasnovas, A.; Pombo-Arias, M.; Tojo-Sierra, R.

2015-01-01

Purpose To evaluate the relationship between unilateral or bilateral criptorchidism, patient age, primary location of the gonad and modality of treatment with testicular volume and hormonal status at 18 years in patients diagnosed and treated for cryptorchidism during childhood. Materials and Methods Testicular volume, LH, FSH, and testosterone were evaluated in 143 young men at 18 years treated in childhood for unilateral (n=103) or bilateral (n=40) cryptorchidism. Results Unilateral cryptorchidism: Location of testis was prescrotal in 36 patients, inguinal in 52 and non-palpable in 15. The mean volume was 9.7 mL compared to 16.2 mL. for the spontaneously descended testicle in unilateral cryptorchidism. However, 22 patients who received HCG had a significantly bigger testis (11.8 mL.) than those treated with primary surgery (9.2 mL). The results showed a significant positive correlation between testicular volume and patient age at treatment. Bilateral cryptorchidism Location of testis was prescrotal in 34 cases, inguinal in 40 and 6 patients with non-palpable testicles. Mean volume at 18 years was 12.9 mL, greater than unilateral cryptorchid testis (9.7 mL) but smaller than healthy contralateral in unilateral cases (16.2 mL). There were significant differences in the testicular growth for bilateral patients with testicular descent after being treated with HCG (14.4 mL) in respect with those untreated (11.1 mL) or those who underwent primary surgery (11.4 mL). There was a significant positive correlation between the testicular volume and palpable (12.4 mL) or non-palpable testis (10.4 mL). There was a correlation between unilateral or bilateral cryptorchidism and levels of FSH. Conclusions Testicular volume and hormonal function at 18 years for patients diagnosed and treated for cryptorchidism during childhood are strongly influenced by whether the undescended testis was unilateral or bilateral. Location of the testes at diagnosis or age of initial treatment exerts no definite effect on testicular volume improvement or hormonal levels at 18 years of age. PMID:25928530

Relationship of cryptorchidism with sex ratios and litter sizes in 12 dog breeds.

PubMed

Gubbels, Ed J; Scholten, Janneke; Janss, Luc; Rothuizen, Jan

2009-07-01

The aim of this study was to identify the influence of genetic carriership for cryptorchidism on litter sizes and sex ratios in the offspring. Weaning data of 11,230 litters in 12 purebred dog breeds were evaluated. Parents were classified as cryptorchidism 'carriers' (C) when at least one of their offspring was found cryptorchid. Subsequently the effects of 'carrier' and 'non-carrier' (NC) parents on their litters were studied. In litters from C x C parents we found an increased number of males per litter in all breeds, a reduced number of females per litter in 8 breeds and an increased litter size in 11 breeds in comparison with litters from NC x NC parents. Over all breeds the effects on litter size, on number of males per litter and on sex ratio were highly significant. Mixed litters from C x NC and NC x C did not show these effects and were not significantly different from the NC x NC offspring. Our results suggest a general mechanism in the dog species which causes cryptorchidism as well as increased male/female ratios and increased litter sizes. A consequence of such a mechanism is that selection in favor of increasing reproduction output frustrates selective efforts to eliminate cryptorchidism.

[Discussion of new classification of epididymal malformation in cryptorchidism of children].

PubMed

Zhang, Dian-Liang; Li, Zhen; Xie, Jia-Lun

2002-12-01

To discuss the new classification of epididymal malformation in cryptorchidism. One hundred and fifty-three boys who were two to four year old underwent orchidopexy for cryptorchidism and 144 hydroceles who were two to eight year old were enrolled into control. Based on the observation of the status between testis and epididymia, the length of epididymis and the configuration of epididymis as well as spermaduct, we divided epididymal malformations in cryptorchidism into three types. Type I: obstruction of sperm transport, including I A, I B and I C; Type II: possible obstruction of sperm transport, defined by II A and II B; Type III: no obstruction of sperm transport, classified into III A and III B. There were 47 (23.4%) out of 201 undescended testes with malformation of epididymides and 16 (10.3%) out of 155 testes in the control(P < 0.05). 11 of 48 cases of bilateral cryptorchidism had the same malformations, with 2 cases of type IB, 2 of IC, 1 of II A, 4 of III A and 2 of IV B underwent orchidopexy or orchiectomy. These data showed that the incidence of epididymal abnormalities in cryptorchidism was higher than that in the hydroceles and it's not essential to have orchiectomy unlimitedly to serious epididymal abnormalities.

Anogenital Distance and Penile Length in Infants with Hypospadias or Cryptorchidism: Comparison with Normative Data

PubMed Central

Thankamony, Ajay; Lek, Ngee; Carroll, Dan; Williams, Martyn; Dunger, David B.; Acerini, Carlo L.; Ong, Ken K.

2013-01-01

Background: Anogenital distance (AGD) in animals is a sensitive biomarker of fetal endocrine disruption and the associated testicular dysgenesis syndrome (TDS). However, AGD in human infants with cryptorchidism and hypospadias, which are potential manifestations of TDS during childhood, is not clearly described. Objective: Our aim was to compare AGD in boys with cryptorchidism or hypospadias against normative data. Methods: Boys with isolated cryptorchidism (n = 71, age 13.4 ± 5.8 months) or hypospadias (n = 81, age 11.4 ± 6.2 months) were recruited from a tertiary center for measurement of AGD and penile length; they were compared with 487 healthy full-term boys from a birth cohort by deriving age-specific standard deviation scores (SDS). Results: Boys with cryptorchidism were older (p = 0.048) compared with boys with hypospadias. Boys with hypospadias had shorter mean AGD and penile length SDS than healthy boys (both p < 0.0001). Mean AGD and penile length SDS values in boys with cryptorchidism were longer than mean values in boys with hypospadias (both p < 0.01) and shorter than mean values in healthy boys (both p < 0.0001). Mean penile length SDS decreased as the severity of hypospadias increased (ptrend = 0.078). Conclusions: In the study population, AGD and penile length were reduced in boys with hypospadias or cryptorchidism relative to normative data derived from a longitudinal birth cohort. The findings support the use of AGD as a quantitative biomarker to examine the prenatal effects of exposure to endocrine disruptors on the development of the male reproductive tract. Citation: Thankamony A, Lek N, Carroll D, Williams M, Dunger DB, Acerini CL, Ong KK, Hughes IA. 2014. Anogenital distance and penile length in infants with hypospadias or cryptorchidism: comparison with normative data. Environ Health Perspect 122:207–211; http://dx.doi.org/10.1289/ehp.1307178 PMID:24316680

Cryptorchidism and Maternal Alcohol Consumption during Pregnancy

PubMed Central

Damgaard, Ida N.; Jensen, Tina K.; Petersen, Jørgen H.; Skakkebæk, Niels E.; Toppari, Jorma; Main, Katharina M.

2007-01-01

Background Prenatal exposure to alcohol can adversely affect the fetus. We investigated the association between maternal alcohol consumption during pregnancy and cryptorchidism (undescended testis) among newborn boys. Methods We examined 2,496 boys in a prospective Danish–Finnish birth cohort study for cryptorchidism at birth (cryptorchid/healthy: 128/2,368) and at 3 months of age (33/2,215). Quantitative information on alcohol consumption (average weekly consumption of wine, beer, and spirits and number of binge episodes), smoking, and caffeine intake was obtained by questionnaire and/or interview once during the third trimester of pregnancy, before the outcome of the pregnancy was known. For a subgroup (n = 465), information on alcohol consumption was obtained twice during pregnancy by interviews. Results We investigated maternal alcohol consumption both as a continuous variable and categorized. The odds for cryptorchidism increased with increasing weekly alcohol consumption. After adjustment for confounders (country, smoking, caffeine intake, binge episodes, social class, maternal age, parity, maturity, and birth weight) the odds remained significant for women with a weekly consumption of five or more alcoholic drinks (odds ratio = 3.10; 95% confidence interval, 1.05–9.10). Conclusions Regular alcohol intake during pregnancy appears to increase the risk of congenital cryptorchidism in boys. The mechanisms for this association are unknown. Counseling of pregnant women with regard to alcohol consumption should also consider this new finding. PMID:17384777

Risk factors for cryptorchidism

PubMed Central

Gurney, Jason K.; McGlynn, Katherine A.; Stanley, James; Merriman, Tony; Signal, Virginia; Shaw, Caroline; Edwards, Richard; Richiardi, Lorenzo; Hutson, John; Sarfati, Diana

2018-01-01

The condition known as cryptorchidism – undescended testis – is one of the most common congenital abnormalities found among males, and is one of the few known risk factors for testicular cancer (TC). Like testicular cancer, the key exposures in the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases – between 8–15 weeks and 25–35 weeks gestation – and while it is clear that a failure of testes to descend permanently is likely due to disruptions to one or both of these phases, the cause(s) and mechanism(s) of such disruption are still unclear. In this manuscript, we review the broad range of putative risk factors that have been evaluated in relation to the development of cryptorchidism to date, discuss their plausibility, and make suggestions regarding further approaches to understand aetiology. There are few exposures for which there is consistent evidence of an association with cryptorchidism; and in those cases where evidence appears unequivocal – for example, the relationship between cryptorchidism and gestational measures such as low birth weight – the measured exposure is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor may vary considerably between mother/son pairs depending on an array of genetic, maternal, placental and foetal factors – all of which could vary between regions. PMID:28654092

Two Closely Related Ubiquitin C-Terminal Hydrolase Isozymes Function as Reciprocal Modulators of Germ Cell Apoptosis in Cryptorchid Testis

PubMed Central

Kwon, Jungkee; Wang, Yu-Lai; Setsuie, Rieko; Sekiguchi, Satoshi; Sato, Yae; Sakurai, Mikako; Noda, Mami; Aoki, Shunsuke; Yoshikawa, Yasuhiro; Wada, Keiji

2004-01-01

The experimentally induced cryptorchid mouse model is useful for elucidating the in vivo molecular mechanism of germ cell apoptosis. Apoptosis, in general, is thought to be partly regulated by the ubiquitin-proteasome system. Here, we analyzed the function of two closely related members of the ubiquitin C-terminal hydrolase (UCH) family in testicular germ cell apoptosis experimentally induced by cryptorchidism. The two enzymes, UCH-L1 and UCH-L3, deubiquitinate ubiquitin-protein conjugates and control the cellular balance of ubiquitin. The testes of gracile axonal dystrophy (gad) mice, which lack UCH-L1, were resistant to cryptorchid stress-related injury and had reduced ubiquitin levels. The level of both anti-apoptotic (Bcl-2 family and XIAP) and prosurvival (pCREB and BDNF) proteins was significantly higher in gad mice after cryptorchid stress. In contrast, Uchl3 knockout mice showed profound testicular atrophy and apoptotic germ cell loss after cryptorchid injury. Ubiquitin level was not significantly different between wild-type and Uchl3 knockout mice, whereas the levels of Nedd8 and the apoptotic proteins p53, Bax, and caspase3 were elevated in Uchl3 knockout mice. These results demonstrate that UCH-L1 and UCH-L3 function differentially to regulate the cellular levels of anti-apoptotic, prosurvival, and apoptotic proteins during testicular germ cell apoptosis. PMID:15466400

Testicular descent: INSL3, testosterone, genes and the intrauterine milieu.

PubMed

Bay, Katrine; Main, Katharina M; Toppari, Jorma; Skakkebæk, Niels E

2011-04-01

Complete testicular descent is a sign of, and a prerequisite for, normal testicular function in adult life. The process of testis descent is dependent on gubernacular growth and reorganization, which is regulated by the Leydig cell hormones insulin-like peptide 3 (INSL3) and testosterone. Investigation of the role of INSL3 and its receptor, relaxin-family peptide receptor 2 (RXFP2), has contributed substantially to our understanding of the hormonal control of testicular descent. Cryptorchidism is a common congenital malformation, which is seen in 2-9% of newborn boys, and confers an increased risk of infertility and testicular cancer in adulthood. Although some cases of isolated cryptorchidism in humans can be ascribed to known genetic defects, such as mutations in INSL3 or RXFP2, the cause of cryptorchidism remains unknown in most patients. Several animal and human studies are currently underway to test the hypothesis that in utero factors, including environmental and maternal lifestyle factors, may be involved in the etiology of cryptorchidism. Overall, the etiology of isolated cryptorchidism seems to be complex and multifactorial, involving both genetic and nongenetic components.

Cryptorchidism and delayed testicular descent in Florida black bears.

PubMed

Dunbar, M R; Cunningham, M W; Wooding, J B; Roth, R P

1996-10-01

Retained testes were found in 11 (16%) of 71 black bears (Ursus americanus) examined over a 3-year period in Florida (USA). Four of the 11 bears were older than one year and weighed more than 32 kg; therefore, they were considered to be cryptorchid. The remaining seven bears may have had delayed testicular descent due to their apparent normal immature development. This is the first known published report of the prevalence of cryptorchidism and apparently normal delayed testicular descent in a black bear population.

Genome-wide association study using deregressed breeding values for cryptorchidism and scrotal/inguinal hernia in two pig lines.

PubMed

Sevillano, Claudia A; Lopes, Marcos S; Harlizius, Barbara; Hanenberg, Egiel H A T; Knol, Egbert F; Bastiaansen, John W M

2015-03-21

Cryptorchidism and scrotal/inguinal hernia are the most frequent congenital defects in pigs. Identification of genomic regions that control these congenital defects is of great interest to breeding programs, both from an animal welfare point of view as well as for economic reasons. The aim of this genome-wide association study (GWAS) was to identify single nucleotide polymorphisms (SNPs) that are strongly associated with these congenital defects. Genotypes were available for 2570 Large White (LW) and 2272 Landrace (LR) pigs. Breeding values were estimated based on 1 359 765 purebred and crossbred male offspring, using a binary trait animal model. Estimated breeding values were deregressed (DEBV) and taken as the response variable in the GWAS. Heritability estimates were equal to 0.26 ± 0.02 for cryptorchidism and to 0.31 ± 0.01 for scrotal/inguinal hernia. Seven and 31 distinct QTL regions were associated with cryptorchidism in the LW and LR datasets, respectively. The top SNP per region explained between 0.96% and 1.10% and between 0.48% and 2.77% of the total variance of cryptorchidism incidence in the LW and LR populations, respectively. Five distinct QTL regions associated with scrotal/inguinal hernia were detected in both LW and LR datasets. The top SNP per region explained between 1.22% and 1.60% and between 1.15% and 1.46% of the total variance of scrotal/inguinal hernia incidence in the LW and LR populations, respectively. For each trait, we identified one overlapping region between the LW and LR datasets, i.e. a region on SSC8 (Sus scrofa chromosome) between 65 and 73 Mb for cryptorchidism and a region on SSC13 between 34 and 37 Mb for scrotal/inguinal hernia. The use of DEBV in combination with a binary trait model was a powerful approach to detect regions associated with difficult traits such as cryptorchidism and scrotal/inguinal hernia that have a low incidence and for which affected animals are generally not available for genotyping. Several novel QTL regions were detected for cryptorchidism and scrotal/inguinal hernia, and for several previously known QTL regions, the confidence interval was narrowed down.

Early life risk factors for testicular cancer: a case-cohort study based on the Copenhagen School Health Records Register.

PubMed

Piltoft, Johanne Spanggaard; Larsen, Signe Benzon; Dalton, Susanne Oksbjerg; Johansen, Christoffer; Baker, Jennifer L; Cederkvist, Luise; Andersen, Ingelise

2017-02-01

One established risk factors for testicular cancer is cryptorchidism. However, it remains unclear whether cryptorchidism is a risk factor in itself or whether the two conditions share common causes in early life (estrogen hypothesis), such as birth weight and birth order. The objective of this study is to utilize data from the Copenhagen School Health Records Register (CSHRR) to evaluate cryptorchidism, birth weight and birth order as risk factors for testicular cancer. The study population consisted of 408 cases of testicular cancer identified by a government issued identification number linkage of the entire CSHRR with the Danish Cancer Registry and a random subsample of 4819 males from the CSHRR. The study design was case-cohort and the period of follow-up between 2 April 1968 and 31 December 2003. Cryptorchidism was significantly associated with testicular cancer in crude analyses [hazard ratio (HR) = 3.60, 95% CI 2.79-4.65]. Birth weight was inversely associated with testicular cancer and no clear association with birth order was observed. The positive association between cryptorchidism and testicular cancer was only slightly attenuated controlling for birth weight and birth order and stratified on birth cohort (HR = 3.46, 95% CI 2.67-4.48). This study confirmed the robustness of the association between cryptorchidism and testicular cancer even after adjustment for birth weight and birth order. Furthermore, the study showed an inverse association between birth weight and testicular cancer.

A history of cryptorchidism: lessons from the eighteenth century.

PubMed

Tackett, Leslie D; Patel, Sutchin R; Caldamone, Anthony A

2007-12-01

John Hunter in 1786 opened the door to more than 200 years of study and discussion of the cryptorchid testis. We review the history that has brought us to our current surgical treatment of this condition. We performed a review of the medical and historical surgical literature pertaining to cryptorchidism. The study of cryptorchidism began with the anatomical descriptions of Baron Albrecht von Haller and John Hunter. Attempts at surgical correction of the undescended testis began in the early 1800s, culminating in the first successful orchidopexy by Thomas Annandale in 1877. Further contributions to the surgical technique include: (1) Arthur Dean Bevan's division of the processus vaginalis to prevent reascent and his stress on the importance of adequate mobilization of the spermatic cord, (2) the description by Robert Prentiss of surgical triangles which allowed for mobilization of the spermatic cord and placement of the testis into the scrotum without tension, and (3) Lattimer's subdartos pouch. Our understanding and the surgical treatment of cryptorchidism have continued to evolve over the last 200 years. A study of the history of surgical management of the undescended testis sheds light on the rationale behind current management.

A novel Alu-mediated microdeletion at 11p13 removes WT1 in a patient with cryptorchidism and azoospermia.

PubMed

Seabra, Catarina M; Quental, Sofia; Neto, Ana Paula; Carvalho, Filipa; Gonçalves, João; Oliveira, João Paulo; Fernandes, Susana; Sousa, Mário; Barros, Alberto; Amorim, António; Lopes, Alexandra M

2014-09-01

This article describes a patient with cryptorchidism and nonobstructive azoospermia presenting a novel microdeletion of approximately 1 Mb at 11p13. It was confirmed by multiplex ligation-dependent probe amplification that this heterozygous deletion spanned nine genes (WT1, EIF3M, CCDC73, PRRG4, QSER1, DEPDC7, TCP11L1, CSTF3 and HIPK3) and positioned the breakpoints within highly homologous repetitive elements. As far as is known, this is the smallest deletion as-yet described encompassing the WT1 gene and was detected only once in a total of 32 Portuguese patients with isolated uni- or bilateral cryptorchidism. These findings suggest that molecular analysis in patients with genitourinary features suggestive of WT1 impairment, namely cryptorchidism and renal abnormalities, may reveal cryptic genetic defects. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Hypertensive Disorders of Pregnancy and Genital Anomalies in Boys: A Danish Nationwide Cohort Study.

PubMed

Arendt, Linn Håkonsen; Henriksen, Tine Brink; Lindhard, Morten Søndergaard; Parner, Erik T; Olsen, Jørn; Ramlau-Hansen, Cecilia Høst

2018-06-14

Although congenital abnormalities in the male reproductive tract are common, their causes remain poorly understood. We studied associations between hypertensive disorders of pregnancy (pre-gestational hypertension, gestational hypertension, and preeclampsia) and the genital anomalies, cryptorchidism (undescended testes), and hypospadias (ventrally displaced urethral meatus). We established a population of 1,073,026 Danish boys born alive between 1 January 1978 and 31 December 2012. By means of Cox regression analyses, we estimated hazard ratios with 95% confidence intervals for cryptorchidism and hypospadias according to type and severity of hypertensive disorder. Further, we used restricted cubic spline analyses to investigate the association between gestational age at onset of severe and moderate preeclampsia and the two genital anomalies. We found associations between pre-gestational hypertension and cryptorchidism [HR: 1.3 (95% CI: 1.1, 1.6)] and hypospadias [HR: 1.7 (95% CI: 1.3, 2.3)], whereas gestational hypertension was only associated with cryptorchidism [HR: 1.2 (95% CI: 1.1, 1.4)]. Boys of mothers with preeclampsia had the highest occurrence of cryptorchidism and hypospadias, increasing with preeclampsia severity. Women with HELLP syndrome faced the highest risk of having a child with both cryptorchidism [HR: 2.1 (95% CI: 1.4, 3.2)] and hypospadias [HR: 3.9 (95% CI: 2.5, 6.1)]. Further, the occurrence increased with early onset of preeclampsia diagnosis. These findings support the hypotheses that preeclampsia and genital anomalies share common etiologic factors and that placental dysfunction and androgen deficiency in early pregnancy are important in the etiology of male genital anomalies.

Gene Expression Changes Underlying Idiopathic Central Hypogonadism in Cryptorchidism with Defective Mini-Puberty.

PubMed

Hadziselimovic, Faruk; Gegenschatz-Schmid, Katharina; Verkauskas, Gilvydas; Docampo-Garcia, Maria J; Demougin, Philippe; Bilius, Vytautas; Malcius, Dalius; Dasevicius, Darius; Stadtler, Michael B

2016-01-01

The whole genome RNA profiling of testicular biopsies by DNA strand-specific RNA sequencing was examined to determine a potential causative role of isolated congenital cryptorchidism in azoospermia and/or infertility in the context of our previously published GeneChip data. Cryptorchid patients, aged 7 months to 5 years and otherwise healthy, were enrolled in this prospective study. During surgery, testicular tissue biopsies were obtained for histological examination and RNA sequencing. Fifteen patients were selected based on the histological results and were divided into 2 groups. Seven were classified as belonging to the high infertility risk (HIR) and 8 to the low infertility risk (LIR) group. Cryptorchid boys in the HIR group lacked transformation of gonocytes into Ad spermatogonia due to impaired mini-puberty. This group of patients will be infertile despite successful surgery. The new important finding was a decreased PROK2, CHD7, FGFR1, and SPRY4 gene expression in the HIR group. Furthermore, identification of multiple differences in gene expression between HIR and LIR groups underscores the importance of an intact hypothalamic-pituitary-gonadal axis for fertility development. Our RNA profiling data strongly support the theory that in the HIR group of cryptorchid boys insufficient PROK2/CHD7/FGFR1/SPRY4 gene expression induces deficient LH secretion, resulting in impaired mini-puberty and infertility. We therefore recommend hormonal treatment for this cohort of cryptorchid boys with defective mini-puberty following a seemingly successful orchidopexy. © 2016 The Author(s) Published by S. Karger AG, Basel.

Persistent müllerian duct syndrome associated with irreducible inguinal hernia, bilateral cryptorchidism and testicular neoplasia: a case report.

PubMed

Yuksel, B; Saygun, O; Hengirmen, S

2006-01-01

Persistent müllerian duct syndrome is a rare form of male pseudohermaphroditism. A case is reported of normal male appearance with bilateral cryptorchidism and a right irreducible inguinal hernia. On exploration, an uterus with two fallopian tubes and a testicle were found in the hernia sac. The uterus, fallopian tubes and left testicle were en bloc removed. Right orchidopexy and hernia repair were performed. In conclusion, if there is an adult bilateral cryptorchidism, surgeons should take into consideration a persistent müllerian duct syndrome.

Ethnic patterns of hypospadias in New Zealand do not resemble those observed for cryptorchidism and testicular cancer: evidence of differential aetiology?

PubMed

Gurney, J K; Stanley, J; Shaw, C; Sarfati, D

2016-01-01

It has been proposed that hypospadias, cryptorchidism, poor semen quality and testicular cancer might share common prenatal causes. We have previously demonstrated similar ethnic patterns for the incidence of testicular cancer and cryptorchidism - a known risk factor for testicular cancer. If the underlying exposure(s) that cause hypospadias, cryptorchidism and testicular cancer are shared, then we would expect the incidence relationship between ethnic groups to follow the same pattern across all three conditions. We followed a birth cohort of 318 345 eligible male neonates born in New Zealand between 2000-2010, and linked routinely collected maternity records with inpatient hospitalization and mortality records through to 2011. We searched hospitalization records for diagnoses of hypospadias, and used mortality records for censoring. We used Poisson regression methods to compare the relative risk of hypospadias between ethnic groups, adjusting for perinatal risk factors and total person time. We observed that European/Other children had the highest risk of hypospadias, with Māori, Pacific and Asian boys having around 40% lower risk of disease compared with this group (adjusted relative risk [RR]: Māori 0.62, 95% CI 0.55-0.70; Pacific 0.62, 95% CI 0.53-0.72; Asian 0.57, 95% CI 0.47-0.69). This contrasts substantially with our previous observations for cryptorchidism and testicular cancer, where Māori males have the greatest risk. Our observations suggest that - at least in New Zealand - the exposures that drive the development of hypospadias may differ to those that that drive the development of cryptorchidism and/or testicular cancer. © 2015 American Society of Andrology and European Academy of Andrology.

Cryptorchidism due to chromosome 5q inversion duplication.

PubMed

Dutta, M K; Gundgurthi, A; Garg, M K; Pakhetr, R

2013-12-01

We present a 15 year old boy who was born out of a non consanguineous marriage, and presented with bilateral cryptorchidism, mental retardation, facial dysmorphism, hypergonadotrophic hypogonadism with failure of anatomical and biochemical localisation of testes. Karyotype analysis showed 46 XY with inverted duplication on chromosome 5q22-31.

Analgesia use during pregnancy and risk of cryptorchidism: a systematic review and meta-analysis.

PubMed

Gurney, Jason; Richiardi, Lorenzo; McGlynn, Katherine A; Signal, Virginia; Sarfati, Diana

2017-05-01

Are boys who are born to mothers who use analgesics during pregnancy at increased risk of cryptorchidism compared to those born to mothers who do not take analgesia? In this systematic review and meta-analysis of 10 published studies, we observed only weak evidence of an association between analgesia use during pregnancy and risk of cryptorchidism in the son. Concentrations of analgesia relevant to human exposure have been implicated as causing endocrine disturbances in the developing foetal testis. However, when viewed collectively there appears to be conflicting evidence regarding an association between maternal use of analgesics and development of cryptorchidism. A systematic review and meta-analysis of studies on analgesia use during pregnancy and risk of cryptorchidism was performed. The search terms used were (analges* OR paracetamol OR acetaminophen) AND (cryptorchidism OR cryptorchism OR undescended test* OR non-descended test* OR non descended test*) for the databases Ovid Medline, Embase, Scopus and Web of Science. The search included all published articles up until 23 May 2016 and no limits were set in terms of language. Abstracts were screened by one reviewer to remove irrelevant studies, with a 10% random sample of these verified by a second reviewer. The full text of all remaining papers was assessed by two reviewers. Abstracts included in the final analysis were studies which reported associations between the exposure (analgesia) and the outcome (cryptorchidism). Studies were only included if data were provided from which summary associations (odds ratios (ORs) or relative risks) and their 95% CIs could be calculated, or if summary associations were provided by the authors themselves. For each included study, two reviewers independently extracted study meta-data in line with PRISMA recommendations. We assessed study quality and potential for bias using the criteria outlined in the Newcastle-Ottawa Quality Assessment Scale, but did not determine a quality score. Two reviewers independently assessed study quality against these criteria. After screening 350 manuscripts, 10 were included in our review (5 case-control studies, 5 cohort studies). We observed weak evidence of an association between ever use of analgesia and risk of cryptorchidism (pooled crude OR: 1.11, 95% CI: 1.00-1.23), with case-control studies revealing a marginally stronger association (1.23, 95% CI: 0.85-1.78) than cohort studies (1.09, 95% CI: 0.97-1.22). We observed weak evidence of a dose-response relationship between increasing weeks of analgesia exposure and risk of cryptorchidism, as well as weak evidence of an effect of timing on analgesia exposure and risk of cryptorchidism. Assessment of study quality via the Newcastle-Ottawa criteria revealed little (if any) evidence of substantial bias that may have meaningfully affected a given study's results. While confounding does not appear to be important, misclassification of the exposure is possibly an important source of measurement error in this context. The systematic review is open to reporting bias. Owing to scant data, no meta-analyses for two key questions (relating to dose-response and timing of exposure) could be performed. Medications were grouped based on their common effect and this offers little insight into the relation between specific types of analgesia and cryptorchidism. Finally, there are limitations in assuming that analgesia use reported by mothers is synonymous with actual intrauterine exposure. The ubiquity of analgesia use during pregnancy makes this exposure particularly important from a population health perspective. About 9 of the 10 studies were conducted in Europe or USA, limiting generalizability of our observations. While the observations from our systematic review and meta-analysis suggest that analgesia use during pregnancy is not strongly associated with cryptorchidism development in the son, they also highlight the need for further detailed assessments of this relationship. This study was funded by the Health Research Council of New Zealand (reference #: 14/052). The authors have no conflict of interest to declare. CRD42016041414. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities.

PubMed

Gill, W B; Schumacher, G F; Bibbo, M; Straus, F H; Schoenberg, H W

1979-07-01

Epididymal cysts and/or hypoplastic testes have been found in 31.5 per cent of 308 men exposed to diethylstilbestrol in utero, compared to 7.8 per cent of 307 placebo-exposed controls. Analyses of the spermatozoa have revealed severe pathological changes (Eliasson score greater than 10) in 134 diethylstilbestrol-exposed men (18 per cent) and 87 placebo-exposed men (8 per cent). Further investigation of the 26 diethylstilbestrol-exposed men with testicular hypoplasia has revealed that 65 per cent had a history of cryptorchidism. Only 1 of the 6 placebo-exposed controls with testicular hypoplasia had a history of testicular maldescent. Although none of our Diekmann's lying-in study group has had carcinoma to date one must keep in mind the reported increased risk of testicular carcinoma in testes that are or were cryptorchid. A 25-year-old man who was not part of the study group was treated recently by us for a testicular carcinoma ( mixed anaplastic seminoma plus embryonal cell carcinoma) and he had a history of diethylstilbestrol exposure in utero and cryptorchidism.

Persistent Mullerian duct syndrome with transverse testicular ectopia and seminoma.

PubMed

Alp, Bilal Fırat; Demirer, Zafer; Gürağaç, Ali; Babacan, Oğuzhan; Sarı, Erkan; Sarı, Sebahattin; Yavan, Ibrahim

2014-08-01

Persistent Mullerian duct syndrome (PMDS) is a rare form of the 46 XY disorders of sexual differentiation, characterized by the presence of a uterus and fallopian tubes due to the failure of Mullerian duct regression in genotypically normal males. More than 150 cases have been recorded, most of them in adults. In most cases, the PMDS is discovered during surgery for inguinal hernia or cryptorchidism, or by the presence of transverse testicular ectopia (TTE). The presence of PMDS with TTE is even more uncommon. In TTE, both testes descend through the same inguinal canal into the same scrotal sac. Patients with TTE present with symptoms of unilateral cryptorchidism and a contralateral inguinal hernia. For patients with inguinal hernia and cryptorchidism associated with TTE, PMDS should be kept in mind, and radiologic evaluation such as ultrasonography or magnetic resonance imaging of the genitourinary system and karyotyping are recommended. Whereas radiologic evaluation could be helpful in the diagnosis of TTE, it cannot diagnose the malignancy itself. The case explained in this report will offer urologists additional useful treatment strategies for patients with inguinal hernia and cryptorchidism.

Protective Effect of Decursin Extracted from Angelica gigas in Male Infertility via Nrf2/HO-1 Signaling Pathway

PubMed Central

Bae, Woong Jin; Ha, U. Syn; Choi, Jin Bong; Kim, Kang Sup; Kim, Su Jin; Cho, Hyuk Jin; Hong, Sung Hoo; Lee, Ji Youl; Wang, Zhiping; Hwang, Sung Yeoun; Kim, Sae Woong

2016-01-01

Higher testicular temperature results in altered spermatogenesis due to heat-related oxidative stress. We examined the effects of decursin extracted from Angelica gigas Nakai on antioxidant activity in vitro and in a cryptorchidism-induced infertility rat model. TM3 Leydig cell viability was measured based on oxidative stress according to treatment. Either distilled water or AG 400 mg/kg of A. gigas extract was administered orally for 4 weeks after unilateral cryptorchidism was induced. After 1, 2, and 4 weeks, six rats from the control group and six rats from treatment group were sacrificed. Testicular weight, semen quality, antioxidant activities, nuclear factor erythroid 2-related factor 2 (Nrf2) protein, and mRNA expression of Nrf2-regulated genes were analyzed. Treatment with A. gigas extract (1) protected TM3 cells against oxidative stress in a dose-dependent manner, (2) improved the mean weight of the cryptorchid testis, (3) maintained sperm counts, motility, and spermatogenic cell density, (4) decreased levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and increased levels of superoxide dismutase (SOD), (5) significantly increased Nrf2 and heme oxygenase-1 (HO-1), and (6) significantly decreased apoptosis. This study suggests that decursin extracted from A. gigas is a supplemental agent that can reduce oxidative stress by Nrf2-mediated upregulation of HO-1 in rat experimentally induced unilateral cryptorchidism and may improve cryptorchidism-induced infertility. PMID:27034737

Protective Effect of Decursin Extracted from Angelica gigas in Male Infertility via Nrf2/HO-1 Signaling Pathway.

PubMed

Bae, Woong Jin; Ha, U Syn; Choi, Jin Bong; Kim, Kang Sup; Kim, Su Jin; Cho, Hyuk Jin; Hong, Sung Hoo; Lee, Ji Youl; Wang, Zhiping; Hwang, Sung Yeoun; Kim, Sae Woong

2016-01-01

Higher testicular temperature results in altered spermatogenesis due to heat-related oxidative stress. We examined the effects of decursin extracted from Angelica gigas Nakai on antioxidant activity in vitro and in a cryptorchidism-induced infertility rat model. TM3 Leydig cell viability was measured based on oxidative stress according to treatment. Either distilled water or AG 400 mg/kg of A. gigas extract was administered orally for 4 weeks after unilateral cryptorchidism was induced. After 1, 2, and 4 weeks, six rats from the control group and six rats from treatment group were sacrificed. Testicular weight, semen quality, antioxidant activities, nuclear factor erythroid 2-related factor 2 (Nrf2) protein, and mRNA expression of Nrf2-regulated genes were analyzed. Treatment with A. gigas extract (1) protected TM3 cells against oxidative stress in a dose-dependent manner, (2) improved the mean weight of the cryptorchid testis, (3) maintained sperm counts, motility, and spermatogenic cell density, (4) decreased levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and increased levels of superoxide dismutase (SOD), (5) significantly increased Nrf2 and heme oxygenase-1 (HO-1), and (6) significantly decreased apoptosis. This study suggests that decursin extracted from A. gigas is a supplemental agent that can reduce oxidative stress by Nrf2-mediated upregulation of HO-1 in rat experimentally induced unilateral cryptorchidism and may improve cryptorchidism-induced infertility.

The Second-to-Fourth Digit Ratio in Cryptorchidism: A Case-Control Study

PubMed Central

Hwang, Hawook; Jo, Hyun Wook; Yun, Bongju; Kim, Taewoo; Yu, Daeseon; Park, Jinsung; Kim, Dae Kyeng

2014-01-01

Purpose The homeobox (Hox) genes a and d controlling limb and genital development influence the digit ratio and the fetal production of testicular androgen, which may result in testicular descent in boys. To assess whether the digit ratio reflects disease status, we investigated the second and fourth finger lengths in children with cryptorchidism, in children with hydrocele as a disease control, and in healthy controls (boys and girls). Materials and Methods One hundred ninety-six children (46 with cryptorchidism, 50 with hydrocele, 50 healthy boys, and 50 healthy girls) who were 6 to 23 months of age were prospectively enrolled. Digit lengths were measured by 2 investigators, and the mean value was recorded. Results The second-to-fourth digit ratios (2D:4Ds) of the left hand in the cryptorchidism group, hydrocele group, healthy boys, and healthy girls were 0.958, 0.956, 0.950, and 0.956, respectively. The 2D:4D values of the right hand were 0.946, 0.945, 0.952, and 0.969, respectively. The right and left 2D:4D ratios were not significantly different among groups. The 2D:4D of both hands was not related to age, weight, or height. Conclusions According to these results, the 2D:4D was not significantly different in boys with cryptorchidism than in boys with hydrocele or in healthy controls (boys and girls) and failed to reflect disease conditions in the infant period. PMID:24578812

Organic Food Consumption during Pregnancy and Hypospadias and Cryptorchidism at Birth: The Norwegian Mother and Child Cohort Study (MoBa).

PubMed

Brantsæter, Anne Lise; Torjusen, Hanne; Meltzer, Helle Margrete; Papadopoulou, Eleni; Hoppin, Jane A; Alexander, Jan; Lieblein, Geir; Roos, Gun; Holten, Jon Magne; Swartz, Jackie; Haugen, Margaretha

2016-03-01

The etiologies of the male urogenital anomalies hypospadias and cryptorchidism remain unclear. It has been suggested that maternal diet and environmental contaminants may affect the risk of these anomalies via placental or hormonal disturbances. We examined associations between organic food consumption during pregnancy and prevalence of hypospadias and cryptorchidism at birth. Our study includes 35,107 women participating in the Norwegian Mother and Child Cohort Study (MoBa) who delivered a singleton male infant. Information about use of six groups of organically produced food (vegetables, fruit, bread/cereal, milk/dairy products, eggs, and meat) during pregnancy was collected by a food frequency questionnaire. Women who indicated that they sometimes, often, or mostly consumed organic foods in at least one of the six food groups were classified as organic food consumers in analyses. Hypospadias and cryptorchidism diagnoses were retrieved from the Medical Birth Registry of Norway. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression. Seventy-four male newborns were diagnosed with hypospadias (0.2%), and 151 with cryptorchidism (0.4%). Women who consumed any organic food during pregnancy were less likely to give birth to a boy with hypospadias (OR = 0.42; 95% CI: 0.25, 0.70, based on 21 exposed cases) than women who reported they never or seldom consumed organic food. Associations with specific organic foods were strongest for vegetable (OR = 0.36; 95% CI: 0.15, 0.85; 10 exposed cases) and milk/dairy (OR = 0.43; 95% CI: 0.17, 1.07; 7 exposed cases) consumption. No substantial association was observed for consumption of organic food and cryptorchidism. Consumption of organically produced foods during pregnancy was associated with a lower prevalence of hypospadias in our study population. These findings were based on small numbers of cases and require replication in other study populations.

Organic Food Consumption during Pregnancy and Hypospadias and Cryptorchidism at Birth: The Norwegian Mother and Child Cohort Study (MoBa)

PubMed Central

Brantsæter, Anne Lise; Torjusen, Hanne; Meltzer, Helle Margrete; Papadopoulou, Eleni; Hoppin, Jane A.; Alexander, Jan; Lieblein, Geir; Roos, Gun; Holten, Jon Magne; Swartz, Jackie; Haugen, Margaretha

2015-01-01

Background The etiologies of the male urogenital anomalies hypospadias and cryptorchidism remain unclear. It has been suggested that maternal diet and environmental contaminants may affect the risk of these anomalies via placental or hormonal disturbances. Objectives We examined associations between organic food consumption during pregnancy and prevalence of hypospadias and cryptorchidism at birth. Methods Our study includes 35,107 women participating in the Norwegian Mother and Child Cohort Study (MoBa) who delivered a singleton male infant. Information about use of six groups of organically produced food (vegetables, fruit, bread/cereal, milk/dairy products, eggs, and meat) during pregnancy was collected by a food frequency questionnaire. Women who indicated that they sometimes, often, or mostly consumed organic foods in at least one of the six food groups were classified as organic food consumers in analyses. Hypospadias and cryptorchidism diagnoses were retrieved from the Medical Birth Registry of Norway. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression. Results Seventy-four male newborns were diagnosed with hypospadias (0.2%), and 151 with cryptorchidism (0.4%). Women who consumed any organic food during pregnancy were less likely to give birth to a boy with hypospadias (OR = 0.42; 95% CI: 0.25, 0.70, based on 21 exposed cases) than women who reported they never or seldom consumed organic food. Associations with specific organic foods were strongest for vegetable (OR = 0.36; 95% CI: 0.15, 0.85; 10 exposed cases) and milk/dairy (OR = 0.43; 95% CI: 0.17, 1.07; 7 exposed cases) consumption. No substantial association was observed for consumption of organic food and cryptorchidism. Conclusions Consumption of organically produced foods during pregnancy was associated with a lower prevalence of hypospadias in our study population. These findings were based on small numbers of cases and require replication in other study populations. Citation Brantsæter AL, Torjusen H, Meltzer HM, Papadopoulou E, Hoppin JA, Alexander J, Lieblein G, Roos G, Holten JM, Swartz J, Haugen M. 2016. Organic food consumption during pregnancy and hypospadias and cryptorchidism at birth: the Norwegian Mother and Child Cohort Study (MoBa). Environ Health Perspect 124:357–364; http://dx.doi.org/10.1289/ehp.1409518 PMID:26307850

CHANGES IN FETAL TESTIS GENE EXPRESSION AND STEROID HORMONE SYNTHESIS INDUCED IN MALE OFFSPRING AFTER MATERNAL TREATMENT WITH PHTHALATE ESTERS

EPA Science Inventory

Targeted inactivation of the insulin-like hormone 3 (insl3) gene in male mice results in altered gubernacular development, disrupted testis decent, and cryptorchidism. Cryptorchidism is a fairly common human malformation, being displayed in 1-3% of males at birth. Since only a s...

Positive Oct -3/4 and D2-40 Immunohistochemical Expression in Germ Cells and Suspected Histology Pattern of Intratubular Germ Cell Neoplasia in Boys with Cryptorchidism Vanish after the Age of 2 Years.

PubMed

Thorup, Jorgen; Clasen-Linde, Erik; Cortes, Dina

2017-08-01

Introduction  Intratubular germ cell neoplasia (ITGCN) is a precursor to testicular germ cell cancer. Adult germ cell cancer immunohistochemical markers may fail to detect ITGCN in prepubertal boys with congenital cryptorchidism, because positive immunohistochemistry is commonly seen in boys younger than the age of 2 years, where most orchiopexies are performed. The aim of the study was to evaluate the diagnostic challenge to differentiate between a histological pattern of ITGCN and a histological pattern with some atypical germ cells and all positive cancer immunohistochemical markers, but no increased risk of malignancy. Materials and Methods  Histology sections from 373 testicular biopsies from 289 boys aged 1 month to 2 years operated for cryptorchidism were incubated with primary antibodies including anti-placental-like-alkaline phosphatase, antiOct-3/4, anti-C-kit, anti-D2-40, and in case of repeat biopsy with anti-stem cell factor (SCF) receptor. Results  The prevalence of Oct-3/4 and D2-40-positive staining of germ cells in testicular biopsies were in age groups less than 6 months, 100% and 50%; 6-12 months, 60% and 17%; and 1-2 years, 12% and 4%. A 1 year, 1-month-old boy with Prader-Willi syndrome treated with growth hormone had ITGCN in both cryptorchid testes. In another three bilateral nonsyndromic cases, 8 months, 8 months and 1-year-old, a histological pattern in accordance with ITGCN was found. These three boys had a repeat biopsy from both testes performed at the age of 3 years, 4 months, 3.5 years, and 3 years, 10months, respectively. In all cases, the Oct-3/4 and D2-40 positive germ cells turned negative and the histological pattern normalized completely. The primary biopsies had SCF negative germ cells. Conclusion  This study is valuable in identifying the age-related change in Oct-3/4 or D2-40 immunopositive germ cells in seminiferous tubules. An ITGCN-like histological pattern in nonsyndromic cryptorchidism will vanish after the age of 3 years. Even when immunohistochemistry is applied, prepubertal ITGCN is so rarely demonstrated in cryptorchid testes, that it is not plausible that ITGCN generally originates during fetal development in cryptorchidism. Georg Thieme Verlag KG Stuttgart · New York.

Post-fertilization effect of bilateral primary testicular damage induced by unilateral cryptorchidism in the rat model.

PubMed

Tsounapi, P; Honda, M; Dimitriadis, F; Shimizu, S; Hikita, K; Muraoka, K; Sejima, T; Saito, M; Tomita, S; Sofikitis, N; Takenaka, A

2016-03-01

Cryptorchidism, a common anomaly of the male genitalia, affects 2-4% of male infants. The post-fertilization effects of unilateral cryptorchidism model in the rat and the effects of antioxidant treatment were investigated. Six-week-old male Wistar rats were randomly separated into four groups. Unilateral cryptorchidism was induced in the right testis of three groups. One group was treated with saline intraperitoneally (i.p.) (Crypto), one group was treated with taurine (500 mg/kg, i.p.; Tau), and another group was treated with sivelestat (15 mg/kg i.p.; Siv). The control group was treated with saline i.p. The treatment was daily for 8 weeks. Five days before sacrifice, mating studies were performed. Body, testicular, and epididymal weights were recorded. Malondialdehyde (MDA) levels in the seminal vesicular fluid (SVF) were measured. Testicular levels of MDA and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were determined bilaterally. TUNEL assay was used to examine DNA fragmentation bilaterally. Histological examination and the Johnsen score were used to evaluate morphological testicular alterations. The Crypto group demonstrated significantly lower right testicular and epididymal weights, significantly increased SVF-MDA levels, testicular MDA and 8-OHdG levels, and the apoptotic score bilaterally compared to the controls. Furthermore, histological evaluation revealed significantly reduced spermatogenesis and mild injury to the cryptorchid testes compared to the control. Treatment with both taurine and sivelestat significantly reduced SVF-MDA levels, testicular MDA, 8-OHdG, and apoptosis bilaterally compared to the Crypto group. Antioxidant treatment was unable to ameliorate spermatogenesis. Newborns delivered by females that mated with Crypto-males had significantly lower body weight compared with the respective animals from the control, Tau and Siv groups. The present study demonstrated that unilateral cryptorchidism-induced testicular damage can significantly affect the contralateral testis as well having further deleterious post-fertilization effect on the development of newborns. Treatment with antioxidants can partially improve the testicular damage bilaterally with beneficial effects for the newborns. © 2016 American Society of Andrology and European Academy of Andrology.

An evolution of orchiopexy: historical aspect.

PubMed

Park, Kwanjin; Choi, Hwang

2010-03-01

The history of treatment for cryptorchidism dates back more than 200 years. This review is intended to highlight some historical aspect that led us to our current surgical treatment of this condition. The medical and historical surgical literatures pertaining to cryptorchidism were reviewed. Data sources were PubMed, Embase, conference proceedings, and bibliographies. No language, date, or publication status restrictions were imposed. The study of cryptorchidism began with the anatomical descriptions of Baron Albrecht von Haller and John Hunter. Attempts at surgical correction of the undescended testis began in the early 1800s, culminating in the first successful orchiopexy by Thomas Annandale in 1877. Max Schüller, Arthur Dean Bevan and Lattimer contributed to the establishment of current techniques for standard orchiopexy. Later, laparoscopy, high inguinal incision (Jones' approach) and scrotal approach were added to the list of current orchiopexy.

Genital anomalies in boys and the environment.

PubMed

Main, Katharina M; Skakkebaek, Niels E; Virtanen, Helena E; Toppari, Jorma

2010-04-01

The prevalence of male reproductive disorders, such as testicular cancer and impaired semen quality, is increasing in many, albeit not all, countries. These disorders are aetiologically linked with congenital cryptorchidism and hypospadias by common factors leading to perinatal disruption of normal testis differentiation, the testicular dysgenesis syndrome (TDS). There is recent evidence that also the prevalence of genital malformations is increasing and the rapid pace of increase suggests that lifestyle factors and exposure to environmental chemicals with endocrine disrupting properties may play a role. Recent prospective studies have established links between perinatal exposure to persistent halogenated compounds and cryptorchidism, as well as between phthalates and anti-androgenic effects in newborns. Maternal alcohol consumption, mild gestational diabetes and nicotine substitutes were also identified as potential risk factors for cryptorchidism. It may be the cocktail effect of many simultaneous exposures that result in adverse effects, especially during foetal life and infancy. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Persistent Pesticides in Human Breast Milk and Cryptorchidism

PubMed Central

Damgaard, Ida N.; Skakkebæk, Niels E.; Toppari, Jorma; Virtanen, Helena E.; Shen, Heqing; Schramm, Karl-Werner; Petersen, Jørgen H.; Jensen, Tina K.; Main, Katharina M.

2006-01-01

Introduction Prenatal exposure to some pesticides can adversely affect male reproductive health in animals. We investigated a possible human association between maternal exposure to 27 organochlorine compounds used as pesticides and cryptorchidism among male children. Design Within a prospective birth cohort, we performed a case–control study; 62 milk samples from mothers of cryptorchid boys and 68 from mothers of healthy boys were selected. Milk was collected as individual pools between 1 and 3 months postpartum and analyzed for 27 organochlorine pesticides. Results Eight organochlorine pesticides were measurable in all samples (medians; nanograms per gram lipid) for cases/controls: 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (p,p′-DDE): 97.3/83.8; β-hexachlorocyclohexane (β-HCH): 13.6/12.3; hexachlorobenzene (HCB): 10.6/8.8; α -endosulfan: 7.0/6.7; oxychlordane: 4.5/4.1; 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p′-DDT): 4.6/4.0; dieldrin: 4.1/3.1; cis-heptachloroepoxide (cis-HE): 2.5/2.2. Five compounds [octachlorostyrene (OCS); pentachlorobenzene, 1,1-dichloro-2,2-bis(4-chlorophenyl)ethane (p,p′-DDD); o,p′-DDT; mirex] were measurable in most samples (detection rates 90.8–99.2%) but in lower concentrations. For methoxychlor, cis-chlordane, pentachloroanisole (PCA), γ -HCH, 1,1-dichloro-2-(2-chlorophenyl)-2,2(4-chlorophenyl)ethane, trans-chlordane, α -HCH, and o,p′-DDE, both concentrations and detection rates were low (26.5–71.5%). Heptachlor, HCH (δ, ɛ ), aldrin, β-endosulfan and trans-heptachloroepoxide were detected at negligible concentrations and low detection rates and were not analyzed further. Seventeen of 21 organochlorine pesticides [p,p′-DDT, p,p′-DDE, p,p′-DDD, o,p′-DDT, HCH (α , β, γ ), HCB, PCA, α -endosulfan, cis-HE, chlordane (cis-, trans-) oxychlordane, methoxychlor, OCS, and dieldrin] were measured in higher median concentrations in case milk than in control milk. Apart from trans-chlordane (p = 0.012), there were no significant differences between cryptorchid and healthy boys for individual chemicals. However, combined statistical analysis of the eight most abundant persistent pesticides showed that pesticide levels in breast milk were significantly higher in boys with cryptorchidism (p = 0.032). Conclusion The association between congenital cryptorchidism and some persistent pesticides in breast milk as a proxy for maternal exposure suggests that testicular descent in the fetus may be adversely affected. PMID:16835070

Evaluation of orchiopexy practice patterns in patients with cryptorchidism: a single-centre study.

PubMed

Moslemi, Mohammad Kazem

2014-04-01

A retrospective study was conducted to determine the age at which orchiopexy was performed, and the laterality and anatomic location of undescended testes (UDTs) or non-palpable testes (NPTs). All documented orchiopexies performed in a large referral centre of Qom province, Qom, Iran during a 5 year period were evaluated. A total of 324 patients admitted for surgical correction of cryptorchidism from 2005 to 2009 were eligible for inclusion in our study. The patients were divided into two groups: group A paediatric orchiopexy, and group B adult orchiopexy. There were 252 paediatric patients (78%), with a mean age of 4.44 years, and 72 adult patients (22%). Forty-three patients (17%) were under 2 years of age and 59 patients (23.5%) were between 2 and 3 years. Right-side involvement was seen in 126 patients (50%), left-side in 91 patients (36%), and bilateral involvement in 35 patients (14%). Unilateral cryptorchidism was seen in 217 patients (85%). Regarding the anatomical location of the testes in unilateral cryptorchidism, superficial inguinal testis was seen in 117 patients (54%). The higher age of orchiopexies determined from this study compared with the recommended age for surgery, indicates that active interventions are necessary with public health education programs for patients, parents, midwives and general practitioners. Copyright © 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Clinical and histopathological results of the adult patients with unilateral cryptorchidism

PubMed Central

Ateş, Ferhat; Soydan, Hasan; Okçelik, Sezgin; Çırakoğlu, Abdullah; Yılmaz, İsmail; Malkoç, Ercan; Karademir, Kenan

2016-01-01

Objective To evaluate the clinical and histopathological results of adult unilateral cryptorchidism patients. Material and methods Data from adult unilateral cryptorchidism patients that underwent orchiectomy in our clinic between between January 2004 and March 2013 were retrospectively evaluated. Patients were divided into three groups as intra-abdominal, inguinal canal and superficial inguinal region according to the location of the undescended testes. Patients were also grouped according to their testicular volume (<4 cc, 4.1–12 cc, and >12 cc). Histopathology results of orchiectomy specimens were classified as follows: 1. Sertoli cells only, testicular atrophy and vanished testis (anorchia) 2. Hypospermatogenesis, and 3. Maturation arrest. Patients were grouped as normospermia, azoospermia and oligo/astheno/teratospermia groups according to semen analysis results. Correlations between testicular localization, testicular size, semen analysis and pathology results were evaluated. Incidental tumor detection rates were also calculated. Results Two hundred and forty-four adult unilateral cryptorchidism patients underwent orchiectomy in our clinic. There was no a significant relationship between location of the testis and testicular pathology results (p=0.707). Most common semen analysis results was normospermia in patients with high testicular volume group however azoospermia and oligoasthenospermia observed commonly in patients with low testicular volume group. There was a significant relationship between testicular volume and semen analysis results (p=0.023). No significant relationship was observed between semen analysis and pathological results (p=0.929). After an evaluation of all factors with possible effects on the semen analysis results, only testicular volume (p=0.036) was found to have a significant impact. Only one case (0.4%) was incidentally diagnosed seminoma after a review of 233 patients with available histopathological results on record. Conclusion Adult unilateral cryptorchidism has a minimal effect on male fertility or even this effect can be overlooked. Low detection rates of incidental germ cell tumors also make an orchiectomy decision questionable in such cases. PMID:27274891

[Cryptorchidism with didymo-epididymal dissociation and Robinow's syndrome: 2 case reports].

PubMed

Fabbro, M A; D'Agostino, S; Costa, L; Musi, L; Cappellari, F

1997-01-01

Two brothers of normal not consanguineous parents, with bilateral intrabdominal cryptorchidism, were admitted to our Institution. Both children had short stature, limb and hand malformations and craniofacial patterns of Robinow syndrome. During the orchidopexy, bilateral epididymal and vasal abnormalities were found in both of them. This anomaly associated with Robinow syndrome has never been reported before. These two cases provides the Authors with the opportunity of reviewing clinical features, genetics and radiological patterns of this rare syndrome.

Risk factors for testicular cancer: a case-control study in twins.

PubMed

Swerdlow, A J; De Stavola, B L; Swanwick, M A; Mangtani, P; Maconochie, N E

1999-06-01

Early life and anthropometric risk factors for testicular cancer were examined in a case-control study in England and Wales in which affected male twins were compared with their unaffected male co-twins. Questionnaire data was obtained for 60 twin pairs. Significantly raised risk of testicular cancer occurred in twins who had longer arms and legs than their co-twin. There was a significant excess of testicular cancer reported in non-twin brothers, as well as in twin brothers, of cases. Risk was also significantly raised in relation to cryptorchidism. The results on limb length suggest that factors, perhaps nutritional, affecting growth before puberty, may be causes of testicular cancer. The results on risk in brothers add to evidence of a large genetic component in aetiology of the tumour. The risk associated with cryptorchidism in the twins accords with the hypothesis that cryptorchidism is causally associated with testicular cancer because it is a cause of the malignancy, rather than because the same maternal factors experienced in utero cause both conditions.

Circumcision-incision orchidopexy: A novel technique for palpable, low inguinal undescended testis.

PubMed

Chua, Michael E; Silangcruz, Jan Michael A; Gomez, Odina; Dy, Jun S; Morales, Marcelino L

2017-11-01

Given that both orchidopexy and circumcision are commonly done in a single operative setting, we adopted a technique of combined orchidopexy and circumcision using a single circumcision incision. We applied this new technique to boys with palpable, low inguinal cryptorchidism. Here we describe a case series of 7 boys who underwent concurrent orchidopexy via the circumcision site. We present this novel technique and discuss our preliminary outcomes, including the anatomic basis and feasibility. The technique appears to be an alternative for concurrent circumcision and cryptorchid cases with palpable, low inguinal testes.

Anti-Müllerian hormone (AMH) profiles as a novel biomarker to evaluate the existence of a functional cryptorchid testis in Japanese Black calves.

PubMed

Kitahara, Go; El-Sheikh Ali, Hossam; Sato, Tomohiro; Kobayashi, Ikuo; Hemmi, Koichiro; Shirao, Yuka; Kamimura, Shunichi

2012-01-01

Anti-Müllerian hormone (AMH) and testosterone (T) profiles in blood were investigated before and after an hCG stimulation test to assess their sensitivity and specificity for the existence of a functional cryptorchid testis in Japanese Black calves. The hCG (3,000 IU) was administered on Day 0, and peripheral blood was collected on Days 0 (just before hCG injection), 5 and 7 in intact male calves (Intact; n=19), bilateral castrated calves (Castrated; n=17), unilateral cryptorchid calves, which abdominal testis could been extracted (Uni-crypto; n=9). Castration of a descended testis was carried in the Castrated and Uni-Crypto groups on Day -14. The AMH detectability and the optimum cut-off point for T levels using the receiver operating characteristic curve were verified to characterize the cryptorchid testis. AMH values on Day 0 were 21.1 ± 5.1 and 29.0 ± 7.5 ng/ml in the Intact and Uni-crypto groups, respectively (Mean ± SEM). AMH levels were under the detection limit in the Castrated group (i.e., < 0.006 ng/ml). T showed its peak levels on Day 5 in the Intact group (26.8 ± 4.2 ng/ml), while it remained low in the Castrated group (< 0.9 ng/ml) and did not show a significant difference in the Uni-crypto group. The detectable levels for AMH was 0.006 ng/ml, and the optimum cut-off point for T was 0.9 ng/ml; the sensitivity and specificity for evaluation of testicular descent into the scrotum were 1.0 for both the AMH and T levels. The detection rates in the Uni-crypto group using them were 1.0 and 0.57 for AMH on Day 0 and T on Days 5 or 7, respectively. In conclusion, plasma AMH profiles could be used as a novel biomarker to evaluate the existence of a functional cryptorchid testis in Japanese Black calves.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Virtanen, H.E.; Rajpert-De Meyts, E.; Main, K.M.

Patients with 45,X0/46XY karyotype often present with intersex phenotype and testicular dysgenesis. These patients may also have undescended testes (cryptorchidism), hypospadias and their spermatogenesis is severely disrupted. They have a high risk for testicular cancer. These patients have the most severe form of testicular dysgenesis syndrome (TDS). We have hypothesized that testicular cancer, cryptorchidism, hypospadias and poor spermatogenesis are all signs of a developmental disturbance that was named as testicular dysgenesis syndrome. The hypothesis is based on clinical and epidemiological findings and on biological and experimental evidence. Signs of TDS share several risk factors, such as small birth weight (particularlymore » being small for gestational age), and they are risk factors for each other. All of them have background in fetal development. They show strong epidemiological links so that countries with high incidence of testicular cancer, such as Denmark, tend to also have high prevalence rates of cryptorchidism and hypospadias and poor semen quality. Vice versa, in countries with good male reproductive health, e.g., in Finland, all these aspects are better than in Denmark. Although genetic abnormalities can cause these disorders, in the majority of cases, the reasons remain unclear. Adverse trends in the incidence of male reproductive disorders suggest that environmental and life style factors contribute to the problem. Endocrine disrupters are considered as prime candidates for environmental influence. Fetal exposure to high doses of dibutyl phthalate was shown to cause a TDS-like phenotype in the rats. Studies are underway to assess whether there is any exposure-outcome relation with selected chemicals (persistent organic pollutants, pesticides, phthalates) and cryptorchidism00.« less

Maternal serum level of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene and risk of cryptorchidism, hypospadias, and polythelia among male offspring.

PubMed

Longnecker, Matthew P; Klebanoff, Mark A; Brock, John W; Zhou, Haibo; Gray, Kimberly A; Needham, Larry L; Wilcox, Allen J

2002-02-15

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) is a metabolite of the insecticide 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) and is a ubiquitous environmental contaminant. Nearly everyone in the United States has a detectable serum level of DDE. DDE was recently found to inhibit binding of androgen to its receptor and to block androgen action in rodents. Normal development of male genitalia in mammals depends on androgen action. The authors used stored serum samples to examine the relation between maternal DDE levels during pregnancy and adjusted odds of cryptorchidism (n = 219), hypospadias (n = 199), and polythelia (extra nipples) (n = 167) among male offspring, using a nested case-control design with one control group (n = 552). Subjects were selected from the Collaborative Perinatal Project, a US birth cohort study begun in 1959-1966, when DDE levels were much higher than they are at present. Compared with boys whose mother's recovery-adjusted serum DDE level was less than 21.4 microg/liter, boys with maternal levels greater than or equal to 85.6 microg/liter had adjusted odds ratios of 1.3 (95% confidence interval (CI): 0.7, 2.4) for crypt-orchidism, 1.2 (95% CI: 0.6, 2.4) for hypospadias, and 1.9 (95% CI: 0.9, 4.0) for polythelia. For cryptorchidism and polythelia, the results were consistent with a modest-to-moderate association, but in no instance was the estimate very precise. The results were inconclusive.

Testicular leiomyosarcoma and marked alopecia in a cryptorchid ferret (Mustela putorius furo).

PubMed

Kammeyer, P; Ziege, S; Wellhöner, S; Cichowski, S; Baumgärtner, W

2014-01-01

A 3.5-year-old male ferret, bought as male castrated, was presented to the veterinarian with marked alopecia of back, neck, abdomen and tail, a pronounced sexual behaviour and weight loss. An inguinal mass of about 2.5 cm in diameter was diagnosed as potentially tumorous inguinal testicle by ultrasound and fine-needle aspiration. Adrenal glands and prostate were ultrasonographically unremarkable. The surgically removed cryptorchid testicle contained a greyish tumour that was histologically composed of spindle-shaped cells with elongated nuclei, embedded in a fibro-vascular stroma. Up to two mitotic figures per high power field were noted. Additionally, an interstitial cell hyperplasia and marked reactive proliferation of a collagen-rich fibrous tissue were observed. Tumour cells were positive for α-smooth muscle actin, desmin, and occasionally vimentin and S-100, leading to the diagnosis of an intratesticular leiomyosarcoma. As an adrenal-associated endocrinopathy was excluded and a complete fur recovery was observed after removal of the cryptorchid testicle the alopecia was eventually due to hormones produced by the hyperplastic interstitial (Leydig) cells.

Coincidence of Persistent Müllerian duct syndrome and testicular tumors in dogs.

PubMed

Park, Eun Jung; Lee, Seok-Hee; Jo, Young-Kwang; Hahn, Sang-Eun; Go, Do-Min; Lee, Su-Hyung; Lee, Byeong-Chun; Jang, Goo

2017-06-02

Persistent Müllerian duct syndrome (PMDS), a rare form of male pseudohermaphroditism in dogs, is an abnormal sexual phenotype in males that is characterized by the existence of a hypoplastic oviduct, uterus, and cranial part of the vagina. Dogs suffering from PMDS are often accompanied by cryptorchidism. To date, it has been mainly found in the Miniature Schnauzer breed. In this report, two cases of PMDS with a malignant testicular tumor originating from cryptorchidism in breeds other than the Miniature Schnauzer breed are described. The patients were a seven-year-old male Maltese dog and a 17-year-old male mixed-breed dog weighing 3.8 kg. They also exhibited an enlarged prostate with or without abscess and an elevated serum estradiol level and were surgically treated to remove the testicular tumor and Müllerian duct derivatives. It is recommended that PMDS should be differentially diagnosed by ultrasonography and that orchiectomy be performed at an early age in patients suspected to have cryptorchidism to prevent the ectopic testes from becoming tumorous.

[Causes of orchiectomy: An analysis of 291 cases].

PubMed

Long, Zhi; He, Le-ye; Tang, Yu-xin; Jiang, Xian-zhen; Wang, Jin-wei; Chen, Wen-hang; Tang, Jin; Zhang, Yi-chuan; Yang, Chi

2015-07-01

To study the causes of orchiectomy in different age groups. We retrospectively reviewed the clinical data about 291 cases of orchiectomy performed between March 1993 and October 2014 and analyzed the causes of surgery and their distribution in different age groups. The main causes of orchiectomy were testicular torsion (45.8%), cryptorchidism (32.5%) and testicular tumor (16.9%) in the patients aged 0-25 years, testicular tumor (42.4%), cryptorchidism (25.9%) and tuberculosis (10.6%) in those aged 26-50 years. Prostate cancer was the leading cause in those aged 51-75 years (77.6%) or older (84.0%)), and testicular tumor was another cause in the 51-75 years old men (10.2%). Prostate cancer, testicular tumor, cryptorchidism, and testicular torsion were the first four causes of orchiectomy between 1993 and 2009. From 2010 to 2014, however, testicular tumor rose to the top while prostate cancer dropped to the fourth place. The causes of orchiectomy vary in different age groups. The proportion of castration for prostate cancer patients significantly reduced in the past five years, which might be attributed to the improvement of comprehensive health care service.

Circumcision-incision orchidopexy: A novel technique for palpable, low inguinal undescended testis

PubMed Central

Silangcruz, Jan Michael A.; Gomez, Odina; Dy, Jun S.; Morales, Marcelino L.

2017-01-01

Given that both orchidopexy and circumcision are commonly done in a single operative setting, we adopted a technique of combined orchidopexy and circumcision using a single circumcision incision. We applied this new technique to boys with palpable, low inguinal cryptorchidism. Here we describe a case series of 7 boys who underwent concurrent orchidopexy via the circumcision site. We present this novel technique and discuss our preliminary outcomes, including the anatomic basis and feasibility. The technique appears to be an alternative for concurrent circumcision and cryptorchid cases with palpable, low inguinal testes. PMID:29124248

Prenatal exposure to glycol ethers and cryptorchidism and hypospadias: a nested case-control study.

PubMed

Warembourg, Charline; Botton, Jérémie; Lelong, Nathalie; Rouget, Florence; Khoshnood, Babak; Le Gléau, Florent; Monfort, Christine; Labat, Laurence; Pierre, Fabrice; Heude, Barbara; Slama, Rémy; Multigner, Luc; Charles, Marie-Aline; Cordier, Sylvaine; Garlantézec, Ronan

2018-01-01

Glycol ethers (GE) are oxygenated solvents frequently found in occupational and consumer products. Some of them are well-known testicular and developmental animal toxicants. This study aims to evaluate the risk of male genital anomalies in association with prenatal exposure to GE using urinary biomarkers of exposure. We conducted a case-control study nested in two joint mother-child cohorts (5303 pregnant women). Cases of cryptorchidism and hypospadias were identified at birth and confirmed during a 2-year follow-up period (n=14 cryptorchidism and n=15 hypospadias). Each case was matched to three randomly selected controls within the cohorts for region of inclusion and gestational age at urine sampling. Concentrations of five GE acidic metabolites were measured in spot maternal urine samples collected during pregnancy. ORs were estimated with multivariate conditional logistic regressions including a Firth's penalisation. Detection rates of urinary GE metabolites ranged from 8% to 93% and only two were sufficiently detected (>33%) in each cohort to be studied: methoxyacetic acid (MAA) and phenoxyacetic acid (PhAA). A significantly higher risk of hypospadias was associated with the highest tertile of exposure to MAA: OR (95% CI) 4.5(1.4 to 23.4). No association were observed with urinary concentration of PhAA, nor with the risk of cryptorchidism. In view of the toxicological plausibility of our results, this study, despite its small sample size, raises concern about the potential developmental toxicity of MAA on the male genital system and calls for thorough identification of current sources of exposure to MAA. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Canine cryptorchism and subsequent testicular neoplasia: case-control study with epidemiologic update.

PubMed

Hayes, H M; Wilson, G P; Pendergrass, T W; Cox, V S

1985-08-01

A retrospective study of 2,912 cryptorchid dogs identified 14 breeds with significantly high risk. Among six distinct closely interrelated breed groups (e.g., toy, miniature, and standard poodles), the risk in the smaller breed was always greater than that in the larger relative, suggesting that genetically influenced maldescent could be, in part, related to physical size or the rate of growth of the involved structures. Testicular tumors were diagnosed in 5.7% of the cryptorchid dogs; half had only Sertoli cell tumors, one-third had only seminomas. The relative risk for Sertoli cell tumor or seminoma was not directly related to a familial risk for cryptorchism. Using the health experience of a control population composed of male dogs with anal sac disease (N = 4,184), there is an estimated relative risk of 9.2 in cryptorchid dogs to develop a testis tumor (95% confidence interval, 5.9-14.3) and 4.2 in dogs with inguinal hernia (95% confidence interval, 1.8-9.5). Considering that the anatomical development of the genital tract, testis descent, and tunic relationships in dog are very similar to that in man, and that the associations of cryptorchism and inguinal hernia with testis neoplasms are also similar, the dog should be an excellent model system to further investigate the causes of human cryptorchism.

The number of spermatogonia in various congenital testicular disorders.

PubMed

Saito, S; Kumamoto, Y

1989-05-01

Various congenital testicular disorders, including monorchism, retractile testis, cryptorchidism and male intersex, were investigated by counting the number of spermatogonia per seminiferous tubule. The results showed that all 7 cases of monorchism had normal numbers of spermatogonia per seminiferous tubule. However, in 29 cases of a retractile testis a normal testis was observed in 13 (44.8 per cent). Therefore testicular dysgenesis is suggested to exist in more than half of cases of the retractile testis. Of 150 cases of cryptorchidism 82 were bilateral and 68 were unilateral. There was no significant difference in the number of spermatogonia per seminiferous tubule between these 2 groups. The higher the testes were located the worse the ratio of spermatogonia per seminiferous tubule. Fewer or absent spermatogonia were observed in 2 patients less than 2 years old. Of 28 contralateral scrotal testes in patients with unilateral cryptorchidism 4 (14.3 per cent) had no spermatogonia per seminiferous tubule and 8 (28.0 per cent) had a decreased number of spermatogonia per seminiferous tubule. The male intersex patients had much damage even in the scrotal testes. From these results it is suggested that these congenital testicular disorders, except monorchism, have similar histological features. Moreover, these conditions are possibly related in etiology to the phenomenon of deficient androgen stimulation.

A Case-Control Study of Maternal Polybrominated Diphenyl Ether (PBDE) Exposure and Cryptorchidism in Canadian Populations.

PubMed

Goodyer, Cynthia G; Poon, Shirley; Aleksa, Katarina; Hou, Laura; Atehortua, Veronica; Carnevale, Amanda; Jednak, Roman; Emil, Sherif; Bagli, Darius; Dave, Sumit; Hales, Barbara F; Chevrier, Jonathan

2017-05-26

Polybrominated diphenyl ethers (PBDEs) are flame retardants found in North American household products during the past four decades. These chemicals leach out in dust as products age, exposing individuals daily through inhalation and ingestion. Animal studies suggest that PBDEs disrupt sex hormones and adversely affect development of the reproductive system. In the present study, we examined whether there is a link between maternal hair PBDE concentrations and the risk of cryptorchidism (undescended testes) in male infants; testis descent is known to be dependent on androgens. Full-term male infants were recruited through clinics in Montreal, Toronto, and London, Canada. Boys with cryptorchidism at 3-18 months of age ( n =137) were identified by pediatric urologists and surgeons; similar-aged controls ( n =158) had no genitourinary abnormalities as assessed by pediatricians. Eight BDE congeners (BDE-28, -47, -99, -100, -153, -154, -183, -209) were measured by GC-MS (gas chromatography-mass spectrometry) in maternal hair samples collected at the time of recruitment. The ∑PBDE geometric mean for maternal hair was 45.35 pg/mg for controls and 50.27 pg/mg for cases; the concentrations of three BDEs (BDE-99, -100, and -154) were significantly higher in cases than controls in unadjusted models. In adjusted models, every 10-fold increase in the concentration of maternal hair BDE-99 [OR=2.53 (95% CI: 1.29, 4.95) or BDE-100 [OR=2.45 (95% CI: 1.31, 4.56)] was associated with more than a doubling in the risk of cryptorchidism. BDE-154 [OR=1.88 (95% CI: 1.08, 3.28) was also significant. Our results suggest that maternal exposure to BDE-99, -100, and -154 may be associated with abnormal migration of testes in the male fetus. This may be due to the anti-androgenic properties of the PBDEs. https://doi.org/10.1289/EHP522.

Adolescent testicular microlithiasis: A case-based, multinational survey of clinical management practices.

PubMed

Brodie, Katie E; Saltzman, Amanda F; Cost, Nicholas G

2018-04-01

Testicular microlithiasis (TM) is a condition characterized by calcium deposits within the testis, usually detected incidentally during ultrasonography of the scrotum. TM has been associated with the presence of, and possibly the development of, testicular malignancy. Our aim was to document international clinical management practices for TM and to analyze what factors and perception of risk influence conservative versus active management and follow-up. European Society for Paediatric Urology (ESPU) and Society for Pediatric Urology (SPU) members were invited to complete an online case-based survey of clinical management practices of TM. Eight cases had a single variable changed each time (classic versus limited TM, unilateral versus bilateral, prior cryptorchidism versus no cryptorchidism) to ascertain the provider's perception of risk. The respondents completed multiple choice questions on initial management, follow-up plan, length and interval of follow-up. Multivariate logistic regression was performed to determine factors associated with decisions on management and follow-up. There were 265 respondents to the survey from 35 countries (Table). Median time in practice was 13 years. Factors that were significantly associated with more aggressive initial management (more than counseling on self-examination) included: not yet in independent practice, low volume TM cases per year, those practicing pediatric and adult urology, classic appearance of TM and cryptorchidism. Factors that were significantly associated with urologist follow-up and active investigation included: European practitioners, low TM case volume per year, those practicing both pediatric urology and pediatric surgery, classic TM appearance and a case history of cryptorchidism. Interval and length of follow-up was wide-ranging, with most respondents favoring annual follow-up. Management of TM varies and a mix of surgeon and case factors significantly influences management strategies. This baseline understanding of the lack of systematic management suggests the need for the development of consensus guidelines and prospective study. Copyright © 2018 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

The mechanism underlying dibutyl phthalate induced shortened anogenital distance and hypospadias in rats.

PubMed

Li, Ning; Chen, Xuyong; Zhou, Xuefeng; Zhang, Wen; Yuan, Jiyan; Feng, Jiexiong

2015-12-01

The purpose of this study was to investigate the mechanism of dibutyl phthalate (DBP) induced hypospadias and shortened anogenital distance (AGD). AGD, hypospadias, and cryptorchidism incidence was observed in male offspring of DBP treated pregnant Wistar rats. Testicular development and testosterone levels of normal and DBP-treated rat embryos were compared. Male offspring of 300mg and 900mg DBP-treated pregnant Wistar rats exhibited shortened average AGD compared with the control group. A 22.7% hypospadias incidence was observed in the 300mg group, but no offspring with cryptorchidism were identified. In the 900mg group, hypospadias and cryptorchidism incidence reached 43.5% and 17.4%, respectively. Between E15.5 and E17.5, the 300mg group exhibited delayed testicular development and testosterone secretion. However, testicular development and testosterone secretion subsequently recovered. The 300mg treated and control groups had similar measures after E19.5. Contrastingly, testicular development and testosterone secretion were significantly diminished throughout development in the 900mg group. Exogenous testosterone partially counteracted DBP-induced changes in the reproductive organs of male offspring of DBP-treated rats. High-dose DBP exposure may induce testicular dysgenesis in rat embryos. Additionally, low-dose DBP may delay testicular development and testosterone secretion during urethral development. This disruption may result in hypospadias. Copyright © 2015 Elsevier Inc. All rights reserved.

International geographic correlation study of the prevalence of disorders of male reproductive health.

PubMed

Serrano, T; Chevrier, C; Multigner, L; Cordier, S; Jégou, B

2013-07-01

Is there evidence at the population level of associations between different male genital disorders, outside Scandinavian countries? At an international scale, there is evidence for a number of correlations between rates of four male reproductive disorders (hypospadias, cryptorchidism, testicular cancer and low sperm concentration). Some associations between these outcomes have been shown in studies focusing on individuals and mainly in Nordic European countries. These associations, together with histological evidence of a dysgenesis pattern in testicular tissue specimens, have generated the concept of the existence of a 'testicular dysgenesis syndrome' originating in utero. This is a geographical correlation study using cancer, malformations rates and sperm quality data collected between the years 1998 and 2005. Incidence rates of testicular cancer were extracted from International Agency for Research on Cancer registries and Globocan, while cryptorchidism and hypospadias prevalence rates were obtained from EUROCAT and International Clearinghouse for Birth Defects Surveillance and Research registries. Sperm concentration data were extracted from recent studies using standardized methodology. A total of 39 registries and 9 sperm studies were selected. Non-parametric Spearman correlation tests were used to test the association between these four disorders. Correlations were computed for all registries together, for registries with high-quality matching coverage only and by continents. Sensitivity analyses were also conducted using data from prospective clinical studies to take into account potential bias related mainly to ascertainment of malformation rates. We found positive correlations between testicular cancer and hypospadias (r = 0.32, P = 0.05) and between hypospadias and cryptorchidism (r = 0.70, P = 0.008). Stronger correlations were observed when using registries with high-quality matching coverage. Among these registries, differences between Europe and the rest of the world appeared (the positive correlation between testicular cancer and cryptorchidism was stronger outside Europe, r = 0.83, P = 0.01 compared with 0.40, P = 0.60 for European registries). A negative correlation between testicular cancer and sperm concentration was observed (r = -0.88, P = 0.002). These correlations support our initial hypothesis but remain only suggestive due to the intrinsic limitations in the study design (i.e. geographical correlation study) and do not allow causal inference. Differences in the ascertainment of malformations rates (definition, length of follow-up) make the international comparison difficult. The small number of registries for some conditions (cryptorchidism) or of studies (for sperm quality) and the absence of information about major risk factors such as ethnicity and socioeconomic status in the registries are also limitations. Our findings are in agreement with results of studies focusing on individuals and suggest that shared risk factors are present in the populations studied.

[How and when to evaluate hypospadias?].

PubMed

Bouvattier, C

2013-09-01

Hypospadias is a frequent congenital malformation, which severity is connected to the spongiosum divergence. Biological and anatomical explorations are necessary, before the recourse to the surgeon, in posterior hypospadias, familial hypospadias, but also in any type of hypospadias associated with cryptorchidism, bifid scrotum, micropenis less than 20mm (full-term newborn), or any other anomaly (skeletal, renal, cardiac…). The "mini-puberty", occurring in the first 4-6 months of life, is a period of intense gonadotropic activity in male newborns. It allows an easy investigation of the testicular function in boys with hypospadias. Hormonal evaluation (testosterone, AMH) should be done the first day of life. Let us remind that a newborn with "hypospadias" and bilateral cryptorchidism must be considered, until proved otherwise, as a girl with congenital adrenal hyperplasia. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Testicular descent related to growth hormone treatment.

PubMed

Papadimitriou, Anastasios; Fountzoula, Ioanna; Grigoriadou, Despina; Christianakis, Stratos; Tzortzatou, Georgia

2003-01-01

An 8.7 year-old boy with cryptorchidism and growth hormone (GH) deficiency due to septooptic dysplasia presented testicular descent related to the commencement of hGH treatment. This case suggests a role for GH in testicular descent.

[Medical treatment of cryptorchism. "Vanitas vanitatum et omnia vanitas"].

PubMed

Parigi, G B

2001-01-01

Aiming to study the effectiveness of medical therapy in cryptorchidism, a computerised Medline research from 1985 to 1999 on the thesaurus word "cryptorchidism" with the filter "drug therapy" was conducted. Of the 147 papers thus retrieved, only those dealing with more than 50 patients were considered. Factors studied were: ultimate aims of therapy, different drugs and/or associations used, suggested age of treatment, dosages and cycles, anatomical position of the testis, mono- or bilaterality of cryptorchidism. For every considered factor results heavily conflicting were found. According to the various Authors, medical treatment has different goals: not only to induce testicular descent but also to improve testicular trophism, to help in diagnosis and/or in surgical treatment, to increase postsurgical fertility, to reduce neoplastic risks, to reduce the psychological stress. About relative effectiveness of drugs, hCG seems to be more effective than LH-RH in most papers; the latter resulted slightly more effective than placebo (from 37% vs 18% to 9% vs 8%). Suggested age for treatment goes from less than 6 months to more than 6 years. In relation to the position, non palpable testes resulted almost uniformly not responding to the therapy, while testes in prescrotal position responded from 17% to 100%. According to the mono- or bilaterality of the lesion, results vary respectively from 58% vs 50% to 14% vs 64%. Relapse rate as well shows a variability from 10% to 63%; effectiveness of a second treatment in such cases goes from 0% to 100%. Drawing definite conclusions from this analysis turned out to be impossible because of the steady high variability in published results, leaving at the end of the day an unappealing sensation of "vanitas" (vacuity).

Aetiological diagnosis of male sex ambiguity: a collaborative study.

PubMed

Morel, Yves; Rey, Rodolfo; Teinturier, Cécile; Nicolino, Marc; Michel-Calemard, Laurence; Mowszowicz, Irène; Jaubert, Francis; Fellous, Marc; Chaussain, Jean-Louis; Chatelain, Pierre; David, Michel; Nihoul-Fékété, Claire; Forest, Maguelone G; Josso, Nathalie

2002-01-01

A collaborative study, supported by the Biomed2 Programme of the European Community, was initiated to optimise the aetiological diagnosis in genetic or gonadal males with intersex disorders, a total of 67 patients with external sexual ambiguity, testicular tissue and/or a XY karyotype. In patients with gonadal dysgenesis or true hermaphroditism, the incidence of vaginal development was 100%, a uterus was present in 60%; uni or bilateral cryptorchidism was seen in nearly all cases of testicular dysgenesis (99%) but in only 57% of true hermaphrodites. Mean serum levels of anti-mullerian hormone and of serum testosterone response to chorionic gonadotropin stimulation were significantly decreased in both conditions, by comparison with patients with unexplained male pseudohermaphroditism or partial androgen insensitivity (PAIS). Mutations in the androgen receptor, 90% within exons 2-8, were detected in patients with PAIS. Clinically, a vaginal pouch was present in 90%, cryptorchidism in 36%. In 52% of cases, no diagnosis could be reached, despite an exhaustive clinical and laboratory work-up, including routine sequencing of exons 2-8 of the androgen receptor. By comparison with PAIS, unexplained male pseudohermaphroditism was characterised by a lower incidence of vaginal pouch (55%) and cryptorchidism (22%) but a high incidence of prematurity/intrauterine growth retardation (30%) or mild malformations (14%). reaching an aetiological diagnosis in cases of male intersex is difficult because of the variability of individual cases. Hormonal tests may help to discriminate between partial androgen insensitivity and gonadal dysgenesis/true hermaphroditism but are of less use for differentiating from unexplained male pseudohermaphroditism. Sequencing of exons 2-8 of the androgen receptor after study of testosterone precursors following human chorionic gonadotrophin stimulation is recommended when gonadal dysgenesis and true hermaphroditism can be excluded.

Cryptorchidism and pesticides: Is there a connection?

PubMed

Fratrić, Ivana; Varga, Jan; Vukmirović, Saša; Sudji, Jan; Živković, Dragana

2017-07-01

The aim of our study was to compare the level of the most common organophosphate metabolite, dimethyl phosphate, in urine of women giving birth to both boys with cryptorchidism (study group), and healthy boys (control group), as well as to compare the level of dimethyl phosphate in our population with the results obtained in other populations. After the ethical approval we included thirty women in both study and control groups. All newborns were born between 38 and 42weeks' gestation. Urine samples were taken on 3rd postpartal day. Gas chromatography with flame photometric detection was used to analyze dimethyl phosphate in urine following the method of Wu et al. Statistical analysis was done using Mann-Whitney test to compare the results in the two groups. Geometric mean of dimethyl phosphate in the study group was 7.18±8.26μg/L and the creatinine-corrected level was 5.63±5.95μg/L, and in the control group, the values are 7.98±6.75μg/L and 6.15±7.01μg/L, respectively. There was not a statistically significant difference in levels of dimethyl phosphate between these two groups (p=0.72786). Dimethyl phosphate levels obtained in similar studies are: 14.4μg/L in Israel, 3.7μg/L in Palestine, 10.3μg/L in Jerusalem, 1.60μg/L in Caribbean islands and 2.60μg/L in Canada. Pregnant women in our country are exposed to organophosphate pesticides, but a correlation between the exposure to organophosphate pesticides and cryptorchidism was not found. I. Prognostic study, prospective study. Copyright © 2016 Elsevier Inc. All rights reserved.

Temporal trends in orchidopexy, Great Britain, 1992-1998.

PubMed

Toledano, Mireille B; Hansell, Anna L; Jarup, Lars; Quinn, Mike; Jick, Susan; Elliott, Paul

2003-01-01

Concern has been expressed in recent years about worsening male reproductive health, possibly mediated by increasing exposures to environmental endocrine-disrupting agents. Trends suggested large increases in cryptorchidism in Britain and the United States between the 1950s and 1980s, although published data on recent trends have been scarce. We examined numbers of orchidopexy procedures, as a marker for cryptorchidism, using routine hospital admission data for England, Wales, and Scotland for fiscal years 1992-1993 through 1998-1999. Annual trends in orchidopexy rates were analyzed by age, in-patient admission versus day case, and geographical region. Orchidopexy rates were also obtained from the General Practice Research Database (GPRD) for England to cross-validate the hospital admissions data. Orchidopexy rates for boys 0-14 years old fell by 33% (from 23.5 to 15.8 per 10,000 population) between 1992 and 1998, with the steepest decline (50%) in 5-9-year-olds. The decreasing trend for 0-14-year-olds was evident in every region in England, in Wales, and in Scotland. Rates remained stable for men 15 or more years old, at 0.7 per 10,000. There was a marked shift from in-patient to day-case procedures. Rates from the GPRD showed a similar downward trend to the hospital data. Our findings could represent either an underlying decrease in the frequency of undescended testis or a fairly dramatic improvement in the diagnosis of cryptorchidism--resulting in fewer orchidopexies performed for retractile testis--in Great Britain during the 1990s, or both. Either way, our findings do not support the postulate of a recent worsening of male reproductive health of the scale suggested by some recent commentators on the endocrine disruptor hypothesis.

Temporal trends in orchidopexy, Great Britain, 1992-1998.

PubMed Central

Toledano, Mireille B; Hansell, Anna L; Jarup, Lars; Quinn, Mike; Jick, Susan; Elliott, Paul

2003-01-01

Concern has been expressed in recent years about worsening male reproductive health, possibly mediated by increasing exposures to environmental endocrine-disrupting agents. Trends suggested large increases in cryptorchidism in Britain and the United States between the 1950s and 1980s, although published data on recent trends have been scarce. We examined numbers of orchidopexy procedures, as a marker for cryptorchidism, using routine hospital admission data for England, Wales, and Scotland for fiscal years 1992-1993 through 1998-1999. Annual trends in orchidopexy rates were analyzed by age, in-patient admission versus day case, and geographical region. Orchidopexy rates were also obtained from the General Practice Research Database (GPRD) for England to cross-validate the hospital admissions data. Orchidopexy rates for boys 0-14 years old fell by 33% (from 23.5 to 15.8 per 10,000 population) between 1992 and 1998, with the steepest decline (50%) in 5-9-year-olds. The decreasing trend for 0-14-year-olds was evident in every region in England, in Wales, and in Scotland. Rates remained stable for men 15 or more years old, at 0.7 per 10,000. There was a marked shift from in-patient to day-case procedures. Rates from the GPRD showed a similar downward trend to the hospital data. Our findings could represent either an underlying decrease in the frequency of undescended testis or a fairly dramatic improvement in the diagnosis of cryptorchidism--resulting in fewer orchidopexies performed for retractile testis--in Great Britain during the 1990s, or both. Either way, our findings do not support the postulate of a recent worsening of male reproductive health of the scale suggested by some recent commentators on the endocrine disruptor hypothesis. PMID:12515691

Laterality, maldescent, trauma and other clinical factors in the epidemiology of testis cancer in Victoria, Australia.

PubMed Central

Stone, J. M.; Cruickshank, D. G.; Sandeman, T. F.; Matthews, J. P.

1991-01-01

Clinical factors were studied in a population based survey of 1,116 cases of testicular neoplasms in Victoria, Australia, between 1950 and 1978. The ratio of right to left sided tumours was 54:46, but the left side predominated among sarcomas (P = 0.006), and in older men. The relative risk (RR) for men with unilateral maldescent was 15 (CI 10-23) and for men with bilateral maldescent 33 (CI 20-55) (odds ratio 1.4, CI 0.5-4, P = 0.7). Calculations per testis in men with unilateral maldescent showed an elevated risk for both the maldescended testis (RR 28, CI 19-41, P less than 0.0001) and the normally descended testis (RR 3, CI 1.2-6, P = 0.04). The RR for men with abdominal maldescent was 55 (CI 36-83) compared to 7 (CI 4-11) for those with inguinal maldescent (odds ratio 8, CI 3-20, P less than 0.0001). Seminomas were more common than nonseminomas (NSGCT) in men with a history of maldescent (odds ratio 1.7, CI 1.1-3, P = 0.02) and also among corrected cryptorchids compared to uncorrected (P = 0.005). Seminomas were diagnosed at an earlier median age in men with corrected cryptorchid testes compared to uncorrected (P = 0.03) and in men with corrected cryptorchid testes compared to normally descended (P = 0.001). Maldescent was also associated with hernia (P = 0.04). Twenty-eight per cent of patients recorded a history of trauma with a higher proportion among NSGCT than among seminomas (P = 0.03). Prior malignancies were reported in nine patients, compared to 3.6 expected; prostate cancer (2) and malignant melanoma (2) were the greatest contributors to the excess. PMID:1677257

Computational Modeling of Male Reproductive Tract Development for Use in Predictive Toxicology (ASCCT meeting)

EPA Science Inventory

Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male...

EMERGING ISSUES RELATED TO ENDOCRINE DISRUPTING CHEMICALS AND ENVIRONMENTAL ANDROGENS AND ANTIANDROGENS

EPA Science Inventory

Wildlife populations from contaminated ecosystems display a variety of reproductive alterations including cryptorchidism in the Florida panther, small baculum in young male otters, small penises in alligators, sex reversal in fish, and altered social behavior in birds. In some c...

[Hypogonadism caused by Gorlin-Goltz syndrome].

PubMed

Marín Romero, Olivia; Hernández Marín, Imelda; Ayala Ruiz, Aquiles R

2006-09-01

The Gorlin-Goltz syndrome is a dominant autosomic disorder characterized by cancerigenic predisposition and multiple development defects, apparently without reproductive compromise. The complex is characterized by four primary symptoms, which include nevoid basal cell epitheliomas malignantly prone, keratocystic jaw, skeletal abnormalities and intracranial calcifications. Apparently, reproductive problems reported had been rarely associated with this syndrome. We present the case of a patient with clinic stigmatae of Gorlin-Goltz syndrome, who had a characteristic progress as seen in the literature; he was the fifth product of a 43 year-old female (father was 48 years old); who at birth disclosed right eye microftalmy, bilateral cryptorchidism surgically treated at age of six. At puberty, an odontogenic cyst of the jaw was noted and enucleated. He also showed facial nevi in neck, thorax and abdomen. When he was admitted being 14 years old in our clinic, he had recurrent bilateral cryptorchidism, sexual immatturity and infertility. It is important to take into consideration Gorlin-Goltz stigmatae in cases of hypogonadism in order to recognize a further genetic influence.

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

EPA Science Inventory

Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male...

TOXICOLOGY OF MALE REPRODUCTIVE DEVELOPMENT: PROFILING 774 CHEMICALS FOR MOLECULAR TARGETS AND ADVERSE OUTCOMES (SOT)

EPA Science Inventory

Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male...

The relationship between muscularity, muscle:bone ratio and cut dimensions in male and female lamb carcasses and the measurement of muscularity using image analysis.

PubMed

Hopkins, D L

1996-12-01

Dorsal images of 57 whole lamb carcasses (mean 22.5 kg, SD 2.3 kg) were obtained on a slaughter chain using a video camera. The lambs represented two sexes (29 cryptorchids, 28 ewes) and one genotype (Poll Dorset × Border Leicester × Merino). Cryptorchid carcasses were significantly (P < 0.05) leaner than ewe carcasses at a common weight but there was little difference in dimensional measurements of M. longissimus thoracis et lumborum (LL). The cryptorchid carcasses had a significantly better conformation (based on the EUROP system) even when adjusted to the same carcass weight and subcutaneous fat level. From the hindleg and chump the following muscles were dissected and weighed: M. semimembranosus, M. adductor femoris, M. semitendinosus, M. biceps femoris, and M. quadriceps femoris. The femur was weighed, the length measured and a muscularity value calculated as described by Purchas et al. (1991 Meat Sci., 30, 181). There was no significant effect of sex on muscularity or muscle to bone ratio (M:B). Cryptorchid carcasses produced heavier (P < 0.05) round and midloin cuts but lighter (P < 0.05) chump and ribloin cuts. Overall there was no significant sex effect on the yield of hindquarter cuts. Correlation showed a significant (P < 0.001) association between LL area and muscularity, with a lower correlation between round and topside cross-sectional area and muscularity. Neither muscle cross-sectional area nor muscularity was significantly related to M:B ratios. Muscularity increased with increasing carcass weight (P < 0.001) but M:B did not. Prediction of muscularity was significantly (P < 0.05) improved by adding to hot carcass weight a measure of the combined width across the hind legs at interval three, as taken from video images, there being five equally-spaced intervals from the groin to the gambrel. A similar result was achieved by using carcass width at the third interval of five-eventy spaced intervals between the minimum shoulder width and the point of maximum loin width. There was no significant (P > 0.05) effect of sex on the relationships. It is concluded that muscularity could be used to indicate carcasses that have cuts with greater cross-sectional areas and that a video image analysis approach could potentially be used to derive an estimate of muscularity. The value to the meat marketing chain of identifying carcasses with large crosssectional areas remains to be established.

Proposal for a Study of the Incidence and Occupational Distribution of Testicular Neoplasms in United States Air Force Personnel

DTIC Science & Technology

1988-04-01

anomalies (including duplication of the ureters, hypospadias and ectopic kidney) in 6%.(34) I. Pottern reports on 73 testicular cancer patients seen...urogenital anomalies such as hypospadias and ureteral duplication.( 5 2 ) Among 100 consecutive urograms performed on cryptorchid boys -. anomalies were

Factors other than light affecting the pineal gland: hypophysectomy, testosterone, dihydrotestosterone, estradiol, cryptorchidism, and stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Urry, R.L.; Dougherty, K.A.; Frehn, J.L.

The article reviews those factors other than light that affect the activity of the pineal gland. Both testosterone and dihydroterosterone were shown to have tissue-specific inhibitory effects on pineal MAO activity concomitant with an increased activity of the gland. The effect also was tissue-specific. Bilateral and unilateral experimental cryptorchidism also decreased pineal MAO activity 3 to 4 weeks after surgery. Acute stresses appear to increase adrenal catecholamine output (epinephrine and norepinephrine) as well as to stimulate local adrenergic pathways, while chronic stress, such as starvation, appears to act through the adrenal corticosteroids by decreasing pineal MAO activity thereby indirectly increasingmore » melatonin synthesis. Thus, both components of the adrenal gland appear to act in concert to increase effectively melatonin synthesis by the pineal function----the latter specifically inhibits HIOMT activity. These observations indicate that many factors other than light affect pineal morphology and melatonin synthesis. The pineal appears to be a true neuroendocrine organ that is affected by hypophysectomy and is responsive to feedback and control from other organs within the mammalian organism. (auth)« less

Management of an invasive and metastatic Sertoli cell tumor with associated myelotoxicosis in a dog

PubMed Central

Withers, Sita S.; Lawson, Corinne M.; Burton, Andrew G.; Rebhun, Robert B.; Steffey, Michele A.

2016-01-01

We describe the surgical and post-operative management of a large, invasive, and metastatic functional Sertoli cell tumor in a 9-year-old cryptorchid male Labrador retriever dog. Despite residual disease after surgery, bone marrow recovery occurred without administration of bone marrow stimulants and serum estradiol accurately predicted tumor recurrence. PMID:26933269

DEHP (DI-N-ETHYLHEXYL PHTHALATE), WHEN ADMINISTERED DURING SEXUAL DIFFERENTIATION, INDUCES DOSE DEPENDENT DECREASES IN FETAL TESTIS INSL3 GENE EXPRESSION AND STERIOD HORMONE SYNTHESIS

EPA Science Inventory

Cryptorchidism is a fairly common human malformation, being displayed in 1-3 males per 100 at birth. Since only a small percentage of these lesions can be linked to known genetic defects, developmental exposure to man-made chemicals has been implicated in the increase in thisrepr...

Feasibility and Efficacy of a Urologic Profession Campaign on Cryptorchidism Using Internet and Social Media.

PubMed

Borgmann, Hendrik; Kliesch, Sabine; Roth, Stephan; Roth, Mael; Degener, Stephan

2017-01-01

We performed a professional campaign in Germany intending to establish the urologic profession as a competent and helpful point of contact for patients with cryptorchidism. The aim of this study was to assess the feasibility of this campaign and to quantify the efficacy of using Internet vs. social media. The strategic design of the campaign comprised a strategy meeting, creation of a landing page, and targeted advertisements on Google in the form of Adwords and on Facebook in the form of sidebar ads and sponsored posts. Outcome measurements were number of impressions, homepage sessions, and downloads of an information brochure. The campaign generated 2,511,923 impressions, 7,369 homepage sessions and 1,086 downloads of information brochures using a total investment budget of 7,500€. Use of Google Adwords was more efficient on outcome measurements than Facebook. A subanalysis of Facebook advertisements showed that sidebar ads and sponsored posts were equally efficient. New media are an effective platform for a profession campaign. Google Adwords is a more effective and cost-efficient platform than Facebook for a targeted campaign. © 2016 S. Karger AG, Basel.

A de novo interstitial 6q deletion in a boy with a split hand malformation.

PubMed

Duran-Gonzalez, Jorge; Gutierrez-Angulo, Melva; Garcia-Cruz, Diana; Ayala, Maria de la Luz; Padilla, Miguel; Davalos, Ingrid P

2007-01-01

We report on a de novo interstitial deletion of (6)(q15q22.2) in a 5-year-old boy with developmental delay, microcephaly, facial dysmorphism, cryptorchidism, congenital heart defect, and split-hand malformation. Previous reports and this patient suggest that 6q21 may contain a gene or genes related either directly or indirectly to limb development.

Paediatric germ cell tumours and congenital abnormalities: a Children's Oncology Group study

PubMed Central

Johnson, K J; Ross, J A; Poynter, J N; Linabery, A M; Robison, L L; Shu, X O

2009-01-01

Methods: Maternally reported congenital abnormalities (CAs) were examined in a case–control study of 278 cases of paediatric germ cell tumours (GCTs) and 423 controls. Results and conclusions Germ cell tumours were significantly associated with cryptorchidism in males (OR=10.8, 95% CI: 2.1–55.1), but not with any other specific CA in either sex. PMID:19603020

Bilateral cryptorchidism in a dog with persistent cranial testis suspensory ligaments and inverted gubernacula: report of a case with implications for understanding normal and aberrant testis descent.

PubMed Central

Kersten, W; Molenaar, G J; Emmen, J M; van der Schoot, P

1996-01-01

The genital system of a dog with bilateral intra-abdominal testes is described. External virilisation was normal except for an empty scrotum. Internally there was a prostate of normal macroscopic and histological appearances and, bilaterally, a fully developed male genital tract. Testicular vasculature was normal. Cranial to each testis, there was a strong ligament lying at the free edge of the gonadal/genital mesentery and running between the cranial tip of the testis/epididymis and the area craniolateral of the ipsilateral kidney. It was impossible to push the testes into the inguinal canal because of this strong ligament. Caudal to each testis, there was an elongated whitish structure between the caudal pole of the epididymis and the area of the internal inguinal ring. On closer inspection this structure appeared to be the inverted and elongated processus vaginalis sac. There was a minor ligament at the free border of the inguinal fold of the genital mesentery between the tip of this inverted processus vaginalis and the adjacent junction of the cauda epididymidis and vas deferens. The findings suggest that persistence of the fetal cranial gonadal suspensory ligaments could have been the major aetiological factor in this case of cryptorchidism. Their persistence could have prevented caudal outgrowth of the processus vaginalis with its consequent development into an intra-abdominal papilla-like structure. Inappropriate persistence of the cranial suspensory ligaments in male rodents, pig, and cattle has been associated with insufficient exposure of their primordia to androgen during fetal life. It is uncertain whether a similar deficiency could underlie persistence of these structures in the present specimen. The findings add further weight to the hypothesis that regression of the cranial gonadal suspensory ligament in males is a key event in the process of testis descent. The human homologue of this ligament deserves more attention in the analysis and treatment of human cryptorchidism. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 PMID:8771408

Vascular Ehlers-Danlos syndrome with cryptorchidism, recurrent pneumothorax, and pulmonary capillary hemangiomatosis-like foci: A case report.

PubMed

Park, Min A; Shin, So Youn; Kim, Young Jin; Park, Myung Jae; Lee, Seung Hyeun

2017-11-01

Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal dominant inherited collagen disorder caused by defects or deficiency of pro-alpha 1 chain of type III procollagen encoded by COL3A1. vEDS is characterized not only by soft tissue manifestations including hyperextensibility of skin and joint hypermobility but also by early mortality due to rupture of arteries or vital organs. Although pulmonary complications are not common, vEDS cases complicated by pneumothorax, hemothorax, or intrapulmonary hematoma have been reported. When a patient initially presents only with pulmonary complications, it is not easy for clinicians to suspect vEDS. We report a case of an 18-year-old high school student, with a past history of cryptorchidism, presenting with recurrent pneumothorax. Routine laboratory findings were unremarkable. Chest high resolution computed tomographic scan showed age-unmatched hyperinflation of both lungs, atypical cystic changes and multifocal ground glass opacities scattered in both lower lobes. His slender body shape, hyperflexible joints, and hyperextensible skin provided clue to suspicion of a possible connective tissue disorder. The histological examination of the lung lesions showed excessive capillary proliferation in the pulmonary interstitium and pleura allowing the diagnosis of pulmonary capillary hemangiomatosis (PCH)-like foci. Genetic study revealed COL3A1 gene splicing site mutation confirming his diagnosis as vEDS. Although his diagnosis vEDS is notorious for fatal vascular complication, there was no evidence of such complication at presentation. Fortunately, he has been followed up for 10 months without pulmonary or vascular complications. To the best of our knowledge, both cryptorchidism and PCH-like foci have never been reported yet as complications of vEDS, suggesting our case might be a new variant of this condition. This case emphasizes the importance of comprehensive physical examination and history-taking, and the clinical suspicion of a possible connective tissue disorder when we encounter cases with atypical presentation and/or unique chest radiologic findings especially in young patients. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Vascular Ehlers–Danlos syndrome with cryptorchidism, recurrent pneumothorax, and pulmonary capillary hemangiomatosis-like foci

PubMed Central

Park, Min A.; Shin, So Youn; Kim, Young Jin; Park, Myung Jae; Lee, Seung Hyeun

2017-01-01

Abstract Rationale: Vascular Ehlers–Danlos syndrome (vEDS) is a rare autosomal dominant inherited collagen disorder caused by defects or deficiency of pro-alpha 1 chain of type III procollagen encoded by COL3A1. vEDS is characterized not only by soft tissue manifestations including hyperextensibility of skin and joint hypermobility but also by early mortality due to rupture of arteries or vital organs. Although pulmonary complications are not common, vEDS cases complicated by pneumothorax, hemothorax, or intrapulmonary hematoma have been reported. When a patient initially presents only with pulmonary complications, it is not easy for clinicians to suspect vEDS. Patient concerns: We report a case of an 18-year-old high school student, with a past history of cryptorchidism, presenting with recurrent pneumothorax. Diagnoses: Routine laboratory findings were unremarkable. Chest high resolution computed tomographic scan showed age-unmatched hyperinflation of both lungs, atypical cystic changes and multifocal ground glass opacities scattered in both lower lobes. His slender body shape, hyperflexible joints, and hyperextensible skin provided clue to suspicion of a possible connective tissue disorder. Interventions: The histological examination of the lung lesions showed excessive capillary proliferation in the pulmonary interstitium and pleura allowing the diagnosis of pulmonary capillary hemangiomatosis (PCH)-like foci. Genetic study revealed COL3A1 gene splicing site mutation confirming his diagnosis as vEDS. Outcomes: Although his diagnosis vEDS is notorious for fatal vascular complication, there was no evidence of such complication at presentation. Fortunately, he has been followed up for 10 months without pulmonary or vascular complications. Lessons: To the best of our knowledge, both cryptorchidism and PCH-like foci have never been reported yet as complications of vEDS, suggesting our case might be a new variant of this condition. This case emphasizes the importance of comprehensive physical examination and history-taking, and the clinical suspicion of a possible connective tissue disorder when we encounter cases with atypical presentation and/or unique chest radiologic findings especially in young patients. PMID:29381997

Sequelae in male rabbits following developmental exposure to p,p'-DDT or a mixture of p,p'-DDT and vinclozolin: cryptorchidism, germ cell atypia, and sexual dysfunction.

PubMed

Veeramachaneni, D N R; Palmer, J S; Amann, R P; Pau, K-Y F

2007-01-01

Rabbit does (7-9 per group) were treated daily per orum from gestation day 15 through post-natal week 4 to provide per kg body wt 25 micaromol (low) or 250 micromol (high) p,p'-DDT or a mixture of DDT and vinclozolin (12.5 and 125 micromol each). Developmental as well as post-pubertal reproductive sequelae of male progeny were studied. Testicular descent in some pups was impaired by DDT. Serum LH or testosterone was not affected. FSH was lower in mixture- but not in DDT-exposed rabbits. Lack of sexual interest, penile erection and ejaculation were observed in some mixture rabbits. Sperm counts were unaffected, but morphologically normal spermatozoa were fewer; nuclear and acrosomal morphogenesis was disrupted. Atypical germ cells resembling carcinoma in situ were found. Also considering data for vinclozolin [Veeramachaneni DNR, Palmer JS, Amann RP, Kane CM, Higuchi TT, Pau K-YF. Disruption of sexual function, FSH secretion, and spermiogenesis in rabbits following developmental exposure to vinclozolin, a fungicide. Reproduction 2006;131:805-16], we concluded that DDT causes cryptorchidism and germ cell atypia, vinclozolin permanently disrupts FSH secretion and sexual function, and the mixture causes the full spectrum of dysgenesis.

A systematic review and meta-analysis of comparative studies assessing the efficacy of luteinizing hormone-releasing hormone therapy for children with cryptorchidism.

PubMed

Li, Tao; Gao, Liang; Chen, Peng; Bu, Siyuan; Cao, Dehong; Yang, Lu; Wei, Qiang

2016-05-01

To assess the efficacy of intranasal luteinizing hormone-releasing hormone (LHRH) therapy for cryptorchidism. Eligible studies were identified by two reviewers using PubMed, Embase, and Web of Science databases. Primary outcomes were complete testicular descent rate, complete testicular descent rate for nonpalpable testis, and pre-scrotal and inguinal testis. Secondary outcomes included testicular descent with different medicines strategy and a subgroup analysis. Pooled data including the 1255 undescended testes showed that complete testicular descent rate was 20.9 % in LHRH group versus 5.6 % in the placebo group, which was significantly different [relative risk (RR) 3.94, 95 % confidence interval (CI) 2.14-7.28, P < 0.0001]. There was also a significant difference in the incidence of pre-scrotal and inguinal position testis descent, with 22.8 % in the LHRH group versus 3.6 % in the placebo group (RR 5.79, 95 % CI 2.94-11.39, P < 0.00001). However, side effects were more frequent in the LHRH group (RR 2.61, 95 % CI 1.52-4.49, P = 0.0005). There were no significant differences for nonpalpable testes. LHRH had significant benefits on testicular descent, particularly for inguinal and pre-scrotal testes, which was also accompanied by temporary slight side effects.

Carcinoma in situ testis, the progenitor of testicular germ cell tumours: a clinical review.

PubMed

Hoei-Hansen, C E; Rajpert-De Meyts, E; Daugaard, G; Skakkebaek, N E

2005-06-01

Testicular germ cell tumours (TGCT), including seminomas, embryonal carcinomas, teratomas and yolk sac tumours, have a common precursor, the carcinoma in situ (CIS) cell. Recent gene expression studies displaying close similarity of CIS cells to embryonic stem cells support the longstanding theory that CIS most likely originates in utero from fetal gonocytes. The clinical association between the testicular dysgenesis syndrome components (TGCT, cryptorchidism, genital malformations, some forms of decreased spermatogenesis) also implies a prenatal origin. Despite high cure rates of TGCT, efforts should be made to obtain diagnosis at the CIS stage, as intervention is possible before an invasive tumour develops, thus reducing the necessity for intensive therapy. CIS may be suspected in patients with an assumed extragonadal GCT or cryptorchidism, and in intersex patients and selected cases with infertility (presenting with atrophic testes and ultrasonic microlithiasis). Surgical testicular biopsy seems the only reliable diagnostic method. The management of choice of unilateral CIS is orchidectomy, or localised irradiation in bilateral cases. At least 5% of TGCT patients present with contralateral CIS; therefore, contralateral biopsy is recommended at the time of orchidectomy. Further research is warranted to identify causal factors explaining the increasing incidence of TGCT and to obtain a method of non-invasive CIS detection.

Congenital grouped albinotic spots of the retinal pigment epithelium in a patient with hemihypertrophy and café au lait spots.

PubMed

White, Eugenia C; Sengillo, Jesse D; Cho, Galaxy Y; Bakhoum, Mathieu F; Tsang, Stephen H

2018-05-16

To describe the finding of circularly grouped hypomelanotic spots in the central macula of a patient with syndromic characteristics. Case report of a patient with albinotic spots grouped within the macula, café au lait spots, and left-sided hemihypertrophy. A 15-year-old boy presented with hypomelanotic spots which were hyperautofluorescent on fundus autofluorescence imaging with no disruption of the retinal laminae or photoreceptor inner and outer segment (IS/OS) junction on spectral domain optical coherence tomography. His developmental history included hemihypertrophy, café au lait spots over his axilla and extremities, and surgically corrected left-sided cryptorchidism. Other ocular history included resolved convergence insufficiency and red-green color blindness. It is essential to recognize that circularly grouped hypomelanotic spots are a benign condition. The location and arrangement of the hypomelanotic spots were atypical for congenital grouped albinotic spots of the retinal pigment epithelium (CGAS) as they were grouped within the macula in addition to a more characteristic linear "bear track" formation in the periphery. To the authors' knowledge, this is the first report of CGAS present in a patient with hemihypertrophy, café au lait spots, and cryptorchidism and may represent a novel syndromic association.

Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism.

PubMed

Xu, C; Lang-Muritano, M; Phan-Hug, F; Dwyer, A A; Sykiotis, G P; Cassatella, D; Acierno, J; Mohammadi, M; Pitteloud, N

2017-08-01

Neonatal micropenis and cryptorchidism raise the suspicion of congenital hypogonadotropic hypogonadism (CHH), a rare genetic disorder caused by gonadotropin-releasing hormone deficiency. Low plasma testosterone levels and low gonadotropins during minipuberty provide a clinical diagnostic clue, yet these tests are seldomly performed in general practice. We report a male neonate with no family history of reproductive disorders who was born with micropenis and cryptorchidism. Hormonal testing at age 2.5 months showed low testosterone (0.3 nmol/L) and undetectable gonadotropins (luteinizing hormone and follicle-stimulating hormone both <0.5 U/L), suggestive of CHH. Genetic testing identified a de novo, heterozygous mutation in fibroblast growth factor receptor 1 (FGFR1 p.L630P). L630 resides on the ATP binding cleft of the FGFR1 tyrosine kinase domain, and L630P is predicted to cause a complete loss of receptor function. Cell-based assays confirmed that L630P abolishes FGF8 signaling activity. Identification of a loss-of-function de novo FGFR1 mutation in this patient confirms the diagnosis of CHH, allowing for a timely hormonal treatment to induce pubertal development. Therefore, genetic testing can complement clinical and hormonal assessment for a timely diagnosis of CHH in childhood. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mucopolysaccharidosis type VI in a juvenile miniature schnauzer dog with concurrent hypertriglyceridemia, necrotizing pancreatitis, and diabetic ketoacidosis.

PubMed

Pérez, Mayrim L; Kridel, Heather A; Gallagher, Alex; Sheppard, Barbara J; Reese, Shona; Kondo, Hirotaka; Alleman, Rick; Giger, Urs

2015-03-01

A 7-month-old, neutered male miniature schnauzer dog with a history of cryptorchidism and umbilical hernia was referred for diabetic ketoacidosis. Clinical evaluation revealed stunted growth, skeletal abnormalities, hypertriglyceridemia, diabetic ketoacidosis, and acute necrotizing pancreatitis. Further testing was diagnostic for mucopolysaccharidosis type VI causing the stunted growth and skeletal deformities, but no connection between mucopolysaccharidosis type VI, hypertriglyceridemia, and pancreatic diseases was found.

Mucopolysaccharidosis type VI in a juvenile miniature schnauzer dog with concurrent hypertriglyceridemia, necrotizing pancreatitis, and diabetic ketoacidosis

PubMed Central

Pérez, Mayrim L.; Kridel, Heather A.; Gallagher, Alex; Sheppard, Barbara J.; Reese, Shona; Kondo, Hirotaka; Alleman, Rick; Giger, Urs

2015-01-01

A 7-month-old, neutered male miniature schnauzer dog with a history of cryptorchidism and umbilical hernia was referred for diabetic ketoacidosis. Clinical evaluation revealed stunted growth, skeletal abnormalities, hypertriglyceridemia, diabetic ketoacidosis, and acute necrotizing pancreatitis. Further testing was diagnostic for mucopolysaccharidosis type VI causing the stunted growth and skeletal deformities, but no connection between mucopolysaccharidosis type VI, hypertriglyceridemia, and pancreatic diseases was found. PMID:25750448

[Unilateral laparoscopic cryptorchidectomy in a llama].

PubMed

Zulauf, M; Bergadano, A; Steiner, A

2002-05-01

Cryptorchism is an inherited congenital abnormality characterized by the failure of one or both testes to descend into the scrotum. Diagnosis can be difficult if the retained testicular tissue cannot be localized during clinical examination and the history of the animal is unknown, or if the animal shows persistent male behaviour despite the history of successful previous castration. The present case report describes the history of a cryptorchid Lama and the techniques of general anesthesia and laparoscopic cryptorchidectomy advocated.

Exposure to hazardous substances and male reproductive health: a research framework.

PubMed Central

Moline, J M; Golden, A L; Bar-Chama, N; Smith, E; Rauch, M E; Chapin, R E; Perreault, S D; Schrader, S M; Suk, W A; Landrigan, P J

2000-01-01

The discovery in the mid-1970s that occupational exposures to pesticides could diminish or destroy the fertility of workers sparked concern about the effects of hazardous substances on male reproductive health. More recently, there is evidence that sperm quantity and quality may have declined worldwide, that the incidence of testicular cancer has progressively increased in many countries, and that other disorders of the male reproductive tract such as hypospadias and cryptorchidism may have also increased. There is growing concern that occupational factors and environmental chemical exposures, including in utero and childhood exposures to compounds with estrogenic activity, may be correlated with these observed changes in male reproductive health and fertility. We review the evidence and methodologies that have contributed to our current understanding of environmental effects on male reproductive health and fertility and discuss the methodologic issues which confront investigators in this area. One of the greatest challenges confronting researchers in this area is assessing and comparing results from existing studies. We elaborate recommendations for future research. Researchers in the field of male reproductive health should continue working to prioritize hazardous substances; elucidate the magnitude of male reproductive health effects, particularly in the areas of testicular cancer, hypospadias, and cryptorchidism; develop biomarkers of exposure to reproductive toxins and of reproductive health effects for research and clinical use; foster collaborative interdisciplinary research; and recognize the importance of standardized laboratory methods and sample archiving. PMID:11017884

A 5-year-old boy with cryptorchidism and pubic hair: investigation and management of apparent male disorders of sex development in mid-childhood.

PubMed

Keir, L S; O'Toole, S; Robertson, A L; Wallace, A M; Ahmed, S F

2009-01-01

Late presentation of congenital adrenal hyperplasia as a 46,XX disorder of sex development due to 11-beta hydroxylase deficiency is uncommon. Such a case raises issues regarding appropriate investigation and management. A 5-year-old boy who had recently moved to the United Kingdom presented at the endocrinology clinic with recurrent abdominal pain. He was normotensive and had a history of ambiguous genitalia since birth, a relatively small penis, bilateral cryptorchidism and pubic hair. A systematic workup revealed low anti-Mullerian hormone levels for age and sex and elevated serum testosterone, androstenedione and deoxycortisol levels. A urinary steroid profile confirmed a diagnosis of 11-beta hydroxylase deficiency. The child's karyotype was 46,XX. Further genetic analysis revealed a compound heterozygote mutation in the CYP11B1 gene. Ultrasound scan showed evidence of Mullerian structures and accumulation of menstrual blood in the vagina (haematocolpos). Following discussion at a multidisciplinary clinic, the patient did not undergo sex reassignment and subsequently proceeded to surgery for removal of the Mullerian structures. This case emphasizes the importance of a systematic approach to investigation of older children presenting with apparent male undermasculinisation. It also raises important issues about gender reassignment in mid-childhood and the indications for removal of Mullerian organs in a 46,XX boy. Copyright 2009 S. Karger AG, Basel.

Acro-spondylo-pubic dysostosis associated with cataracts, microcephaly, and normal intelligence.

PubMed

Chacon-Camacho, Oscar F; Villegas-Ruiz, Vanessa; Buentello-Volante, Beatriz; Piña-Aguilar, Raul E; Peláez-González, Hugo; Ramírez, Magdalena; González-Rodríguez, Johanna; Zenteno, Juan Carlos

2015-02-01

We report on an adult male with normal intelligence who exhibited an unusual combination of microcephaly, dysostoses of limbs, vertebrae, patellae, and pubic bone, camptodactyly of all fingers, and syndactyly of toes, absent nails on thumbs and some fingers, bilateral cataract, cryptorchidism, polythelia, and nipple-like skin pigmentations of shoulders and upper back. We have been unable to find a description of a similar combination of manifestations in literature. The cause of the anomalies remains unknown. © 2014 Wiley Periodicals, Inc.

A novel PAX3 mutation in a Japanese boy with Waardenburg syndrome type 1.

PubMed

Yoshida, Yu; Doi, Rieko; Adachi, Kaori; Nanba, Eiji; Kodani, Isamu; Ryoke, Kazuo

2016-01-01

Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant disorder characterized by hair hypopigmentation, abnormal iris pigmentation, and congenital hearing loss. WS1 is caused by mutations in paired box gene 3 (PAX3). We identified a novel PAX3 mutation (c.1107 C>G, p.Ser369Arg) in a Japanese WS1 patient showing abnormal right iris pigmentation, right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism.

A novel PAX3 mutation in a Japanese boy with Waardenburg syndrome type 1

PubMed Central

Yoshida, Yu; Doi, Rieko; Adachi, Kaori; Nanba, Eiji; Kodani, Isamu; Ryoke, Kazuo

2016-01-01

Waardenburg syndrome type 1 (WS1) is a rare autosomal dominant disorder characterized by hair hypopigmentation, abnormal iris pigmentation, and congenital hearing loss. WS1 is caused by mutations in paired box gene 3 (PAX3). We identified a novel PAX3 mutation (c.1107 C>G, p.Ser369Arg) in a Japanese WS1 patient showing abnormal right iris pigmentation, right-sided congenital hearing loss, synophrys, incomplete left cleft lip, and cryptorchidism. PMID:27081571

[Bernhard Schapiro (1888-1966): Talmudic scholar - andrologist - pioneer of hormonal treatment for cryptorchidism].

PubMed

Borgwardt, Götz

2004-01-01

Bernhard Schapiro was the first to recommend anterior pituitary lobe hormone for the treatment of cryptorchidism. He was born in 1888 into an orthodox family in Dvinsk (Daugavplis/Latvia), in the Pale of Settlements for Jewish Russian subjects. In simple schools he learned Hewbrew and basics of Torah and Talmud. Then he turned to the Talmudic Academy "Slobodka" in Kovno (Kaunas/Lithuania) for advanced studies. Here he internalized the "Musar" teachings, a doctrine of high-standard ethical behavior towards fellow beings, until he was eighteen. He abandoned a rabbincal carrer and studied medicine in Switzerland. After exams in 1919, he received a training in dermatology with JADASSOHN in Breslau. From 1922 until 1933 he worked at HIRSCHFELD's Institute for Sexual Science in Berlin. Here he pioneered in andrology working on the problems of impotency and premature ejaculation and developing new drug combinations. In males with underdeveloped genitalia he proved the cryptorch testicles may descend under treatment with anterior pituitary lobe. After Nazi students had looted the Institute in May, 1933 he left Germany with wife and four children and established a practice in Zurich. He chaired the Swiss branch of Mizrakhi, which aimed at influencing Zionism with orthodox spirituality. In 1940 he turned to New York where even rabbis recommended his treatment as in accordance with talmudic laws. From 1951 until his death in 1966 he lived and worked on the same issues in Jerusalem. His entire life was guided by Musar.

Do environmental factors play a role in the aetiology of carcinoma in situ testis and the testicular dysgenesis syndrome?

PubMed

Sonne, S B; Hoei-Hansen, C E; Fisher, J S; Leffers, H; Rajpert-de Meyts, E; Skakkebaek, N E

2004-01-01

The hypothesis of the Testicular Dysgenesis Syndrome (TDS), first suggested in 2001, propose that several disorders of the male reproductive system such as infertility, hypospadias, cryptorchidism and testicular cancer are all symptoms of TDS, which is most likely initiated during early foetal development, and may be provoked by external factors such as endocrine disruptors in addition to genetic predisposition. Testicular germ cell tumours (TGCTs), considered the most severe symptom of TDS, have increased in incidence during the last 60 years, to become the most common malignancy in young Caucasian men aged 17-45 years. TGCTs of young men originate from carcinoma in situ (CIS) cells. In the last few years, progress has been made identifying candidate genes involved in the neoplastic development of CIS, which may elucidate the timing of the initiation of CIS, currently thought to originate in foetal life from primordial germ cells or early gonocytes. Histological dysgenetic features are frequently seen in testes affected with the TDS components testis cancer or cryptorchidism. A TDS-like phenotype can be induced in male rats by in utero exposure to high concentrations of dibutyl phthalate (DBP) suggesting that ubiquitously present environmental endocrine disruptors may play a role in the aetiology of human TDS. So far, no animal model has been able to mimick all the symptoms of TDS including TGCTs although CIS-like cells have been found in a spontaneous testicular neoplasm in a rabbit.

Surgical correction of ectopic penis and scrotum associated with bilateral orchidopexy.

PubMed

Sobral, Daniel Santos Rocha; Silva, Helder Damásio da; Damázio, Eulálio

2017-01-01

Ectopic penis is usually associated with penoscrotal transposition, and it is rarely observed in isolation. We report a surgical approach for an extremely rare case. A 10-year-old male patient with bilateral cryptorchidism and ectopic penis and scrotum in perineal area, with no penoscrotal transposition, representing an association not yet described in literature. A previous orchiopexy failed due to ectopic scrotum. By means of an inverted Y incision, the penis was mobilized and a perineal skin flap in form of a testicular sac was prepared. Finally orchiopexy was performed. The surgery was essential to treat cryptorchidism and to improve the self-image of the patient. RESUMO O pênis ectópico geralmente ocorre associado à transposição peno-escrotal, sendo raro isoladamente. Relatamos uma abordagem cirúrgica para um caso extremamente raro. Tratava-se de paciente do sexo masculino, 10 anos, com criptorquidia bilateral e pênis e escroto ectópicos, na região perineal, sem transposição peno-escrotal, representando uma associação ainda não descrita na literatura. Orquidopexia prévia sem sucesso, devido à ectopia do escroto. Por meio de uma incisão em Y invertido, mobilizou-se o pênis e preparou-se um retalho da pele perineal em forma de bolsa testicular. Por fim, realizou-se a orquidopexia. A cirurgia foi fundamental para tratar a criptorquidia e promover ganho na autoimagem do paciente.

Spontaneous renal hemorrhage secondary to choriocarcinoma in a man with congenital hypospadias and cryptorchidism: a case report and literature review.

PubMed

Li, Yi; Chen, Gang; Chen, Han; Wen, Shuang; Xiong, Chao-Yu; Yang, Zi-Yi; Zhu, Yun-Xiao; Jeffreys, Nathan

2018-05-08

Choriocarcinoma is a rare malignant germ-cell tumour, most commonly found in adult women. It infrequently presents as spontaneous renal haemorrhage (SRH). Genital malformation and SRH secondary to choriocarcinoma has previously been only reported in females. We present what we believe to be the first case of a male patient with genital malformation (hypospadias and cryptorchidism) and SRH at presentation of choriocarcinoma. A 25-year-old man presented to the department with intense pain in the right flank region and lower back. Initial investigations showed spontaneous renal haemorrhage, for which an emergency partial nephrectomy was performed. Clinical, radiological, and pathological investigations suggested a diagnosis of testicular choriocarcinoma with metastases to the right kidney, both lungs, and brain. Initial treatment was with a chemotherapy regimen of cisplatin, etoposide and bleomycin and whole brain radiotherapy; however, 6 months after diagnosis the patient developed liver metastasis, after which time the BEP protocol was switched to ITP with oral apatinib. Despite best efforts, the liver and lung metastasis continued to grow and a decision was made to discontinue active treatment and provide only palliative care until the patient passed away. Choriocarcinoma is a difficult cancer to diagnose pre-operatively. In male patients with early metastasis, prognosis may be much poorer than in the commoner gestational choriocarcinoma. A multidisciplinary with comprehensive post-surgical intervention is of great importance in the treatment of these patients.

Does the cranial suspensory ligament have a role in cryptorchidism?

PubMed

Kassim, Normadiah M; Russell, D A; Payne, A P

2010-01-01

The cranial suspensory ligament (CSL) is a fibromuscular structure anchoring the embryonic gonad to the posterior abdominal wall in male and female mammals. Its persistence in females is believed to be responsible for retaining the ovaries within the abdomen, while its regression in males permits testis descent. Embryonic loss of the CSL in males is believed to be an androgen-dependent event, and failure of this process has been proposed as a cause of cryptorchidism. The present study demonstrates that the nuclei of mesenchymal cells in the caudal part of the CSL are immunoreactively positive for androgen receptor. We examined the effects of exposure of the non-steroidal antiandrogen flutamide during the period from gestational day 10 to birth on the development of the CSL and on testis descent. Exposure of male Albino Swiss rats to the antiandrogen flutamide during this period resulted in feminization of the external genitalia and the suppression of growth of the testes and male reproductive tracts. In adulthood, testes were found to be located in diverse positions including normal scrotal (50%), intra-abdominal (10%) and ectopic suprainguinal (40%). The CSL of the testis persisted into adulthood in all flutamide-treated males, regardless of testis location. In all cases, the ligament consisted of bundles of smooth muscle fibres in the retroperitoneal fat of the posterior abdominal wall. These findings suggest that androgen blockade during embryonic development interferes with testicular descent, but that maldescent cannot be correlated with either the persistence of the CSL of the testis or its structure.

Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center.

PubMed

Varimo, Tero; Miettinen, Päivi J; Känsäkoski, Johanna; Raivio, Taneli; Hero, Matti

2017-01-01

What diagnoses underlie delayed puberty (DP) and predict its outcome? A multitude of different diagnoses underlie DP, and in boys a history of cryptorchidism, small testicular size and slow growth velocity (GV) predict its clinical course. DP is caused by a variety of underlying etiologies. Hormonal markers can be used in the differential diagnosis of DP but none of them have shown complete diagnostic accuracy. Medical records of 589 patients evaluated for DP in a single tertiary care center between 2004 and 2014 were retrospectively reviewed. Clinical and biochemical data of 174 boys and 70 girls who fulfilled the criteria of DP were included in the analyses. We characterized the frequencies of underlying conditions and evaluated the predictive efficacy of selected clinical and hormonal markers. Thirty etiologies that underlie DP were identified. No markers of clinical value could be identified in the girls, whereas a history of cryptorchidism in the boys was associated with an increase in the risk of permanent hypogonadism (odds ratio 17.2 (95% CI; 3.4-85.4, P < 0.001)). The conditions that cause functional hypogonadotropic hypogonadism were more frequent in boys with a GV below 3 cm/yr than in those growing faster (19% vs 4%, P < 0.05). In this series, the most effective markers to discriminate the prepubertal boys with constitutional delay of growth and puberty (CDGP) from those with congenital hypogonadotropic hypogonadism (CHH) were testicular volume (cut-off 1.1 ml with a sensitivity of 100% and a specificity of 91%), GnRH-induced maximal LH (cut-off 4.3 IU/L; 100%, 75%) and basal inhibin B (INHB) level (cut-off 61 ng/L; 90%, 83%). The main limitation of the study is the retrospective design. Prior cryptorchidism and slow GV are two important clinical cues that may help clinicians to predict the clinical course of DP in boys, whereas markers of similar value could not be identified in girls. In prepubertal boys, testicular size appeared as effective as INHB and GnRH-induced LH levels in the differential diagnosis between CHH and CDGP. This study was supported by the Academy of Finland (268356), Foundation for Pediatric Research (7495), Sigrid Juselius Foundation (2613) and the Finnish Medical Foundation (011115). The authors have no competing interests to report. Not applicable. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis

PubMed Central

Martin, Olwenn V.; Shialis, Tassos; Lester, John N.; Scrimshaw, Mark D.; Boobis, Alan R.; Voulvoulis, Nikolaos

2008-01-01

Background Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. Objectives We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α–mediated mode of action was specifically explored. Results We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. Conclusions The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population. PMID:18288311

Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis.

PubMed

Martin, Olwenn V; Shialis, Tassos; Lester, John N; Scrimshaw, Mark D; Boobis, Alan R; Voulvoulis, Nikolaos

2008-02-01

Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-alpha-mediated mode of action was specifically explored. We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population.

Clinical features and prognosis of a sample of patients with trisomy 13 (Patau syndrome) from Brazil.

PubMed

Petry, Patrícia; Polli, Janaina B; Mattos, Vinícius F; Rosa, Rosana C M; Zen, Paulo R G; Graziadio, Carla; Paskulin, Giorgio A; Rosa, Rafael F M

2013-06-01

Trisomy 13 or Patau syndrome (PS) is a chromosomal disorder characterized by a well known presentation of multiple congenital anomalies. Our objective was to determine the clinical features and prognosis observed in a sample of patients with PS. The series was composed of patients with diagnosis of PS consecutively evaluated by a Clinical Genetics Service from a reference hospital of southern Brazil, in the period between 1975 and 2012. Statistical analysis was performed using PEPI program (version 4.0), with two-tailed Fisher's exact test for comparison of frequencies (P<0.05). The sample consisted of 30 patients, 60% male, median age at first evaluation of 9 days. Full trisomy of chromosome 13 was the main cytogenetic alteration (73%). The major clinical findings included: cryptorchidism (78%), abnormal auricles (77%), congenital heart defects (76%), polydactyly (63%), microphthalmia (60%) and micrognathia (50%). Four patients (13%) simultaneously had micro/anophthalmia, oral clefts and polydactyly. Some findings were only observed in our sample and included, among others, preauricular tags (10%), duplication of the hallux (3%) and spots following the lines of Blaschko (3%). Mosaicism (20% of cases) had a statistically significant association only with absence of cryptorchidism. The median of survival was 26 days. Patients with and without mosaicism had similar median of survival. Our findings, in agreement with the literature, show that the anomalies in patients with PS can be quite variable, sometimes even atypical. There is no pathognomonic finding, which may make the early identification of these patients challenging. Copyright © 2013 Wiley Periodicals, Inc.

Human Fetal Testis Xenografts Are Resistant to Phthalate-Induced Endocrine Disruption

PubMed Central

Heger, Nicholas E; Hall, Susan J; Sandrof, Moses A; McDonnell, Elizabeth V; Hensley, Janan B; McDowell, Erin N; Martin, Kayla A; Gaido, Kevin W; Johnson, Kamin J

2012-01-01

Background: In utero exposure to endocrine-disrupting chemicals may contribute to testicular dysgenesis syndrome (TDS), a proposed constellation of increasingly common male reproductive tract abnormalities (including hypospadias, cryptorchidism, hypospermatogenesis, and testicular cancer). Male rats exposed in utero to certain phthalate plasticizers exhibit multinucleated germ cell (MNG) induction and suppressed steroidogenic gene expression and testosterone production in the fetal testis, causing TDS-consistent effects of hypospadias and cryptorchidism. Mice exposed to phthalates in utero exhibit MNG induction only. This disparity in response demonstrates a species-specific sensitivity to phthalate-induced suppression of fetal Leydig cell steroidogenesis. Importantly, ex vivo phthalate exposure of the fetal testis does not recapitulate the species-specific endocrine disruption, demonstrating the need for a new bioassay to assess the human response to phthalates. Objectives: In this study, we aimed to develop and validate a rat and mouse testis xenograft bioassay of phthalate exposure and examine the human fetal testis response. Methods: Fetal rat, mouse, and human testes were xenografted into immunodeficient rodent hosts, and hosts were gavaged with a range of phthalate doses over multiple days. Xenografts were harvested and assessed for histopathology and steroidogenic end points. Results: Consistent with the in utero response, phthalate exposure induced MNG formation in rat and mouse xenografts, but only rats exhibited suppressed steroidogenesis. Across a range of doses, human fetal testis xenografts exhibited MNG induction but were resistant to suppression of steroidogenic gene expression. Conclusions: Phthalate exposure of grafted human fetal testis altered fetal germ cells but did not reduce expression of genes that regulate fetal testosterone biosynthesis. PMID:22511013

Study of two patients with craniosynostosis and deletions of 11q: One with features of Saethre-Chotzen syndrome and the other with concomitant partial trisomy 4q

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morsey, S.; Lewanda, A.F.; Reid, C.S.

1994-09-01

Partial monosomy 11q is associated with metopic craniosynostosis and trigonocephaly. Prominant features in the over 30 reported cases include downslanting palpebral fissures, epicanthal folds, hypertelorism, ptosis, wide/depressed nasal bridge, low set malformed ears, downturned mouth, micro/retrognathia, digital and cardiac anomalies and psychomotor retardation. We evaluated two patients referred for abnormal head shape. The first carried a diagnosis of Saethre-Chotzen syndrome due to brachycephaly, facial asymmetry, ptosis, cupped ears, sundactyly of 2nd and 3rd digits, developmental delay, and VSD. Karyotype revealed 46,XY,del(11)(q24.1{yields}qter). No abnormality was noted of chromosome 7p, where the Saethre-Chotzen syndrome locus has been mapped. This suggests genetic heterogeneitymore » for this condition. The second patient had no prior diagnosis. He had trigonocephaly, bilateral cryptorchidism and inguinal hernias. He also had hypotelorism, epicanthal folds, synophrys, posteriorly rotated ears, horizontal crease below his lower lip, unilateral single palmar crease, mild soft tissue syndactyly and a shawl scrotum. His karyotype of 46,XY,-11,+der(11)t(4;11)(q31.3;q25) revealed both partial 11q monosomy and partial 4q trisomy (the latter associated with cryptorchidism, horizontal chin crease and single palmar crease). Deletions of 11q appear to produce a wide spectrum of defects, which may even mimic other known craniosynostotic conditions. Study of these patients may lead to the identification of new genes involved in craniofacial morphogenesis.« less

Detection of polybrominated biphenyl ethers (PBDEs) in pediatric hair as a tool for determining in utero exposure.

PubMed

Aleksa, Katarina; Carnevale, Amanda; Goodyer, Cynthia; Koren, Gideon

2012-05-10

Cryptorchidism, or undescended/maldescended testis, is the most common birth defect of male genitalia. Its prevalence has been increasing over the past few decades. This may be due to an increase in the prevalence of anti-androgenic chemicals such as polychlorinated biphenyls, organochloride pesticides, plasticizers and fungicides. A newer group of chemicals, brominated flame retardants (BFRs), are being implicated as endocrine-disrupting chemicals. These chemicals are used worldwide in polymers that are incorporated into a variety of consumer products (e.g., textile, computers and televisions, insulating foam, electrical equipment and kitchen appliances). In order to quantify BFRs we introduce the use of hair levels of polybrominated diphenyl esters (PBDEs) as biomarkers of systemic exposure. This approach will allow for the estimation of in utero BFR exposure, in the process of evaluating the potential link between the incidence of cryptorchidism in newborn males and level of exposure of the pregnant mother to environmentally relevant BFRs. For that end we have developed a GC/MS assay in which children's hair is analyzed for the presence of polybrominated biphenyl ethers (PBDEs). In this pilot, 10-40mg of hair from 24 children (12 newborn and 12 from children 1 to 15 years) was extracted overnight at 40°C with 4N HCl and hexane (4:1). The samples were eluted from 2g NaSO(4):2g Florisil SPE columns with 8mL hexane. Dried samples are reconstituted with anhydrous isooctane and injected onto a GC/MS and analyzed for BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154, BDE-183 and BDE-209. PBDEs were detected in all of the newborn and child hair. The ΣPBDE ranged from 0.038 to 1.01pg/mg newborn hair and from 0.208 to 2.695ng/mg child hair. The most abundant PBDE in newborn hair was BDE-153 while in child hair the variable PBDEs were BDE-47 and BDE-99. The highest molecular weight congener BDE-209 was detected in 10/24 pediatric hair samples. The LOQ is 0.0625pg/mg (BDE-209 0.625pg/mg) and the efficiency of extraction was between 70 and 90%. This GC/MS method is sufficiently sensitive to detect the presence of all 8 PBDE congeners tested in as little as 10mg of pediatric hair. The results show that PBDEs are present in newborn hair, making this matrix useful in examining in utero exposure to PBDEs and linking it to cryptorchidism. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Prevalence of the AMHR2 mutation in Miniature Schnauzers and genetic investigation of a Belgian Malinois with persistent Müllerian duct syndrome.

PubMed

Smit, M M; Ekenstedt, K J; Minor, K M; Lim, C K; Leegwater, Paj; Furrow, E

2018-04-01

Persistent Müllerian duct syndrome (PMDS) is a sex-limited disorder in which males develop portions of the female reproductive tract. Important consequences of PMDS are cryptorchidism and its sequelae of infertility and increased risk of testicular cancer. Anti-Müllerian hormone (AMH) and its receptor (AMHR2) induce the regression of the Müllerian ducts in male embryos. In Miniature Schnauzer dogs, the genetic basis has been identified as an autosomal recessive nonsense mutation in AMHR2, but the allele frequency of the mutation is unknown. Thus, the primary objective of this study was to estimate the prevalence of the AMHR2 mutation in North American Miniature Schnauzers, in order to ascertain the value of genetic testing in this breed. An additional objective was to determine whether mutations in AMH or AMHR2 were responsible for PMDS in a Belgian Malinois; this would aid development of a genetic test for the Belgian Malinois breed. Genomic DNA from 216 Miniature Schnauzers (including one known PMDS case) was genotyped for the AMHR2 mutation, and DNA from a single PMDS-affected Belgian Malinois was sequenced for all coding exons of AMH and AMHR2. The Miniature Schnauzer cohort had an AMHR2 mutation allele frequency of 0.16 and a carrier genotypic frequency of 0.27. The genetic basis for PMDS in the Belgian Malinois was not determined, as no coding or splicing mutations were identified in either AMH or AMHR2. These findings support a benefit to AMHR2 mutation testing Miniature Schnauzers used for breeding or with cryptorchidism. © 2017 Blackwell Verlag GmbH.

Analysis of single nucleotide polymorphisms in the 3' region of the estrogen receptor 1 gene in normal and cryptorchid Miniature Dachshunds and Chihuahuas.

PubMed

Pathirana, Indunil Nishantha; Tanaka, Kakeru; Kawate, Noritoshi; Tsuji, Makoto; Kida, Kayoko; Hatoya, Shingo; Inaba, Toshio; Tamada, Hiromichi

2010-08-01

This study was performed to examine the distribution of single nucleotide polymorphisms (SNPs) and estimated haplotypes in the canine estrogen receptor (ER) alpha gene (ESR1) and the association of them with different phenotypes of cryptorchidism (CO) in Miniature Dachshunds and Chihuahuas. Forty CO and 68 normal dogs were used, and CO was classified into unilateral (UCO; n=33) and bilateral CO (BCO; n=5) or into abdominal (ACO; n=16) and inguinal CO (ICO; n=22). Thirteen DNA fragments located in the 70-kb region at the 3' end of ESR1 were amplified by PCR and sequenced to examine 13 SNPs (#1-#13) reported in a canine SNP database. Ten SNPs (#1-#4, #7, #8, #10-#13) were not polymorphic, and 5 new SNPs (#14-#18) were discovered. A common haplotype block in normal, CO and CO phenotypes was identified for an approximately 20-kb region encompassing 4 SNPs (#14-#17). Allele, genotype and haplotype frequencies in CO without classification by phenotype and also in UCO, ACO and ICO phenotypes were not statistically different from the normal group. Significant differences in genotype frequencies and homozygosity for the estimated GTTG haplotype within the block were observed in BCO compared with the normal group, although the number of BCO animals was small. Our results demonstrate that the examined SNPs and haplotypes in the 3' end of canine ESR1 are not associated with unilateral, abdominal and inguinal CO phenotypes and CO per se in Miniature Dachshunds and Chihuahuas. Further studies are necessary to suggest a clear association between the ESR1 SNPs and bilateral CO in dogs.

Endocrine testicular function and spermatogenesis persist in calves after partial scrotal resection but not Burdizzo castration.

PubMed

Pieler, D; Wohlsein, P; Peinhopf, W; Aurich, J E; Erber, R; Ille, N; Baumgärtner, W; Aurich, C

2014-06-01

Bull calves for fattening are often castrated during the first weeks of life. Because androgens stimulate growth, there is an interest in males that are infertile but exposed to endogenous testicular steroids. Such a situation occurs in cryptorchids and has been imitated by shortening the scrotum to an extent that the testes are located in a near-inguinal position. In this study, effects of partial scrotal resection (SR) and Burdizzo castration (BZ) on endocrine testicular function, testes histology and on weight at slaughter were studied and compared to orchidectomized (OR) and gonad-intact calves (CO; n = 10 per group; age at castration, 54 ± 3 days; fattening period, 474 ± 11 days). Plasma testosterone concentrations were determined repeatedly, and testes were collected for histopathology at slaughter. We hypothesized that SR inhibits spermatogenesis without loss of testicular steroidogenesis. Group SR animals gained more weight than groups OR and BZ (P < 0.01). Plasma testosterone concentration increased in groups SR and CO (P < 0.01 vs. BZ and OR). Histologically, in all SR animals, testicular and epididymal tissue was identified with a seminiferous epithelium of up to three-cell layers in two animals. Germ cells including elongated spermatids were present in three animals. Shortening of the scrotum thus induced varying degrees of testicular degeneration but 3/10 animals had to be suspected as fertile. In one BZ animal, spermatids were identified whereas in the remaining BZ animals, testes and epididymides consisted of sclerotic fibrous tissue. Partial SR thus induced a cryptorchid-like status but fertility in individual animals must be assumed. Copyright © 2014 Elsevier Inc. All rights reserved.

Anti-Muellerian hormone, inhibin A, gonadotropins, and gonadotropin receptors in bull calves after partial scrotal resection, orchidectomy, and Burdizzo castration.

PubMed

Scarlet, Dragos; Aurich, Christine; Ille, Natascha; Walter, Ingrid; Weber, Corinna; Pieler, Dagmar; Peinhopf, Walter; Wohlsein, Peter; Aurich, Jörg

2017-01-01

Eight-week-old calves were either castrated by partial scrotal resection (SR) without removing the testes (n = 10), Burdizzo (BZ) clamp (n = 10), orchidectomy (OR; n = 10), or were left gonad intact as controls (CO; n = 10). Concentrations of anti-Muellerian hormone (AMH), inhibin A, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in plasma were determined from 16 to 48 weeks of age. At 18 months, testes of SR, BZ, and CO bulls were obtained and the immunolocalization of LH and FSH receptors and AMH analyzed. Concentration of AMH in plasma of CO and SR bulls decreased with increasing age (P < 0.001). A similar AMH profile in CO and SR indicates that SR did not induce a true cryptorchid state. In groups OR and BZ, AMH was undetectable. Plasma inhibin concentration was higher in groups CO and SR than BZ and OR (P < 0.001). Plasma LH and FSH concentrations decreased over time (P < 0.001) and were higher in groups BZ and OR than SR and CO (P < 0.001). In the testes, immunolabeling for AMH existed in Sertoli cells of CO and SR but not BZ bulls. FSH receptors were localized in Sertoli cells, Leydig cells, spermatocytes, and the epididymis of CO and SR animals, whereas LH receptors were restricted to Leydig cells. In BZ animals, FSH and LH receptors and AMH were absent, indicating complete testicular degeneration. In conclusion, AMH is a more reliable marker for the presence of testicular tissue in bulls than inhibin. Scrotal resection did not induce a true inguinal cryptorchid state but affected testicular responsiveness to gonadotropic stimulation. Copyright © 2016 Elsevier Inc. All rights reserved.

[Relationship between phthalates and testicular dysgenesis syndrome].

PubMed

Chen, Guo-Rong; Dong, Lei; Ge, Ren-Shan; Hardy, Matthew P

2007-03-01

Recent epidemiological evidence demonstrates that boys born to women exposed to phthalates during pregnancy have an increased incidence of cryptorchidism, hypospadias, testicular cancer and spermatogenic dysfunction, which are collectively referred to as testicular dysgenesis syndrome (TDS). TDS may be attributed to the dysfunction of Leydig cells and Sertoli cells during their differentiation after exposure to phthalates in utero. Fox example, Leydig cell functions are significantly affected by phthalates, leading to the decrease of two Leydig cell products--insulin-like growth factor 3 (INSL3) and testosterone, which are critical factors for testis descent. The disorientation of Leydig cells and Sertoli cells in the adult testis may be the cause of spermatogenic dysfunction.

Persistent müllerian duct syndrome and prostate cancer.

PubMed

Mitre, Anuar Ibrahim; Castilho, Lisias Nogueira; Avarese de Figueiredo, Andre; Arap, Sami

2002-10-01

A localized Gleason score 6 (3 + 3) prostate cancer was found in a 56-year-old man with bilateral cryptorchidism. Radical laparoscopic prostatectomy was performed. However, at the beginning of the procedure, a uterus, two fallopian tubes, and two intra-abdominal gonads were endoscopically identified. The müllerian rests were excised and the gonads biopsied. The histologic examination showed testicular tissue. The association of prostate cancer and persistent müllerian duct syndrome to our knowledge has not previously been reported. Prostate cancer is an androgen-dependent neoplasm, and patients with male pseudohermaphroditism have poor androgen production that should provide protection against it.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Birnbaum, L.S.

Recent findings have raised the level of concern that chemicals in the environment can interfere with the endocrine systems of both people and wildlife. It has been reported that in men, sperm counts have decreased over the last 50 years. There appears to be an increase in cryptorchidism (undescended testicles), testicular cancer, and hypospadias (abnormal urethral opening). Young girls are reaching puberty earlier, the incidence of endometriosis is increasing, and the age of onset of endometriosis may be decreasing. Breast cancer incidence has increased approximately 1% per year over the past 50 years. Many of these conditions could be associatedmore » with elevated exposure to estrogens, either prenatally or during early post-natal life. 53 refs.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lopez, M.; Torres, L.; Cervantes, A.

Most individuals with the rare 46,XX male {open_quotes}syndrome{close_quotes} arise due to an unequal interchange between Xp and Yp termini during paternal meiosis. The pattern of Y-sequences in these patients varies considerably, but very few cases have been reported showing only SRY. The phenotype in these patients is also variable ranging from severe impairment of the external genitalia through hypospadias and/or cryptorchidism to occasional normal male phenotype. We report a Mexican 46,XX male patient without genital ambiguities in whom DNA analysis showed the presence of SRY and the absence of ZFY. We conclude that in this case SRY alone was enoughmore » for complete male sexual differentiation. 25 refs., 1 fig.« less

Two-Stage Urethroplasty with Buccal Mucosa for Penoscrotal Hypospadias Reconstruction in a Male with a 46,XX Karyotype.

PubMed

D'hulst, Pieter; Darras, Jochen; Joniau, Steven; Mattelaer, Pieter; Winne, Linsey; Ponette, Diederik

2017-09-01

We present a case regarding a 32-year old African male with penoscrotal hypospadias, left cryptorchidism and a left inguinal hernia. There were moderate masculinization characteristics. He underwent a Lichtenstein hernia repair with perioperative biopsies of the left inguinal testis and epididymis. Microscopic examination showed a Sertoli-only left testis with Leydig-cell hyperplasia and the left epididymis consisted of ovarian tissue with corpora albicantia and maturing follicles. Endocrinological evaluation showed a sex-determining region Y (SRY) negative 46,XX karyotype. We successfully performed a two-stage urethroplasty with buccal mucosa graft to reconstruct his penoscrotal hypospadias.

Doubtful descent, dilemma and diagnosis: a case of Kallmann syndrome.

PubMed

Chakraborty, P P; Chowdhury, S R; Mandal, S K; Bandyopadhyay, D

2007-03-01

A 16-year-old boy with a diagnosis of bilateral cryptorchidism was referred for preoperative evaluation. He had diminished hearing and difficulty in vision since birth, with inattentiveness, poor school performance and delayed milestones. He was previously operated on for cleft lip. General survey revealed bilateral short fourth metacarpals and an operative scar mark over the left nostril and upper lip. He had a micropenis, small soft testes with anosmia, and sensory-motor deafness. The hormonal assay was consistent with hypogonadotrophic hypogonadism. Magnetic resonance imaging of the brain and computed tomography cisternography revealed almost hypoplastic olfactory bulb with an ill-defined olfactory tract and sulci, supporting the clinical diagnosis of Kallmann syndrome.

Probable Opitz trigonocephaly C syndrome with medulloblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Omran, H.; Hildebrandt, F.; Brandis, M.

1997-04-14

We report on a patient with trigonocephaly, biparietal widening as a result of metopic synostosis, strabismus, upslanted palpebral fissures, apparently low-set ears with abnormal helices, deeply furrowed palate, postaxial polysyndactyly of the feet, ankle flexion deformities, cryptorchidism, loose skin, and severe mental retardation, findings compatible with a diagnosis of the Opitz trigonocephaly C syndrome (OTS). At the age of 12 years this patient presented with symptoms of raised intracranial pressure. A biopsy showed findings diagnostic of a medulloblastoma WHO Grade IV, an unprecedented finding in OTS. The possibility of coincidence should not prevent continued surveillance of OTS patients in themore » future for the occurrence of malignancy. 33 refs., 4 figs., 1 tab.« less

Phthalate-induced testicular dysgenesis syndrome: Leydig cell influence.

PubMed

Hu, Guo-Xin; Lian, Qing-Quan; Ge, Ren-Shan; Hardy, Dianne O; Li, Xiao-Kun

2009-04-01

Phthalates, the most abundantly produced plasticizers, leach out from polyvinyl chloride plastics and disrupt androgen action. Male rats that are exposed to phthalates in utero develop symptoms characteristic of the human condition referred to as testicular dysgenesis syndrome (TDS). Environmental influences have been suspected to contribute to the increasing incidence of TDS in humans (i.e. cryptorchidism and hypospadias in newborn boys and testicular cancer and reduced sperm quality in adult males). In this review, we discuss the recent findings that prenatal exposure to phthalates affects Leydig cell function in the postnatal testis. This review also focuses on the recent progress in our understanding of how Leydig cell factors contribute to phthalate-mediated TDS.

Adverse testicular effects of Botox® in mature rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Breikaa, Randa M.; Mosli, Hisham A.; Nagy, Ayman A.

Botox® injections are taking a consistently increasing place in urology. Intracremasteric injections, particularly, have been applied for cryptorchidism and painful testicular spasms. Studies outlining their safety for this use are, however, scanty. Thus, the present study aimed at evaluating possible testicular toxicity of Botox® injections and their effect on male fertility. Mature rats were given intracremasteric Botox® injections (10, 20 and 40 U/kg) three times in a two-week interval. Changes in body and testes weights were examined and gonadosomatic index compared to control group. Semen quality, sperm parameters, fructose, protein, cholesterol and triglycerides contents were assessed. Effects on normal testicularmore » function were investigated by measuring testosterone levels and changes in enzyme activities (lactate dehydrogenase-X and acid phosphatase). To draw a complete picture, changes in oxidative and inflammatory states were examined, in addition to the extent of connective tissue deposition between seminiferous tubules. In an attempt to have more accurate information about possible spermatotoxic effects of Botox®, flowcytometric analysis and histopathological examination were carried out. Botox®-injected rats showed altered testicular physiology and function. Seminiferous tubules were separated by dense fibers, especially with the highest dose. Flowcytometric analysis showed a decrease in mature sperms and histopathology confirmed the findings. The oxidative state was, however, comparable to control group. This study is the first to show that intracremasteric injections of Botox® induce adverse testicular effects evidenced by inhibited spermatogenesis and initiation of histopathological changes. In conclusion, decreased fertility may be a serious problem Botox® injections could cause. - Highlights: • Botox® injections are the trend nowadays, for both medical and non-medical uses. • They were recently suggested for cryptorchidism and testicular spasms. • This study outlines possible testicular adverse effects of these injections. • Botox® affected normal testicular function and physiology. • Infertility is a serious problem that Botox® injections could cause.« less

Association of placenta organotin concentrations with growth and ponderal index in 110 newborn boys from Finland during the first 18 months of life: a cohort study

PubMed Central

2014-01-01

Background Humans are exposed to tributyltin (TBT), previously used as an antifouling paint in ships, mainly through fish consumption. As TBT is a known obesogen, we studied the association of placenta TBT and other organotin compounds (OTCs) with ponderal index (PI) and growth during the first 18 months of life in boys. Methods In a prospective Finnish study, 110 placenta samples were collected from mothers of boys born in 1997–1999 with (n = 55) and without (n = 55) cryptorchidism. To account for the original study design, linear regression, weighted for sampling fractions of boys with (121/55) and without (5677/55) cryptorchidism from the total cohort, was used to study the association between placenta OTCs and children’s weight, length, growth rates and PI up to 18 months of age. Results Placenta TBT concentrations were above the limit of quantification (LOQ) in 99% of the samples. However, monobutyltin (MBT), dibutyltin (DBT) and triphenyltin (TPhT) concentrations were below LOQ in 90%, 35% and 57% of samples, respectively. Placenta TBT was positively associated (p = 0.024) with weight gain during the first three months of life, but no other significant associations were observed for weight or length gain. Also, no significant associations between placenta OTC concentrations and child length, weight or PI at any time point were found. Conclusions We observed a trend towards higher weight gain from birth to 3 months of age with increasing placenta TBT concentration. These results should be interpreted with caution because obesogenic effects in animal experiments were seen after in-utero TBT exposures to doses that were orders of magnitude higher. Also the number of study subjects included in this study was limited. PMID:24899383

A novel heterozygous RIT1 mutation in a patient with Noonan syndrome, leukopenia, and transient myeloproliferation-a review of the literature.

PubMed

Nemcikova, Michaela; Vejvalkova, Sarka; Fencl, Filip; Sukova, Martina; Krepelova, Anna

2016-04-01

Noonan syndrome (NS) is a genetic condition presenting with typical facies, cardiac defects, short stature, variable developmental deficit, cryptorchidism, skeletal, and other abnormalities. Germline mutations in genes involved in the RAS/MAPK signaling have been discovered to underlie NS. Recently, missense mutations in RIT1 have been reported as causative for individuals with clinical signs of NS. We report on a 2.5-year-old boy with NS phenotype with a novel heterozygous change in the RIT1 gene. The patient was born prematurely from pregnancy monitored for polyhydramnios. At 7 months of age, non-immune neutropenia and splenomegaly have been observed. During the severe pneumonia at 10 months, significant progression of hepatosplenomegaly, leukopenia with monocytosis (15-29 %), and thrombocytopenia occurred. Bone marrow evaluation showed myeloid hyperplasia and monocytosis, suggestive of myeloproliferative syndrome. Clinical phenotype (facial dysmorphism, soft hair, short neck, broad chest, widely spaced nipples, mild pectus carinatum, deep palmar creases, unilateral cryptorchidism), and moderate pulmonary valve stenosis with mild psychomotor delay were indicative of NS. DNA analysis identified a de novo heterozygous variant c.69A >T, p.(Lys23Asn) in exon 2 of the RIT1 gene, presumed to be causative. We present a patient with a clinical suspicion of NS carrying a novel substitution in RIT1 and hematologic findings not being observed in RIT1 positive patients to date. Thus, the case broadens variability of hematologic symptoms in RIT1 positive NS individuals. • Noonan syndrome is a common genetically heterogeneous disorder of autosomal dominant inheritance characterized by craniofacial dysmorphism, short stature, congenital heart defects, variable cognitive deficit, and other anomalies. What is new: • We report on a 2.5-year-old male patient with clinical signs of NS and hematologic abnormalities, in whom a novel heterozygous substitution in RIT1 with probable pathogenicity was detected.

Insulin-like peptide 3 (INSL3) in men with congenital hypogonadotropic hypogonadism/Kallmann syndrome and effects of different modalities of hormonal treatment: a single-center study of 281 patients.

PubMed

Trabado, Séverine; Maione, Luigi; Bry-Gauillard, Hélène; Affres, Hélène; Salenave, Sylvie; Sarfati, Julie; Bouvattier, Claire; Delemer, Brigitte; Chanson, Philippe; Le Bouc, Yves; Brailly-Tabard, Sylvie; Young, Jacques

2014-02-01

Insulin-like factor 3 (INSL3) is a testicular hormone secreted during fetal life, the neonatal period, and after puberty. To measure INSL3 levels in a large series of men with congenital hypogonadotropic hypogonadism (CHH)/ Kallmann syndrome (KS), in order to assess its diagnostic value and to investigate its regulation. We studied 281 CHH/KS patients (91 untreated, 96 receiving T, and 94 receiving combined gonadotropin therapy [human chorionic gonadotropin, hCG, and FSH]) and 72 age-matched healthy men. Serum INSL3 was immunoassayed with a validated RIA. Mean (±SD) INSL3 levels (pg/mL) were 659 ± 279 in controls and lower (60 ± 43; P < .001) in untreated CHH/KS patients, with no overlap between the two groups, when the threshold of 250 pg/mL was used. Basal INSL3 levels were lower in both untreated CHH/KS men with cryptorchidism than in those with intrascrotal testes and in patients with testicular volumes below 4 mL. Significant positive correlations between INSL3 and both serum total T and LH levels were observed in untreated CHH/KS. Mean INSL3 levels remained low in T-treated CHH/KS patients and were significantly higher in men receiving combined hCG-FSH therapy (P < .001), but the increase was lower cryptorchid patients. FSH-hCG combination therapy or hCG monotherapy, contrary to T and FSH monotherapies, significantly increased INSL3 levels in CHH/KS. INSL3 is as sensitive a marker as T for the evaluation of altered Leydig cell function in CHH/KS patients. INSL3 levels correlate with LH levels in CHH/KS men showing, together with the rise in INSL3 levels during hCG therapy, that INSL3 secretion seems not constitutively secreted during adulthood but is dependence on pituitary LH.

Congenital Hypogonadotropic Hypogonadism during Childhood: Presentation and Genetic Analyses in 46 Boys

PubMed Central

Vizeneux, Audrey; Hilfiger, Aude; Bouligand, Jérôme; Pouillot, Monique; Brailly-Tabard, Sylvie; Bashamboo, Anu; McElreavey, Ken; Brauner, Raja

2013-01-01

Background The majority of the patients reported with mutations in isolated hypogonadotropic hypogonadism (HH) are adults. We analysed the presentation and the plasma inhibin B and anti-müllerian hormone (AMH) concentrations during childhood and adolescence, and compared them to the genetic results. Methods This was a retrospective, single-center study of 46 boys with HH. Results Fourteen (30.4%) had Kallmann syndrome (KS), 4 (8.7%) had CHARGE syndrome and 28 (60.9%) had HH without olfaction deficit nor olfactive bulb hypoplasia. Eighteen (39%) had an associated malformation or syndromes. At diagnosis, 22 (47.8%) boys were aged

De novo 911 Kb interstitial deletion on chromosome 1q43 in a boy with mental retardation and short stature.

PubMed

Perrone, M D; Rocca, M S; Bruno, I; Faletra, F; Pecile, V; Gasparini, P

2012-02-01

Patients with distal deletions of chromosome 1q have a recognizable syndrome that includes microcephaly, hypoplasia or agenesis of the corpus callosum, and psychomotor retardation. Although these symptoms have been attributed to deletions of 1q42-1q44, the minimal chromosomal region involved has not yet defined. In this report, we describe a 7 years old male with mental retardation, cryptorchid testes, short stature and alopecia carrying only an interstitial de novo deletion of 911 Kb in the 1q43 region (239,597,095-240,508,817) encompassing three genes CHRM3, RPS7P5 and FMN2. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Prune Belly syndrome: A rare case report

PubMed Central

Samal, Sunil Kumar; Rathod, Setu

2015-01-01

Prune Belly syndrome (PBS) is a rare congenital anomaly of uncertain etiology almost exclusive to males. We report a case of term male baby born to a 39-year-old grand multipara with previous four normal vaginal births. There was no history of genetic or congenital anomaly in her family. Examination of the baby revealed hypotonia, deficient abdominal muscle, cryptorchidism, palpable kidney, and bladder. Ultrasound examination of the abdomen revealed bilateral gross hydronephrosis and megaureter. Provisional diagnosis of PBS was made and the baby was admitted in neonatal intensive care units for further management. Routine antenatal care with ultrasonography will help in detecting renal anomalies, which can be followed postnatally. Early diagnosis of this syndrome and determining its optimal treatment are very important in helping to avoid its fatal course. PMID:25810678

[Children with idiopathic hypogonadotropic hypogonadism: clinical data analysis and mutations analysis of KAL1 and FGFR1 gene].

PubMed

Qin, Miao; Gong, Chunxiu; Qi, Zhan; Wu, Di; Liu, Min; Gu, Yi; Cao, Bingyan; Li, Wenjing; Liang, Xuejun

2014-12-01

To summarize the clinical features of idiopathic hypogonadotropic hypogonadism (IHH) diagnosed during childhood, and detect mutations in KAL1 and FGFR1, acting as key clues for diagnoses. We collected and analyzed clinical data of 21 cases (including demographic data, chief complaint, history of present illness, family history, physical examination, laboratory tests and imaging studies, etc.) diagnosed with IHH from December 2008 to February 2013. Polymerase chain reaction and gene sequencing was applied to detect mutations on KAL1 and FGFR1. Fifty healthy unrelated individuals were choosen as controls. Of 21 patients with IHH, 19 were males and 2 females, they visited us initially from 8-17 years old, with an average of (13.58 ± 2.38) years old. Sixteen cases were KS patients (76%). One boy reported abnormal sense of smelling but having olfactory perfect picture on MRI; 2/19 male cases had no puberty when they were over 13-14 years old without abnormal external genitalia. 8/19 cases only had small penis, 8/19 had both of cryptorchidism and small penis, and the Case 2 also had hypospadias. One boy had cryptorchidism combined with a normal penis. Only 2 girls diagnosed as IHH who visited us because of no puberty signs when they were 13 and 16 years old, respectively. Other clinical manifestations included: one with gynecomastia, 2 had mental retardation, and one was deaf; one with high palatal arch; one with mirror-movement and one with left renal agenesis but normal renal function respectively. Laboratory tests showed that the basic testosterone (T) is low and with inappropriately low or normal gonadotropin hormones. The results of cases of standard human chorionic gonadotropin (HCG) test of 7 cases out of 19 male children's were normal (testosterone>1 100 ng/L), and another nine cases continued to complete the extended HCG test, and the testosterone levels of two of them (cases 6, 8) were still lower than 1 000 ng/L. Family history: the parents in 9/21 family had delayed puberty, involving only one parent in 6 families, involving both in 2 families and the other one was an uncle having micropenis with a child. Among these 21 cases, only one boy's father had hyposmia and his first emission age was 14-15 years. Eleven patients accompanied abnormal sense of smelling and the olfactory organ abnormalities on MRI, 4 had olfactory organ abnormalities on MRI while they had good smelling function self-reportedly. We got 15 samples (12 KS and 3 nIHH cases) to screen the mutation of KAL1 (14 exons) and FGFR1 (18 exons). A splicing mutation c.1062+1G>A in KAL1 is identified in case 17 with IHH. One novel heterozygous FGFR1 mutation, a single base deletion mutation on the exon 1 c.27delC is identified in case 14. This mutation causes the premature termination codons. This pilot research showed that IHH/KS diagnosis in children depends on clinical manifestation rather than gene analysis. Small penis or cryptorchidism, smelling abnormality and positive familial history may contribute to the KS/HH diagnosis. MRI of olfactory bulb acts as important proof for diagnosis of KS. Mutations in KAL1 and FGFR1 gene are not main causes of Kallmann syndrome.

The use of human chorionic gonadotropin (HCG) for penile reconstruction in bladder exstrophy and total epispadias patients.

PubMed

Makedonsky, I A

2006-12-01

The effect of intramuscular human chorionic gonadotropin (HCG) administration on penile enlargement before genital surgery, its influence on penile skin histology and testicular descent were investigated. We examined 45 male patients (median age, 8 months; range 3-28) with total epispadias and classic bladder exstrophy, combined with cryptorchidism. 30 patients were administered 250-500 IU HCG intramuscularly 2 times per week for 3 weeks before reconstructive surgery. Skin biopsies were obtained for human epidermal growth factor (EGF) and human epidermal growth factor receptor (Her2/neu) determination. Skin specimens of the prepuce of 18 circumcised patients were used as controls. Post treatment testicle position was evaluated. HCG caused a mean increase in penile length of 1.8 cm (p < 0.01) and in circumference of 1.2 cm (p < 0.05) as well as improved local vascularity in all patients. Compared to the controls, the penile skin of exstrophy/epispadias patients showed a significant decrease in the average amount per field of EGF and Her2/neu positive material (controls 81% [mean 79, SE 2.3] vs. 31% [mean 28, SE 3.6; p < 0.001]). Treatment with HCG led to an increase in average EGF and Her2/neu positive material by 10% (mean 8, SE 2; p < 0.05). The potential side effects of HCG treatment were monitored 3 to 6 months postoperatively. Basal testosterone and LH levels were obtained in patients before and during therapy and postoperatively. Testicular descent was achieved in 21 patients (70%). No significant side effects or complications were encountered in any of our patients. Mean EGF and Her2/neu values are decreased in the penile skin of exstrophy/epispadias patients. The use of preoperative HCG administration leads to an increase in EGF and Her2/neu values and significantly contributes to successful reconstruction in these patients, especially in cases with a paucity of penile skin and in patients who have undergone previous repairs. Temporary penile stimulation by HCG in patients with bladder exstrophy combined with cryptorchidism allows the penile operation to be carried out earlier and contributes to testicular descent while demonstrating negligible side effects.

Human Exposure to Endocrine-Disrupting Chemicals and Prenatal Risk Factors for Cryptorchidism and Hypospadias: A Nested Case–Control Study

PubMed Central

Fernandez, Mariana F.; Olmos, Begoña; Granada, Alicia; López-Espinosa, Maria José; Molina-Molina, José-Manuel; Fernandez, Juan Manuel; Cruz, Milagros; Olea-Serrano, Fátima; Olea, Nicolás

2007-01-01

Background Exposure to xenoestrogens during pregnancy may disturb the development and function of male sexual organs. Objective In this study we aimed to determine whether the combined effect of environmental estrogens measured as total effective xenoestrogen burden (TEXB) is a risk factor for male urogenital malformations. Methods In a case–control study, nested in a mother–child cohort (n = 702) established at Granada University Hospital, we compared 50 newborns with diagnosis of cryptorchidism and/or hypospadias with 114 boys without malformations matched by gestational age, date of birth, and parity. Controls did not differ from the total cohort in confounding variables. TEXB and levels of 16 organochlorine pesticides were measured in placenta tissues. Characteristics of parents, pregnancy, and birth were gathered by questionnaire. We used conditional and unconditional regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results TEXB from organohalogenated compounds was detectable in 72% and 54% of case and control placentas, respectively. Compared with controls, cases had an OR for detectable versus non-detectable TEXB of 2.82 (95% CI, 1.10–7.24). More pesticides were detected in cases than in controls (9.34 ± 3.19 vs. 6.97 ± 3.93). ORs for cases with detectable levels of pesticides, after adjusting for potential confounders in the conditional regression analysis, were o,p′-DDT (OR = 2.25; 95% CI, 1.03–4.89), p,p′-DDT (OR = 2.63; 95% CI, 1.21–5.72), lindane (OR = 3.38; 95% CI, 1.36–8.38), mirex (OR = 2.85; 95% CI, 1.22–6.66), and endosulfan alpha (OR = 2.19; 95% CI, 0.99–4.82). Engagement of mothers in agriculture (OR = 3.47; 95% CI, 1.33–9.03), fathers’ occupational exposure to xenoestrogens (OR = 2.98; 95% CI, 1.11–8.01), and history of previous stillbirths (OR = 4.20; 95% CI, 1.11–16.66) were also associated with risk of malformations. Conclusions We found an increased risk for male urogenital malformations related to the combined effect of environmental estrogens in placenta. PMID:18174944

Breeding soundness evaluations of Senepol bulls in the US Virgin Islands.

PubMed

Godfrey, R W; Dodson, R E

2005-02-01

The breeding soundness evaluation (BSE) was used to evaluate Senepol (Bos taurus) bulls (n = 495) on St. Croix over a 7-year period. Young, unproven bulls (10-26 months of age) and breeding bulls (16 months to 8.5 years) were tested prior to sale or use in breeding. Inbreeding coefficients were determined for a subset of bulls (n = 290). The percentage of bulls passing the BSE increased (P < 0.0001) with age. Bulls that passed had a higher percentage (P < 0.0001) of normal and motile sperm as well as a larger (P < 0.0001) scrotal circumference than bulls that failed. No bulls failed the BSE for physical soundness traits or other health reasons. The incidence of testicular hypoplasia was 2.5 and 3.3% and the incidence of cryptorchidism was 1.4 and 0.9% in 12- and 16-month-old bulls, respectively, with no occurrence in bulls >20 months. The proportion of all bulls that failed the BSE and received an Unsatisfactory rating for scrotal circumference or sperm motility decreased (P < 0.0001) from >90 to <25% with age. The proportion of all bulls that failed the BSE and received an Unsatisfactory rating for sperm morphology decreased (P < 0.0001) from 99 to 83.3% with age. The inbreeding coefficient was higher (P < 0.03) in bulls that failed the BSE than in those that passed (2.24 +/- 0.19% versus 1.40 +/- 0.32%, respectively). There was a tendency for bulls with testicular hypoplasia or cryptorchidism to have a higher (P = 0.09) inbreeding coefficient than bulls with normal testes (2.90 +/- 0.46% versus 2.13 +/- 0.11%, respectively). In conclusion, Senepol bulls raised under tropical conditions had a low probability of passing the BSE at young ages, but the passing rate increased with age. Older Senepol bulls were more likely to fail the BSE due to abnormal sperm morphology than due to inadequate testicular size or sperm motility. To prevent unnecessary culling, a BSE should not be performed on Senepol bulls <16 months old.

Persistent Mullerian duct syndrome in a Miniature Schnauzer dog with signs of feminization and a Sertoli cell tumour.

PubMed

Vegter, A R; Kooistra, H S; van Sluijs, F J; van Bruggen, L W L; Ijzer, J; Zijlstra, C; Okkens, A C

2010-06-01

A 5-year-old male Miniature Schnauzer was presented with unilateral cryptorchidism and signs of feminization. Abdominal ultrasonography revealed an enlarged right testis and a large, fluid-filled cavity that appeared to arise from the prostate. Computed tomography revealed the cavity to be consistent with an enlarged uterine body, arising from the prostate, and showed two structures resembling uterine horns that terminated close to the adjacent testes. The dog had a normal male karyotype, 78 XY. Gonadohysterectomy was performed and both the surgical and the histological findings confirmed the presence of a uterus in this male animal, resulting in a diagnosis of persistent Mullerian duct syndrome (PMDS). The enlarged intra-abdominal testis contained a Sertoli cell tumour. Computed tomography proved to be an excellent diagnostic tool for PMDS.

Studies of malformation syndromes in man XXXX: multiple congenital anomalies/mental retardation syndrome or variant familial developmental pattern; differential diagnosis and description of the McDonough syndrome (with XXY son from XY/XXY father).

PubMed

Neuhäuser, G; Opitz, J M

1975-11-13

The McDonough syndrome is a "new" MCA/MR syndrome which was found in 3 children (1 girl, 2 boys) of non-consanguineous parents. The affected children were mentally retarded (IQ 47--67) and had congenital heart defect, sternal deformity, kyphosis and craniofacila anomalies (anteverted auricles, upward slanted palpebral fissures, squint); cryptorchidism was present in the 2 boys. In addition a possible VFDP is postulated as the explanation for similar features in affected and unaffected siblings and parents. However, the McDonough syndrome may be an autosomal recessive trait with minor manifestations in heterozygotes. The klinefelter syndrome in one affected boy and a 46,XY/47,XXY chromosome constitution in the father was a coincidental finding.

Treatment for incarcerated indirect hernia with "Cross-Internal Ring" inguinal oblique incision in children.

PubMed

Yan, Xue-Qiang; Yang, Jun; Zheng, Nan-Nan; Kuang, Hou-Fang; Duan, Xu-Fei; Bian, Hong-Qiang

2017-01-01

This study aims to evaluate the utility of the "Cross-Internal Ring" inguinal oblique incision for the surgical treatment of incarcerated indirect hernia (IIH) complicated with severe abdominal distension. Patients of IIH complicated with severe abdominal distension were reviewed retrospectively. All patients received operation through the "Cross-Internal Ring" inguinal oblique incision. There were totally 13 patients were included, male to female ratio was 9-4. The time for patients to resume oral feeding varying from 2 to 5 days after operation, no complications include delayed intestinal perforation, intra-abdominal abscess, and incision infection happened. Average postoperative hospital stay was 5.2 days. All cases were followed up for 6-18 months. No recurrence or iatrogenic cryptorchidism happened. "Cross-Internal Ring" inguinal oblique incision is a simple, safe, and reliable surgical method to treat pediatric IIH complicated with severe abdominal distension.

De morseir syndrome presenting as ambiguous genitalia.

PubMed

Thukral, Anubhav; Chitra, S; Chakraborty, Partho P; Roy, Ajitesh; Goswami, Soumik; Bhattacharjee, Rana; Dutta, Deep; Maisnam, Indira; Ghosh, Sujoy; Mukherjee, Satinath; Chowdhury, Subhankar

2012-12-01

A 10-year-old boy presented with genital ambiguity, poor linear growth, and delayed milestones. The aim and to highlight that although rare but congenital, hypogonadotropic hypogonadism may rarely present as ambiguity. The patient was found to have bilateral cryptorchidism with proximal penile hypospadias, microphallus with a proportionate dwarfism with mildly delayed bone age, and karyotype 46XY. Euthyroid with normal steroid axis, growth hormone insufficient as suggested by auxology, low IGF1, and poor response to clonidine stimulation. MRI brain shows hypoplastic corpus callosum, hypoplastic anterior pituitary, and ectopic posterior pituitary bright spot. The patient underwent laparoscopic removal of right intrabdominal testis and orchidoplexy was performed on the left one. Testicular biopsy revealed no malignancy and growth hormone replacement was initiated. The patient awaits definitive repair of hypospadias. As a provisional diagnosis of combined growth hormone and gonadotropin deficiency, most probable diagnosis is septo-optic dysplasia or de moseir syndrome leading to genital ambiguity.

Polish Society of Endocrinology Position statement on endocrine disrupting chemicals (EDCs).

PubMed

Rutkowska, Aleksandra; Rachoń, Dominik; Milewicz, Andrzej; Ruchała, Marek; Bolanowski, Marek; Jędrzejuk, Diana; Bednarczuk, Tomasz; Górska, Maria; Hubalewska-Dydejczyk, Alicja; Kos-Kudła, Beata; Lewiński, Andrzej; Zgliczyński, Wojciech

2015-01-01

With the reference to the position statements of the Endocrine Society, the Paediatric Endocrine Society, and the European Society of Paediatric Endocrinology, the Polish Society of Endocrinology points out the adverse health effects caused by endocrine disrupting chemicals (EDCs) commonly used in daily life as components of plastics, food containers, pharmaceuticals, and cosmetics. The statement is based on the alarming data about the increase of the prevalence of many endocrine disorders such as: cryptorchidism, precocious puberty in girls and boys, and hormone-dependent cancers (endometrium, breast, prostate). In our opinion, it is of human benefit to conduct epidemiological studies that will enable the estimation of the risk factors of exposure to EDCs and the probability of endocrine disorders. Increasing consumerism and the industrial boom has led to severe pollution of the environment with a corresponding negative impact on human health; thus, there is great necessity for the biomonitoring of EDCs in Poland.

Multifocal tenosynovial giant cell tumors in a child with Noonan syndrome.

PubMed

Meyers, Arthur B; Awomolo, Agboola O; Szabo, Sara

2017-03-01

Noonan syndrome is a genetic disorder with variable expression of distinctive facial features, webbed neck, chest deformity, short stature, cryptorchidism and congenital heart disease. The association of Noonan syndrome and giant cell granulomas of the mandible is widely reported. However, Noonan syndrome may also be associated with single or multifocal tenosynovial giant cell tumors, also referred to as pigmented villonodular synovitis. We report a child with Noonan syndrome, giant cell granulomas of the mandible and synovial and tenosynovial giant cell tumors involving multiple joints and tendon sheaths who was initially misdiagnosed with juvenile idiopathic arthritis. It is important for radiologists to be aware of the association of Noonan syndrome and multifocal giant cell lesions, which can range from the more commonly described giant cell granulomas of the mandible to isolated or multifocal intra- or extra-articular tenosynovial giant cell tumors or a combination of all of these lesions.

Noonan syndrome.

PubMed

Bhambhani, Vikas; Muenke, Maximilian

2014-01-01

Noonan syndrome is a common genetic disorder that causes multiple congenital abnormalities and a large number of potential health conditions. Most affected individuals have characteristic facial features that evolve with age; a broad, webbed neck; increased bleeding tendency; and a high incidence of congenital heart disease, failure to thrive, short stature, feeding difficulties, sternal deformity, renal malformation, pubertal delay, cryptorchidism, developmental or behavioral problems, vision problems, hearing loss, and lymphedema. Familial recurrence is consistent with an autosomal dominant mode of inheritance, but most cases are due to de novo mutations. Diagnosis can be made on the basis of clinical features, but may be missed in mildly affected patients. Molecular genetic testing can confirm diagnosis in 70% of cases and has important implications for genetic counseling and management. Most patients with Noonan syndrome are intellectually normal as adults, but some may require multidisciplinary evaluation and regular follow-up care. Age-based Noonan syndrome-specific growth charts and treatment guidelines are available.

46,XY hypergonadotropic hypogonadism and myasthenia gravis.

PubMed

Lichiardopol, Corina; Herlea, V; Ioan, Virginia; Tomulescu, V; Mixich, F

2006-01-01

Both hypergonadotropic hypogonadism and myasthenia gravis can be parts of type II autoimmune polyendocrine syndrome and association between the two disorders has been reported in few cases. A 14 year old male patient with a personal history of bilateral cryptorchidism and ptosis was referred for delayed puberty. Clinical examination revealed eunuchoid habitus, small, soft testes, gynecomastia, ptosis, a myasthenic deficit score of 22.5 points and an IQ of 84 points. Decreased testosterone (0.064 ng/mL) and elevated LH (64.5 mUI/mL) were consistent with hypergonadotropic hypogonadism and karyotype was normal: 46,XY. Thyroid function, haematologic evaluation, BUN, electrolytes, and glycemia were in the normal range. Therapy consisted of anticholinesterase inhibitors, immunosuppressants, corticotherapy, testosterone; thoracoscopic thymectomy was performed showing thymic lymphoid hyperplasia on histopathologic examination. Myasthenic score improved (12.5 points), progressive virilization occurred, and a year later the patient presented with cushingoid features and obesity.

Risk factors for hypospadias in China

PubMed Central

Xu, Ling-Fan; Liang, Chao-Zhao; Lipianskaya, Julia; Chen, Xian-Guo; Fan, Song; Zhang, Li; Zhou, Jun; Tai, Sheng; Jiang, Chang-Qin

2014-01-01

This case-controlled study was designed to evaluate the association between various baseline parental factors and the risk of hypospadias in China. Patients were selected from tertiary referral hospitals in Anhui, a province in mid-eastern China. A questionnaire was given to the parents of each patient. The final database included 193 cases and 835 controls. The incidence of additional coexistent anomalies was 13.0%, primarily cryptorchidism (9.8%). Ten patients (5.1%) were from families with genital anomaly, including five families (2.6%) with hypospadias. The risks of hypospadias was higher for children of mothers > 35 (odds ratio [OR] =1.47) and < 18 (OR = 2.95) years of age, and in mothers who had consumed alcohol (OR = 2.67), used drugs (OR = 1.53) and had an infection (OR = 1.87) during pregnancy. The risk of hypospadias was also higher when mothers (OR = 1.68) and fathers (OR = 1.74) were engaged in agriculture. Other factors assessed were not associated with the risk of hypospadias. PMID:24875823

Ovotesticular disorder of sexual development and a rare 46,XX/47,XXY karyotype.

PubMed

Ozsu, Elif; Mutlu, Gul Yesiltepe; Cizmecioglu, Filiz M; Ekingen, Gülsen; Muezzinoglu, Bahar; Hatun, Sukru

2013-01-01

Ovotesticular disorder of sexual development (DSD) is characterized by the presence of both ovarian and testicular tissues in the same individual. The most common karyotype is 46,XX. Here, we report the case of a boy with a 46,XX/47,XXY karyotype diagnosed as ovotesticular DSD by gonadal biopsy. A 5-month-old boy presented with hypospadias, unilateral cryptorchidism, and a micropenis. Pelvic magnetic resonance imaging revealed a suspicious gonad tissue that is solid in structure in the right scrotum and a suspicious gonad that is cystic in structure in the left inguinal canal. He underwent a diagnostic laparoscopy. Cytogenetic analysis of peripheral blood revealed a 46,XX/47,XXY karyotype. Histopathologic examination of the left gonad showed ovarian tissue containing primordial follicles with ipsilateral undifferentiated tuba uterina. The right gonad showed immature testis tissue. He underwent left gonadectomy and hypospadias repair, and was raised as a male. Through this rare case, we highlight the importance of histological and cytogenetic investigation in DSD.

Modulating reproductive activity in stallions: a review.

PubMed

Stout, T A E

2005-10-01

Situations in which suppression or stimulation of reproductive activity in stallions has been attempted, or is desired, include resolution of the equine arteritis virus 'shedding' state, induction of testicular descent in inguinal cryptorchids, and the improvement of sperm production capacity and/or semen quality in sub-fertile stallions. However, the most common reason for wanting to modulate reproductive activity in a stallion is to alter the expression of sexual behaviour. In the case of intact stallions used for competitive or recreational purposes, the overt expression of sexual or aggressive behaviour can be distracting for both animal and owner and, in some cases, dangerous to all concerned. By the same token, a breeding stallion that displays little interest in mounting a mare/phantom, or is slow to achieve erection and/or ejaculation, can be extremely frustrating. This paper reviews the major pharmacological agents reported to usefully modify reproductive activity in stallions, and outlines their pros and cons when compared to training, management or surgical alternatives.

22.5 MB DELETION OF 13q31.1-q34 ASSOCIATED WITH HPE, DWM, AND HSCR: A CASE REPORT AND REDEFINING THE SMALLEST DELETED REGIONS.

PubMed

Alp, M Y; Çebi, A H; Seyhan, S; Cansu, A; Aydin, H; Ikbal, M

2016-01-01

Partial deletion of the long arm of the chromosome 13, 13q deletion syndrome is a rare chromosomal disorder characterized by severe growth and mental retardation, microcephaly, facial dysmorphism, brain malformations (holoprosencephaly, Dandy-Walker malformation), distal limb defects, eye anomalies, genitourinary and gastrointestinal tract malformations (Hirschsprung's disease). Approximately 1.2 Mb region in 13q32 was suggested as minimal critical region which is responsible for severe mental and growth retardation and brain anomalies. Here we described a male patient with de novo interstitial deletion of 13q31.1-q34 associated with short stature, microcephaly, facial dysmorphism, clinodactyly, cryptorchidism, micropenis, epilepsy, HPE, DWM, and HSCR. According to the literature review, present case indicated that smallest deleted region associated with DWM and HPE might be located at the 13q32.3, limb defects 13q34, anogenital malformations 13q33.3-34, and HSCR 13q31.1-32.1.

[Research progress of health effect of polybrominated diphenyl ethers].

PubMed

Zhai, J X; Tong, S L

2016-06-01

Polybrominated diphenyl ethers (PBDEs) was one of the most common brominated flame retardants, it has been widely used in products such as furnitures, polymer and plastical material, textiles, electronic products and building materials. PBDEs have potential effect such as neurodevelopmental toxicity, reproductive toxicity, thyroid toxicity, immunological toxicity, embryo toxicity, liver toxicity, teratogenicity and potential carcinogenicity. This paper was aimed to review the environmental exposure way, current level, neurotoxicity, neurodevelopmental toxicity and reproductive toxicity of PBDEs. In recent years, PBDEs has been detected in environment, wildlife animal and human body around the world, there were the significant differences of exposure levels of PBDEs. The most abundant congener were tetra-BDE or BDE-47, hexa-BDE or BDE-153, and deca-BDE or BDE-209. Prenatal exposure to PBDEs has great impact on the infants' neurodevelopmental function, induces changes in neuropsychological developmental behavior, decreases of congnition, motivation and attention. High levels of PBDEs have positive relationship with Luteinizing hormone levels, testis disfunction and children's cryptorchidism, and have negative relationship with sperm number and testis size.

Association of Down's syndrome and testicular cancer.

PubMed

Dieckmann, K P; Rübe, C; Henke, R P

1997-05-01

We present additional clinical evidence for the suspected association of Down's syndrome and testicular germ cell tumors. Four cases of Down's syndrome and testicular cancer are reported. The literature was reviewed for previous cases and analysis regarding common features. The 4 patients were 29 to 35 years old and had clinical stage I seminoma of the testis. Two patients received prophylactic abdominal radiotherapy, 1 is being followed and 1 received adjuvant carboplatin treatment. There was no relapse at followup of 1 to 8 years. One patient also had contralateral cryptorchidism. A total of 16 cases with the association of Down's syndrome and testicular germ cell cancer was documented previously. Evidence for the suspected association of Down's syndrome and testicular cancer is now accumulating. Etiologically it is suspected that, along with genetically determined malformations in many other organs in trisomy 21, the gonads also undergo maldevelopment, thus creating the conditions for step 1 of germ cell tumor oncogenesis in utero. Physicians caring for patients with Down's syndrome should be aware of the possible association with testicular neoplasms.

Effect of feeding graded doses of Citrinin on clinical and teratology in female Wistar rats.

PubMed

Singh, N D; Sharma, A K; Patil, R D; Rahman, S; Leishangthem, G D; Kumar, M

2014-02-01

Citrinin is the one of the well-known mycotoxins, which is possibly spread all over the world. The graded doses of citrinin (1, 3 and 5 ppm CIT in feed) in female Wistar rats 10 weeks prior to mating, during mating and during organogenesis resulted in resorptions and post implantation losses, decreased fetal body weights and crown-rump lengths in fetuses of all groups. Various developmental anomalies recorded in fetuses of treated rats included gross (wrist drop, curled tail, stretched forelimb, subcutaneous haematoma), skeletal (incomplete ossification of skull bones, incomplete fusion of vertebral bodies, complete and partial agenesis of sternaebrae, metacarpals, metatarsals and phalanges, fused ribs and swing out ribs) and visceral (internal and external hydrocephalus, cerebellar hypoplasia, microphthalmia, roundening of heart, contracted kidneys, dilated renal pelvis and cryptorchid testes). The results suggest that CIT has adverse effects on fetal development which may be due to the longer bioavailability of citrinin in the animals.

Hypogonadotropic hypogonadism in a female patient with congenital arhinia.

PubMed

Hunter, Janel Darcy; Davis, Melissa Ann; Law, Jennifer Rachel

2017-01-01

The association of anosmia and congenital hypogonadotropic hypogonadism (CHH) is well described; however, congenital arhinia is a malformation associated with CHH that occurs much more rarely. There have been three reports of male patients with hypogonadism and congenital arhinia in the literature to date. We present the first case of arhinia associated with CHH in a female patient. A 14 years and 8 months female with congenital arhinia presented with delayed puberty. Physical examination and laboratory evaluation were consistent with hypogonadotropic hypogonadism. She had no other hormone deficiencies and brain magnetic resonance imaging demonstrated a normal pituitary gland. Abdominal ultrasound showed a prepubertal uterus and ovaries. She was subsequently started on sex steroid treatment to induce secondary sexual characteristics. This case demonstrates that abnormalities of nasal development may provide an early diagnostic clue to hypogonadotropic hypogonadism, particularly in female patients who would not manifest classic signs of CHH in infancy (micropenis and cryptorchidism). Early diagnosis of CHH and timely initiation of sex steroid therapy is important to prevent comorbidities related to pubertal delay.

DOE Office of Scientific and Technical Information (OSTI.GOV)

van Heyningen, V.; Bickmore, W.A.; Seawright, A.

Detailed molecular definition of the WAGR region at chromosome 11p13 has been achieved by chromosome breakpoint analysis and long-range restriction mapping. Here the authors describe the molecular detection of a cytogenetically invisible 1-megabase deletion in an individual with aniridia, cryptorchidism, and hypospadias but no Wilms tumor (WT). The region of overlap between this deletion and one associated with WT and similar genital anomalies but no aniridia covers a region of 350-400 kilobases, which is coincident with the extent of homozygous deletion detected in tumor tissue from a sporadic WT. A candidate WT gene located within this region has recently beenmore » isolated, suggesting nonpenetrance for tumor expression in the first individual. The inclusion within the overlap region of a gene for WT predisposition and a gene for the best-documented WT-associated genitourinary malformations leads to suggest that both of these anomalies result from a loss-of-function mutation at the same locus. This in turn implies that the WT gene exerts pleiotropic effect on both kidney and genitourinary development, a possibility supported by the observed expression pattern of the WT candidate gene in developing kidney and gonads.« less

Feline reproduction: problems and clinical challenges.

PubMed

Little, Susan

2011-07-01

Many veterinarians are closely involved with pedigree cat breeding and have become familiar with the unique characteristics of feline reproduction and breeding management. However, even veterinarians who do not have involvement with the pedigree cat fancy require a basic knowledge of the reproductive problems that are most likely to be encountered in working with non-breeding pet cats as well as stray and feral cats. This article reviews reproductive problems and challenges in both sexes - namely, ovarian remnant syndrome, mammary fibroadenomatous hyperplasia, congenital anomalies of the reproductive tract and pregnancy diagnosis in the queen, and cryptorchidism and low libido in the tom. Feline reproduction has not received the amount of investigation and attention that has been directed at canine reproduction. The result is that less data is available both for description of normal reproduction and for management of common problems. This article reviews most of the available evidence for the conditions discussed. Efforts should focus on making information more readily available to the practitioner and expanding the knowledge base in this important area of feline medicine. Copyright © 2011 ISFM and AAFP. Published by Elsevier Ltd. All rights reserved.

Caudal dysplasia sequence with penile enlargement: case report and a potential pathogenic hypothesis.

PubMed

Makhoul, I R; Aviram-Goldring, A; Paperna, T; Sujov, P; Rienstein, S; Smolkin, T; Epelman, M; Gershoni-Baruch, R

2001-02-15

The clinical spectrum of caudal dysplasia sequence (CDS) is noted for its diversity. The origin of CDS remains unknown, though poorly controlled gestational diabetes has been implicated in some cases. Here we describe the case of a newborn with CDS associated with penile enlargement (PE). The main anomalies included anal atresia, agenesis of the kidneys and of the sacrococcygeal vertebrae, dysgenesis of lumbar vertebrae, and bilateral cryptorchidism. Penile enlargement (7 cm), a rather unusual finding, has so far not been reported in association with CDS. Chromosomal analysis failed, and the neonate died 30 min after birth. Comparative genomic hybridization analysis using stored DNA showed a balanced normal male DNA content, which negates chromosomal losses or gains as a cause of CDS and/or PE. PE due to virilizing-type adrenal hyperplasia, caused by common mutations in the genes encoding for the adrenal enzymes 21-hydroxylase and 11-hydroxylase, was ruled out. We report on a previously unpublished case of the coexistence of PE and severe CDS and propose a possible pathogenetic hypothesis of this association. Copyright Wiley-Liss. Inc.

Testicular microlithiasis: recent advances in understanding and management.

PubMed

Tan, Min-Han; Eng, Charis

2011-03-01

Testicular microlithiasis is an infrequent but well recognized condition, which is usually incidentally identified on testicular ultrasound scan. Interest in testicular microlithiasis has increased over the past few years, owing to an observed association with testicular germ cell tumor (TGCT) and intratubular germ cell neoplasia of unclassified type (ITGCNU). This association has added to evidence that testicular microlithiasis is a feature of the testicular dysgenesis syndrome (TDS), which is postulated to underpin disorders of male reproduction such as subfertility, testicular atrophy, cryptorchidism, TGCT and other abnormalities of sexual development. Although the genetic and environmental components of TDS remain unclear, studies of the molecular basis of TGCT support a genetic component for testicular microlithiasis and have identified multiple genes that are associated with TGCT. These advances in the biological understanding of testicular microlithiasis and TGCT have not, however, resolved key clinical dilemmas in the management of patients with these diseases. The role of testicular microlithiasis in the clinical consideration of testicular biopsy is discussed in the context of the apparently healthy individual, the individual with TGCT and the individual with TDS.

Effects of Caudal Elevation on Testicular Function in Rats: Separation of Effects on Spermatogenesis and Steroidogenesis

NASA Technical Reports Server (NTRS)

Deaver, D. R.; Amann, R. P.; Hammerstedt, R. H.; Ball, R.; Veeramachaneni, D. N. R.; Musacchia, X. J.

1992-01-01

A variety of biologic processes are perturbed when exposed to microgravity (space flight) for more than 7 days, including testicular function. Suspension of rats in a special harness (caudal elevation) to induce thoracic pooling of blood fluids and remove the support function of the hind limbs is used to mimic, on earth, the effects of microgravity encountered during space flight. Typically, this induces cryptorchidism in male rats. Three experiments were conducted to differentiate the effects of caudal elevation (30 deg angle) and anatomic location of testes on spermatogenesis and steroidogenesis. Rats were subjected to caudal elevation for 7 days using either a tail harness or a whole-body harness. Testes of rats fell into the abdominal cavity when a tail harness was used, but ligation of the iguinal canal prevented this repositioning. For rats with abdominal testes, testicular weight was reduced (P less than 0.05) and histology of testes was abnormal; the number of spermatids per gram parenchyma was lower (P less than 0.05) in tail-suspended rats compared with control rats.

Testicular cancer in two brothers of a quadruplet: a case report and a review of literature.

PubMed

Ulytė, Agnė; Ulys, Albertas; Sužiedėlis, Kęstutis; Patašius, Aušvydas; Smailytė, Giedrė

2017-01-01

Introduction. Testicular cancer and a multiple birth are both rare events, and the risk of testicular cancer is increased in twins. In Lithuania, only five quadruplets have been recorded since the middle of the 20th century. In this report, we present two rare events in one family: testicular cancer in two brothers of a quadruplet (three brothers and a sister). Case description. Both patients were diagnosed at 21 years of age and died within two years from the diagnosis despite treatment. The third symptomless brother did not have testicular pathology. We also review the risk factors associated with testicular cancer, and the proposed hypotheses how a multiple birth results in an increased risk. The most consistent risk factors for testicular cancer are cryptorchidism, prior history of testicular cancer, and a positive familial history. According to different studies, the risk of testicular cancer in twins is higher from 22% to 30%, compared to the general population. Conclusions. To our knowledge, we have presented the first case of testicular teratoblastoma in brothers of a quadruplet.

Testicular microlithiasis and testicular cancer: review of the literature.

PubMed

Pedersen, Malene Roland; Rafaelsen, Søren Rafael; Møller, Henrik; Vedsted, Peter; Osther, Palle Jörn

2016-07-01

To perform a systematic literature review to assess whether the occurrence of testicular microlithiasis (TML) in conjunction with other risk factors is associated with testicular cancer. A systematic literature search was performed of original articles in English published 1998 to 2015. Relevant studies were selected by reading the title and abstract by two of the authors. Studies were included if TML was diagnosed by ultrasonography and a risk condition was reported. Studies were only eligible if the particular risk condition was reported in more than one article. In total, 282 abstracts in were identified. Based on title and abstract the eligibility was assessed and 31 studies were included. Five conditions in relation to TML and testicular cancer emerged: Down syndrome, McCune-Albright syndrome, cryptorchidism, infertility and familial disposition of testicular cancer. Data support the conclusion that TML is not an independent risk factor for testicular cancer but associated with testicular cancer through other conditions. In male infertility, TML appears to be related to an increased risk of testicular cancer possibly as part of a testicular dysgenesis syndrome.

Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development.

PubMed

Kilcoyne, Karen R; Mitchell, Rod T

2017-12-01

Human male reproductive disorders (cryptorchidism, hypospadias, testicular cancer and low sperm counts) are common and some may be increasing in incidence worldwide. These associated disorders can arise from subnormal testosterone production during fetal life. This has resulted in a focus on in-utero environmental influences that may result in reproductive effects on the offspring in later life. Over recent years, there has been a dramatic increase in the scientific literature describing associations between in-utero environmental exposures (eg, industrial chemicals and pharmaceuticals) and subsequent reproductive outcomes in male offspring. This includes studies investigating a potential role for in-utero analgesic exposure(s) on the fetal testis; however, providing definitive evidence of such effects presents numerous challenges. In this review, we describe an approach to assessing the potential clinical relevance of in-utero (and postnatal) environmental exposures on subsequent male reproductive function using exposure to the analgesic paracetamol as an example. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

High resolution replication banding combined with in situ hybridization for the delineation of a subtle chromosome rearrangement.

PubMed

Qumsiyeh, M B; Wilroy, R S; Peeden, J N; Tharapel, A T

1991-10-01

Molecular cytogenetic techniques were used to delineate a subtle chromosome rearrangement in an infant with growth and psychomotor retardation, abnormal scalp hair pattern, narrow palpebral fissures, broad nasal bridge, bulbous nose, small nostrils, thin lips in a cupid's bow configuration, bilateral simian creases, and unilateral cryptorchidism. Analysis using GTG-banded chromosomes at about 400 band level showed no obvious abnormality. Prometaphase analysis at about 600 band level showed an extra band at 14q32 on GTG-banding. The father had the same extra band suggesting a reciprocal translocation but the second chromosome involved in the translocation could not be identified. High resolution replication banding on the father's lymphocytes showed a balanced reciprocal translocation 46,XY,rcp(8;14)(q24.1;q32.1). The translocation was confirmed by in situ hybridization with an immunoglobulin heavy chain probe which maps to 14q32.3. The infant therefore had duplication of 8q24.1----qter and deficiency of 14q32.1----qter. His phenotype resembled that of patients with partial duplications of the distal long arm of chromosome 8.

A Brief Review of the Link between Environment and Male Reproductive Health: Lessons from Studies of Testicular Germ Cell Cancer.

PubMed

Skakkebaek, Niels E

2016-01-01

During the past few decades there has been a significantly increasing trend in germ cell tumours all over the world, particularly in countries with Caucasian populations. The changes in incidence have occurred so fast that only environmental factors can explain this development. This review focuses on the hypothesis that testicular germ cell cancer, which originates from germ cell neoplasia in situ, is of foetal origin and associated with other male reproductive problems through a testicular dysgenesis syndrome, also including foetal origin of impaired spermatogenesis, hypospadias and cryptorchidism. There is little doubt that environmental factors associated with modern lifestyles have - in a broad sense - had an adverse influence on male reproductive health. The hypothesis that exposure to endocrine-disrupting chemicals plays a fundamental role in this trend is plausible. This is based on evidence from animal studies that demonstrate adverse reproductive effects caused by a number of endocrine-disrupting chemicals to which humans are exposed as part of our modern lifestyle. © 2016 S. Karger AG, Basel.

Simpson-Golabi-Behmel syndrome associated with renal dysplasia and embryonal tumor: localization of the gene to Xqcen-q21.

PubMed

Hughes-Benzie, R M; Hunter, A G; Allanson, J E; Mackenzie, A E

We report 6 affected males in a 5-generation family with x-linked Simpson-Golabi-Behmel (SGB) syndrome. All had pre- and postnatal overgrowth with 2 adult males attaining heights over 195 cm. Other features included "coarse" face with hypertelorism, broad nasal root, cleft palate, full lips with a midline groove of the lower lip, grooved tongue with tongue tie, prominent mandible, congenital heart defects, arrhythmias, supernumerary nipples, splenomegaly, large dysplastic kidneys, cryptorchidism, hypospadias, skeletal abnormalities and postaxial hexadactyly. All affected individuals were of normal intelligence. One boy died at age 19 months of a neuroblastoma. The putative origin of the gene in this family was the maternal great grandmother of the propositus. Eight carrier females, who showed varying manifestations of the gene, have been identified. Anthropometric analysis has identified preliminary characteristic craniofacial dimensions in this syndrome. Molecular studies have shown a maximal lod score of 2.81 with no recombinants observed for the SGB-DXYS68 pairing, mapping the disorder to Xqcen-Xq21.3.

Bladder injuries during laparoscopic orchiopexy: incidence and lessons learned.

PubMed

Hsieh, Michael H; Bayne, Aaron; Cisek, Lars J; Jones, Eric A; Roth, David R

2009-07-01

Laparoscopic orchiopexy is a safe operation. However, the bladder can be injured during creation of the transperitoneal tunnel for the cryptorchid testis. We reviewed our experience with this complication. We searched the operative notes of patients who had undergone laparoscopic orchiopexy between August 15, 2002 and October 1, 2008, and identified bladder injuries and their treatment. A total of 93 patients underwent laparoscopic orchiopexies for 101 undescended testes during the study interval, with 3 procedures resulting in bladder injuries. The 3 operations varied with regard to whether the injury was recognized intraoperatively or postoperatively, and repaired in an open or laparoscopic fashion. Bladder injury during laparoscopic orchiopexy is a rare but serious complication that can be managed by an open or laparoscopic approach. We recommend placement of a urethral catheter and syringe assisted drainage of all urine from the bladder at the beginning of the operation, careful perivesical dissection particularly in children with prior inguinal surgery, filling and emptying of the bladder during the procedure, and maintaining a high index of suspicion especially when hematuria is observed.

Noonan Syndrome: An Underestimated Cause of Severe to Profound Sensorineural Hearing Impairment. Which Clues to Suspect the Diagnosis?

PubMed

Ziegler, Alban; Loundon, Natalie; Jonard, Laurence; Cavé, Hélène; Baujat, Geneviève; Gherbi, Souad; Couloigner, Vincent; Marlin, Sandrine

2017-09-01

To highlight Noonan syndrome as a clinically recognizable cause of severe to profound sensorineural hearing impairment. New clinical cases and review. Patients evaluated for etiological diagnosis by a medical geneticist in a reference center for hearing impairment. Five patients presenting with confirmed Noonan syndrome and profound sensorineural hearing impairment. Diagnostic and review of the literature. Five patients presented with profound sensorineural hearing impairment and molecularly confirmed Noonan syndrome. Sensorineural hearing impairment has been progressive for three patients. Cardiac echography identified pulmonary stenosis in two patients and was normal for the three other patients. Short stature was found in two patients. Mild intellectual disability was found in one patient. Inconspicuous clinical features as facial dysmorphism, cryptorchidism, or easy bruising were of peculiar interest to reach the diagnosis of Noonan syndrome. Profound sensorineural hearing impairment can be the main feature of Noonan syndrome. Associated features are highly variable; thus, detailed medical history and careful physical examination are mandatory to consider the diagnosis in case of a sensorineural hearing impairment.

Variants in congenital hypogonadotrophic hypogonadism genes identified in an Indonesian cohort of 46,XY under-virilised boys.

PubMed

Ayers, Katie L; Bouty, Aurore; Robevska, Gorjana; van den Bergen, Jocelyn A; Juniarto, Achmad Zulfa; Listyasari, Nurin Aisyiyah; Sinclair, Andrew H; Faradz, Sultana M H

2017-02-16

Congenital hypogonadotrophic hypogonadism (CHH) and Kallmann syndrome (KS) are caused by disruption to the hypothalamic-pituitary-gonadal (H-P-G) axis. In particular, reduced production, secretion or action of gonadotrophin-releasing hormone (GnRH) is often responsible. Various genes, many of which play a role in the development and function of the GnRH neurons, have been implicated in these disorders. Clinically, CHH and KS are heterogeneous; however, in 46,XY patients, they can be characterised by under-virilisation phenotypes such as cryptorchidism and micropenis or delayed puberty. In rare cases, hypospadias may also be present. Here, we describe genetic mutational analysis of CHH genes in Indonesian 46,XY disorder of sex development patients with under-virilisation. We present 11 male patients with varying degrees of under-virilisation who have rare variants in known CHH genes. Interestingly, many of these patients had hypospadias. We postulate that variants in CHH genes, in particular PROKR2, PROK2, WDR11 and FGFR1 with CHD7, may contribute to under-virilisation phenotypes including hypospadias in Indonesia.

Abnormal pituitary-gonadal axis may be responsible for rat decreased testicular function under simulated microgravity

NASA Astrophysics Data System (ADS)

Zhou, Yi; Tan, Xin; Zhu, Bao-an; Qi, Meng-di; Ding, Su-ling

Space flight and simulated microgravity lead to suppression of mammalian spermatogenesis and decreased plasma testosterone level. In order to explain the mechanism behind the depression, we used rat tail-suspended model to simulate weightless conditions. To prevent cryptorchidism caused by tail-suspension, some experimental animals received inguinal canal ligation. The results showed that mass of testis decreased significantly and seminiferous tubules became atrophied in rats after tail-suspension. The levels of plasma testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in tail-suspended rats with or without inguinal canal ligation decreased significantly compared with controls, and an increased level of plasma estradiol (E) was revealed in tail-suspended rats. The results indicate that besides the direct influence of fluid shift upon testis under short-term simulated microgravity, the pituitary function is also disturbed as a result of either immobilization stress or weight loss during tail-suspension treatment, which is responsible to some extent for the decreased testosterone secretion level and the atrophia of testis. The conversion of testosterone into E under simulated microgravity is another possible cause for the decline of plasma testosterone.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farren-Chavez, D.M.; Guzman, E.R.; Peters, T.L.

A 32-year-old G{sub 3}P{sub 2002} Hispanic female presented at 14 weeks gestation for routine dating ultrasound. At that time ultrasonography revealed a septated cystic hygroma, omphalocele, bilateral talipes equinovarus, and hydrops. Amniocentesis was performed at 15 weeks and revealed a 46,XX,9p+ chromosome complement. The origin of the extra material on the terminal short arm of chromosome 9 could not be identified. Chromosome analysis was performed on the parents and the mother was found to carry the balanced translocation 46,XX,p(3;9)(q23;p13). Further analysis revealed that the fetus had inherited the derivative 9 chromosome. The fetus was therefore monosomic for 9p13-9pter and trisomicmore » for 3q23-3pter. The patient chose to continue the pregnancy. Serial ultrasonography later demonstrated a sloping forehead, small nose, micrognathia, ventriculomegaly, possible VSD, micropenis, hypospadias, cryptorchidism and post-axial polydactyly of the hands. The fetus was delivered prematurely at 31 weeks and survived one hour. Post-mortem examination confirmed the ultrasound findings and revealed additional stigmata consistent with both 9p monosomy and 3q trisomy. A review of the literature indicates no previous report of both syndromes concurrently.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tar, A.; Ion, A.; Gyoervari, B.

A de novo apparently balanced translocation involving chromosomes 8 and 20 was found in a 14-year-old boy with minor anomalies, mild skeletal abnormalities and ambiguous external genitalia including perineoscrotal hypospadias, rudimentary fused labioscrotal folds, bilateral cryptorchidism, and small penis. The karyotype was 46,XY, t(8;20)(q22.3-23;p13). No signs of other conditions known to be associated with structural anomalies of either chromosome 8 or 20 were present and incomplete masculinisation of the external genitalia appears to be the main component of the phenotype. Clinical and biological studies showed apparently normal testicular function in utero and after birth. Examinations excluded 5{alpha}-reductase deficiency or amore » block in any enzymatic steps of testosterone, glucocorticoid and mineralocorticoid biosynthesis. Coding sequences of the sex-determining gene (SRY) and androgen receptor gene (AR) were found to be identical to those of a normal male excluding their role in the cause of the present condition. Since several other reports describe the association of hypospadias and hypertelorism with deletions or translocations involving 8q, we suggest that a locus necessary for male sex differentiation is located at distal 8q. 24 refs., 3 figs.« less

Anti-Müllerian hormone levels in serum from human foetuses and children: pattern and clinical interest.

PubMed

Guibourdenche, J; Lucidarme, N; Chevenne, D; Rigal, O; Nicolas, M; Luton, D; Léger, J; Porquet, D; Noël, M

2003-12-15

Serum anti-Müllerian hormone (AMH) determination has been used to investigate gonadal development and abnormal sexual differentiation, but until recently, it was based on assays developed by specialized laboratories. A short time ago, a sensitive assay kit was developed commercially (Immunotech-Beckman Coulter) for clinical use. With this method, we established usual levels of serum AMH in fetuses, newborns, and pre-pubertal children, and evaluated the clinical value of this assay. AMH measurement required only 25 microl of sample and could be performed within 3 h. In females, AMH emerged after birth at low levels (median: 4 ng/ml). In males, AMH levels remained stable during fetal life (median: 44.4 ng/ml), peaked in the first months of life to reach a median of 124.7 ng/ml, then fell with wide individual variations. Cord blood AMH levels at birth may be useful to investigate ambiguous genitalia suspected prenatally. In children with isolated microphallus or hypospadias, decreased AMH values are in favor of testis dysfunction. When testes cannot be palpated, a single determination of serum AMH levels can distinguish between anorchia and cryptorchidism.

The oligosaccharidic content of the glycoconjugates of the prepubertal descended and undescended testis: lectin histochemical study.

PubMed

Gheri, Gherardo; Sgambati, Eleonora; Thyrion, Giorgia D Zappoli; Vichi, Debora; Orlandini, Giovanni E

2004-01-01

The saccharidic content of the glycoconjugates has been studied in the descended the undescended testes of a 8 years old boy. For this purpose, a battery of seven HRP-conjugated lectins (SBA, DBA,PNA,WGA,UEAI, LTA and ConA) was used. D-galactose-N-acetyl-D-galactosamine and alpha-L-fucose sugar residues, which were present in the cytoplasm of the Sertoli cells of the normally positioned prepubertal testis, were not detected in the same cells of the undescended testis. The Leydig's cells of the descended testis appeared characterized by N-acetyl-D-glucosamine which was absent in the rare and atrophic Leydig's cells of the cryptorchid testis. Differences in sugar residues distribution between the descended and the undescended testis were also detected in the lamina propria of the seminiferous tubules. Peritubular myoid cells in the undescended testis only reacted with PNA, after neuraminidase digestion, thus revealing the presence of D-galactose (beta1-->3)-N-acetyl-D-galactosamine and sialic acid. In this study a complete distributional map of the sugar residues of the glycoconjugates in the descended and undescended prepubertal testis is reported.

A novel mutation in SMOC1 and variable phenotypic expression in two patients with Waardenburg anophthalmia syndrome.

PubMed

Jamshidi, Javad; Abdollahi, Shokoufeh; Ghaedi, Hamid; Alehabib, Elham; Tafakhori, Abbas; Alinaghi, Somayeh; Chapi, Marjan; Johari, Amir Hossein; Darvish, Hossein

2017-11-01

Waardenburg anophthalmia syndrome (WAS) is a rare disorder that mostly affects the eyes and distal limbs. In the current study we reported two Iranian patients with WAS. The first case was a 26-year-old girl with unilateral anophthalmia, bilateral camptodactyly and clinodactyly in her hands, oligodactly in her left foot and syndactyly of the second to fifth toes in her right foot. She also had severe hearing loss in both ears. The second case was a 12-year-old boy with bilateral anophthalmia, camptodactyly in his right hand, oligodactyly in his foot, clubfoot, and cryptorchidism. Both patients were mentally normal. To detect the causative mutation all exons and exon-intron boundaries of SMOC1 gene were sequenced in patients and other normal family members. We found a homozygous missense mutation (NM_001034852.2(SMOC1):c.367T > C) in exon 3 of SMOC1 gene in both patients. As the mutation segregated with the disease in the family, it should be the causative mutation. Our study extended the mutation spectrum of SMOC1 gene related to WAS. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

[The regulation of FSH release by the testis. Studies on inhibin].

PubMed

Krause, W

1977-05-12

The FSH release from the hypophysis is suggested to be particularly regulated by a testicular hormone called inhibin. Origin, structure and target organs of inhibin are unknown. Experiments to test some hypotheses in this field are described. Adult male rats, prenatally treated with busulfan, show only Sertoli cells in the semiferous tubules. Experimental cryptorchidism and orchidectomy, however, leads to an increase in FSH levels as observed in normal animals. This indicates the role of Sertoli cells in FSH regulation. Ligation of efferent ducts of testes leads to an increase of FSH levels, too, indicating that an FSH-inhibiting principle cannot be absorbed. Interstitial testis fluid (ITF) of normal rats was applicated to immature female rats. Their FSH release is inhibited, visible in the lower ovarian weight gain following additional hCG-administration. Orchidectomized animals react with a decrease of FSH levels to the application of ITF. Therefore ITF seems to contain a FSH-inhibiting factor. Androgen binding protein-content of epididymes, however, is increased after repeated injections of ITF. It is concluded that testis (probably the Sertoli cells) produces a FSH-inhibiting factor, but ITF contains only small amounts of inhibin.

A case of an infant with congenital combined pituitary hormone deficiency and normalized liver histology of infantile cholestasis after hormone replacement therapy.

PubMed

Wada, Keisuke; Kobayashi, Hironori; Moriyama, Aisa; Haneda, Yasuhiro; Mushimoto, Yuichi; Hasegawa, Yuki; Onigata, Kazumichi; Kumori, Koji; Ishikawa, Noriyoshi; Maruyama, Riruke; Sogo, Tsuyoshi; Murphy, Lynne; Taketani, Takeshi

2017-01-01

Congenital combined pituitary hormone deficiency (CPHD) may present with cholestasis in the neonate or during early infancy. However, its precise mechanism is unknown. A 3-mo-old boy presented with cryptorchidism and hypoplastic scrotum after birth. Neonatal jaundice was noted but temporarily improved with phototherapy. Jaundice recurred at 2 mo of age. Elevated direct bilirubin (D-Bil) and liver dysfunction were found but cholangiography showed no signs of biliary atresia (BA). Liver biopsy findings showed giant cell formation of hepatocytes with hypoplastic bile ducts. Subsequent magnetic resonance imaging (MRI) of the head revealed a hypoplastic pituitary gland with an ectopic posterior lobe, and the patient was diagnosed with congenital CPHD based on decreased secretion of cortisol and GH by the pituitary anterior lobe load test. D-Bil levels promptly improved after hydrocortisone (HDC) replacement. We subsequently began replacement with levothyroxine (L-T 4 ) and GH, and liver histology showed normal interlobular bile ducts at 8 mo old. This is the first case report of proven histological improvement after hormone replacement therapy. This suggested that pituitary-mediated hormones, especially cortisol, might be involved in the development of the bile ducts.

A case of an infant with congenital combined pituitary hormone deficiency and normalized liver histology of infantile cholestasis after hormone replacement therapy

PubMed Central

Wada, Keisuke; Kobayashi, Hironori; Moriyama, Aisa; Haneda, Yasuhiro; Mushimoto, Yuichi; Hasegawa, Yuki; Onigata, Kazumichi; Kumori, Koji; Ishikawa, Noriyoshi; Maruyama, Riruke; Sogo, Tsuyoshi; Murphy, Lynne; Taketani, Takeshi

2017-01-01

Abstract. Congenital combined pituitary hormone deficiency (CPHD) may present with cholestasis in the neonate or during early infancy. However, its precise mechanism is unknown. A 3-mo-old boy presented with cryptorchidism and hypoplastic scrotum after birth. Neonatal jaundice was noted but temporarily improved with phototherapy. Jaundice recurred at 2 mo of age. Elevated direct bilirubin (D-Bil) and liver dysfunction were found but cholangiography showed no signs of biliary atresia (BA). Liver biopsy findings showed giant cell formation of hepatocytes with hypoplastic bile ducts. Subsequent magnetic resonance imaging (MRI) of the head revealed a hypoplastic pituitary gland with an ectopic posterior lobe, and the patient was diagnosed with congenital CPHD based on decreased secretion of cortisol and GH by the pituitary anterior lobe load test. D-Bil levels promptly improved after hydrocortisone (HDC) replacement. We subsequently began replacement with levothyroxine (L-T4) and GH, and liver histology showed normal interlobular bile ducts at 8 mo old. This is the first case report of proven histological improvement after hormone replacement therapy. This suggested that pituitary-mediated hormones, especially cortisol, might be involved in the development of the bile ducts. PMID:29026274

Similar causes of various reproductive disorders in early life.

PubMed

Svechnikov, Konstantin; Stukenborg, Jan-Bernd; Savchuck, Iuliia; Söder, Olle

2014-01-01

During the past few decades, scientific evidence has been accumulated concerning the possible adverse effects of the exposure to environmental chemicals on the well-being of wildlife and human populations. One large and growing group of such compounds of anthropogenic or natural origin is referred to as endocrine-disrupting chemicals (EDCs), due to their deleterious action on the endocrine system. This concern was first focused on the control of reproductive function particularly in males, but has later been expanded to include all possible endocrine functions. The present review describes the underlying physiology behind the cascade of developmental events that occur during sexual differentiation of males and the specific role of androgen in the masculinization process and proper organogenesis of the external male genitalia. The impact of the genetic background, environmental exposures and lifestyle factors in the etiology of hypospadias, cryptorchidism and testicular cancer are reviewed and the possible role of EDCs in the development of these reproductive disorders is discussed critically. Finally, the possible direct and programming effects of exposures in utero to widely use therapeutic compounds, environmental estrogens and other chemicals on the incidence of reproductive abnormalities and poor semen quality in humans are also highlighted.

New X-linked mental retardation syndrome with the gene mapped tentatively in Xp22.3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wittwer, B.; Kircheisen, R.; Leutelt, J.

1996-07-12

X-linked mental retardation (XLMR) is genetically heterogeneous and clinically variable. We describe a new XLMR syndrome of severe mental retardation and multiple congenital anomalies. Two sisters have (with 3 different partners) 3 severely handicapped sons. In 2 cases, oligohydramnios and intrauterine growth retardation were noted. Common anomalies included a square-shaped face, high and broad forehead, frontal bossing, downward slant of palpebral fissures, hypertelorism, epicanthic folds, long philtrum, thin upper lip, and apparently low-set ears. One boy has bilateral microphthalmos and sclerocornea, and his cousin has atrophy of the optic nerve. All 3 patients are blind and have profound statomotor andmore » mental retardation, seizures, and a grossly abnormal electroencephalographic pattern. Additional findings are short stature, delayed bone matuation, hydronephrosis, vesicorenal reflux, cryptorchidism, clinodactyly of the 5th fingers, and transverse palmar creases. The karyotype is normal (46,XY). Segregation analysis showed perfect coinheritance between the clinical phenotype and alleles at several loci in Xp22.3, whereas recombinants were identified with marker loci from Xp22.2-qter. Analysis of multiple informative meioses suggests that the disease locus maps in Xp22.3 distal to DXS16. 9 refs., 5 figs., 2 tabs.« less

The association between prune belly syndrome and dental anomalies: a case report.

PubMed

Basso, Maria Daniela; Favretto, Carla Oliveira; Cunha, Robson Frederico

2012-12-18

Prune belly syndrome is a rare condition produced by an early mesodermal defect that causes abdominal abnormalities. However, the literature indicates that disturbances related to ectodermal development may also be present. This is the first case report in the literature to suggest that dental abnormalities are part of the broad spectrum of clinical features of prune belly syndrome. Because the syndrome causes many serious medical problems, early diagnosis of abnormalities involving the primary and permanent dentitions are encouraged. The authors report the clinical case of a 4-year-old Caucasian boy with prune belly syndrome. In addition to the triad of abdominal muscle deficiency, abnormalities of the gastrointestinal and urinary tracts, and cryptorchidism, a geminated mandibular right central incisor, agenesis of a mandibular permanent left incisor, and congenitally missing primary teeth (namely, the mandibular right and left lateral incisors) were noted. This original case report about prune belly syndrome highlights the possibility that dental abnormalities are a part of the broad spectrum of clinical features of the syndrome. Therefore, an accurate intra-oral clinical examination and radiographic evaluation are required for patients with this syndrome in order to provide an early diagnosis of abnormalities involving the primary and permanent dentitions.

Testicular biopsy: clinical practice and interpretation

PubMed Central

Dohle, Gert R; Elzanaty, Saad; van Casteren, Niels J

2012-01-01

Testicular biopsy was considered the cornerstone of male infertility diagnosis for many years in men with unexplained infertility and azoospermia. Recent guidelines for male infertility have limited the indications for a diagnostic testicular biopsy to the confirmation of obstructive azoospermia in men with normal size testes and normal reproductive hormones. Nowadays, testicular biopsies are mainly performed for sperm harvesting in men with non-obstructive azoospermia, to be used for intracytoplasmic sperm injection. Testicular biopsy is also performed in men with risk factors for testicular malignancy. In a subgroup of infertile men, there is an increased risk for carcinoma in situ of the testis, especially in men with a history of cryptorchidism and testicular malignancy and in men with testicular atrophy. Ultrasonographic abnormalities, such as testicular microlithiasis, inhomogeneous parenchyma and lesions of the testes, further increase the risk of carcinoma in situ (CIS) in these men. For an accurate histological classification, proper tissue handling, fixation, preparation of the specimen and evaluation are needed. A standardized approach to testicular biopsy is recommended. In addition, approaches to the detection of CIS of the testis testicular immunohistochemistry are mandatory. In this mini-review, we describe the current indications for testicular biopsies in the diagnosis and management of male infertility. PMID:22157985

Epidemiology of testicular cancer: an overview.

PubMed

Garner, Michael J; Turner, Michelle C; Ghadirian, Parviz; Krewski, Daniel

2005-09-01

Testicular cancer is a rare disease, accounting for 1.1% of all malignant neoplasms in Canadian males. Despite the low overall incidence of testicular cancer, it is the most common malignancy among young men. The incidence rate of testicular cancer has been increasing since the middle of the 20th century in many western countries. However, the etiology of testicular cancer is not well understood. A search of the peer-reviewed literature was conducted to identify important articles for review and inclusion in this overview of the epidemiology of testicular cancer. Most of the established risk factors are related to early life events, including cryptorchidism, carcinoma in situ and in utero exposure to estrogens. Occupational, lifestyle, socioeconomic and other risk factors have demonstrated mixed associations with testicular cancer. Although there are few established risk factors for testicular cancer, some appear to be related to hormonal balance at various life stages. Lifestyle and occupational exposures occurring later in life may play a role in promoting the disease, although they are not likely involved in cancer initiation. In addition to summarizing the current epidemiologic evidence on risk factors for testicular cancer, we suggest future research directions that may elucidate the etiology of testicular cancer.

Epigenetic: a molecular link between testicular cancer and environmental exposures.

PubMed

Vega, Aurelie; Baptissart, Marine; Caira, Françoise; Brugnon, Florence; Lobaccaro, Jean-Marc A; Volle, David H

2012-01-01

In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the testicular dysgenesis syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations. Furthermore, infertility has been stated as a risk factor for testicular cancer (TC). The incidence of TC has been increasing over the past decade. Most of testicular germ cell cancers develop through a pre-invasive carcinoma in situ from fetal germ cells (primordial germ cell or gonocyte). During their development, fetal germ cells undergo epigenetic modifications. Interestingly, several lines of evidence have shown that gene regulation through epigenetic mechanisms (DNA and histone modifications) plays an important role in normal development as well as in various diseases, including TC. Here we will review chromatin modifications which can affect testicular physiology leading to the development of TC; and highlight potential molecular pathways involved in these alterations in the context of environmental exposures.

Epigenetic: a molecular link between testicular cancer and environmental exposures

PubMed Central

Vega, Aurelie; Baptissart, Marine; Caira, Françoise; Brugnon, Florence; Lobaccaro, Jean-Marc A.; Volle, David H.

2012-01-01

In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the testicular dysgenesis syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations. Furthermore, infertility has been stated as a risk factor for testicular cancer (TC). The incidence of TC has been increasing over the past decade. Most of testicular germ cell cancers develop through a pre-invasive carcinoma in situ from fetal germ cells (primordial germ cell or gonocyte). During their development, fetal germ cells undergo epigenetic modifications. Interestingly, several lines of evidence have shown that gene regulation through epigenetic mechanisms (DNA and histone modifications) plays an important role in normal development as well as in various diseases, including TC. Here we will review chromatin modifications which can affect testicular physiology leading to the development of TC; and highlight potential molecular pathways involved in these alterations in the context of environmental exposures. PMID:23230429

Mixed Germ Cell Tumour in an Infertile Male Having Unilateral Cryptorchidism: A Rare Case Report.

PubMed

Singla, Anand; Kaur, Navneet; Sandhu, Gunjeet; Nagori, Rupesh

2016-02-01

Mixed germ cell tumours with multiple components occur more frequently than the pure varieties of germ cell tumours. Embryonal carcinoma and teratoma together form the most common components of the mixed germ cell tumour but the yolk sac tumour is usually seen as a minor component in patients presenting with mixed germ cell tumour. We report a rare case of 27-year-old Hepatitis C positive male presenting with pain in left lower abdomen with associated history of same sided undescended testis and infertility. Right sided testis lying in scrotal sac appeared normal on ultrasonography but patient was azoospermic. He had raised levels of serum markers, alpha feto protein and beta HCG. Examination showed a large mass in left lower abdomen involving the sigmoid colon with the absence of left testis in left scrotum which was confirmed on CT scan. Excision of the mass was done and histopathology examination revealed it as a malignant mixed germ cell tumour composed predominantly of a yolk sac tumour, with minor component as seminoma and embryonal carcinoma in an undescended testis. Following this, the level of serum markers came down. The patient is now undergoing adjuvant chemotherapy and is doing well.

[A case of partial 1p36.1 deletion and partial trisomy 6p diagnosed by karyotype].

PubMed

Fernández Pineda, Monica; Ramírez-Cheyne, Julián; Isaza, Carolina; Saldarriaga, Wilmar

The deletion of chromosomal region 1p36 is one of the most common sub-telomeric microdeletion syndromes and has distinctive dysmorphic features. On the other hand, partial trisomy of the short arm of chromosome 6 is a rare chromosomal abnormality with a variable phenotype. To report a case with both chromosome abnormalities, and to highlight the importance of the karyotype as a diagnostic tool in dysmorphology. The case of is presented of a two month-old infant with several craniofacial anomalies, neck haemangioma, sacral pit, rhizomelic shortening, small hands and feet, left unilateral cryptorchidism, and hypotonia. The infant also suffered intrauterine growth restriction and is the product of the eighth pregnancy of a 28 years old woman. Due to the unspecific findings in phenotype, a karyotype was requested, which showed a partial deletion of 1p36.1 and a partial trisomy of chromosome 6. The development of new techniques in molecular biology has improved diagnostic possibilities in medical genetics. However, the traditional karyotype remains as an important diagnostic tool in patients with multiple congenital anomalies. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Interstitial deletion of chromosome 1q [del(1)(q24q25.3)] identified by fluorescence in situ hybridization and gene dosage analysis of apolipoprotein A-II, coagulation factor V, and antithrombin III

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takano, Takako; Yamanouchi, Yasuko; Mori, Yosuke

We report on a 12-month-old Japanese boy with an interstitial deletion of the long-arm of chromosome 1 and meningomyelocele, hydrocephalus, anal atresia, atrial septal defect, left renal agenesis, bilateral cryptorchidism, talipes equinovarus, low birth weight, growth/developmental retardation, and many minor anomalies. By conventional GTG-banding, his karyotype was first interpreted as 46,XY,de1(1)(q23q24), but it was corrected as 46,XY.ish del(1)(q24q25.3) by fluorescence in situ hybridization using 11 known cosmid clones as probes. His serum levels of apolipoprotein A-II (gene symbol: APOA2, previously assigned to 1q21-q23) and coagulation factor V (F5, 1q21-q25) were normal, while serum concentration and activity of antithrombin III (AT3,more » 1q23-q25.1) was low. The results indicated that localization of APOA2 and F5 are proximal to the deleted region and AT3 is located within the deletion extent in the patient. 16 refs., 4 figs.« less

Multiple roles of the prostaglandin D2 signaling pathway in reproduction.

PubMed

Rossitto, Moïra; Ujjan, Safdar; Poulat, Francis; Boizet-Bonhoure, Brigitte

2015-01-01

Prostaglandins signaling molecules are involved in numerous physiological processes. They are produced by several enzyme-limited reactions upon fatty acids, which are catalyzed by two cyclooxygenases and prostaglandin synthases. In particular, the prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2 α) have been shown to be involved in female reproductive mechanisms. Furthermore, widespread expression of lipocalin- and hematopoietic-PGD2 synthases in the male reproductive tract supports the purported roles of PGD2 in the development of both embryonic and adult testes, sperm maturation, and spermatogenesis. In this review, we summarize the putative roles of PGD2 signaling and the roles of both PGD2 synthases in testicular formation and function. We review the data reporting the involvement of PGD2 signaling in the differentiation of Sertoli and germ cells of the embryonic testis. Furthermore, we discuss the roles of lipocalin-PGD2 synthase in steroidogenesis and spermatogenesis, in terms of lipid molecule transport and PGD2 production. Finally, we discuss the hypothesis that PGD2 signaling may be affected in certain reproductive diseases, such as infertility, cryptorchidism, and testicular cancer. © 2015 Society for Reproduction and Fertility.

Hypogonadism and fertility issues following primary treatment for testicular cancer.

PubMed

Oldenburg, Jan

2015-09-01

The majority of testicular cancer (TC) patients are cured and expected to live for decades after treatment, such that knowledge about hypogonadism and fertility issues is particularly important for the group of testicular cancer survivors (TCSs). Hypogonadism and fertility issues are related to treatment intensity. In order to give an overview about hypogonadism in testicular cancer survivors (TCSs) the literature was reviewed. Testicular dysfunction was defined as inadequate spermatogenesis, as reflected by increased levels of Follicle Stimulating Hormone (FSH) and reduced fertility and/with or without insufficient testosterone (T) production with or without compensatory increased Luteinizing Hormone (LH) levels. Hypogonadism may lead to reduced sexual functioning and well-being, fertility problems, muscle weakness, loss of energy, and depression. Furthermore, hypogonadism also increases the risk of osteoporosis and is associated with the metabolic syndrome and cardiovascular disease (CVD). The hypothesized "Testicular Dysgenesis Syndrome" comprising low sperm counts, hypospadias, cryptorchidism, and finally TC, probably contributes to hypogonadism independent of applied TC treatment. Recently, an increased risk of accelerated hormonal ageing has been reported in TCSs in the very long term, i.e. 20 years after TC treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

How to recognize late-onset hypogonadism in men with sexual dysfunction

PubMed Central

Corona, Giovanni; Rastrelli, Giulia; Vignozzi, Linda; Mannucci, Edoardo; Maggi, Mario

2012-01-01

Late-onset hypogonadism (LOH) has been considered the most common form of male hypogonadism with a prevalence of approximately 1 in 100 men. Diagnosis of LOH should be made in symptomatic men with unequivocally low serum testosterone (T) levels. However, its clinical presentation is often insidious and difficult to recognize because it is characterized by nonspecific symptoms that make differential diagnosis with physiological ageing problematic. Sexual dysfunction is the most important determinant for medical consultation and the most specific symptom associated with low T. We therefore analysed a consecutive series of 1734 subjects who attended our unit for sexual dysfunction to investigate the associations between low T (different thresholds), sexual parameters, medical history data (delayed puberty, pituitary disease or cryptorchidism) and their physical exam results. Metabolic parameters, in particular waist circumference, display the greatest accuracy in detecting low T. We found that only the association of several symptoms and signs could significantly raise the clinical suspicion of low T. Structured inventories, which cluster together symptoms and signs of hypogonadism, can help clinicians suspect androgen deficiency. In particular, structured interviews, such as ANDROTEST, have been demonstrated to have a greater accuracy when compared to self reported questionnaires in detecting low T levels. PMID:22286862

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis.

PubMed

Bonde, Jens Peter; Flachs, Esben Meulengracht; Rimborg, Susie; Glazer, Clara Helene; Giwercman, Aleksander; Ramlau-Hansen, Cecilia Høst; Hougaard, Karin Sørig; Høyer, Birgit Bjerre; Hærvig, Katia Keglberg; Petersen, Sesilje Bondo; Rylander, Lars; Specht, Ina Olmer; Toft, Gunnar; Bräuner, Elvira Vaclavik

2016-12-01

More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder. The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

[The effect of diethylstilbestrol on inducing abdominal cryptorchidism and relevant genetic expression in rats].

PubMed

Zhang, Lin; Zheng, Xin-min; Zheng, Hang; Yang, Zhi-wei; Li, Shi-wen

2009-05-01

To study the effect of diethylstilbestrol (DES) at different doses on transabdominal testicular descent in rats and the expression of INSL3 in the testis and HOXA10 in the gubernaculum. Fifty E13.5 (embryonic day 13.5) pregnant female SD rats were randomly divided into five groups that received a subcutaneous injection of DMSO, 2.5, 5.0, 10.0 and 20.0 mg/kg DES (group A, B, C, D and E), respectively. Male offspring were killed at E19.5, and then fetal mortality, the degree of transabdominal testicular ascent (DTA) was determined by a stereomicroscope. The mRNA expressions of INSL3 in the testis and HOXA10 in the gubernaculum were determined by RT-PCR. The expression of INSL3 protein was determined by Western blotting. Male fetal mortality in group A, B, C, D, and E were 3.57%, 6.90%, 12.00%, 19.23% and 36.36%, respectively, which showed a dose-effect relationship between DES and the male fatal mortality (r=0.999, P<0.01). DTA in group B, C, D and E were (23.7+/-1.7) U, (38.8+/-1.9) U, (49.3+/-1.8) U and (58.6+/-2.1) U that were significantly larger than that in group A [(8.5+/-1.3) U] (q=46.12, 88.53, 120.44 and 141.37, respectively, P<0.01). There was also a dose-effect relationship between DES and DTA. In group B, C, D, and E, the expression of INSL3 mRNA were 0.9570+/-0.1490, 0.6760+/-0.1380, 0.0170+/-0.0040 and 0.0013+/-0.0003, respectively; the expressions of INSL3 protein were 0.8360+/-0.1520, 0.5310+/-0.1070, 0.0140+/-0.0020 and 0.0011+/-0.0003, respectively, which were significantly larger than the expression of INSL3 mRNA (1.801+/-0.126) and INSL3 protein (1.612+/-0.134) in group A (qmRNA=40.4840, 52.4402, 83.1585 and 82.0582, respectively, and qprotein=38.6151, 52.2747, 77.2756 and 76.1983, respectively, P<0.01). The expression of HOXA10 mRNA in group A, B, C, D, and E were 0.945+/-0.125, 0.940+/-0.119, 0.656+/-0.115, 0.544+/-0.118 and 0.463+/-0.114, respectively. Compared with the expression of HOXA10 mRNA in group A, the expression of group B was not significantly different (q=0.2213, P>0.05), those in other groups were down-regulated significantly (q=12.4304, 17.2477 and 20.2789, respectively, P<0.01). DES inhibited transabdominal testicular descent dose-dependently via down-regulating the expression of INSL3. HOXA10 may play no role in low-dosage DES induced intra-abdominal cryptorchidism, but down-regulated HOXA10 mRNA was involved in high-dosage DES induced ones.

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis

PubMed Central

Bonde, Jens Peter; Flachs, Esben Meulengracht; Rimborg, Susie; Glazer, Clara Helene; Giwercman, Aleksander; Ramlau-Hansen, Cecilia Høst; Hougaard, Karin Sørig; Høyer, Birgit Bjerre; Hærvig, Katia Keglberg; Petersen, Sesilje Bondo; Rylander, Lars; Specht, Ina Olmer; Toft, Gunnar; Bräuner, Elvira Vaclavik

2017-01-01

BACKGROUND More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. OBJECTIVE AND RATIONALE The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. SEARCH METHODS A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. OUTCOMES The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91–1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p′-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04–1.74). The data did not indicate that this increased risk was driven by any specific disorder. WIDER IMPLICATIONS The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure–response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure–outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field. PMID:27655588

Congenital combined pituitary hormone deficiency patients have better responses to gonadotrophin-induced spermatogenesis than idiopathic hypogonadotropic hypogonadism patients.

PubMed

Mao, Jiangfeng; Xu, Hongli; Wang, Xi; Huang, Bingkun; Liu, Zhaoxiang; Zhen, Junjie; Nie, Min; Min, Le; Wu, Xueyan

2015-09-01

Do patients with congenital combined pituitary hormone deficiency (CCPHD) have different responses to gonadotrophin-induced spermatogenesis compared with those with idiopathic hypogonadotropic hypogonadism (IHH)? CCPHD patients have a better response to gonadotrophin therapy than IHH patients. Gonadotrophins are effective in inducing spermatogenesis in patients with hypogonadotropic hypogonadism. This retrospective cohort study included 75 patients, 53 of whom had IHH and 22 CCPHD. They were diagnosed, treated and followed up between January 2008 and December 2013. Combined gonadotrophin therapy, consisting of human chorionic gonadotrophin and human menopausal gonadotrophin, was administered for 24 months. The success rate of spermatogenesis (≥1 sperm in ejaculate), serum total testosterone level, testicle size and sperm concentration during the treatment, as well as the first time sperm were detected in the ejaculate, were compared between the two diagnostic groups. All patients were treated in Peking Union Medical College Hospital. Spermatogenesis was successfully induced in 85% of IHH patients and 100% of CCPHD patients after 24-month combined gonadotrophin treatment (P = 0.03). In comparison with IHH, CCPHD patients had larger mean testicle sizes during the gonadotrophin treatment at 6, 12, 18 and 24 months (all P < 0.05). The initial time for sperm appearance in IHH group (n = 45) and CCPHD group (n = 22) was 13.2 ± 5.9 versus 10.4 ± 3.8 months (P = 0.045). Generally, CCPHD patients had higher sperm counts [median (quartiles)] than IHH patients during the treatment, but the difference was only statistically significant at 12 months of treatment, 3.3 (1.8, 12.0) versus 1.0 (0.0, 4.6) million/ml, P = 0.001. There was a higher level of serum total testosterone [mean (SD)] in the CCPHD group than the IHH group (676 ± 245 versus 555 ± 209 ng/dl, P = 0.035). First, the inherent nature of a retrospective designed study was a main shortcoming. Secondly, pathological gene mutations in IHH and CCPHD patients should be further investigated. Clarification of the underlying mechanisms between cryptorchidism and mutated genes may provide more information for the divergent therapeutic responses between two groups. Only a minority of patients were actively seeking to have children so information about fertility is limited. CCPHD patients had a lower incidence of cryptorchidism and a better response to gonadotrophin therapy than IHH patients, reflecting multiple defects on the different levels of reproduction axis in IHH. Furthermore, growth hormone is not indispensable for spermatogenesis in CCPHD patients. The study was supported by Natural Science Foundation of China (No: 81100416). None of the authors has any conflicts of interest to declare. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Limb/pelvis hypoplasia/aplasia with skull defect (Schinzel phocomelia): distinctive features and prenatal detection.

PubMed

Olney, R S; Hoyme, H E; Roche, F; Ferguson, K; Hintz, S; Madan, A

2001-11-01

Schinzel phocomelia syndrome is characterized by limb/pelvis hypoplasia/aplasia: specifically, intercalary limb deficiencies and absent or hypoplastic pelvic bones. The phenotype is similar to that described in a related multiple malformation syndrome known as Al-Awadi/Raas-Rothschild syndrome. The additional important feature of large parietooccipital skull defects without meningocele, encephalocele, or other brain malformation has thus far been reported only in children with Schinzel phocomelia syndrome. We recently evaluated a boy affected with Schinzel phocomelia born to nonconsanguineous healthy parents of Mexican origin. A third-trimester fetal ultrasound scan showed severe limb deficiencies and an absent pelvis. The infant died shortly after birth. Dysmorphology examination, radiographs, and autopsy revealed quadrilateral intercalary limb deficiencies with preaxial toe polydactyly; an absent pelvis and a 7 x 3-cm skull defect; and extraskeletal anomalies including microtia, telecanthus, micropenis with cryptorchidism, renal cysts, stenosis of the colon, and a cleft alveolar ridge. A normal 46,XY karyotype was demonstrated, and autosomal recessive inheritance was presumed on the basis of previously reported families. This case report emphasizes the importance of recognizing severe pelvic and skull deficiencies (either post- or prenatally) in differentiating infants with Schinzel phocomelia from other multiple malformation syndromes that feature intercalary limb defects, including thalidomide embryopathy and Roberts-SC phocomelia. Copyright 2001 Wiley-Liss, Inc.

Intrapartum diagnostic of Roberts syndrome - case presentation.

PubMed

Socolov, Răzvan Vladimir; Andreescu, Nicoleta Ioana; Haliciu, Ana Maria; Gorduza, Eusebiu Vlad; Dumitrache, Florentin; Balan, Raluca Anca; Puiu, Maria; Dobrescu, Mihaela Amelia; Socolov, Demetra Gabriela

2015-01-01

Roberts syndrome is a rare disease, with multiple limb and skeletal abnormalities (called "pseudothalidomide disease"). There are only around 150 cases described in literature. We present a case of Roberts syndrome, diagnosed in moment of delivery, after a pregnancy without prenatal follow-up. The stillborn baby was naturally delivered by a 17-year-old primiparous woman at 38 weeks of amenorrhea. The pregnancy was not followed due to socioeconomic and family situation, and no prenatal ultrasound was performed. The male baby has 2650 g and presented several morphological abnormalities and tight double umbilical abdominal loop. The macroscopic evaluation showed: dolichocephaly, hypoplastic inferior maxilla with micrognathia, antimongoloid palpebral slant, pterygium colli, abnormal and lower implanted ears, superior limbs phocomelia, syndactyly at lower left limb and tetradactyly in all limbs, bilateral cryptorchidism, pancreatic aplasia. Roberts syndrome is a rare genetic disease with recessive autosomal transmission generated by mutations in ESCO2 gene, located on chromosome 8. The disease should be easy to diagnose by antenatal ultrasound examination, but in our case, the lack of prenatal follow-up determined the diagnostic at term. We believe consider this case is an argument towards introducing ultrasound-screening compulsory to all pregnancies. To identify a possible genetic mutation, further investigations of the parents are in progress, but classically the disease has a recessive autosomal transmission.

The association between prune belly syndrome and dental anomalies: a case report

PubMed Central

2012-01-01

Background Prune belly syndrome is a rare condition produced by an early mesodermal defect that causes abdominal abnormalities. However, the literature indicates that disturbances related to ectodermal development may also be present. This is the first case report in the literature to suggest that dental abnormalities are part of the broad spectrum of clinical features of prune belly syndrome. Because the syndrome causes many serious medical problems, early diagnosis of abnormalities involving the primary and permanent dentitions are encouraged. Case presentation The authors report the clinical case of a 4-year-old Caucasian boy with prune belly syndrome. In addition to the triad of abdominal muscle deficiency, abnormalities of the gastrointestinal and urinary tracts, and cryptorchidism, a geminated mandibular right central incisor, agenesis of a mandibular permanent left incisor, and congenitally missing primary teeth (namely, the mandibular right and left lateral incisors) were noted. Conclusion This original case report about prune belly syndrome highlights the possibility that dental abnormalities are a part of the broad spectrum of clinical features of the syndrome. Therefore, an accurate intra-oral clinical examination and radiographic evaluation are required for patients with this syndrome in order to provide an early diagnosis of abnormalities involving the primary and permanent dentitions. PMID:23249412

An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.

PubMed

Reynaud, Rachel; Barlier, Anne; Vallette-Kasic, Sophie; Saveanu, Alexandru; Guillet, Marie-Pierre; Simonin, Gilbert; Enjalbert, Alain; Valensi, Paul; Brue, Thierry

2005-08-01

PROP1 gene mutations are usually associated with childhood onset GH and TSH deficiencies, whereas gonadotroph deficiency is diagnosed at pubertal age. We report a novel PROP1 mutation revealed by familial normosmic hypogonadotropic hypogonadism. We performed in vitro transactivation and DNA binding experiments to study functional consequences of this mutation. Three brothers were followed in the Department of Endocrinology of a French university hospital. These patients from a consanguineous kindred were referred for cryptorchidism and/or delayed puberty. Initial investigations revealed hypogonadotropic hypogonadism. One of the patients had psychomotor retardation, intracranial hypertension, and minor renal malformations. The brothers reached normal adult height and developed GH and TSH deficiencies after age 30. A novel homozygous nonsense mutation (W194X) was found in the PROP1 gene, indicating that the protein is truncated in its transactivation domain. Transfection studies confirmed the deleterious effect of this mutation, whose transactivation capacity was only 34.4% of that of the wild-type. Unexpectedly altered DNA-binding properties suggested that the C-terminal end of the factor plays a role in protein-DNA interaction. PROP1 mutations should be considered among the growing number of genetic causes of initially isolated hypogonadotropic hypogonadism. This report extends the phenotype variability associated with PROP1 mutations.

Origins and molecular biology of testicular germ cell tumors.

PubMed

Reuter, Victor E

2005-02-01

Testicular germ cell tumors can be divided into three groups (infantile/prepubertal, adolescent/young adult and spermatocytic seminoma), each with its own constellation of clinical histology, molecular and clinical features. They originate from germ cells at different stages of development. The most common testicular cancers arise in postpubertal men and are characterized genetically by having one or more copies of an isochromosome of the short arm of chromosome 12 [i(12p)] or other forms of 12p amplification and by aneuploidy. The consistent gain of genetic material from chromosome 12 seen in these tumors suggests that it has a crucial role in their development. Intratubular germ cell neoplasia, unclassified type (IGCNU) is the precursor to these invasive tumors. Several factors have been associated with their pathogenesis, including cryptorchidism, elevated estrogens in utero and gonadal dysgenesis. Tumors arising in prepubertal gonads are either teratomas or yolk sac tumors, tend to be diploid and are not associated with i(12p) or with IGCNU. Spermatocytic seminoma (SS) arises in older patients. These benign tumors may be either diploid or aneuploid and have losses of chromosome 9 rather than i(12p). Intratubular SS is commonly encountered but IGCNU is not. The pathogenesis of prepubertal GCT and SS is poorly understood.

Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window

PubMed Central

van den Driesche, Sander; Kilcoyne, Karen R.; Wagner, Ida; Rebourcet, Diane; Mitchell, Rod; McKinnell, Chris; Macpherson, Sheila; Donat, Roland; Shukla, Chitranjan J.; Jorgensen, Anne; Skakkebaek, Niels E.; Sharpe, Richard M.

2017-01-01

The testicular dysgenesis syndrome (TDS) hypothesis, which proposes that common reproductive disorders of newborn and adult human males may have a common fetal origin, is largely untested. We tested this hypothesis using a rat model involving gestational exposure to dibutyl phthalate (DBP), which suppresses testosterone production by the fetal testis. We evaluated if induction of TDS via testosterone suppression is restricted to the “masculinization programming window” (MPW), as indicated by reduction in anogenital distance (AGD). We show that DBP suppresses fetal testosterone equally during and after the MPW, but only DBP exposure in the MPW causes reduced AGD, focal testicular dysgenesis, and TDS disorders (cryptorchidism, hypospadias, reduced adult testis size, and compensated adult Leydig cell failure). Focal testicular dysgenesis, reduced size of adult male reproductive organs, and TDS disorders and their severity were all strongly associated with reduced AGD. We related our findings to human TDS cases by demonstrating similar focal dysgenetic changes in testes of men with preinvasive germ cell neoplasia (GCNIS) and in testes of DBP-MPW animals. If our results are translatable to humans, they suggest that identification of potential causes of human TDS disorders should focus on exposures during a human MPW equivalent, especially if negatively associated with offspring AGD. PMID:28352662

Anosmia predicts hypogonadotropic hypogonadism in CHARGE syndrome.

PubMed

Bergman, Jorieke E H; Bocca, Gianni; Hoefsloot, Lies H; Meiners, Linda C; van Ravenswaaij-Arts, Conny M A

2011-03-01

To test the hypothesis that a smell test could predict the occurrence of hypogonadotropic hypogonadism (HH) in patients with CHARGE syndrome, which is a variable combination of ocular coloboma, heart defects, choanal atresia, retardation of growth/development, genital hypoplasia, and ear anomalies or hearing loss caused by mutations in the CHD7 (chromodomain helicase DNA binding protein 7) gene. We performed endocrine studies and smell testing (University of Pennsylvania Smell Identification Test) in 35 adolescent patients with molecularly confirmed CHARGE syndrome. Complete data on smell and puberty were available for 15 patients; 11 patients had both anosmia and HH, whereas 4 patients had normosmia/hyposmia and spontaneous puberty. In addition, 7 boys were highly suspected of having HH (they were too young for definite HH diagnosis, but all had cryptorchidism, micropenis, or both) and had anosmia. The type of CHD7 mutation could not predict HH because a father and daughter with the same CHD7 mutation were discordant for HH and anosmia. Anosmia and HH were highly correlated in our cohort, and therefore smell testing seems to be an attractive method for predicting the occurrence of HH in patients with CHARGE syndrome. The use of this test could prevent delay of hormonal pubertal induction, resulting in an age-appropriate puberty. Copyright © 2011 Mosby, Inc. All rights reserved.

Male reproductive health and environmental xenoestrogens.

PubMed Central

Toppari, J; Larsen, J C; Christiansen, P; Giwercman, A; Grandjean, P; Guillette, L J; Jégou, B; Jensen, T K; Jouannet, P; Keiding, N; Leffers, H; McLachlan, J A; Meyer, O; Müller, J; Rajpert-De Meyts, E; Scheike, T; Sharpe, R; Sumpter, J; Skakkebaek, N E

1996-01-01

Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention. Images Figure 3. A Figure 3. B Figure 3. C Figure 3. D Figure 3. E Figure 3. F PMID:8880001

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

EPA Pesticide Factsheets

Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies.Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system.Methods: We used U.S. EPA??s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA??s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarch

Systems Toxicology of Male Reproductive Development ...

EPA Pesticide Factsheets

Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male reproductive developmental defects. The present study established the links between environmental chemicals, molecular targets, and adverse outcomes using U.S. EPA animal study (ToxRefDB) and high-throughput screening (ToxCast) databases. This systems-based approach revealed a phenotypic hierarchy across 63 chemicals and a pleiotropic in vitro bioactivity profile. Although estrogenic and anti-androgenic activities have been extensively studied in male reproductive developmental toxicity, the present study showed these receptor targets to be only a subset of the potential landscape of molecular targets. A variety of chemical (e.g. phthalates, conazoles, carbamates, and phenol compounds) and bioactivity (e.g. nuclear receptors, vascular remodeling proteins, and cytochrome-P450 reductases) clusters further suggested multiple pathways leading to the adverse outcomes. This points to the need for multi-scale systems models to predict whether the occurrence of one adverse outcome may predict the risk of another. Imbalances in androgen and estrogen signaling have been a general focus in male reproductive toxicology research. While a number of recent studies have demonstrated that both hormonal

Characteristics of boys with the so-called true undescended testis diagnosed at the third postnatal month--a population-based case-control study.

PubMed

Mavrogenis, Stelios; Urbán, Robert; Czeizel, Andrew E

2015-07-01

Undescended testis (cryptorchidism) is a common congenital abnormality of male genital organs diagnosed at birth followed with frequent postnatal descensus. However, the so-called isolated true undescended testis (ITUT) diagnosed at the third postnatal month seems to be an independent defect-entity, and this hypothesis was planned to confirm or reject in the study. The evaluation of birth outcomes and maternal socio-demographic data of cases with ITUT in the population-based large dataset of the Hungarian Congenital Abnormality Registry. There was a higher rate of preterm birth and particularly of low birthweight in 2052 cases with ITUT compared to 24,814 population male controls without any defects. The rate of twins was not higher in cases with older mothers, higher birth order and lower socio-economic status. The comparison of data of boys with undescended testis diagnosed at birth found in the previous study and with ITUT in this study confirmed our hypothesis. Undescended testis can be differentiated into two subgroups: boys with frequent postnatal descensus mainly after preterm delivery and boys with ITUT without postnatal testis descensus with frequent intrauterine growth restriction, older mothers with higher birth order and low socio-economic status.

Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly.

PubMed

Kernohan, K D; McBride, A; Xi, Y; Martin, N; Schwartzentruber, J; Dyment, D A; Majewski, J; Blaser, S; Boycott, K M; Chitayat, D

2017-05-01

Post-translational protein modifications exponentially expand the functional complement of proteins encoded by the human genome. One such modification is the covalent addition of a methyl group to arginine or lysine residues, which is used to regulate a substantial proportion of the proteome. Arginine and lysine methylation are catalyzed by protein arginine methyltransferase (PRMTs) and protein lysine methyltransferase proteins (PKMTs), respectively; each methyltransferase has a specific set of target substrates. Here, we report a male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism and seizures who was found to have a homozygous 15,309 bp deletion encompassing the transcription start site of PRMT7, which we confirmed is functionally a null allele. We show that the patient's cells have decreased levels of protein arginine methylation, and that affected proteins include the essential histones, H2B and H4. Finally, we demonstrate that patient cells have altered Wnt signaling, which may have contributed to the skeletal abnormalities. Our findings confirm the recent disease association of PRMT7, expand the phenotypic manifestations of this disorder and provide insight into the molecular pathogenesis of this new condition. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

ENU Mutagenesis in Mice Identifies Candidate Genes For Hypogonadism

PubMed Central

Weiss, Jeffrey; Hurley, Lisa A.; Harris, Rebecca M.; Finlayson, Courtney; Tong, Minghan; Fisher, Lisa A.; Moran, Jennifer L.; Beier, David R.; Mason, Christopher; Jameson, J. Larry

2012-01-01

Genome-wide mutagenesis was performed in mice to identify candidate genes for male infertility, for which the predominant causes remain idiopathic. Mice were mutagenized using N-ethyl-N-nitrosourea (ENU), bred, and screened for phenotypes associated with the male urogenital system. Fifteen heritable lines were isolated and chromosomal loci were assigned using low density genome-wide SNP arrays. Ten of the fifteen lines were pursued further using higher resolution SNP analysis to narrow the candidate gene regions. Exon sequencing of candidate genes identified mutations in mice with cystic kidneys (Bicc1), cryptorchidism (Rxfp2), restricted germ cell deficiency (Plk4), and severe germ cell deficiency (Prdm9). In two other lines with severe hypogonadism candidate sequencing failed to identify mutations, suggesting defects in genes with previously undocumented roles in gonadal function. These genomic intervals were sequenced in their entirety and a candidate mutation was identified in SnrpE in one of the two lines. The line harboring the SnrpE variant retains substantial spermatogenesis despite small testis size, an unusual phenotype. In addition to the reproductive defects, heritable phenotypes were observed in mice with ataxia (Myo5a), tremors (Pmp22), growth retardation (unknown gene), and hydrocephalus (unknown gene). These results demonstrate that the ENU screen is an effective tool for identifying potential causes of male infertility. PMID:22258617

A Mouse Model of Hypospadias Induced by Estradiol Benzoate.

PubMed

He, Hou-Guang; Han, Cong-Hui; Zhang, Wei

2015-12-01

We wished to establish a mouse model of hypospadias using injections of estradiol benzoate for investigating the molecular mechanisms of hypospadias. Fifty timed pregnant mice were randomly divided into five study groups: A, B, C, D, and E. These groups were injected subcutaneously with estradiol benzoate mixed with sesame oil at, respectively, the doses of 0, 0.1, 0.5, 2.5, or 12.5 mg kg(-1) days(-1) from gestation day (GD) 12 to GD 16. The pups' mortality was recorded on the day of delivery. Urethras and positions of testes were examined on postnatal day 28. The numbers of live pups were significantly lower in the study groups D and E compared to study group A (p < 0.01). Hypospadias was seen in groups C (3.3 %; 1/30), D (18.2 %; 4/22), and E (21.4 %; 3/14), while cryptorchidism was observed in groups C (10 %; 3/30), D (31.8 %; 7/22), and E (57.1 %; 8/14) on postnatal day 28. The experimental model of hypospadias induced by estradiol benzoate in the group D (2.5 mg kg(-1) days(-1)) was more reliable considering high mortality of the study group E. The dose of estradiol benzoate used in the group D is suitable for establishing mouse model of hypospadias.

Trisomy 9 syndrome: Report of a case with Crohn disease and review of the literature

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolldridge, J.; Zuncih, J.

1995-04-10

We report on a 6-year-old boy with mosaic trisomy 9. The patient was born at 42 weeks of gestation to a 27-year-old G1 white woman. Birth weight was 2,820 g, length 52 cm, and Apgar scores were 4 and 6 at 1 and 5 min, respectively. The infant presented with apparently low-set ears, overfolded helices, epicanthal folds, prominent nasal bridge, high-arched palate, micrognathia, bilateral dislocated hips, left genu recurvatum, and cryptorchidism. Chromosome analysis showed an unusual karyotype: 47,XY,+inv(9qh+)/47,XY,+mar. The marker chromosome was thought to be a remnant of the inv (9qh+), while the father`s was 46,XY. At age 5 months,more » the patient developed seizures and gastroesophageal reflux. Crohn disease was diagnosed at age 2 years, although symptoms began at age 1 year. Recurrent bouts of pneumonia have occurred since the patient`s birth. Severe psychomotor retardation was also noted. Trisomy 9 syndrome was first reported in 1973. Over 30 cases have been reported since then. Of these case reports, only 5 patients were older than 1 year. Inflammatory bowel disease has been reported in association with other chromosome abnormalities, but to our knowledge, has not been reported in trisomy 9 syndrome. 39 refs., 4 figs., 2 tabs.« less

NOGGIN IS REQUIRED FOR NORMAL LOBE PATTERNING AND DUCTAL BUDDING IN THE MOUSE PROSTATE

PubMed Central

Cook, Crist; Vezina, Chad M.; Hicks, Sarah M.; Shaw, Aubie; Yu, Min; Peterson, Richard E.; Bushman, Wade

2008-01-01

Mesenchymal expression of the BMP antagonist NOGGIN during prostate development plays a critical role in pre-natal ventral prostate development and opposes BMP4-mediated inhibition of cell proliferation during postnatal ductal development. Morphologic examination of newborn Noggin-/- male fetuses revealed genitourinary anomalies including cryptorchidism, incomplete separation of the hindgut from the urogenital sinus (UGS), absence of the ventral mesenchymal pad and a complete loss of ventral prostate (VP) budding. Examination of lobe-specific marker expression in the E14 Noggin-/- UGS rescued by transplantation under the renal capsule of a male nude mouse confirmed a complete loss of VP determination. More modest effects were observed in the other lobes, including decreased number of ductal buds in the dorsal and lateral prostates of newborn Noggin-/- males. BMP4 and BMP7 have been shown to inhibit ductal budding and outgrowth by negatively regulating epithelial cell proliferation. We show here that NOGGIN can neutralize budding inhibition by BMP4 and rescues branching morphogenesis of BMP4-exposed UGS in organ culture and show that the effects of BMP4 and NOGGIN activities converge on P63+ epithelial cells located at nascent duct tips. Together, these studies show that the BMP-NOGGIN axis regulates patterning of the ventral prostate, regulates ductal budding, and controls proliferation of P63+ epithelial cells in the nascent ducts of developing mouse prostate. PMID:18028901

Assessment of phthalates/phthalate alternatives in children's toys and childcare articles: Review of the report including conclusions and recommendation of the Chronic Hazard Advisory Panel of the Consumer Product Safety Commission.

PubMed

Lioy, Paul J; Hauser, Russ; Gennings, Chris; Koch, Holger M; Mirkes, Philip E; Schwetz, Bernard A; Kortenkamp, Andreas

2015-01-01

The Consumer Product Safety Commission (CPSC) convened a Chronic Hazard Advisory Panel (CHAP) on Phthalates found in children's toys, and childcare products, and in products used by women of childbearing age. The CHAP conducted a risk assessment on phthalates and phthalate substitutes, and made recommendations to either ban, impose an interim ban, or allow the continued use of phthalates and phthalate substitutes in the above products. After a review of the literature, the evaluation included toxic end points of primary concern, biomonitoring results, extant exposure reconstruction, and epidemiological results. The health end points chosen were associated with the rat phthalate syndrome, which is characterized by malformations of the epididymis, vas deferens, seminal vesicles, prostate, external genitalia (hypospadias), and by cryptorchidism (undescended testes), retention of nipples/areolae, and demasculinization (~incomplete masculinization) of the perineum, resulting in reduced anogenital distance. Risk assessment demonstrated that some phthalates should be permanently banned, removed from the banned list, or remain interim banned. Biomonitoring and toxicology data provided the strongest basis for a mixture risk assessment. In contrast, external exposure data were the weakest and need to be upgraded for epidemiological studies and risk assessments. Such studies would focus on routes and sources. The review presents recommendations and uncertainties.

A rare case of lateral ovotesticular disorder with Klinefelter syndrome mosaicism 46, XX/47, XXY: An unusual presentation.

PubMed

Talreja, Shyam M; Banerjee, Indraneel; Yadav, Sher Singh; Tomar, Vinay

2015-01-01

Ovotesticular disorder of sex development (OT-DSD) is a rare disorder of sexual differentiation characterized by the presence of both ovarian and testicular tissues in the same individual. It's incidence ranges from 3% to 10% of all disorder of DSD's, and the most common presentation is 46, XX followed by 46, XX/46, XY mosaicism and 46, XY. Klinefelter syndrome (KS) mosaicism 46, XX/47, XXY is extremely rare, and its association with the ovotesticular disorder is even rarer. We report an unusual case of 16-year-old with male habitus who presented with complains of cyclic hematuria. On examination, he had bilateral gynecomastia, unilateral left cryptorchidism, absent facial hair, sparse axillary hair growth, and pubic hair distribution of feminine type. The right testis was of normal size located normally in hemiscrotum and was confirmed by radio imaging. Ultrasonography and magnetic resonance imaging revealed a cystic area behind posterior half of urinary bladder. Chromosomal analysis revealed 46, XX/47, XXY mosaicism of female karyotype and KS. Histopathological report of this left side excised specimen confirmed the structures to be ovary, uterus, and fallopian tube, thus confirming our diagnosis of the lateral ovotesticular disorder. Meticulous workup combined interdisciplinary approach will lead to early diagnosis and resolve timely sex reassignment issues and also prevent consequences arising due to gonadal insufficiency.

Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model

PubMed Central

Anderson, Richard A.; Johnston, Zoe C.; Chetty, Tarini; Smith, Lee B.; Mckinnell, Chris; Dean, Afshan; Homer, Natalie Z.; Jorgensen, Anne; Camacho-Moll, Maria-Elena; Sharpe, Richard M.; Mitchell, Rod T.

2016-01-01

Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons, but effects on fetal testosterone production have not been demonstrated. We used a validated xenograft model to expose human fetal testes to clinically relevant doses and regimens of acetaminophen. Exposure to a therapeutic dose of acetaminophen for 7 days significantly reduced plasma testosterone (45% reduction; p=0.025) and seminal vesicle weight (a biomarker of androgen exposure; 18% reduction; p=0.005) in castrate host mice bearing human fetal testis xenografts, whereas acetaminophen exposure for just 1 day did not alter either parameter. Plasma acetaminophen concentrations (at 1 hour after the final dose) in exposed host mice were substantially below those reported in humans after a therapeutic oral dose. Subsequent in utero exposure studies in rats indicated that the acetaminophen-induced reduction in testosterone likely results from reduced expression of key steroidogenic enzymes (Cyp11a1, Cyp17a1). Our results suggest that protracted use of acetaminophen (1 week) may suppress fetal testosterone production, which could have adverse consequences. Further studies are required to establish the dose-response and treatment-duration relationships to delineate the maximum dose and treatment period without this adverse effect. PMID:25995226

Congenital hypogonadotropic hypogonadism: implications of absent mini-puberty.

PubMed

Dwyer, Andrew A; Jayasena, Channa N; Quinton, Richard

2016-06-01

The phenomenon known as "mini-puberty" refers to activation of the neonatal hypothalamo-pituitary axis causing serum concentrations of gonadotrophins and testosterone (T) to approach adult male levels. This early neonatal period is a key proliferative window for testicular germ cells and immature Sertoli cells. Although failure to spontaneously initiate (adolescent) puberty is the most evident consequence of a defective gonadotropin-releasing hormone (GnRH) neurosecretory network, absent mini-puberty is also likely to have a major impact on the reproductive phenotype of men with congenital hypogonadotrophic hypogonadism (CHH). Furthermore, the phase of male mini-puberty represents a key window-of-opportunity to identify congenital GnRH deficiency (either isolated CHH, or as part of combined pituitary hormone deficiency) in childhood. Among male neonates exhibiting "red flag" indicators for CHH (i.e. maldescended testes with or without cryptorchidism) a single serum sample (between 4-8 weeks of life) can pinpoint congenital GnRH deficiency far more rapidly and with much greater accuracy than dynamic tests performed in later childhood or adolescence. Potential consequences for missing absent mini-puberty in a male neonate include the lack of monitoring of pubertal progression/lack of progression, and the missed opportunity for early therapeutic intervention. This article will review our current understanding of the mechanisms and clinical consequences of mini-puberty. Furthermore, evidence for the optimal clinical management of patients with absent mini-puberty will be discussed.

Magnetic resonance angiography for the nonpalpable testis: a cost and cancer risk analysis.

PubMed

Eggener, S E; Lotan, Y; Cheng, E Y

2005-05-01

For the unilateral nonpalpable testis standard management is open surgical or laparoscopic exploration. An ideal imaging technique would reliably identify testicular nubbins and safely allow children to forgo surgical exploration without compromising future health or fertility. Our goal was to perform a cost and risk analysis of magnetic resonance angiography (MRA) for unilateral nonpalpable cryptorchid testes. A search of the English medical literature revealed 3 studies addressing the usefulness of MRA for the nonpalpable testicle. We performed a meta-analysis and applied the results to a hypothetical set of patients using historical testicular localization data. Analysis was then performed using 3 different management protocols-MRA with removal of testicular nubbin tissue, MRA with observation of testicular nubbin tissue and diagnostic laparoscopy. A cancer risk and cost analysis was then performed. MRA with observation of testicular nubbin tissue results in 29% of patients avoiding surgery without any increased cost of care. Among the 29% of boys with testicular nubbins left in situ and observed the highest estimated risk was 1 in 300 of cancer developing, and 1 in 5,300 of dying of cancer. A protocol using MRA with observation of inguinal nubbins results in nearly a third of boys avoiding surgical intervention at a similar cost to standard care without any significant increased risk of development of testis cancer.

Idiopathic hypogonadotropic hypogonadism in a mother and her monozygotic twins born after a single embryo transfer.

PubMed

Laitinen, Eeva-Maria; Tommiska, Johanna; Dunkel, Leo; Sankilampi, Ulla; Vaaralahti, Kirsi; Raivio, Taneli

2010-04-01

To describe a mother with idiopathic hypogonadotropic hypogonadism (IHH) and her monozygotic (MZ) twin boys who all have the same heterozygous fibroblast growth factor receptor-1 (FGFR1) gene mutation. Case report. University hospital. A 28-year-old mother with normosmic IHH gave birth to MZ twin boys after a transfer of a single frozen-thawed embryo. Clinical and biochemical evaluation of IHH. Sequence analysis of the 17 coding exons (exons 2-18) and exon-intron boundaries of FGFR1 from polymerase chain reaction-amplified genomic DNA from peripheral blood leukocytes of the subjects. Phenotypic features of the subjects. All subjects harbored a previously undescribed heterozygous FGFR1 mutation (c.2049-1 G-->C), leading to the skipping of exon 16 and thus a loss of amino acids 684-726 in the tyrosine kinase domain of the receptor. The absence of exon 16 was verified at the cDNA level. The twins manifested with microphallus, cryptorchidism, and deficient postnatal activation of the hypothalamic-pituitary-gonadal axis, findings consistent with IHH. Our report underlines that assisted reproductive techniques enable the inheritance of gene mutations causing infertility. This is the first report on the phenotypic features of MZ twins with an FGFR1 mutation. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Subtotal obstruction of the male reproductive tract.

PubMed

Dohle, G R; van Roijen, J H; Pierik, F H; Vreeburg, J T M; Weber, R F A

2003-03-01

Bilateral obstruction of the male reproductive tract is suspected in men with azoospermia, normal testicular volume and normal FSH. A testicular biopsy is required to differentiate between an obstruction and a testicular insufficiency. Unilateral or subtotal bilateral obstructions and epididymal dysfunction may cause severe oligozoospermia in men with a normal spermatogenesis. However, information on spermatogenesis in oligozoospermic men is lacking, since testicular biopsy is not routinely performed. Men with a sperm concentration of <1 x 10(6) spermatozoa/ml were investigated for possible partial obstruction by performing a testicular biopsy under local anaesthesia. Spermatogenesis was determined by the Johnsen scoring method. A testicular biopsy was performed in 78 men with severe oligozoospermia. The medical history showed male accessory gland infection in 12.8%, previous hernia repair in 14.1% and a history of cryptorchidism in 12.8%. A normal or slightly disturbed spermatogenesis (Johnsen score >8) was present in 39/78 (50%) of the men. Hernia repair occurred more often in men with normal spermatogenesis. A varicocele was predominantly seen in men with a disturbed spermatogenesis. FSH was significantly lower ( P<0.0001) in men with normal spermatogenesis. Subtotal obstruction of the male reproductive tract is a frequent cause of severe oligozoospermia in men with a normal testicular volume and a normal FSH. In other cases, an epididymal dysfunction might explain the oligozoospermia in men with a normal testicular biopsy score.

The histologic features of intratubular germ cell neoplasia and its correlation with tumor behavior.

PubMed

Basiri, Abbas; Movahhed, Saeed; Parvin, Mahmood; Salimi, Maziar; Rezaeetalab, Gholam Hossein

2016-05-01

To assess the prevalence of intratubular germ cell neoplasia (ITGCN) in patients with concurrent testis tumor and its correlation with histologic features and serum tumor markers. From 2003 to 2015, 179 patients underwent radical orchiectomy due to testicular mass. Tissue specimens were evaluated by an expert uro-pathologist using immunohistochemistry (IHC) staining, in addition to light microscopy, to identify presence of ITGCN. Patients' demographic characteristics, histologic subtypes, pathologic stage of tumor and serum tumor markers were gathered and analyzed. Eighty-five out of 179 patients (47.5%) had concomitant ITGCN according to IHC staining. There was not statistically significant difference in histologic type, histologic components, cryptorchidism, and lymphovascular invasion between the 2 groups (p=0.151, p=0.11, p=0.233, p=0.413, and p=0.14, respectively). The prevalence of ITGCN was significantly higher in patients with stage T2 and T3 of tumor than those with stage T1. Elevated serum alpha feto protein level is much common in patients with ITGCN (p<0.001). The prevalence of concurrent ITGCN in our region is lower than previous data from western countries. ITGCN is more common in higher tumor stages and is accompanied with elevated serum alpha feto protein levels before surgery. Presence of ITGCN in adjacent tissue may suggest a negative cancer behavior.

Ubiquitin C-terminal hydrolase L-1 is essential for the early apoptotic wave of germinal cells and for sperm quality control during spermatogenesis.

PubMed

Kwon, Jungkee; Mochida, Keiji; Wang, Yu-Lai; Sekiguchi, Satoshi; Sankai, Tadashi; Aoki, Shunsuke; Ogura, Atsuo; Yoshikawa, Yasuhiro; Wada, Keiji

2005-07-01

Ubiquitination is required throughout all developmental stages of mammalian spermatogenesis. Ubiquitin C-terminal hydrolase (UCH) L1 is thought to associate with monoubiquitin to control ubiquitin levels. Previously, we found that UCHL1-deficient testes of gad mice have reduced ubiquitin levels and are resistant to cryptorchid stress-related injury. Here, we analyzed the function of UCHL1 during the first round of spermatogenesis and during sperm maturation, both of which are known to require ubiquitin-mediated proteolysis. Testicular germ cells in the immature testes of gad mice were resistant to the early apoptotic wave that occurs during the first round of spermatogenesis. TUNEL staining and cell quantitation demonstrated decreased germ cell apoptosis and increased numbers of premeiotic germ cells in gad mice between Postnatal Days 7 and 14. Expression of the apoptotic proteins TRP53, Bax, and caspase-3 was also significantly lower in the immature testes of gad mice. In adult gad mice, cauda epididymidis weight, sperm number in the epididymis, and sperm motility were reduced. Moreover, the number of defective spermatozoa was significantly increased; however, complete infertility was not detected. These data indicate that UCHL1 is required for normal spermatogenesis and sperm quality control and demonstrate the importance of UCHL1-dependent apoptosis in spermatogonial cell and sperm maturation.

Physical health problems in adults with Prader-Willi syndrome.

PubMed

Sinnema, Margje; Maaskant, Marian A; van Schrojenstein Lantman-de Valk, Henny M J; van Nieuwpoort, I Caroline; Drent, Madeleine L; Curfs, Leopold M G; Schrander-Stumpel, Constance T R M

2011-09-01

Prader-Willi syndrome (PWS) is a genetic disorder which is characterized by severe hypotonia and feeding problems in early infancy. In later childhood and adolescence, this is followed by hyperphagia and extreme obesity if the diet is not strictly controlled. Data on physical health problems in adults with PWS are scarce. We report on the prevalence of physical health problems in a Dutch cohort of adults with PWS in relation to age, BMI, and genetic subtype. Participants (n = 102) were retrieved via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with intellectual disabilities (ID). Details regarding physical health problem spanning the participants' lifespan were collected from caretakers through semi-structured interviews. Cardiovascular problems included diabetes mellitus, hypertension, and cerebrovascular accidents. Respiratory infections were frequent in adulthood. In males, cryptorchidism was almost universal, for which 28/48 males had a history of surgery, mostly orchidopexy. None of the women had a regular menstrual cycle. Sixteen individuals had a diagnosis of osteoporosis. Spinal deformation, hip dysplasia, and foot abnormalities were common. Skinpicking, leg edema, and erysipelas were frequent dermatological problems. The findings in our group support the notion that the prevalence of physical health problems is underestimated. This underscores the importance of developing monitoring programs which would help to recognize physical health problems at an early stage. Copyright © 2011 Wiley-Liss, Inc.

Allopurinol Use during Pregnancy - Outcome of 31 Prospectively Ascertained Cases and a Phenotype Possibly Indicative for Teratogenicity

PubMed Central

Hoeltzenbein, Maria; Stieler, Katja; Panse, Mary; Wacker, Evelin; Schaefer, Christof

2013-01-01

Allopurinol is a purine analogue that inhibits xanthine oxidase. It is mainly used for the treatment of hyperuricemia in patients with gout or tumor lysis syndrome. Experience with allopurinol in pregnancy is scarce. In 2011, Kozenko et al. reported on a child with multiple malformations after maternal treatment with allopurinol throughout pregnancy. Possible teratogenicity of allopurinol was proposed due to the similarity of the pattern of malformations in children with mycophenolate embryopathy. A possible common mechanism of both drugs, i.e. disruption of purine synthesis, was discussed. We report on the outcome of 31 prospectively ascertained pregnancies with allopurinol exposure at least during first trimester. Pregnancy outcomes were 2 spontaneous abortions, 2 elective terminations of pregnancy and 27 live born children. The overall rate of major malformations (3.7%) and of spontaneous abortions (cumulative incidence 11%, 95%-CI 3–40) were both within the normal range. However, there was one child with severe malformations including microphthalmia, cleft lip and palate, renal hypoplasia, low-set ears, hearing deficit, bilateral cryptorchidism, and micropenis. The striking similarity of the anomalies in this child and the case described by Kozenko et al. might be considered as a signal for teratogenicity. Thus, we would recommend caution with allopurinol treatment in the first trimester, until further data are available. PMID:23840514

Prader-Willi Syndrome due to an Unbalanced de novo Translocation t(15;19)(q12;p13.3).

PubMed

Dang, Vy; Surampalli, Abhilasha; Manzardo, Ann M; Youn, Stephanie; Butler, Merlin G; Gold, June-Anne; Kimonis, Virginia E

2016-01-01

Prader-Willi syndrome (PWS) is a complex, multisystem genetic disorder characterized by endocrine, neurologic, and behavioral abnormalities. We report the first case of an unbalanced de novo reciprocal translocation of chromosomes 15 and 19, 45,XY,-15,der(19)t(15;19)(q12;p13.3), resulting in monosomy for the PWS critical chromosome region. Our patient had several typical features of PWS including infantile hypotonia, a poor suck and feeding difficulties, tantrums, skin picking, compulsions, small hands and feet, and food seeking, but not hypopigmentation, a micropenis, cryptorchidism or obesity as common findings seen in PWS at the time of examination at 6 years of age. He had seizures noted from 1 to 3 years of age and marked cognitive delay. High-resolution SNP microarray analysis identified an atypical PWS type I deletion in chromosome 15 involving the proximal breakpoint BP1. The deletion extended beyond the GABRB3 gene but was proximal to the usual distal breakpoint (BP3) within the 15q11q13 region, and GABRA5, GABRG3, and OCA2 genes were intact. No deletion of band 19p13.3 was detected; therefore, the patient was not at an increased risk of tumors from the Peutz-Jeghers syndrome associated with a deletion of the STK11 gene. © 2016 S. Karger AG, Basel.

Analgesic use in pregnancy and male reproductive development

PubMed Central

Hurtado-Gonzalez, Pablo; Mitchell, Rod T.

2017-01-01

Purpose of review Male reproductive disorders are common and increasing in incidence in many countries. Environmental factors (including pharmaceuticals) have been implicated in the development of these disorders. This review aims to summarise the emerging epidemiological and experimental evidence for a potential role of in-utero exposure to analgesics in the development of male reproductive disorders. Recent findings A number of epidemiological studies have demonstrated an association between in-utero exposure to analgesics and the development of cryptorchidism, although these findings are not consistent across all studies. Where present, these associations primarily relate to exposure during the second trimester of pregnancy. In-vivo and in-vitro experimental studies have demonstrated variable effects of exposure to analgesics on Leydig cell function in the fetal testis of rodents, particularly in terms of testosterone production. These effects frequently involve exposures that are in excess of those to which humans are exposed. Investigation of the effects of analgesics on human fetal testis have also demonstrated effects on Leydig cell function. Variation in species, model system, dosage and timing of exposure is likely to contribute to differences in the findings between studies. Summary There is increasing evidence for analgesic effects on the developing testis that have the potential to impair reproductive function. However, the importance of these findings in relation to human-relevant exposures and the risk of male reproductive disorders remains unclear. PMID:28277341

Deficiency in GnRH receptor trafficking due to a novel homozygous mutation causes idiopathic hypogonadotropic hypogonadism in three prepubertal siblings.

PubMed

Zhang, Rui; Linpeng, Siyuan; Li, Zhuo; Cao, Yingxi; Tan, Hu; Liang, Desheng; Wu, Lingqian

2018-08-30

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by low levels of gonadotropins and delayed or absent sexual development. Most of the patients are diagnosed in late adolescence or early adulthood. Determining the diagnosis of IHH in prepubertal patients can be challenging. Making a timely, correct diagnosis has important clinical implications. Here we aimed to identify the genetic cause of IHH in three prepubertal siblings from a Chinese Han family and give appropriate treatment advice. Using whole exome sequencing (WES), we identified a novel homozygous GNRHR mutation (NM_000406; c.364C>T, p.L122F) in two prepubertal boys with cryptorchidism and micropenis. Sanger sequencing showed that their younger asymptomatic sister also had the homozygous GNRHR mutation. This mutation was inherited from the father and the mother. Immunofluorescence analysis showed that in permeabilized cells, expression of the mutant receptor on the cell membrane was significantly lower than that of wild-type. Calcium mobilization assays demonstrated that c.364C>T in the GNRHR gene is a complete loss-of-function mutation that caused IHH. These results may contribute to the genetic diagnosis of the three prepubertal siblings with IHH. According to this diagnosis, timely hormonal treatment can be given for the three prepubertal patients to induce pubertal development, especially for the asymptomatic female. Copyright © 2018 Elsevier B.V. All rights reserved.

Fetal growth restriction but not preterm birth is a risk factor for severe hypospadias.

PubMed

Hashimoto, Yukiko; Kawai, Masahiko; Nagai, Sizuyo; Matsukura, Takashi; Niwa, Fusako; Hasegawa, Takeshi; Heike, Toshio

2016-07-01

Hypospadias has multifactorial causes and occurs at a high frequency among very low-birthweight infants. Placental insufficiency is hypothesized to be one cause of hypospadias; that is, decreased human chorionic gonadotropin (hCG) secretion caused by placental insufficiency is suspected to result in abnormal male external genitalia, but there is little direct evidence to support this. The aim of this study was therefore to identify the features of hypospadias and to clarify the male genital abnormalities caused by fetal growth restriction (FGR). We reviewed the clinical data of boys who underwent hypospadias repair between 2005 and 2011 at Kyoto University Hospital. Twenty boys were included in this study. Fifteen (75%) of the subjects were preterm or low-birthweight infants. Thirteen (65%) had FGR, 60% of whom had severe hypospadias regardless of gestational age. In addition, 92% of the FGR infants also had other genital anomalies, such as cryptorchidism, bifid scrotum, or micropenis. In contrast, only 14% and 43% of the non-FGR infants had severe hypospadias or genital anomalies other than hypospadias, respectively. Placental histopathology was available in eight FGR infants, in seven of whom it was suggestive of blood flow deficiency such as infarction and single umbilical artery. Infants with FGR have a high incidence of hypospadias. FGR caused by placental dysfunction, but not low birthweight, is a risk factor for severe hypospadias associated with multiple genital anomalies. © 2015 Japan Pediatric Society.

Gonadotrophic status in adolescents with pituitary stalk interruption syndrome.

PubMed

Rottembourg, Diane; Linglart, Agnès; Adamsbaum, Catherine; Lahlou, Najiba; Teinturier, Cécile; Bougnères, Pierre; Carel, Jean-Claude

2008-07-01

Pituitary stalk interruption syndrome (PSIS) is a frequent cause of GH deficiency (GHD) and is commonly associated with other PH deficiencies (PHDs). Although previous reports have correlated multiple PHDs with severe anatomical lesions, the status of the gonadotrophic axis has not yet been thoroughly analysed. We retrospectively reviewed the medical records of 27 patients (15 males, 12 females) with GHD and PSIS defined by MRI findings. The status of the gonadotrophic axis was evaluated in children who were at least 14.5 years (boys) or 13 years (girls). Out of 27 patients, five displayed spontaneous full pubertal development with normal hormonal values at the final evaluation, whereas 22 of 27 patients (81%) had complete (n = 18) or partial pubertal deficiency. Three girls had primary amenorrhoea with normal gonadotrophin values, raising the possibility of subtle disturbances of gonadotrophin pulsatility. Of the 21 patients with TSH or ACTH deficiency, 17 (81%) had complete gonadotrophin deficiency. Two of our six patients with apparently isolated GHD during childhood had gonadotrophin deficiency. Cryptorchidism was present at birth in six boys (40%). Of these six boys, one had normal pubertal development. Ten of 11 boys with micropenis at birth had gonadotrophin deficiency. Gonadotrophin deficiency is a common finding in adolescents with PSIS and is frequently associated with other PHDs. However its severity is variable, ranging from complete gonadotrophin deficiency to normogonadotrophic amenorrhoea. The occurrence of gonadotrophin deficiency in 33% of children with apparently isolated GHD and PSIS has important implications for the counselling and follow-up of these patients.

The Mosaicism Ratio of 45,X May Explain the Phenotype in a Case of Mixed Gonadal Dysgenesis.

PubMed

Hatano, Megumi; Fukuzawa, Ryuji; Hasegawa, Yukihiro

2018-06-08

Some patients with mixed gonadal dysgenesis (MGD), whose prototypical karyotype is 45,X/46,XY, are known to manifest complications characteristic of Turner syndrome. We report a 16-year-old social male with MGD presenting with coarctation of the aorta, one of the common complications for Turner syndrome. At birth, the patient was found to have hypospadias, bifid scrotum, and cryptorchidism. Chromosomal analysis of his lymphocytes revealed the karyotype 45,X[7]/46,X,dic(Y;22)(p11.3;q13.3)[23] (named 45,X/46,X+Y fragment in this article). A left gonadectomy was performed at 1 year of age, and the histology showed a streak gonad with an epithelial cord-like structure compatible with MGD. At the age of 10 years, coarctation of the aorta was discovered by chance, for which the patient underwent surgical repair. The ratio of mosaicism in the gonad and aortic tissues was estimated by FISH with probes to identify the X centromere-specific repeat sequence and Yp11.2. The mosaicism ratio of 45,X/46,X+Y fragment varied among the tissues, with those having a higher ratio being more likely to exhibit the Turner syndrome phenotype. Some 90% of cells in the aortic tissues and 80% in the gonadal tissues lacked a Y chromosome. In conclusion, the mosaicism ratio in the different tissues may explain the phenotypes in MGD. © 2018 S. Karger AG, Basel.

Genetics of congenital hypogonadotropic hypogonadism in Denmark.

PubMed

Tommiska, Johanna; Känsäkoski, Johanna; Christiansen, Peter; Jørgensen, Niels; Lawaetz, Jacob Gerner; Juul, Anders; Raivio, Taneli

2014-07-01

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by incomplete/absent puberty caused by deficiency or defective action of gonadotropin-releasing hormone (GnRH). The phenotypic features of patients with CHH vary from genital hypoplasia and absent puberty to reversal of HH later in life. We examined the genetics and clinical features of CHH in Denmark. Forty-one male patients were screened for mutations in KAL1, FGFR1, FGF8, PROK2, PROKR2, GNRHR, TAC3, TACR3, and KISS1R. CHD7 was screened in two patients with hearing loss. In 12 patients, a molecular genetic cause for CHH was found. Four patients had mutations in KAL1 (C105VfsX13, C53X, ex5-8del, R257X), and five in FGFR1 (G97S, R209C, A512V, R646W, and c.1614C>T, (p.I538I), predicted to affect splicing). All 9 had severe HH (cryptorchidism and/or micropenis), and 2 had cleft lip/palate. One patient with a previously reported homozygous R262Q mutation in GNRHR displayed fascinating temporal variation in his phenotype. Two patients with hearing loss had CHD7 mutations (c.7832_7841del (p.K2611MfsX25) and c.2443-2A>C), confirming that CHH patients with CHARGE syndrome-associated features should be screened for mutations in CHD7. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Differential Response to Abiraterone Acetate and Di-n-butyl Phthalate in an Androgen-Sensitive Human Fetal Testis Xenograft Bioassay

PubMed Central

Boekelheide, Kim

2014-01-01

In utero exposure to antiandrogenic xenobiotics such as di-n-butyl phthalate (DBP) has been linked to congenital defects of the male reproductive tract, including cryptorchidism and hypospadias, as well as later life effects such as testicular cancer and decreased sperm counts. Experimental evidence indicates that DBP has in utero antiandrogenic effects in the rat. However, it is unclear whether DBP has similar effects on androgen biosynthesis in human fetal testis. To address this issue, we developed a xenograft bioassay with multiple androgen-sensitive physiological endpoints, similar to the rodent Hershberger assay. Adult male athymic nude mice were castrated, and human fetal testis was xenografted into the renal subcapsular space. Hosts were treated with human chorionic gonadotropin for 4 weeks to stimulate testosterone production. During weeks 3 and 4, hosts were exposed to DBP or abiraterone acetate, a CYP17A1 inhibitor. Although abiraterone acetate (14 d, 75mg/kg/d po) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500mg/kg/d po) had no effect on androgenic endpoints. DBP did produce a near-significant trend toward increased multinucleated germ cells in the xenografts. Gene expression analysis showed that abiraterone decreased expression of genes related to transcription and cell differentiation while increasing expression of genes involved in epigenetic control of gene expression. DBP induced expression of oxidative stress response genes and altered expression of actin cytoskeleton genes. PMID:24284787

Brachymesomelic dysplasia with Peters anomaly of the eye results from disruptions of the X chromosome near the SHOX and SOX3 genes.

PubMed

Bleyl, Steven B; Byrne, Janice L B; South, Sarah T; Dries, David C; Stevenson, David A; Rope, Alan F; Vianna-Morgante, Angela M; Schoenwolf, Gary C; Kivlin, Jane D; Brothman, Arthur; Carey, John C

2007-12-01

We report on a mother and son affected with an unusual skeletal dysplasia and anterior segment eye abnormalities. Their skeletal phenotype overlaps with the SHOX-related skeletal dysplasias and is intermediate between Leri-Weill dyschondrosteosis (LWD) and Langer Mesomelic dysplasia (LMD). The mother has bilateral Peters anomaly of the eye and was reported as having a new syndrome; the son had severe bilateral sclerocornea. Chromosome analysis showed that the mother has a pericentric inversion of the X chromosome [46,X,inv(X)(p22.3q27)] and the son, a resultant recombinant X chromosome [46,Y,rec(X)dup(Xq)inv(X)(p22.3q27)]. The observed skeletal and ophthalmologic abnormalities in both patients were similar in severity. The additional features of developmental delay, growth retardation, agenesis of the corpus callosum, cryptorchidism and hypoplastic scrotum in the son are consistent with Xq28 duplication. Analysis of the son's recombinant X chromosome showed that the Xp22.33 breakpoint lies 30-68 kb 5' of the SHOX gene. This finding suggests that the skeletal dysplasia in both mother and son is allelic with LWD and LMD and results from a novel misexpression of SHOX. Analysis of the Xq27.1 breakpoint localized it to a 90 kb interval 3' of the SOX3 gene, supporting a novel role of SOX3 misexpression in the development of Peters anomaly of the eye. (c) 2007 Wiley-Liss, Inc.

The effects of pre- and postnatal exposure to the nonsteroidal antiandrogen flutamide on testis descent and morphology in the Albino Swiss rat

PubMed Central

KASSIM, NORMADIAH M.; McDONALD, S. W.; REID, O.; BENNETT, N. K.; GILMORE, D. P.; PAYNE, A. P.

1997-01-01

Exposure of male Albino Swiss rats to the nonsteroidal antiandrogen flutamide during the period from gestational day (d) 10 to birth resulted in feminisation of the external genitalia and the suppression of growth of the male reproductive tract. In adulthood, testes were found to be located in diverse positions. True cryptorchidism occurred in 10% of cases, whereas 50% of testes descended to the scrotum and 40% were located in a suprainguinal ectopic region. Varying degrees of tubule abnormality were seen in the testes of flutamide-treated animals, ranging from completely normal tubules with full spermatogenesis (and the expected frequency of the stages of spermatogenesis) to severely abnormal tubules lined with Sertoli cells only. For each individual testis, the overall severity of tubule damage was strongly correlated with its adult location, with intra-abdominal testes worst affected and scrotally-located testes least; only the latter contained normal tubules. Similarly, intra-abdominal testes were the smallest in weight and contained the least testosterone. By contrast, postnatal treatment of male rats with flutamide from birth to postnatal d 14 did not impair development of the external genitalia, the process of testicular descent or adult spermatogenesis. These findings confirm that androgen blockade during embryonic development interferes with testicular descent but also demonstrate that (1) prenatal flutamide treatment per se has a detrimental effect on adult testis morphology but (2) the degree of abnormality of the testes is strongly influenced by location. PMID:9183680

[Clinicopathological characterization of true hermaphroditism complicated with seminoma and review of the literature].

PubMed

Hua, Xing; Liu, Shao-Jie; Lu, Lin; Li, Chao-Xia; Yu, Li-Na

2012-08-01

To study the clinicopathological characteristics and diagnosis of true hermaphroditism complicated with seminoma. We retrospectively analyzed the clinicopathological data of a case of true hermaphroditism complicated with seminoma and reviewed the related literature. The patient was a 42-year-old male, admitted for bilateral lower back pain and discomfort. CT showed a huge mass in the lower middle abdomen. Gross pathological examination revealed a mass of uterine tissue, 7 cm x 2 cm x 6 cm in size, with bilateral oviducts and ovarian tissue. There was a cryptorchidism (4.0 cm x 2.5 cm x 1.5 cm) on the left and a huge tumor (22 cm x9 cm x6 cm) on the right of the uterine tissue. The tumor was completely encapsulated, with some testicular tissue. Microscopically, the tumor tissue was arranged in nests or sheets divided and surrounded by fibrous tissue. The tumor cells were large, with abundant and transparent cytoplasm, deeply stained nuclei, coarse granular chromatins, visible mitosis, and infiltration of a small number of lymphocytes in the stroma. The karyotype was 46, XX. Immunohistochemistry showed that PLAP and CD117 were positive, while the AFP, Vimentin, EMA, S100, CK-LMW, Desmin, CD34 and CD30 were negative, and Ki-67 was 20% positive. A small amount of residual normal testicular tissue was seen in the tumor tissue. True hermaphroditism complicated with seminoma is rare. Histopathological analysis combined with immunohistochemical detection is of great value for its diagnosis and differential diagnosis.

Hypospadias Is Not Rare in Dogs: Five New Cases, a Retrospective Study, and a Review of the Literature.

PubMed

Switonski, Marek; Dzimira, Stanislaw; Aleksiewicz, Roman; Szczerbal, Izabela; Nowacka-Woszuk, Joanna; Krzeminska, Paulina; Deska, Tomasz; Nizanski, Wojciech

2018-06-13

Hypospadias, the abnormal position of the urethral orifice, is considered a rare congenital malformation of the reproductive organs in male dogs. We present 5 new cases of hypospadias - 2 of the penile type in German Shepherd Dogs and 3 perineal types in a Bavarian Mountain Hound, a French Bulldog, and an American Staffordshire Terrier. Other abnormalities (rudimentary or underdeveloped penis, incompletely formed preputial sheath, and bilateral cryptorchidism) were also observed. Molecular analysis of all cases revealed the presence of Y-linked genes (SRY and ZFY). Cytogenetic and histological analysis could be performed for only 2 cases: a normal male sex chromosome complement (78,XY) and spermatogenetically inactive testicles were observed. A retrospective search for hypospadias in 19,950 medical records of male dogs from a single veterinary clinic in Poland (2006-2017) was also performed. Altogether, 10 reports of penile hypospadias were found (0.05%). The majority of the reports concerned German Shepherd Dogs (8 cases among 1,511 male dogs of this breed), and thus, the estimated incidence of hypospadias in this breed was 0.5%. Moreover, we performed a review of 26 cases of canine hypospadias reported in the years 2004-2017. Our study and the review of the literature suggest that hypospadias is not rare in dogs and that some breeds (such as German Shepherd Dog and Boston Terrier) may be prone to this disorder. © 2018 S. Karger AG, Basel.

Two novel translocation breakpoints upstream of SOX9 define borders of the proximal and distal breakpoint cluster region in campomelic dysplasia.

PubMed

Leipoldt, M; Erdel, M; Bien-Willner, G A; Smyk, M; Theurl, M; Yatsenko, S A; Lupski, J R; Lane, A H; Shanske, A L; Stankiewicz, P; Scherer, G

2007-01-01

The semilethal skeletal malformation syndrome campomelic dysplasia (CD) with or without XY sex reversal is caused by mutations within the SOX9 gene on 17q24.3 or by chromosomal aberrations (translocations, inversions or deletions) with breakpoints outside the SOX9 coding region. The previously published CD translocation breakpoints upstream of SOX9 fall into two clusters: a proximal cluster with breakpoints between 50-300 kb and a distal cluster with breakpoints between 899-932 kb. Here, we present clinical, cytogenetic and molecular data from two novel CD translocation cases. Case 1 with karyotype 46,XY,t(1;17)(q42.1;q24.3) has characteristic symptoms of CD, including mild tibial bowing, cryptorchidism and hypospadias. By standard fluorescence in situ hybridization (FISH) and by high-resolution fiber FISH, the 17q breakpoint was mapped 375 kb from SOX9, defining the centromeric border of the proximal breakpoint cluster region. Case 2 with karyotype 46,X,t(Y;17)(q11.2;q24.3) has the acampomelic form of CD and complete XY sex reversal. By FISH and somatic cell hybrid analysis, the 17q breakpoint was mapped 789 kb from SOX9, defining the telomeric border of the distal breakpoint cluster region. We discuss the structure of the 1 Mb cis-control region upstream of SOX9 and the correlation between the position of the 14 mapped translocation breakpoints with respect to disease severity and XY sex reversal.

Familial testicular germ cell tumor: no associated syndromic pattern identified

PubMed Central

2014-01-01

Background Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with genitourinary (GU) tract anomalies have suggested an underlying genetic predisposition. Linkage data have not identified a rare, highly-penetrant, single gene in familial TGCT (FTGCT) cases. Based on its association with congenital GU tract anomalies and suggestions that there is an intrauterine origin to TGCT, we hypothesized the existence of unrecognized dysmorphic features in FTGCT. Methods We evaluated 38 FTGCT individuals and 41 first-degree relatives from 22 multiple-case families with detailed dysmorphology examinations, physician-based medical history and physical examination, laboratory testing, and genitourinary imaging studies. Results The prevalence of major abnormalities and minor variants did not significantly differ between either FTGCT individuals or their first-degree relatives when compared with normal population controls, except for tall stature, macrocephaly, flat midface, and retro-/micrognathia. However, these four traits were not manifest as a constellation of features in any one individual or family. We did detect an excess prevalence of the genitourinary anomalies cryptorchidism and congenital inguinal hernia in our population, as previously described in sporadic TGCT, but no congenital renal, retroperitoneal or mediastinal anomalies were detected. Conclusions Overall, our study did not identify a constellation of dysmorphic features in FTGCT individuals, which is consistent with results of genetic studies suggesting that multiple low-penetrance genes are likely responsible for FTGCT susceptibility. PMID:24559313

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steinberg, L.S.; Bleiman, M.; Punnett, H.H.

Features consistent among reported patients with 2q duplications due to familial translocations or de novo duplications include pre- and postnatal growth failure, ocular defects such as congenital glaucoma, cardiac defects, micrognathia, urogenital defects, renal defects, connective tissue laxity, neurologic defects, and dermatologic abnormalities. Genotype/phenotype correlations of patients with trisomy 2q due to familial translocations are complicated by the presence of the deletions of the other chromosome involved. We have had the opportunity to observe `pure` trisomy 2q31-qter resulting from adjacent-1 segregation from 46,XX,t(2;22)(q31;p12) in a carrier mother with apparent loss of the 22 NOR region. He was the 2453 gmmore » product of a gestation complicated by gestational diabetes to a 29-year-old G1 P0 mother and a 30-year-old father. At birth, he was noted to have hypotonia, micrognathia, microphthalmia, left cryptorchidism, hypospadias, bilateral clinodactyly of the fifth digits, mild hyperextensibility of the joints, dry skin disorder, and bilateral hydronephrosis by ultrasound. He was treated for hypoglycemia in the nursery and had a vesicostomy at two months for vesicoureteral reflux. A hearing test at two months found moderate hearing loss in the right ear and mild to moderate hearing loss in the left ear. At 3 months he had surgery for a PDA and bilateral glaucoma and was treated for periods of hypothermia and type IV renal tubular acidosis. This patient and others with unbalanced translocations involving the NOR region of an acrocentric chromosome allow for genotype/phenotype correlation of the `pure` trisomic region.« less

High frequency of association of rheumatic/autoimmune diseases and untreated male hypogonadism with severe testicular dysfunction

PubMed Central

Jimenez-Balderas, F Javier; Tapia-Serrano, Rosario; Fonseca, M Eugenia; Arellano, Jorge; Beltran, Arturo; Yañez, Patricia; Camargo-Coronel, Adolfo; Fraga, Antonio

2001-01-01

Our goal in the present work was to determine whether male patients with untreated hypogonadism have an increased risk of developing rheumatic/autoimmune disease (RAD), and, if so, whether there is a relation to the type of hypogonadism. We carried out neuroendocrine, genetic, and rheumatologic investigations in 13 such patients and 10 healthy male 46,XY normogonadic control subjects. Age and body mass index were similar in the two groups. Nine of the 13 patients had hypergonadotropic hypogonadism (five of whom had Klinefelter's syndrome [karyotype 47,XXY]) and 4 of the 13 had hypogonadotropic hypogonadism (46,XY). Of these last four, two had Kallmann's syndrome and two had idiopathic cryptorchidism. Eight (61%) of the 13 patients studied had RADs unrelated to the etiology of their hypogonadism. Of these, four had ankylosing spondylitis and histocompatibility B27 antigen, two had systemic lupus erythematosus (in one case associated with antiphospholipids), one had juvenile rheumatoid arthritis, and one had juvenile dermatomyositis. In comparison with the low frequencies of RADs in the general population (about 0.83%, including systemic lupus erythematosus, 0.03%; dermatomyositis, 0.04%; juvenile rheumatoid arthritis, 0.03%; ankylosing spondylitis, 0.01%; rheumatoid arthritis, 0.62%; and other RAD, 0.1%), there were surprisingly high frequencies of such disorders in this small group of patients with untreated hypogonadism (P < 0.001) and very low serum testosterone levels (P = 0.0005). The presence of RADs in these patients was independent of the etiology of their hypogonadism and was associated with marked gonadal failure with very low testosterone levels. PMID:11714390

Population characteristics of feral cats admitted to seven trap-neuter-return programs in the United States.

PubMed

Wallace, Jennifer L; Levy, Julie K

2006-08-01

Internationally, large populations of feral cats constitute an important and controversial issue due to their impact on cat overpopulation, animal welfare, public health, and the environment, and to disagreement about what are the best methods for their control. Trap-neuter-return (TNR) programs are an increasingly popular alternative to mass euthanasia. The objective of this study was to determine the population characteristics of feral cats admitted to large-scale TNR programs from geographically diverse locations in the United States. Data from 103,643 feral cats admitted to TNR programs from 1993 to 2004 were evaluated. All groups reported more intact females (53.4%) than intact males (44.3%); only 2.3% of the cats were found to be previously sterilized. Overall, 15.9% of female cats were pregnant at the time of surgery. Pregnancy was highly seasonal and peaked between March and April for all of the groups. The average prenatal litter size was 4.1+/-0.1 fetuses per litter. Cryptorchidism was observed in 1.3% of male cats admitted for sterilization. A total of 0.4% of cats was euthanased because of the presence of debilitating conditions, and 0.4% died during the TNR clinics. Remarkably similar populations of cats with comparable seasonal variability were seen at each program, despite their wide geographical distribution. These results suggest that it is feasible to safely sterilize large numbers of feral cats and that the experiences of existing programs are a consistent source of information upon which to model new TNR programs.

Fatal haemorrhage and neoplastic thrombosis in a captive African lion (Panthera leo) with metastatic testicular sex cord-stromal tumour.

PubMed

Gonzales-Viera, Omar Antonio; Sánchez-Sarmiento, Angélica María; Fernandes, Natália Coelho Couto de Azevedo; Guerra, Juliana Mariotti; Ressio, Rodrigo Albergaria; Catão-Dias, José Luiz

2017-10-13

The study of neoplasia in wildlife species contributes to the understanding of cancer biology, management practices, and comparative pathology. Higher frequencies of neoplasms among captive non-domestic felids have been reported most commonly in aging individuals. However, testicular tumours have rarely been reported. This report describes a metastatic testicular sex cord-stromal tumour leading to fatal haemorrhage and thrombosis in a captive African lion (Panthera leo). During necropsy of a 16-year-old male African lion, the left testicle and spermatic cord were found to be intra-abdominal (cryptorchid), semi-hard and grossly enlarged with multiple pale-yellow masses. Encapsulated haemorrhage was present in the retroperitoneum around the kidneys. Neoplastic thrombosis was found at the renal veins opening into the caudal vena cava. Metastases were observed in the lungs and mediastinal lymph nodes. Histology revealed a poorly differentiated pleomorphic neoplasm comprised of round to polygonal cells and scattered spindle cells with eosinophilic cytoplasm. An immunohistochemistry panel of inhibin-α, Ki-67, human placental alkaline phosphatase, cytokeratin AE1/AE3, cKit, vimentin and S100 was conducted. Positive cytoplasmic immunolabeling was obtained for vimentin and S100. The gross, microscopic and immunohistochemical findings of the neoplasm were compatible with a poorly differentiated pleomorphic sex cord-stromal tumour. Cause of death was hypovolemic shock from extensive retroperitoneal haemorrhage and neoplastic thrombosis may have contributed to the fatal outcome. To our knowledge, this is the first report of sex cord-stromal tumour in non-domestic felids.

Molecular studies of segmental aneusomy: FISHing for the atypical cry in del(5)(p15.3).

PubMed

Hodge, J C; Lawson-Yuen, A; Stoler, J M; Ligon, A H

2007-01-01

We report a newborn male with multiple congenital anomalies including growth retardation, hypotonia, dysmorphic facies, widely-spaced nipples, micropenis, cryptorchidism, optic nerve hypoplasia, heart disease, and a striking, high-pitched cry. Chromosome analysis revealed de novo partial trisomy 11q due to a der(5)t(5;11)(p15.3;q22). Fluorescence in situ hybridization (FISH) showed loss of the 5p telomere signal on the der(5) chromosome, indicating the infant has partial monosomy 5p in addition to partial trisomy 11q. Among cases involving trisomy 11q, an unusual cry has only been documented in the presence of a der(5)t(5p;11q). This apparent dependence of the abnormal cry on monosomy 5p suggested the same genetic mechanism that occurs in Cri du chat syndrome (CDCS) may be responsible for the atypical cry in der(5)t(5p;11q) individuals. Neither a commercial CDCS probe (LSI D5S23, D5S721) nor a series of BAC clones encompassing distal regions implicated in the CDCS-associated cat-cry were deleted in our patient. These results suggest a second cry-modifying locus maps telomeric to BAC RP11-94J21 in band 5p15.33. This locus may not only cause the abnormal cry in individuals with a der(5)t(5p;11q) but could also contribute to the phenotypic variability and discordant mapping studies observed for CDCS. Copyright (c) 2007 S. Karger AG, Basel.

Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility

PubMed Central

Skakkebaek, Niels E.; Rajpert-De Meyts, Ewa; Buck Louis, Germaine M.; Toppari, Jorma; Andersson, Anna-Maria; Eisenberg, Michael L.; Jensen, Tina Kold; Jørgensen, Niels; Swan, Shanna H.; Sapra, Katherine J.; Ziebe, Søren; Priskorn, Lærke; Juul, Anders

2015-01-01

It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography. PMID:26582516

[Septo-optic dysplasia].

PubMed

Martínez-Sánchez, L; Arce, A; Caritg-Bosch, J; Campistol, J; Pavía, C; Gean-Molins, E

Septo optic syndrome, described by De Morsier in 1956, consists in the hypoplasia of one or both optic nerves, mid line brain malformations and hypothalamohypophysial dysfunction, which is inconstant. It is an infrequent, but treatable, cause of hepatic and neurological damage, and it is important to obtain an early diagnosis and to begin hormone replacement therapy. We report the clinical case of a female baby who was diagnosed early on as suffering from septo?optic dysplasia, after discovery of the existence of cholestatic jaundice. In our case the three components of the syndrome were present: hypothalamohypophysial dysfunction, bilateral hypoplasia of the optic nerves and brain malformations with dysplasia of the transparent septum. All this gives rise to complex clinical features and the predominance of hypernatraemic dehydration secondary to insipid diabetes, nystagmus and serious psychomotor retardation. Our patient died, as in other cases reported in the literature, from an episode of sudden death. Despite the importance of an early diagnosis of this disorder, it is usually late. Most children who present hypopituitarism traits in the neonatal period are not diagnosed at that time, with the subsequent risk of death or brain damage. Some clinical findings, which appear early on and can provide clues which aid us to reach a diagnosis, are the appearance of episodes of hypoglycaemia in the neonatal period, the existence of micropenis and cryptorchidism with hypoplasic testes, jaundice or the appearance of clinical manifestations of insipid diabetes. Later on nystagmus and neurological symptoms may appear. The final diagnosis is performed through the use of neuroimaging techniques (CT or MRI) and hormonal studies.

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations

PubMed Central

Villanueva, Carine; Jacobson-Dickman, Elka; Xu, Cheng; Manouvrier, Sylvie; Dwyer, Andrew A.; Sykiotis, Gerasimos P.; Beenken, Andrew; Liu, Yang; Tommiska, Johanna; Hu, Youli; Tiosano, Dov; Gerard, Marion; Leger, Juliane; Drouin-Garraud, Valérie; Lefebvre, Hervé; Polak, Michel; Carel, Jean-Claude; Phan-Hug, Franziska; Hauschild, Michael; Plummer, Lacey; Rey, Jean-Pierre; Raivio, Taneli; Bouloux, Pierre; Sidis, Yisrael; Mohammadi, Moosa; de Roux, Nicolas; Pitteloud, Nelly

2014-01-01

Purpose Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising CHH and SHFM. Methods We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions, and/or functional assays. Results We identified 8 probands with CHH with (n=3, Kallmann Syndrome) or without anosmia (n=5) and SHFM, 7 of whom (88%) harbor FGFR1 mutations: one individual is homozygous for p.V429E; six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, and p.L712P. All mutations were predicted to be loss-of-function by in silico analysis. Probands with FGFR1 mutations have severe GnRH deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was only observed in the patient with the homozygous p.V429E mutation; V429 maps to the FRS2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of FRS2α to FG FR 1 , thereby resulting in reduced MAPK signaling. Conclusion FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM, because the likelihood of a mutation increases from 10% in the general CHH population to 88%. PMID:25394172

GESTATIONAL AGE AT BIRTH AND RISK OF TESTICULAR CANCER

PubMed Central

Crump, Casey; Sundquist, Kristina; Winkleby, Marilyn A.; Sieh, Weiva; Sundquist, Jan

2011-01-01

Most testicular germ cell tumors originate from carcinoma in situ cells in fetal life, possibly related to sex hormone imbalances in early pregnancy. Previous studies of association between gestational age at birth and testicular cancer have yielded discrepant results and have not examined extreme preterm birth. Our objective was to determine whether low gestational age at birth is independently associated with testicular cancer in later life. We conducted a national cohort study of 354,860 men born in Sweden in 1973–1979, including 19,214 born preterm (gestational age <37 weeks) of whom 1,279 were born extremely preterm (22–29 weeks), followed for testicular cancer incidence through 2008. A total of 767 testicular cancers (296 seminomas and 471 nonseminomatous germ cell tumors) were identified in 11.2 million person-years of follow-up. Extreme preterm birth was associated with an increased risk of testicular cancer (hazard ratio 3.95; 95% CI, 1.67–9.34) after adjusting for other perinatal factors, family history of testicular cancer, and cryptorchidism. Only five cases (three seminomas and two nonseminomas) occurred among men born extremely preterm, limiting the precision of risk estimates. No association was found between later preterm birth, post-term birth, or low or high fetal growth and testicular cancer. These findings suggest that extreme but not later preterm birth may be independently associated with testicular cancer in later life. They are based on a small number of cases and will need confirmation in other large cohorts. Elucidation of the key prenatal etiologic factors may potentially lead to preventive interventions in early life. PMID:22314417

Maternal hormone levels and risk of cryptorchism among populations at high and low risk of testicular germ cell tumors.

PubMed

McGlynn, Katherine A; Graubard, Barry I; Nam, Jun-Mo; Stanczyk, Frank Z; Longnecker, Matthew P; Klebanoff, Mark A

2005-07-01

Cryptorchism is one of the few well-described risk factors for testicular cancer. It has been suggested that both conditions are related to increased in utero estrogen exposure. The evidence supporting the "estrogen hypothesis" has been inconsistent, however. An alternative hypothesis suggests that higher in utero androgen exposure may protect against the development of cryptorchism and testicular cancer. In order to examine both hypotheses, we studied maternal hormone levels in two populations at diverse risks of testicular cancer; Black Americans (low-risk) and White Americans (high-risk). The study population of 200 mothers of cryptorchid sons and 200 mothers of noncryptorchid sons was nested within the Collaborative Perinatal Project, a cohort study of pregnant women and their children. Third trimester serum levels of estradiol (total, free, bioavailable), estriol, testosterone (total, free, bioavailable), sex hormone-binding globulin, alpha-fetoprotein, and the ratios of estradiols to testosterones were compared between the case and control mothers. The results found no significant differences in the levels of testosterone (total, free, bioavailable), alpha-fetoprotein, sex hormone-binding globulin, or in the ratios of estrogens to androgens. Total estradiol, however, was significantly lower in the cases versus the controls (P = 0.03) among all mothers and, separately, among White mothers (P = 0.05). Similarly, estriol was significantly lower among all cases (P = 0.05) and among White cases (P = 0.05). These results do not support either the estrogen or the androgen hypothesis. Rather, lower estrogens in case mothers may indicate that a placental defect increases the risk of cryptorchism and, possibly, testicular cancer.

Urogenital involvement in the Klippel-Trenaunay-Weber syndrome. Treatment options and results.

PubMed

Vicentini, Fabio C; Denes, Francisco T; Gomes, Cristiano M; Danilovic, Alexandre; Silva, Frederico A; Srougi, Miguel

2006-01-01

Klippel-Trenaunay-Weber syndrome (KTWS) is a congenital condition characterized by vascular malformations of the capillary, venous and lymphatic systems associated to soft tissue and bone hypertrophy in the affected areas. This syndrome may involve bladder, kidney, urethra, ureter and genitals. We report the treatment of 7 KTWS patients with urogenital involvement. From 1995 to 2005, 7 patients with KTWS were evaluated and the charts of these patients were reviewed. Patients' median age was 19-years (range 4 to 46-years) and only 1 was female. The clinical presentation included genital deformities in 3 cases, hematuria in 2 and urethrorragia in 2, one of which associated with cryptorchidism and phimosis. Three patients had an association of pelvic and genital malformations, including 2 patients with hematuria due to vesical lesions and 1 patient with left ureterohydronephrosis due to a pelvic mass. Two patients had urethral lesions. Treatment included endoscopic laser coagulation for 1 patient with recurrent hematuria and 1 patient with urethrorrhagia, pelvic radiotherapy for 1 patient with hematuria and circumcision in 2 patients with genital deformities. One patient required placement of a double-J catheter to relieve obstruction. Hematuria and urethrorragia were safely and effectively controlled with laser applications. Circumcision was also effective. The patient treated with radiotherapy developed a contracted bladder and required a continent urinary diversion. Urogenital involvement in patients with KTWS is not rare and must be suspected in the presence of hematuria or significant cutaneous deformity of the external genitalia. Surgical treatment may be warranted in selected cases.

Chronic pain in Noonan Syndrome: A previously unreported but common symptom.

PubMed

Vegunta, Sravanthi; Cotugno, Richard; Williamson, Amber; Grebe, Theresa A

2015-12-01

Noonan syndrome (NS) is a multiple malformation syndrome characterized by pulmonic stenosis, cardiomyopathy, short stature, lymphatic dysplasia, craniofacial anomalies, cryptorchidism, clotting disorders, and learning disabilities. Eight genes in the RAS/MAPK signaling pathway are implicated in NS. Chronic pain is an uncommon feature. To investigate the prevalence of pain in NS, we distributed a two-part questionnaire about pain among NS individuals at the Third International Meeting on Genetic Syndromes of the Ras/MAPK Pathway. The first part of the questionnaire queried demographic information among all NS participants. The second part was completed by individuals with chronic pain. Questions included musculoskeletal problems and clinical features of pain. Forty-five questionnaires were analyzed; 53% of subjects were female. Mean age was 17 (2-48) years; 47% had a PTPN11 mutation. Sixty-two percent (28/45) of individuals with NS experienced chronic pain. There was a significant relationship between prevalence of pain and residing in a cold climate (P = 0.004). Pain occurred commonly in extremities/joints and head/trunk, but more commonly in extremities/joints (P = 0.066). Subjects with hypermobile joints were more likely to have pain (P = 0.052). Human growth hormone treatment was not statistically significant among subjects without chronic pain (P = 0.607). We conclude that pain is a frequent and under-recognized clinical feature of NS. Chronic pain may be associated with joint hypermobility and aggravated by colder climate. Our study is a preliminary investigation that should raise awareness about pain as a common symptom in children and adults with NS. © 2015 Wiley Periodicals, Inc.

Constitutional bone impairment in Noonan syndrome.

PubMed

Baldassarre, Giuseppina; Mussa, Alessandro; Carli, Diana; Molinatto, Cristina; Ferrero, Giovanni Battista

2017-03-01

Noonan syndrome (NS) is an autosomal dominant trait characterized by genotypic and phenotypic variability. It belongs to the Ras/MAPK pathway disorders collectively named Rasopathies or neurocardiofaciocutaneous syndromes. Phenotype is characterized by short stature, congenital heart defects, facial dysmorphisms, skeletal and ectodermal anomalies, cryptorchidism, mild to moderate developmental delay/learning disability, and tumor predisposition. Short stature and skeletal dysmorphisms are almost constant and several studies hypothesized a role for the RAS pathway in regulating bone metabolism. In this study, we investigated the bone quality assessed by phalangeal quantitative ultrasound (QUS) and the metabolic bone profiling in a group of patients with NS, to determine whether low bone mineralization is primary or secondary to NS characteristics. Thirty-five patients were enrolled, including 20 males (55.6%) and 15 females (44.5%) aged 1.0-17.8 years (mean 6.4 ± 4.5, median 4.9 years). Each patients was submitted to clinical examination, estimation of the bone age, laboratory assays, and QUS assessment. Twenty-five percent of the cohort shows reduced QUS values for their age based on bone transmission time. Bone measurement were adjusted for multiple factors frequently observed in NS patients, such as growth retardation, delayed bone age, retarded puberty, and reduced body mass index, potentially affecting bone quality or its appraisal. In spite of the correction attempts, QUS measurement indicates that bone impairment persists in nearly 15% of the cohort studied. Our results indicate that bone impairment in NS is likely primary and not secondary to any of the phenotypic traits of NS, nor consistent with metabolic disturbances. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Behavioural phenotypes associated with specific genetic disorders: evidence from a population-based study of people with Prader-Willi syndrome.

PubMed

Holland, A J; Whittington, J E; Butler, J; Webb, T; Boer, H; Clarke, D

2003-01-01

Prader-Willi syndrome (PWS) is a genetic disorder resulting in obesity, short stature, cryptorchidism, learning disabilities (mental retardation) and severe neonatal hypotonia. Associated with the syndrome are a number of behaviours that are sufficiently distinctive that the syndrome is considered to have a specific 'behavioural phenotype'. Through multiple sources we attempted to identify all people with PWS living in one region in the U K. This cohort was augmented by people with PWS from other regions, and a contrast group of people with learning disabilities of varied aetiologies. The main carers were interviewed, using structured and semi-structured interview schedules, to establish the presence and severity of specific behaviours, and PWS diagnostic criteria. The intellectual functioning and attainments of all were determined. Blood samples were obtained for genetic diagnosis from all consenting participants. Although excessive eating was recognized as a potentially severe problem in those with PWS, it was almost universally controlled by food restriction, and therefore not seen as a 'problem behaviour'. Those with PWS differed from a learning disabled group of other aetiologies in the prevalence rates of skin picking, temper tantrums, compulsive behaviours and mood fluctuations, and also in the profile of their adaptive behaviours. The study confirms the distinct behavioural phenotype of PWS. Specific behaviours occurred significantly more frequently in PWS, compared with an age and BMI matched learning disabled comparison group. A factor analysis of the behaviours involved resulted in three factors that we hypothesized to be independent, and to arise from different mechanisms.

Exposure to metal-working fluids in the automobile industry and the risk of male germ cell tumours.

PubMed

Behrens, Thomas; Pohlabeln, Hermann; Mester, Birte; Langner, Ingo; Schmeisser, Nils; Ahrens, Wolfgang

2012-03-01

In a previous analysis of a case-control study of testicular cancer nested in a cohort of automobile workers, we observed an increased risk for testicular cancer among workers who had ever been involved in occupational metal-cutting tasks. We investigated whether this risk increase was due to exposure to metal-working fluids (MWF). Occupational exposure to MWF was assessed in detail using a job-specific questionnaire for metal-cutting work. We calculated ORs and associated 95% CIs individually matched for age (±2 years) and adjusted for a history of cryptorchidism by conditional logistic regression. The prevalence of exposure to MWF was 39.8% among cases and 40.1% among controls. For total germ cell tumours and seminomas we did not observe risk increases for metal-cutting tasks or occupational exposure to MWF (OR 0.95; 95% CI 0.69 to 1.32 and OR 0.88; 95% CI 0.58 to 1.35, respectively). However, dermal exposure to oil-based MWF was associated with an increased risk for non-seminomatous testicular cancer. Dermal exposure to oil-based MWF for more than 5000 h showed particularly high risk estimates (OR 4.72; 95% CI 1.48 to 15.09). Long-term dermal exposure to oil-based MWF was a risk factor for the development of non-seminomatous testicular germ cell cancer. Possible measures to reduce exposure include the introduction of engineering control measures such as venting or enclosing of machines, and enforcing the use of personal protective equipment during metal cutting.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruening, W.; Nakagama, H.: Bardessy, N.

Wilms` tumor (WT), an embryonal malignancy of the kidney, occurs most frequently in children under the age of 5 years, affecting {approximately}1 in 10,000 individuals. The WT1 tumor suppressor gene, residing at 11p13, is structurally altered in {approximately}10-15% of WT cases. Individuals with germline mutations within the WT1 gene suffer from predisposition to WT and developmental defects of the urogenital system. Patients with heterozygous deletions of the WT1 gene, or mutations predicted to cause inactivation of one WT1 allele, suffer relatively mild genital system defects (notably hypospadias and cryptorchidism in males) and a predisposition to WT. These results suggest thatmore » developing genital system development is sensitive to the absolute concentrations of the WT1 gene products. Patients with missense mutations within the WT1 gene, however, can suffer from a much more severe disorder known as Denys-Drash syndrome (DDS). This syndrome is characterized by intersex disorders, renal nephropathy, and a predisposition to WTs. The increased severity of the developmental defects associated with DDS, compared to those individuals with mild genital system anomalies and WTs, suggests that mutations defined in patients with DDS behave in a dominant-negative fashion. We have identified a novel WT1 mutation in a patient with DDS. This mutation, predicted to produce a truncated WT1 polypeptide encompassing exons 1, 2, and 3, defines a domain capable of behaving as an antimorph. We have also demonstrated that WT1 can self-associate in vivo using yeast two-hybrid systems. Deletion analysis have mapped the interacting domains to the amino terminus of the WT1 polypeptide, within exons 1 and 2. These results provide a molecular mechanism to explain how WT1 mutations can function in a dominant-negative fashion to eliminate wild-type WT1 activity, leading to DDS.« less

Prenatal Anogenital Distance Is Shorter in Fetuses With Hypospadias.

PubMed

Gilboa, Yinon; Perlman, Sharon; Kivilevitch, Zvi; Messing, Baruch; Achiron, Reuven

2017-01-01

Recent research provides evidence that anogenital distance may serve as a novel metric to assess reproductive potential in men. In children, a shorter anogenital distance was linked with cryptorchidism, hypospadias, and micropenis. Scarce data exist in the literature regarding anogenital distance measurement in the fetus. The aim of our study was to assess whether intrauterine measurement of fetal anogenital distance could assist in the differential diagnosis of male genital anomalies. Anogenital distance was prospectively measured in all cases referred for suspected isolated abnormal male genitalia. Final diagnoses, confirmed by a pediatric urologist, were compared with anogenital distance prenatal measurements. Fifty-two cases were referred for evaluation because of suspected male external genital malformation during a 12-month period. Cases with normal-appearing genitalia, associated major malformations, and early severe fetal growth restriction were excluded from the study. Postnatal examination revealed 14 cases of hypospadias in varying severity and 8 cases of a buried penis. All fetuses with hypospadias had an anogenital distance measurement below the fifth percentile. Statistical analysis revealed a significant difference between the normal mean anogenital distance for gestational age versus those with hypospadias (mean ± SD, 16.90 ± 4.08 and 11.68 ± 3.31 mm, respectively; P = .001). No significant difference was found between the normal mean anogenital distance for gestational age versus those with a buried penis (18.85 ± 2.76 and 19.46 ± 3.41 mm; P = .700). Fetuses with hypospadias have a statistically significant shorter anogenital distance compared with the general population. Therefore, anogenital distance may serve as a complementary objective sonographic parameter in the prenatal assessment and counseling of male external genital anomalies. © 2016 by the American Institute of Ultrasound in Medicine.

Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis.

PubMed

Mathew, R M; Vandenberghe, R; Garcia-Merino, A; Yamamoto, T; Landolfi, J C; Rosenfeld, M R; Rossi, J E; Thiessen, B; Dropcho, E J; Dalmau, J

2007-03-20

To report the presence of microscopic neoplasms of the testis in men with anti-Ma2-associated encephalitis (Ma2-encephalitis) and to discuss the clinical implications. Orchiectomy specimens were examined using immunohistochemistry with Ma2 and Oct4 antibodies. Among 25 patients with Ma2-encephalitis younger than 50 years, 19 had germ-cell tumors, and 6 had no evidence of cancer. These 6 patients underwent orchiectomy because they fulfilled five criteria: 1) demonstration of anti-Ma2 antibodies in association with MRI or clinical features compatible with Ma2-encephalitis, 2) life-threatening or progressive neurologic deficits, 3) age < 50 years, 4) absence of other tumors, and 5) new testicular enlargement or risk factors for germ-cell tumors, mainly cryptorchidism or ultrasound evidence of testicular microcalcifications. All orchiectomy specimens showed intratubular-germ cell neoplasms unclassified type (IGCNU) and other abnormalities including microcalcifications, atrophy, fibrosis, inflammatory infiltrates, or hypospermatogenesis. Ma2 was expressed by neoplastic cells in three of three patients examined. Even though most patients had severe neurologic deficits at the time of orchiectomy (median progression of symptoms, 10 months), 4 had partial improvement and prolonged stabilization (8 to 84 months, median 22.5 months) and two did not improve after the procedure. In young men with Ma2-encephalitis, 1) the disorder should be attributed to a germ-cell neoplasm of the testis unless another Ma2-expressing tumor is found, 2) negative tumor markers, ultrasound, body CT, or PET do not exclude an intratubular germ-cell neoplasm of the testis, and 3) if no tumor is found, the presence of the five indicated criteria should prompt consideration of orchiectomy.

Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis

PubMed Central

Mathew, R.M.; Vandenberghe, R.; Garcia-Merino, A.; Yamamoto, T.; Landolfi, J.C.; Rosenfeld, M.R.; Rossi, J.E.; Thiessen, B.; Dropcho, E.J.; Dalmau, J.

2007-01-01

Objective: To report the presence of microscopic neoplasms of the testis in men with anti-Ma2-associated encephalitis (Ma2-encephalitis) and to discuss the clinical implications. Methods: Orchiectomy specimens were examined using immunohistochemistry with Ma2 and Oct4 antibodies. Results: Among 25 patients with Ma2-encephalitis younger than 50 years, 19 had germ-cell tumors, and 6 had no evidence of cancer. These 6 patients underwent orchiectomy because they fulfilled five criteria: 1) demonstration of anti-Ma2 antibodies in association with MRI or clinical features compatible with Ma2-encephalitis, 2) life-threatening or progressive neurologic deficits, 3) age < 50 years, 4) absence of other tumors, and 5) new testicular enlargement or risk factors for germ-cell tumors, mainly cryptorchidism or ultrasound evidence of testicular microcalcifications. All orchiectomy specimens showed intratubular-germ cell neoplasms unclassified type (IGCNU) and other abnormalities including microcalcifications, atrophy, fibrosis, inflammatory infiltrates, or hypospermatogenesis. Ma2 was expressed by neoplastic cells in three of three patients examined. Even though most patients had severe neurologic deficits at the time of orchiectomy (median progression of symptoms, 10 months), 4 had partial improvement and prolonged stabilization (8 to 84 months, median 22.5 months) and two did not improve after the procedure. Conclusions: In young men with Ma2-encephalitis, 1) the disorder should be attributed to a germ-cell neoplasm of the testis unless another Ma2-expressing tumor is found, 2) negative tumor markers, ultrasound, body CT, or PET do not exclude an intratubular germ-cell neoplasm of the testis, and 3) if no tumor is found, the presence of the five indicated criteria should prompt consideration of orchiectomy. PMID:17151337

Long-term (6-wk) hindlimb suspension inhibits spermatogenesis in adult male rats

NASA Technical Reports Server (NTRS)

Tash, Joseph S.; Johnson, Donald C.; Enders, George C.

2002-01-01

The International Space Station will allow extended habitation in space and long-term exposure to microgravity (microG). A concern is the impact of long-term microG exposure on the ability of species to reproduce. The model often used to simulate microG is rat hindlimb suspension (HLS), where the hindlimbs are elevated above the cage floor with a tail harness. Experiments described here are the first to examine the effect of long-term HLS on testicular function in adult male rats. Free-roaming (controls), animals with only the tail harnessed but hindlimbs in contact with the cage floor (TO), and HLS animals were tested for 6 wk. Cryptorchidism was prevented in TO and HLS animals by partial constriction of the inguinal canal with sutures. All parameters were compared at the end of the 6-wk experiment. Testicular weights and spermatogenesis were significantly reduced by HLS, such that no spermatogenic cells beyond round spermatids were present and epididymides were devoid of mature sperm. In many tubules, loss of all germ cells, except a few spermatogonia, resulting in histopathology similar to the Sertoli cell, was observed. Spermatogenesis appeared unaffected in control and TO animals. Sertoli and Leydig cell appearance, testosterone, luteinizing hormone, and follicle-stimulating hormone levels, and epididymal and seminal vesicle weight were unchanged by HLS. Cortisone was not elevated by HLS; thus stress may not be a factor. These results demonstrate that spermatogenesis is severely inhibited by long-term HLS, whereas testicular androgen production is not. These results have significant implications regarding serious effects of long-term exposure to microG on the reproductive capability of scrotal mammals, including humans.

Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis.

PubMed

Trasande, L; Zoeller, R T; Hass, U; Kortenkamp, A; Grandjean, P; Myers, J P; DiGangi, J; Hunt, P M; Rudel, R; Sathyanarayana, S; Bellanger, M; Hauser, R; Legler, J; Skakkebaek, N E; Heindel, J J

2016-07-01

A previous report documented that endocrine disrupting chemicals contribute substantially to certain forms of disease and disability. In the present analysis, our main objective was to update a range of health and economic costs that can be reasonably attributed to endocrine disrupting chemical exposures in the European Union, leveraging new burden and disease cost estimates of female reproductive conditions from accompanying report. Expert panels evaluated the epidemiologic evidence, using adapted criteria from the WHO Grading of Recommendations Assessment, Development and Evaluation Working Group, and evaluated laboratory and animal evidence of endocrine disruption using definitions recently promulgated by the Danish Environmental Protection Agency. The Delphi method was used to make decisions on the strength of the data. Expert panels consensus was achieved for probable (>20%) endocrine disrupting chemical causation for IQ loss and associated intellectual disability; autism; attention deficit hyperactivity disorder; endometriosis; fibroids; childhood obesity; adult obesity; adult diabetes; cryptorchidism; male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation, and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median annual cost of €163 billion (1.28% of EU Gross Domestic Product) across 1000 simulations. We conclude that endocrine disrupting chemical exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those endocrine disrupting chemicals with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs. © 2016 American Society of Andrology and European Academy of Andrology.

Four small supernumerary marker chromosomes derived from chromosomes 6, 8, 11 and 12 in a patient with minimal clinical abnormalities: a case report

PubMed Central

2010-01-01

Introduction Small supernumerary marker chromosomes are still a problem in cytogenetic diagnostic and genetic counseling. This holds especially true for the rare cases with multiple small supernumerary marker chromosomes. Most such cases are reported to be clinically severely affected due to the chromosomal imbalances induced by the presence of small supernumerary marker chromosomes. Here we report the first case of a patient having four different small supernumerary marker chromosomes which, apart from slight developmental retardation in youth and non-malignant hyperpigmentation, presented no other clinical signs. Case presentation Our patient was a 30-year-old Caucasian man, delivered by caesarean section because of macrosomy. At birth he presented with bilateral cryptorchidism but no other birth defects. At age of around two years he showed psychomotor delay and a bilateral convergent strabismus. Later he had slight learning difficulties, with normal social behavior and now lives an independent life as an adult. Apart from hypogenitalism, he has multiple hyperpigmented nevi all over his body, short feet with pes cavus and claw toes. At age of 30 years, cytogenetic and molecular cytogenetic analysis revealed a karyotype of 50,XY,+min(6)(:p11.1-> q11.1:),+min(8)(:p11.1->q11.1:),+min(11)(:p11.11->q11:),+min(12)(:p11.2~12->q10:), leading overall to a small partial trisomy in 12p11.1~12.1. Conclusions Including this case, four single case reports are available in the literature with a karyotype 50,XN,+4mar. For prenatally detected multiple small supernumerary marker chromosomes in particular we learn from this case that such a cytogenetic condition may be correlated with a positive clinical outcome. PMID:20682055

Meier–Gorlin syndrome genotype–phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis

PubMed Central

de Munnik, Sonja A; Bicknell, Louise S; Aftimos, Salim; Al-Aama, Jumana Y; van Bever, Yolande; Bober, Michael B; Clayton-Smith, Jill; Edrees, Alaa Y; Feingold, Murray; Fryer, Alan; van Hagen, Johanna M; Hennekam, Raoul C; Jansweijer, Maaike C E; Johnson, Diana; Kant, Sarina G; Opitz, John M; Ramadevi, A Radha; Reardon, Willie; Ross, Alison; Sarda, Pierre; Schrander-Stumpel, Constance T R M; Schoots, Jeroen; Temple, I Karen; Terhal, Paulien A; Toutain, Annick; Wise, Carol A; Wright, Michael; Skidmore, David L; Samuels, Mark E; Hoefsloot, Lies H; Knoers, Nine V A M; Brunner, Han G; Jackson, Andrew P; Bongers, Ernie M H F

2012-01-01

Meier–Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype–phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months–47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42% predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype–phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed. PMID:22333897

[Correction of early cognitive disorders in school-age children operated under total intravenous anaesthesia].

PubMed

Ovezov, A M; Lobov, M A; Panteleeva, M V; Lugovoĭ, A V; Miatchin, P S; Gus'kov, I E

2012-01-01

The aim of the study was to assess the possibility and effectiveness of hopaten acid use for early postoperative cognitive dysfunction correction in children of school age. In compliance with inclusion and exclusion criteria, totally 40 children of school age (7-16 years old, ASA status I-II) with surgical pathology: (varicocele, cryptorchidism, inguinal hernia) were included A comperative assessment of neuropsychic status during pre - and postoperative are period in children, operated under propofol-fentanyl total intravenous anesthesia (TIVA) was conducted All patients were randomized to the control (without cepebroprotection 1st group, 20 children) and experimental (using cepebroprotection with hopaten acid within 1 month after the operation, 2nd group, 20 children) groups. Dimension of the study: Harvard standard monitoring, respiratory gas composition, neuropsychic tests (Bourdon test, "10 words test", etc.). For full compatibility groups (age, ASA status and anthropometric data, equal operation duration and the equipotential drug dosage adjustment is revealed, that in group of propofol-fentanyl TIVA in the early postoperative period in school age children postoperative cognitive dysfunction (POCD) is developing, which in case of absence of the corresponding correction is maintained after 1 month after operation (at least) in 80% of cases. In the application of hopaten acid cerebroprotection (40 mg/kg per day) severity of POCD reliably is reduced or compensated by the time of discharge from the hospital (3-7-th day when non-traumatic interventions), and 1 month after the operation in 30% of patients experienced improvement of cognitive functions, which proves the effectiveness of hopaten acid for POCD treatment. In case of propofol-fentanyl TIVA anesthesia in children of school age is indicated preventive prescription of multimodal cerebroprotectors without age limitations (for example hopaten acid (40 mg/kg per day) for POCD treatment.

Population-Based Case-Control Study of Recreational Drug Use and Testis Cancer Risk Confirms Association between Marijuana Use and Non-Seminoma Risk

PubMed Central

Lacson, John Charles A.; Carroll, Joshua D.; Tuazon, Ellenie; Castelao, Esteban J.; Bernstein, Leslie; Cortessis, Victoria K.

2013-01-01

Background Testicular germ cell tumor (TGCT) incidence increased steadily in recent decades, but causes remain elusive. Germ cell function may be influenced by cannabinoids, and two prior epidemiologic studies report that use of marijuana may be associated with non-seminomatous TGCT. Here we evaluate the relationship between TGCTs and exposure to marijuana and other recreational drugs using a population-based case-control study. Methods 163 TGCT cases diagnosed in Los Angeles County from December 1986 to April 1991 were enrolled with 292 controls matched on age, race/ethnicity and neighborhood. Participants were asked about drug use by structured in-person interview. Odds ratios and 95% confidence intervals were estimated using conditional logistic regression, adjusted for history of cryptorchidism; education; religiosity; and reported use of marijuana, cocaine and amyl nitrite. Results Compared to never use, ever use of marijuana had two-fold increased risk (OR=1.94, 95%CI: 1.02–3.68) while ever use of cocaine was negatively associated with TGCT (OR=0.54, 95%CI: 0.32–0.91). Stratification on tumor histology revealed a specific association of marijuana use with non-seminoma and mixed histology tumors (OR=2.42, 95%CI: 1.08–5.42). Conclusions We observed a specific association of marijuana use with risk of non-seminoma and mixed tumors. This is the first report of a negative association between cocaine use and TGCT risk. Results warrant mechanistic studies of marijuana’s effect on the endocannabinoid system and TGCT risk, and caution that recreational and therapeutic cannabinoids by young men may confer malignant potential to testicular germ cells. PMID:22965656

A rare 47 XXY/46 XX mosaicism with clinical features of Klinefelter syndrome.

PubMed

Mohd Nor, Noor Shafina; Jalaludin, Muhammad Yazid

2016-01-01

47 XXY/46 XX mosaicism with characteristics suggesting Klinefelter syndrome is very rare and at present, only seven cases have been reported in the literature. We report an Indian boy diagnosed as variant of Klinefelter syndrome with 47 XXY/46 XX mosaicism at age 12 years. He was noted to have right cryptorchidism and chordae at birth, but did not have surgery for these until age 3 years. During surgery, the right gonad was atrophic and removed. Histology revealed atrophic ovarian tissue. Pelvic ultrasound showed no Mullerian structures. There was however no clinical follow up and he was raised as a boy. At 12 years old he was re-evaluated because of parental concern about his 'female' body habitus. He was slightly overweight, had eunuchoid body habitus with mild gynaecomastia. The right scrotal sac was empty and a 2mls testis was present in the left scrotum. Penile length was 5.2 cm and width 2.0 cm. There was absent pubic or axillary hair. Pronation and supination of his upper limbs were reduced and x-ray of both elbow joints revealed bilateral radioulnar synostosis. The baseline laboratory data were LH < 0.1 mIU/ml, FSH 1.4 mIU/ml, testosterone 0.6 nmol/L with raised estradiol, 96 pmol/L. HCG stimulation test showed poor Leydig cell response. The karyotype based on 76 cells was 47 XXY[9]/46 XX[67] with SRY positive. Laparoscopic examination revealed no Mullerian structures. Insisting on an adequate number of cells (at least 50) to be examined during karyotyping is important so as not to miss diagnosing mosaicism.

[Analysis of clinical features and related genes variation in five patients with 46, XX male syndrome].

PubMed

Qin, X Y; Dong, W K; Wang, W; Dong, Z Y; Xiao, Y; Lu, W L; Wang, D F

2016-11-02

Objective: To explore the clinical manifestations and molecular features of 46, XX male syndrome. Method: The clinical and molecular data of five 46, XX male syndrome cases treated in the Department of Pediatrics of Shanghai Ruijin Hospital form August 2010 to August 2014 were retrospectively analyzed. Result: The five patients were all sociopsychologically males and came to hospital respectively for short stature, ambiguous genitalia or gynecomastia. They were all below the normal male's average height, and their karyotype was all 46, XX. One case in five was verified as sex determining region of Y chromosome (SRY gene) positive revealed no abnormality in their external genitalia. He had short stature since childhood, whose SRY gene fragments were shown by FISH transferred to the ends of X chromosome. Three cases in four were SRY gene negative with ambiguous genitalia of cryptorchidism and testicular dysplasia to different degrees. The copy number variations of SOX9 gene was found in one case, the loss of heterozygosity area in DHH gene of one case. Another SRY gene negative patient who had normal male external genitalia, came to the hospital due to puberty gynecomastia, that of SOX9 gene and its upstream gene both increased. Conclusion: The main clinical characteristics of 46, XX male syndrome are male phenotype, 46, XX karyotype, gonad of testis or ovotestis and no uterus. In addition, short stature, ambiguous genitalia or gynecomastia can be one reason for hospital visits. SRY gene translocation, SOX9 gene and its upstream gene copy number increase all can lead to 46, XX male syndrome. The cause of some may play an important role in 46, XX male syndrome, but has not yet been determined.

The thermo-sensitive gene expression signatures of spermatogenesis.

PubMed

Yadav, Santosh K; Pandey, Aastha; Kumar, Lokesh; Devi, Archana; Kushwaha, Bhavana; Vishvkarma, Rahul; Maikhuri, Jagdamba P; Rajender, Singh; Gupta, Gopal

2018-06-02

Spermatogenesis in most mammals (including human and rat) occurs at ~ 3 °C lower than body temperature in a scrotum and fails rapidly at 37 °C inside the abdomen. The present study investigates the heat-sensitive transcriptome and miRNAs in the most vulnerable germ cells (spermatocytes and round spermatids) that are primarily targeted at elevated temperature in a bid to identify novel targets for contraception and/or infertility treatment. Testes of adult male rats subjected to surgical cryptorchidism were obtained at 0, 24, 72 and 120 h post-surgery, followed by isolation of primary spermatocytes and round spermatids and purification to > 90% purity using a combination of trypsin digestion, centrifugal elutriation and density gradient centrifugation techniques. RNA isolated from these cells was sequenced by massive parallel sequencing technique to identify the most-heat sensitive mRNAs and miRNAs. Heat stress altered the expression of a large number of genes by ≥2.0 fold, out of which 594 genes (286↑; 308↓) showed alterations in spermatocytes and 154 genes (105↑; 49↓) showed alterations in spermatids throughout the duration of experiment. 62 heat-sensitive genes were common to both cell types. Similarly, 66 and 60 heat-sensitive miRNAs in spermatocytes and spermatids, respectively, were affected by ≥1.5 fold, out of which 6 were common to both the cell types. The study has identified Acly, selV, SLC16A7(MCT-2), Txnrd1 and Prkar2B as potential heat sensitive targets in germ cells, which may be tightly regulated by heat sensitive miRNAs rno-miR-22-3P, rno-miR-22-5P, rno-miR-129-5P, rno-miR-3560, rno-miR-3560 and rno-miR-466c-5P.

Meier-Gorlin syndrome.

PubMed

de Munnik, Sonja A; Hoefsloot, Elisabeth H; Roukema, Jolt; Schoots, Jeroen; Knoers, Nine V A M; Brunner, Han G; Jackson, Andrew P; Bongers, Ernie M H F

2015-09-17

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia in females and urogenital anomalies, such as cryptorchidism and hypoplastic labia minora and majora. Typical facial characteristics during childhood comprise a small mouth with full lips and micro-retrognathia. During ageing, a narrow, convex nose becomes more prominent. The diagnosis MGS should be considered in patients with at least two of the three features of the clinical triad of microtia, patellar anomalies, and pre- and postnatal growth retardation. In patients with short stature and/or microtia, the patellae should be assessed with care by ultrasonography before age 6 or radiography thereafter. Mutations in one of five genes (ORC1, ORC4, ORC6, CDT1, and CDC6) of the pre-replication complex, involved in DNA-replication, are detected in approximately 67-78% of patients with MGS. Patients with ORC1 and ORC4 mutations appear to have the most severe short stature and microcephaly. Management should be directed towards in-depth investigation, treatment and prevention of associated problems, such as growth retardation, feeding problems, hearing loss, luxating patellae, knee pain, gonarthrosis, and possible pulmonary complications due to congenital pulmonary emphysema with or without broncho- or laryngomalacia. Growth hormone treatment is ineffective in most patients with MGS, but may be effective in patients in whom growth continues to decrease after the first year of life (usually growth velocity normalizes after the first year) and with low levels of IGF1. At present, few data is available about reproduction of females with MGS, but the risk of premature labor might be increased. Here, we propose experience-based guidelines for the regular care and treatment of MGS patients.

An Equine Intersex with Unilateral Gonadal Agenesis

PubMed Central

Basrur, P. K.; Kanagawa, H.; Gilman, J. P. W.

1969-01-01

Cytogenetic and histological studies have been carried out on an intersex horse which was clinically diagnosed as a cryptorchid. The horse had the general conformation of a stallion but the external genitalia included a well developed vulva and a penis. The right testis which was descended was devoid of germ cells and the left “gonad” located in the cavum vaginale contained neither testicular nor ovarian tissue. The male duct system on both sides were relatively well developed despite the absence of a testis on the left side. Chromosome analysis on cultured cells from the descended testis revealed the presence of four chromosomally-distinct cell types with XX, XY, XXY and XO sex complements indicating a quadruple mosaicism. The presence of polymorphonuclear neutrophils exhibiting a drumstick, in the hemopoietic tissues and a sex chromatin body in the nucleated cells of buccal mucosa suggest that mosaicism prevails in other somatic tissues of the horse. On the basis of information derived from similar conditions in humans and some domestic animals it would appear that this horse resulted from an XXY zygote. The four cell types noted in the horse probably resulted through mitotic mechanisms favouring the loss of an X and a Y at different stages during embryonic development. The absence of gonad on the left side of this horse might be causally related to the preponderance of XO cell types in the somatic blastema during early gonadal differentiation. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4.Fig. 5.Fig. 6.Fig. 7.Fig. 8.Fig. 9.Fig. 10.Fig. 11.Fig. 12.Fig. 13.Fig. 14.Fig. 15.Fig. 16.Fig. 17.Fig. 18.Fig. 19. PMID:4391028

Distinctive phenotype in 9 patients with deletion of chromosome 1q24-q25.

PubMed

Burkardt, Deepika D'Cunha; Rosenfeld, Jill A; Helgeson, Maria L; Angle, Brad; Banks, Valerie; Smith, Wendy E; Gripp, Karen W; Moline, Jessica; Moran, Rocio T; Niyazov, Dmitriy M; Stevens, Cathy A; Zackai, Elaine; Lebel, Robert Roger; Ashley, Douglas G; Kramer, Nancy; Lachman, Ralph S; Graham, John M

2011-06-01

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome. Copyright © 2011 Wiley-Liss, Inc.

Distinctive Phenotype in 9 Patients with Deletion of Chromosome 1q24-q25

PubMed Central

Burkardt, Deepika D’Cunha; Rosenfeld, Jill A.; Helgeson, Maria; Angle, Brad; Banks, Valerie; Smith, Wendy; Gripp, Karen W.; Moline, Jessica; Moran, Rocio; Niyazov, Dmitriy M.; Stevens, Cathy; Zackai, Elaine; Lebel, Robert Roger; Ashley, Douglas; Kramer, Nancy; Lachman, Ralph S.; Graham, John M.

2011-01-01

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170135865–172099327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome. PMID:21548129

Congenital hypogonadotropic hypogonadism and Kallmann syndrome as models for studying hormonal regulation of human testicular endocrine functions.

PubMed

Trabado, Séverine; Lamothe, Sophie; Maione, Luigi; Bouvattier, Claire; Sarfati, Julie; Brailly-Tabard, Sylvie; Young, Jacques

2014-05-01

Men with Kallmann syndrome (KS) and those with congenital isolated hypogonadotropic hypogonadism with normal olfaction share a chronic, usually profound deficit, in FSH and LH, the two pituitary gonadotropins. Many studies indicate that this gonadotropin deficiency is already present during fetal life, thus explaining the micropenis, cryptorchidism and marked testicular hypotrophy already present at birth. In addition, neonatal activation of gonadotropin secretion is compromised in boys with severe CHH/Kallmann, preventing the first phase of postnatal testicular activation. Finally, CHH is characterized by the persistence, in the vast majority of cases, of gonadotropin deficiency at the time of puberty and during adulthood. This prevents the normal pubertal testicular reactivation required for physiological sex steroid and testicular peptide production, and for spermatogenesis. CHH/KS thus represents a pathological paradigm that can help to unravel, in vivo, the role of each gonadotropin in human testicular exocrine and endocrine functions at different stages of development. Recombinant gonadotropins with pure LH or FSH activity have been used to stimulate Leydig's cells and Sertoli's cells, respectively, and thereby to clarify their paracrine interaction in vivo. The effects of these pharmacological probes can be assessed by measuring the changes they provoke in circulating testicular hormone concentrations. This review discusses the impact of chronic gonadotropin deficiency on the endocrine functions of the interstitial compartment, which contains testosterone-, estradiol- and INSL3-secreting Leydig's cells. It also examines the regulation of inhibin B and anti-Mullerian hormone (AMH) secretion in the seminiferous tubules, and the insights provided by studies of human testicular stimulation with recombinant gonadotropins, used either individually or in combination. Copyright © 2014. Published by Elsevier Masson SAS.

A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family.

PubMed

Nimri, Revital; Lebenthal, Yael; Lazar, Liora; Chevrier, Lucie; Phillip, Moshe; Bar, Meytal; Hernandez-Mora, Eva; de Roux, Nicolas; Gat-Yablonski, Galia

2011-03-01

The G protein-coupled receptor 54 (GPR54), the kisspeptin receptor, is essential for stimulation of GnRH secretion and induction of puberty. Recently loss-of-function mutations of the GPR54 have been implicated as a cause of isolated idiopathic hypogonadotropic hypogonadism (IHH). The objective of the study was to identify the genetic cause of IHH in a consanguineous pedigree and to characterize the phenotypic features from infancy through early adulthood. In six patients with normosmic IHH belonging to two families of Israeli Muslim-Arab origin highly related to one another, DNA was analyzed for mutations in the GnRHR and GPR54 genes, with functional analysis of the mutation found. The five males underwent comprehensive endocrine evaluation and were under longitudinal follow-up; the one female presented in early adulthood. A new homozygous mutation (c.T815C) in GPR54 leading to a phenylalanine substitution by serine (p.F272S) was detected in all patients. Functional analysis showed an almost complete inhibition of kisspeptin-induced GPR54 signaling and a dramatic decrease of the mutated receptor expression at the cell surface. The males exhibited the same clinical features from infancy to adulthood, characterized by cryptorchidism, a relatively short penis, and no spontaneous pubertal development. The female patient presented at 18 yr with impuberism and primary amenorrhea. Repeated stimulation tests demonstrated complete gonadotropin deficiency throughout follow-up. A novel loss-of-function mutation (p.F272S) in the GPR54 gene is associated with familial normosmic IHH. Underdeveloped external genitalia and impuberism point to the major role of GPR54 in the activation of the gonadotropic axis from intrauterine life to adulthood.

Protective effects of N-acetylcysteine on experimentally undescended testis.

PubMed

Uyeturk, Ugur; Cetinkaya, Ayhan; Ozyalvacli, Gulzade; Tekce, Buket Kin; Ozyalvacli, Mehmet Emin; Kemahli, Eray; Gucuk, Adnan

2014-04-01

We evaluated the efficacy of N-acetylcysteine for testicular damage induced by undescended testes in rats. Flutamide was injected in the abdomen of pregnant rats daily from days 14 to 20 of gestation. Male offspring with cryptorchidism were randomly divided into 2 groups. Healthy male rats without undescended testes comprised the control group (group 1). Group 2 (undescended testes without N-acetylcysteine) received no treatment. Group 3 (undescended testes plus N-acetylcysteine) received intraperitoneal N-acetylcysteine daily. At 70 days after experiment initiation the testes were removed for histopathological and biochemical analysis. Mean malonyl dialdehyde values were lowest in group 1 and highest in group 2. In group 3 malonyl dialdehyde levels were significantly lower than in group 2 (p <0.001). Conversely, mean glutathione peroxidase was highest in group 1 and lowest in group 2. Glutathione peroxidase levels in group 3 were significantly higher than in group 2 (p <0.001). Histopathological differences between groups 1 and 3 in the modified Johnsen score were not significant (p = 0.041). However, the differences between these groups and group 2 were significant (p <0.001). The median apoptotic cell count did not differ between groups 1 and 3 but it was significantly higher in group 2 than in the other groups (p = 0.03 and <0.001, respectively). N-acetylcysteine may alleviate undescended testis induced damage to testes through its antioxidant effects. The underlying mechanism of these effects merits further investigation. Long-term studies are also needed as well as comparative animal and human studies. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Identification of De Novo Copy Number Variants Associated with Human Disorders of Sexual Development

PubMed Central

Tannour-Louet, Mounia; Han, Shuo; Corbett, Sean T.; Louet, Jean-Francois; Yatsenko, Svetlana; Meyers, Lindsay; Shaw, Chad A.; Kang, Sung-Hae L.; Cheung, Sau Wai; Lamb, Dolores J.

2010-01-01

Disorders of sexual development (DSD), ranging in severity from genital abnormalities to complete sex reversal, are among the most common human birth defects with incidence rates reaching almost 3%. Although causative alterations in key genes controlling gonad development have been identified, the majority of DSD cases remain unexplained. To improve the diagnosis, we screened 116 children born with idiopathic DSD using a clinically validated array-based comparative genomic hybridization platform. 8951 controls without urogenital defects were used to compare with our cohort of affected patients. Clinically relevant imbalances were found in 21.5% of the analyzed patients. Most anomalies (74.2%) evaded detection by the routinely ordered karyotype and were scattered across the genome in gene-enriched subtelomeric loci. Among these defects, confirmed de novo duplication and deletion events were noted on 1p36.33, 9p24.3 and 19q12-q13.11 for ambiguous genitalia, 10p14 and Xq28 for cryptorchidism and 12p13 and 16p11.2 for hypospadias. These variants were significantly associated with genitourinary defects (P = 6.08×10−12). The causality of defects observed in 5p15.3, 9p24.3, 22q12.1 and Xq28 was supported by the presence of overlapping chromosomal rearrangements in several unrelated patients. In addition to known gonad determining genes including SRY and DMRT1, novel candidate genes such as FGFR2, KANK1, ADCY2 and ZEB2 were encompassed. The identification of risk germline rearrangements for urogenital birth defects may impact diagnosis and genetic counseling and contribute to the elucidation of the molecular mechanisms underlying the pathogenesis of human sexual development. PMID:21048976

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

PubMed

Villanueva, Carine; Jacobson-Dickman, Elka; Xu, Cheng; Manouvrier, Sylvie; Dwyer, Andrew A; Sykiotis, Gerasimos P; Beenken, Andrew; Liu, Yang; Tommiska, Johanna; Hu, Youli; Tiosano, Dov; Gerard, Marion; Leger, Juliane; Drouin-Garraud, Valérie; Lefebvre, Hervé; Polak, Michel; Carel, Jean-Claude; Phan-Hug, Franziska; Hauschild, Michael; Plummer, Lacey; Rey, Jean-Pierre; Raivio, Taneli; Bouloux, Pierre; Sidis, Yisrael; Mohammadi, Moosa; de Roux, Nicolas; Pitteloud, Nelly

2015-08-01

Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.

A Novel Rasopathy Caused by Recurrent De Novo Missense Mutations In PPP1CB Closely Resembles Noonan Syndrome with Loose Anagen Hair

PubMed Central

Gripp, Karen W.; Aldinger, Kimberly A.; Bennett, James T.; Baker, Laura; Tusi, Jessica; Powell-Hamilton, Nina; Stabley, Deborah; Sol-Church, Katia; Timms, Andrew E.; Dobyns, William B.

2016-01-01

Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase 1 catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB’s effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. PMID:27264673

Postnatal risk factors for testicular cancer: The EPSAM case-control study.

PubMed

Moirano, Giovenale; Zugna, Daniela; Grasso, Chiara; Mirabelli, Dario; Lista, Patrizia; Ciuffreda, Libero; Segnan, Nereo; Merletti, Franco; Richiardi, Lorenzo

2017-11-01

Testicular cancer is considered to originate from an impaired differentiation of fetal germ cells, but puberty could represent another time window of susceptibility. Our study aimed at investigating the association between environmental exposures acting during puberty/adolescence (13-19 years of age) and the risk of testicular cancer. We used data of the EPSAM study, a case-control study on germ-cell testicular cancer conducted in the province of Turin, Italy, involving cases diagnosed between 1997 and 2008. Histologically confirmed cases (n = 255) and controls (n = 459) completed a postal questionnaire focusing in particular on the pubertal period (namely age 13 years) with questions on physical activity (competitive sports, gardening), lifestyle (alcohol consumption, smoking), occupational history and medical conditions. All analyses were adjusted for the matching variables, cryptorchidism and educational level. Having done at least one competitive sport during puberty (odds ratio [OR]: 0.72, 95% confidence interval: 0.52-1.00), gardening activities during puberty (OR: 0.62, 0.42-0.94) and having a lower weight than peers during puberty (OR: 0.64, 0.42-0.97) were all inversely associated with the risk of testicular cancer. No evidence of association between smoking or alcohol consumption during puberty and the risk of testicular cancer was observed. Regarding agriculture-related occupations, we found an association with the risk of testicular cancer both for occasional jobs during puberty (OR: 2.40, 95% CI: 1.08-5.29) and ever employment in adolescence (OR: 2.59, 95% CI: 0.83-8.10). Our results suggest that postnatal exposures could play a role in testicular cancer aetiology, at least when acting in puberty or adolescence. © 2017 UICC.

Cri du Chat syndrome

PubMed Central

Cerruti Mainardi, Paola

2006-01-01

The Cri du Chat syndrome (CdCS) is a genetic disease resulting from a deletion of variable size occurring on the short arm of chromosome 5 (5p-). The incidence ranges from 1:15,000 to 1:50,000 live-born infants. The main clinical features are a high-pitched monochromatic cry, microcephaly, broad nasal bridge, epicanthal folds, micrognathia, abnormal dermatoglyphics, and severe psychomotor and mental retardation. Malformations, although not very frequent, may be present: cardiac, neurological and renal abnormalities, preauricular tags, syndactyly, hypospadias, and cryptorchidism. Molecular cytogenetic analysis has allowed a cytogenetic and phenotypic map of 5p to be defined, even if results from the studies reported up to now are not completely in agreement. Genotype-phenotype correlation studies showed a clinical and cytogenetic variability. The identification of phenotypic subsets associated with a specific size and type of deletion is of diagnostic and prognostic relevance. Specific growth and psychomotor development charts have been established. Two genes, Semaphorin F (SEMAF) and δ-catenin (CTNND2), which have been mapped to the "critical regions", are potentially involved in cerebral development and their deletion may be associated with mental retardation in CdCS patients. Deletion of the telomerase reverse transcriptase (hTERT) gene, localised to 5p15.33, could contribute to the phenotypic changes in CdCS. The critical regions were recently refined by using array comparative genomic hybridisation. The cat-like cry critical region was further narrowed using quantitative polymerase chain reaction (PCR) and three candidate genes were characterised in this region. The diagnosis is based on typical clinical manifestations. Karyotype analysis and, in doubtful cases, FISH analysis will confirm the diagnosis. There is no specific therapy for CdCS but early rehabilitative and educational interventions improve the prognosis and considerable progress has been made in the social adjustment of CdCS patients. PMID:16953888

Oct4-GFP expression during transformation of gonocytes into spermatogonial stem cells in the perinatal mouse testis.

PubMed

Li, Ruili; Vannitamby, Amanda; Zhang, Jian-Guo; Fehmel, Emma L; Southwell, Bridget R; Hutson, John M

2015-12-01

In cryptorchidism perinatal failure to switch off Oct4, a germ cell (GC) marker, may lead to carcinoma in situ. We aimed to analyze Oct4 expression during mouse gonocyte transformation into spermatogonial stem cells (SSC). Testes from OG2 (Oct4-promoter driven eGFP) mice at embryonic day (E) 17 and postnatal day P0-10 underwent immunohistochemistry and immunoblotting. Antibodies against MVH, AMH, Ki67, and c-Kit were visualized by confocal microscopy. Numbers of Oct4-GFP(+) GC and Oct4-GFP(-) GC/tubule were counted using ImageJ. Data were analyzed using nonparametric one-way ANOVA. GC from E17-P4 were Oct4-GFP(+). Numbers of Oct4-GFP(-) GC/tubule increased from P6-10, whereas Oct4-GFP(+) GC/tubule numbers remained similar between P6 and P10. Sertoli cells proliferated from E17-P10, whereas GC only proliferated from P2. Gonocytes (Oct4-GFP(+)/c-Kit(-)) central in tubules migrated to the basement membrane to become prospermatogonia (Oct4-GFP(+)/c-Kit(-)) and then SSC (Oct4-GFP(+)/c-Kit(+)) from day 4 and further developed into Oct4-GFP(-)/c-Kit(+) at P6. In Oct4-GFP mice both centrally located gonocytes and prospermatogonia located at the tubular basement membrane were Oct4-GFP(+)/c-Kit(-) before further developing into SSC (Oct4-GFP(+)/c-Kit(+)). This indicates that Oct4 is important in gonocyte transformation into SSC. Understanding this process will aid GC tumor diagnostics and fertility potential in boys with UDT undergoing orchidopexy. Copyright © 2015 Elsevier Inc. All rights reserved.

Physiological and behavioral stress parameters in calves in response to partial scrotal resection, orchidectomy, and Burdizzo castration.

PubMed

Pieler, D; Peinhopf, W; Becher, A C; Aurich, J E; Rose-Meierhöfer, S; Erber, R; Möstl, E; Aurich, C

2013-10-01

Establishing artificial cryptorchids by partial scrotal resection without removing the testicles is a technique for castration of bull calves that recently has gained new interest. In contrast to orchidectomy and Burdizzo castration, the stress response of calves to shortening of the scrotum is unknown. In this study, partial scrotal resection in bull calves was compared with orchidectomy, Burdizzo castration, and controls without intervention (n=10 per group, ages 56 ± 3 d). Procedures were performed under xylazine sedation and local anesthesia. We hypothesized that partial scrotal resection is least stressful. Salivary cortisol, heart rate, heart rate variability, behavior, and locomotion were analyzed. Cortisol concentration peaked 60 min after start of the procedures. Cortisol release was at least in part xylazine induced and none of the experimental procedures released additional cortisol. Heart rate increased in calves of all groups with initial handling, but immediately after xylazine sedation decreased to 30% below initial values and was not modified by surgical procedures. The heart rate variability variables standard deviation of beat-to-beat interval and root mean square of successive beat-to-beat differences increased when calves were placed on the surgery table but effects were similar in calves submitted to surgeries and control calves. Locomotion increased, whereas lying time decreased in response to all surgeries. Locomotion increase was most pronounced after orchidectomy. Plasma fibrinogen concentrations increased after orchidectomy only. With adequate pain medication, orchidectomy, Burdizzo castration, and partial scrotal resection do not differ with regard to acute stress and, by inference, pain. Partial scrotal resection when carried out under xylazine sedation and local anesthesia thus is an acceptable castration technique in bull calves. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

PubMed

Gripp, Karen W; Zand, Dina J; Demmer, Laurie; Anderson, Carol E; Dobyns, William B; Zackai, Elaine H; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L; Sol-Church, Katia

2013-10-01

Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. Copyright © 2013 Wiley Periodicals, Inc.

Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families.

PubMed

Demirbilek, Huseyin; Ozbek, M Nuri; Demir, Korcan; Kotan, L Damla; Cesur, Yasar; Dogan, Murat; Temiz, Fatih; Mengen, Eda; Gurbuz, Fatih; Yuksel, Bilgin; Topaloglu, A Kemal

2015-03-01

The spectrum of genetic alterations in cases of hypogonadotropic hypogonadism continue to expand. However, KISS1R mutations remain rare. The aim of this study was to understand the molecular basis of normosmic idiopathic hypogonadotropic hypogonadism. Clinical characteristics, hormonal studies and genetic analyses of seven cases with idiopathic normosmic hypogonadotropic hypogonadism (nIHH) from three unrelated consanguineous families are presented. One male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism, while other two males had absence of pubertal onset. Two of four female cases required replacement therapy for pubertal onset and maintenance, whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases. We identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition. Escape from nonsense-mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype-genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH. © 2014 John Wiley & Sons Ltd.

Case-control study of male germ cell tumors nested in a cohort of car-manufacturing workers: Findings from the occupational history.

PubMed

Langner, Ingo; Schmeisser, Nils; Mester, Birte; Behrens, Thomas; Gottlieb, Andrea; Ahrens, Wolfgang

2010-10-01

To examine whether the previously observed excess risk of male germ cell cancer in a cohort of car-manufacturing workers can be attributed to occupational activities inside and/or outside the car industry. A nested case-control study among workers in six plants included 205 cases of germ cell cancer and 1,105 controls, individually matched by year of birth (±2 years). Job periods of the individual occupational histories were coded based on the International Standard Classification of Occupations (ISCO) and the industrial classification of economic activities (NACE). Odds ratios (ORs) and corresponding 95%-confidence intervals (CI) for ever-never and cumulative employment were calculated by conditional multivariate logistic regression adjusted for cryptorchidism. Significantly increased risks were observed for machinery fitters and assemblers (A) (OR = 1.8, 95% CI 1.25-2.53) and "workers not elsewhere classified" (OR = 2.10, 95% CI 1.27-3.54), but no trend was observed for employment duration in either occupational group. Stratification of job group A by metal-cutting and non-cutting jobs yielded ORs of 1.87 (95% CI 1.31-2.67) and of 1.24 (95% CI 0.68-2.28), respectively. Among "plumbers, welders, sheet & structural metal workers" (adjusted OR 1.4, 95% CI 0.99-1.95) only "structural metal preparers and erectors" showed a substantially increased risk (OR = 2.30; 95% CI 1.27-4.27). Our results do not fully explain the increased incidence of germ cell cancer in the cohort, but support previous findings showing increased risks among metal workers. These risks were most strongly pronounced in metal-cutting activities. © 2010 Wiley-Liss, Inc.

Male reproductive disorders, diseases, and costs of exposure to endocrine-disrupting chemicals in the European Union.

PubMed

Hauser, Russ; Skakkebaek, Niels E; Hass, Ulla; Toppari, Jorma; Juul, Anders; Andersson, Anna Maria; Kortenkamp, Andreas; Heindel, Jerrold J; Trasande, Leonardo

2015-04-01

Increasing evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to male reproductive diseases and disorders. To estimate the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific EDC exposures in the European Union (EU). An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. The cost-of-illness estimation utilized multiple peer-reviewed sources. The expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618,000 additional assisted reproductive technology procedures, costing €4.71 billion annually. Low epidemiological and strong toxicological evidence was also identified for cryptorchidism due to prenatal polybrominated diphenyl ether exposure, resulting in a 40-69% probability that 4615 cases result, at a cost of €130 million (sensitivity analysis, €117-130 million). A much more modest (0-19%) probability of causation in testicular cancer by polybrominated diphenyl ethers was identified due to very low epidemiological and weak toxicological evidence, with 6830 potential cases annually and costs of €848 million annually (sensitivity analysis, €313-848 million). The panel assigned 40-69% probability of lower T concentrations in 55- to 64-year-old men due to phthalate exposure, with 24 800 associated deaths annually and lost economic productivity of €7.96 billion. EDCs may contribute substantially to male reproductive disorders and diseases, with nearly €15 billion annual associated costs in the EU. These estimates represent only a few EDCs for which there were sufficient epidemiological studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs.

Estimating burden and disease costs of exposure to endocrine-disrupting chemicals in the European union.

PubMed

Trasande, Leonardo; Zoeller, R Thomas; Hass, Ulla; Kortenkamp, Andreas; Grandjean, Philippe; Myers, John Peterson; DiGangi, Joseph; Bellanger, Martine; Hauser, Russ; Legler, Juliette; Skakkebaek, Niels E; Heindel, Jerrold J

2015-04-01

Rapidly increasing evidence has documented that endocrine-disrupting chemicals (EDCs) contribute substantially to disease and disability. The objective was to quantify a range of health and economic costs that can be reasonably attributed to EDC exposures in the European Union (EU). A Steering Committee of scientists adapted the Intergovernmental Panel on Climate Change weight-of-evidence characterization for probability of causation based upon levels of available epidemiological and toxicological evidence for one or more chemicals contributing to disease by an endocrine disruptor mechanism. To evaluate the epidemiological evidence, the Steering Committee adapted the World Health Organization Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria, whereas the Steering Committee adapted definitions recently promulgated by the Danish Environmental Protection Agency for evaluating laboratory and animal evidence of endocrine disruption. Expert panels used the Delphi method to make decisions on the strength of the data. Expert panels achieved consensus at least for probable (>20%) EDC causation for IQ loss and associated intellectual disability, autism, attention-deficit hyperactivity disorder, childhood obesity, adult obesity, adult diabetes, cryptorchidism, male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median cost of €157 billion (or $209 billion, corresponding to 1.23% of EU gross domestic product) annually across 1000 simulations. Notably, using the lowest end of the probability range for each relationship in the Monte Carlo simulations produced a median range of €109 billion that differed modestly from base case probability inputs. EDC exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those EDCs with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.

Correlation Analysis of Cocoa Consumption Data with Worldwide Incidence Rates of Testicular Cancer and Hypospadias

PubMed Central

Giannandrea, Fabrizio

2009-01-01

The underlying reasons for the increasing occurrence of male reproductive diseases (MRD) such as hypospadias, cryptorchidism, and testicular cancer (TC) over the last decades are still unknown. It has been hypothesized that the risk of MRD is determined in utero and that pregnancy dietary intake could also affect MRD risk in the offspring. Various studies in animals reported that cocoa and theobromine, the main stimulant of cocoa, exert toxic effects on the testis, inducing testicular atrophy and impaired sperm quality. A correlation analysis was conducted to examine the possible role of cocoa consumption on the occurrence of selected MRD during the prenatal and early life period of cases. The incidence rates between 1998–2002 of TC in 18 countries obtained from Cancer Incidence in Five Continents were correlated with the average per-capita consumption of cocoa (kg/capita/year) (FAOSTAT-Database) in these countries from 1965 to 1980, i.e. the period corresponding to the early life of TC cases. In order to test the above correlation in the case of hypospadias, the mean prevalence at birth in 20 countries (1999–2003) with average per-capita consumption of cocoa in these countries in the same period corresponding to pregnancy were used. The consumption of cocoa in the period 1965–80, was most closely correlated with the incidence of TC in young adults (r=0.859; p<0.001). An analogous significant correlation was also observed between early cocoa consumption and the prevalence rates of hypospadias in the period 1999–2003 (r=0.760; p<0.001). Although the ecological approach used in this study cannot provide an answer on the causal relationship between consumption of cocoa in early life and TC and hypospadias, the results are suggestive and indicate the need of further analytic studies to investigate the role of individual exposure to cocoa, particularly during the prenatal and in early life of the patients. PMID:19440400

A survey of dystocia in the Boxer breed

PubMed Central

Linde Forsberg, Catharina; Persson, Gunilla

2007-01-01

Background Dystocia occurs more commonly in some breeds of dogs than others. The Boxer breed is one of the highrisk breeds for whelping problems. The aim of this study was to document some reproductive parameters and the frequency of dystocia in Boxers. Methods Two questionnaires were sent to the breeders of Boxers in Sweden during 1994 to 1997. Data from 253 whelpings and 1671 pups was received, which constitutes 56.5% of all Boxer litters registered with the Swedish Kennel Club during these years. Data was analysed using Chi-square test, and Fischer's exact test. Results Dystocia occurred in 32% of the individual bitches, and in 27.7% of all the whelpings. Caesarian section was performed in 22.8% of all the whelpings and in 80.1% of the cases of dystocia. Medical treatment was tried in 20 cases but was successful only in 5 (25%). The dystocia was of maternal origin in 68.6% and of fetal origin in 28.6% of cases. The most common reasons for dystocia were primary uterine inertia (60%) and malpresentation of the fetus (26%). Dystocia increased with increasing age of the bitch from four years of age. Average litter size was 6.6 (± 2.2) pups born, and 5.0 (± 2.1) pups registered. Pup mortality was 24%. Stillbirths accounted for 6.1% of the pup deaths and 1% died in the neonatal period, while 15.6% of the pups were euthanised, the majority because they had disqualifying white coat colour. Cryptorchidism was observed in 9.8% of the male pups born and in 13.4% of the male pups that were registered. Conclusion The Boxer suffers a high frequency of dystocia, mainly due to uterine inertia, but also fetal malpresentation. Breeders should be adviced to include easy whelpings in their breeding program. PMID:17376241

Prevalence of olfactory and other developmental anomalies in patients with central hypogonadotropic hypogonadism.

PubMed

Della Valle, Elisa; Vezzani, Silvia; Rochira, Vincenzo; Granata, Antonio Raffaele Michele; Madeo, Bruno; Genovese, Elisabetta; Pignatti, Elisa; Marino, Marco; Carani, Cesare; Simoni, Manuela

2013-01-01

Hypogonadotropic hypogonadism (HH) is a heterogeneous disease caused by mutations in several genes. Based on the presence of hyposmia/anosmia it is distinguished into Kallmann syndrome (KS) and isolated HH. The prevalence of other developmental anomalies is not well established. We studied 36 patients with HH (31 males, 5 females, mean age 41.5), 9 with familial and 27 with sporadic HH (33 congenital, 3 adult-onset), by physical examination, smell test (BSIT Sensonics), audiometry, renal ultrasound, and magnetic resonance imaging of the olfactory structures. Based on the smell test, patients were classified as normosmic (n = 21, 58.3%) and hypo/anosmic (n = 15, 41.6%). Hypoplasia/agenesis of olfactory bulbs was found in 40% of patients (10/25; 75% hypo/anosmic, 7.6% normosmic, p < 0.01, Fisher's test). Remarkably, olfactory structures were normal in two anosmic patients, while one normosmic patient presented a unilateral hypoplastic bulb. Fourteen of 33 patients (42.4%) presented neurosensorial hearing loss of various degrees (28.5% hypo/anosmic, 52.6% normosmic, p = NS). Renal ultrasound revealed 27.7% of cases with renal anomalies (26.6% hypo/anosmic, 28.5% normosmic, p = NS). At least one midline defect was found in 50% of the patients (53.3% hypo/anosmic, 47.6% normosmic, p = NS), including abnormal palate, dental anomalies, pectus excavatum, bimanual synkinesis, iris coloboma, and absent nasal cartilage. Anamnestically 4/31 patients reported cryptorchidism (25% hypo/anosmic, 5.2% normosmic, p = NS). Hypo/anosmia is significantly related to anatomical anomalies of the olfactory bulbs/tracts but the prevalence of other developmental anomalies, especially midline defects and neurosensorial hearing loss, is high both in HH and KS and independent of the presence of anosmia/hyposmia. From the clinical standpoint KS and normosmic HH should be considered as the same complex, developmental disease.

Sleep disturbances and semen quality in an Italian cross sectional study.

PubMed

Viganò, Paola; Chiaffarino, Francesca; Bonzi, Viviana; Salonia, Andrea; Ricci, Elena; Papaleo, Enrico; Mauri, Paola Agnese; Parazzini, Fabio

2017-01-01

In order to obtain information about the relationship between sleep disturbances and sperm parameters, we analyzed data from a study conducted in a Italian Fertility Clinic, in men of couples seeking help for infertility. Male partners with or without a medical history of reproductive organ diseases (cryptorchidism, varicocele, orchitis, testicular torsion) were eligible for the study. There were 382 men evaluated from May 2014 to November 2016, all of whom completed a self-administered questionnaire on general lifestyle habits. Then all men underwent semen analysis. A total of 382 men aged 26 to 67 years (median age 39 year interquartile range 37-42) were recruited. A total of 46.3% reported having sleep disturbances. In multivariate analysis, in absence of reproductive organ diseases, semen volume was lower in patients with difficulty in initiating sleep (2.0 ml, IQR 1.5-3.0 vs 3.0 ml, IQR 2.0-3.3, p  = .01), whereas in presence of reproductive organ diseases motility A was lower in patients with early morning awakening (25.0%, IQR 15.0-35.0 vs. 40.0%, IQR 30.0-50.0, p  = .001). In overweight men, semen volume was lower in patients with difficulty in initiating sleep (2.0 ml, IQR 1.5-3.0 vs 3.0 ml, IQR 2.0-3.0, p  = .03). Moreover, among current smokers, patients with difficulty in initiating sleep had semen volume lower (1.5 ml, IQR 1.5-2.5 vs 3.0 ml, IQR 2.0-3.5, p  = .0003) and sperm concentration higher (40 millions/ml, IQR 15-60 vs 10 millions/ml, IQR 5-50 p  = .03) but total sperm count was not significant different. Further studies are necessary to elucidate the relationship between sleep quality and semen parameters, which may have important public health implication.

Subfertility and Risk of Testicular Cancer in the EPSAM Case-Control Study

PubMed Central

Zugna, Daniela; Fiano, Valentina; Robles Rodriguez, Nena; Maule, Milena; Gillio-Tos, Anna; Ciuffreda, Libero; Lista, Patrizia; Segnan, Nereo; Merletti, Franco; Richiardi, Lorenzo

2016-01-01

Background/objectives It has been suggested that subfertility and testicular cancer share genetic and environmental risk factors. We studied both subfertility and the strongest known testicular cancer susceptibility gene, the c-KIT ligand (KITLG), whose pathway is involved in spermatogenesis. Methods The EPSAM case-control study is comprised of testicular cancer patients from the Province of Turin, Italy, diagnosed between 1997 and 2008. The present analysis included 245 cases and 436 controls from EPSAM, who were aged 20 years or older at diagnosis/recruitment. The EPSAM questionnaire collected information on factors such as number of children, age at first attempt to conceive, duration of attempt to conceive, use of assisted reproduction techniques, physician-assigned diagnosis of infertility, number of siblings, and self-reported cryptorchidism. Genotyping of the KITLG single nucleotide polymorphism (SNP) rs995030 was performed on the saliva samples of 202 cases and 329 controls. Results Testicular cancer was associated with the number of children fathered 5 years before diagnosis (odds ratio (OR) per additional child: 0.78, 95% confidence interval (CI): 0.58–1.04) and sibship size (OR per additional sibling: 0.76, 95% CI: 0.66–0.88). When considering the reproductive history until 1 year before diagnosis, attempting to conceive for at least 12 months or fathering a child using assisted reproduction techniques was not associated with the risk of testicular cancer, nor was age at first attempt to conceive or physician-assigned diagnosis of infertility. The SNP rs995030 was strongly associated with risk of testicular cancer (per allele OR: 1.83; 95%CI: 1.26–2.64), but it did not modify the association between number of children and the risk of testicular cancer. Conclusion This study supports the repeatedly reported inverse association between number of children and risk of testicular cancer, but it does not find evidence of an association for other indicators of subfertility. PMID:28036409

Subfertility and Risk of Testicular Cancer in the EPSAM Case-Control Study.

PubMed

Grasso, Chiara; Zugna, Daniela; Fiano, Valentina; Robles Rodriguez, Nena; Maule, Milena; Gillio-Tos, Anna; Ciuffreda, Libero; Lista, Patrizia; Segnan, Nereo; Merletti, Franco; Richiardi, Lorenzo

2016-01-01

It has been suggested that subfertility and testicular cancer share genetic and environmental risk factors. We studied both subfertility and the strongest known testicular cancer susceptibility gene, the c-KIT ligand (KITLG), whose pathway is involved in spermatogenesis. The EPSAM case-control study is comprised of testicular cancer patients from the Province of Turin, Italy, diagnosed between 1997 and 2008. The present analysis included 245 cases and 436 controls from EPSAM, who were aged 20 years or older at diagnosis/recruitment. The EPSAM questionnaire collected information on factors such as number of children, age at first attempt to conceive, duration of attempt to conceive, use of assisted reproduction techniques, physician-assigned diagnosis of infertility, number of siblings, and self-reported cryptorchidism. Genotyping of the KITLG single nucleotide polymorphism (SNP) rs995030 was performed on the saliva samples of 202 cases and 329 controls. Testicular cancer was associated with the number of children fathered 5 years before diagnosis (odds ratio (OR) per additional child: 0.78, 95% confidence interval (CI): 0.58-1.04) and sibship size (OR per additional sibling: 0.76, 95% CI: 0.66-0.88). When considering the reproductive history until 1 year before diagnosis, attempting to conceive for at least 12 months or fathering a child using assisted reproduction techniques was not associated with the risk of testicular cancer, nor was age at first attempt to conceive or physician-assigned diagnosis of infertility. The SNP rs995030 was strongly associated with risk of testicular cancer (per allele OR: 1.83; 95%CI: 1.26-2.64), but it did not modify the association between number of children and the risk of testicular cancer. This study supports the repeatedly reported inverse association between number of children and risk of testicular cancer, but it does not find evidence of an association for other indicators of subfertility.

Correlation analysis of cocoa consumption data with worldwide incidence rates of testicular cancer and hypospadias.

PubMed

Giannandrea, Fabrizio

2009-02-01

The underlying reasons for the increasing occurrence of male reproductive diseases (MRD) such as hypospadias, cryptorchidism, and testicular cancer (TC) over the last decades are still unknown. It has been hypothesized that the risk of MRD is determined in utero and that pregnancy dietary intake could also affect MRD risk in the offspring. Various studies in animals reported that cocoa and theobromine, the main stimulant of cocoa, exert toxic effects on the testis, inducing testicular atrophy and impaired sperm quality. A correlation analysis was conducted to examine the possible role of cocoa consumption on the occurrence of selected MRD during the prenatal and early life period of cases. The incidence rates between 1998-2002 of TC in 18 countries obtained from Cancer Incidence in Five Continents were correlated with the average per-capita consumption of cocoa (kg/capita/year) (FAOSTAT-Database) in these countries from 1965 to 1980, i.e. the period corresponding to the early life of TC cases. In order to test the above correlation in the case of hypospadias, the mean prevalence at birth in 20 countries (1999-2003) with average per-capita consumption of cocoa in these countries in the same period corresponding to pregnancy were used. The consumption of cocoa in the period 1965-80, was most closely correlated with the incidence of TC in young adults (r=0.859; p<0.001). An analogous significant correlation was also observed between early cocoa consumption and the prevalence rates of hypospadias in the period 1999-2003 (r=0.760; p<0.001). Although the ecological approach used in this study cannot provide an answer on the causal relationship between consumption of cocoa in early life and TC and hypospadias, the results are suggestive and indicate the need of further analytic studies to investigate the role of individual exposure to cocoa, particularly during the prenatal and in early life of the patients.

[Status of penis and testicular development and effects of overweight/obesity on them in boys in the Zhengzhou area].

PubMed

Zhang, Yao-Dong; Tan, Li-Na; Luo, Shu-Ying; Chen, Yong-Xing; Wei, Hai-Yan

2015-01-01

To evaluate the current status of penis and testicular development in boys and the effects of overweight/obesity on their development in the Zhengzhou area of Henan Province. Height, weight, waist circumference, hip circumference, penis length and testicular volume were measured in 3 546 4 to 12-year-old boys. The penis length and testicular volume were compared between the overweight/obesity and normal weight groups. Before 9 years of age, the testicular volume was progressively smaller, and after 9 years old, it gradually increased. By the age of 11, it increased rapidly. The penis length increased gradually between 4 and 11 years of age, and after the age of 11 it increased rapidly. Phimosis was found in 144 cases (4.01%) and cryptorchidism was found in 18 cases (0.51%). A total of 639 (18.02%) boys were overweight or obese among 3 546 boys. At the ages of 6 and 7 years, the testicular volume in the overweight/obesity group was greater than in the normal control group (P<0.05). The penis length in the overweight/obesity group was significantly shorter than in the normal control group (P<0.05) by the age of 11 years. The correlation analysis showed that the testicular volume at the ages of 4 and 5 years was positively correlated with height, weight, BMI, waist circumference and hip circumference in overweight/obese boys. The penis length at the ages of 7 and 8 years was negatively correlated with weight, waist circumference and hip circumference. By the age of 12 years, the penis length was positively correlated with the height. The development of penis and testicles in boys in the Zhengzhou area is in line with the level of sex development of Chinese boys. Overweight/obesity adversely affects the development of penis and testicles.

Disruption of Retinol (Vitamin A) Signaling by Phthalate Esters: SAR and Mechanism Studies.

PubMed

Chen, Yanling; Reese, David H

2016-01-01

A spectrum of reproductive system anomalies (cryptorchidism, hypospadias, dysgenesis of Wolffian duct-derived tissues and prostate, and reduced sperm production) in male rats exposed in utero to phthalate esters (PEs) are thought to be caused by PE inhibition of fetal testosterone production. Recently, dibutyl and dipentyl phthalate (DBuP, DPnP) were shown to disrupt the retinol signaling pathway (RSP) in mouse pluripotent P19 embryonal carcinoma cells in vitro. The RSP regulates the synthesis and cellular levels of retinoic acid (RA), the active metabolite of retinol (vitamin A). In this new study, a total of 26 di- and mono-esters were screened to identify additional phthalate structures that disrupt the RSP and explore their mechanisms of action. The most potent PEs, those causing > 50% inhibition, contained aryl and cycloalkane groups or C4-C6 alkyl ester chains and were the same PEs reported to cause malformations in utero. They shared similar lipid solubility; logP values were between 4 and 6 and, except for PEs with butyl and phenyl groups, were stable for prolonged periods in culture. Mono- and cognate di-esters varied in ability to disrupt the RSP; e.g., DEHP was inactive but its monoester was active while DBuP was active yet its monoester was inactive. DBuP and dibenzyl phthalate both disrupted the synthesis of RA from retinol but not the ability of RA to activate gene transcription. Both PEs also disrupted the RSP in C3H10T1/2 multipotent mesenchymal stem cells. Based on this in vitro study showing that some PEs disrupt retinol signaling and previous in vivo studies that vitamin A/RA deficiency and PEs both cause strikingly similar anomalies in the male rat reproductive system, we propose that PE-mediated inhibition of testosterone and RA synthesis in utero are both causes of malformations in male rat offspring.

Estimating Burden and Disease Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union

PubMed Central

Zoeller, R. Thomas; Hass, Ulla; Kortenkamp, Andreas; Grandjean, Philippe; Myers, John Peterson; DiGangi, Joseph; Bellanger, Martine; Hauser, Russ; Legler, Juliette; Skakkebaek, Niels E.; Heindel, Jerrold J.

2015-01-01

Context: Rapidly increasing evidence has documented that endocrine-disrupting chemicals (EDCs) contribute substantially to disease and disability. Objective: The objective was to quantify a range of health and economic costs that can be reasonably attributed to EDC exposures in the European Union (EU). Design: A Steering Committee of scientists adapted the Intergovernmental Panel on Climate Change weight-of-evidence characterization for probability of causation based upon levels of available epidemiological and toxicological evidence for one or more chemicals contributing to disease by an endocrine disruptor mechanism. To evaluate the epidemiological evidence, the Steering Committee adapted the World Health Organization Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria, whereas the Steering Committee adapted definitions recently promulgated by the Danish Environmental Protection Agency for evaluating laboratory and animal evidence of endocrine disruption. Expert panels used the Delphi method to make decisions on the strength of the data. Results: Expert panels achieved consensus at least for probable (>20%) EDC causation for IQ loss and associated intellectual disability, autism, attention-deficit hyperactivity disorder, childhood obesity, adult obesity, adult diabetes, cryptorchidism, male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median cost of €157 billion (or $209 billion, corresponding to 1.23% of EU gross domestic product) annually across 1000 simulations. Notably, using the lowest end of the probability range for each relationship in the Monte Carlo simulations produced a median range of €109 billion that differed modestly from base case probability inputs. Conclusions: EDC exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those EDCs with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs. PMID:25742516

Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

PubMed Central

Leung, Maxwell C.K.; Phuong, Jimmy; Baker, Nancy C.; Sipes, Nisha S.; Klinefelter, Gary R.; Martin, Matthew T.; McLaurin, Keith W.; Setzer, R. Woodrow; Darney, Sally Perreault; Judson, Richard S.; Knudsen, Thomas B.

2015-01-01

Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies. Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system. Methods: We used U.S. EPA’s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s. Citation: Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male reproductive development: profiling 774 chemicals for molecular targets and adverse outcomes. Environ Health Perspect 124:1050–1061; http://dx.doi.org/10.1289/ehp.1510385 PMID:26662846

A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair.

PubMed

Gripp, Karen W; Aldinger, Kimberly A; Bennett, James T; Baker, Laura; Tusi, Jessica; Powell-Hamilton, Nina; Stabley, Deborah; Sol-Church, Katia; Timms, Andrew E; Dobyns, William B

2016-09-01

Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS/MAPK pathway. Despite its variable phenotype, limited genotype-phenotype correlations exist. Noonan syndrome with loose anagen hair (NS-LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense SHOC2 mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen-activated protein kinases of the RAS/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change. All had relative or absolute macrocephaly, low-set and posteriorly angulated ears, and developmental delay. Slow growing and/or sparse hair and/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy-Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS-LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A novel mutation in the human aromatase gene: insights on the relationship among serum estradiol, longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment.

PubMed

Lanfranco, Fabio; Zirilli, Lucia; Baldi, Matteo; Pignatti, Elisa; Corneli, Ginevra; Ghigo, Ezio; Aimaretti, Gianluca; Carani, Cesare; Rochira, Vincenzo

2008-09-01

Here we report on a new case of human aromatase deficiency in a man of 26 years of age and present the results of five year follow-up during trandermal estradiol (tE2) substitution, focusing on bone growth and mineralization. The lack of patient's compliance to tE2 treatment, resulting in low but detectable serum estradiol levels, provides helpful information about the physiological estradiol needed in serum to guarantee a complete bone maturation and mineralization. Clinical case report study. Genetic, biochemical and hormonal evaluations and the study of bone health were performed before and during estrogen treatment. Eunuchoid body proportions, unfused epiphyses, tall stature, osteopenia, increase fasting insulin, mild astenozoospermia and a history of right cryptorchidism were present. Baseline serum FSH was slightly above the normal range and estradiol was undetectable. Genetic analysis revealed a pattern of compound heterozygosity due to 23 bp deletion in exon IV and a point mutation in the first nucleotide of intron IX of the CYP19A1 gene, respectively. The closure of epiphyseal cartilage, the normalization of bone BMD and bone turnover markers, and the improvement of insulin levels were reached during tE2 only when serum estradiol raised above 73 pmol/L. Sperm parameters and overweight did not improve with substitutive therapy. This new case of aromatase deficiency underlines the role of estrogen on skeletal maturation, BMD, metabolic abnormalities and gonadal axis. It provides evidence on the need not only of a continuous estrogen replacement, but also of ensuring adequate estradiol levels in serum in order to ensure a complete bone maturation and mineralization and to prevent the worsening of body skeletal proportions. The comprehension of this physiological aspect has relevant clinical significance especially for the development of new therapeutic strategies useful to treat growth disorders by targeting serum estradiol in men.

Chronic hip pain in a boy with mental retardation and cerebral palsy.

PubMed

Stein, Martin T; Gottsegen, David; Blasco, Peter A; Wolraich, Mark; Hennessy, Michael J

2010-04-01

Jonny is a 13 year old boy with spastic quadriparesis and severe mental retardation following Haemophilus influenza type B (HIB) meningitis at 2-months of age. Signs of meningitis started on the evening of his 2-month immunizations that included the HIB vaccine. He presented to his pediatrician with left hip pain that occurred intermittently for a few years and more frequently in the past six months. His parents initially attributed the pain to whizzing around the back yard in a motorized wheelchair. An earlier evaluation of hip pain led to bilateral femoral osteotomies for hip dysplasia. Obesity, associated with inactivity and a tendency to consume fatty foods, complicates Jonny's disabilities. His only activity is a modest amount of physical therapy at school and "floor time" for about one hour each day at home. In the office of his pediatrician, Jonny is friendly, smiling, and verbalizing a few words with his limited expressive vocabulary. He is resistant to a hip examination and grimaces with manipulation of his left hip. Spasticity of the left leg appears increased compared to previous examinations. He has nonpitting edema of his lower legs and feet, a cryptorchid left testicle, and a somewhat tender left inguinal area. Jonny lives with his mother and father in a small house on a busy street less than one-half mile from the pediatrician's office. Jonny's pediatrician often sees him in his wheelchair, accompanied by his mother or grandmother, and waves or stops to chat. He has van services to school, and there is a Hoyer lift in the home, but his parents do not own a van. Recently, Jonny's father finds it more difficult to lift him. The family has also been challenged by the mental health problems of Jonny's two older brothers, and a serious eye injury suffered by his middle brother in a motor-vehicle accident. Jonny's pediatrician has cared for him and his two brothers since birth. Although the parents continue to believe that the HIB vaccine caused his catastrophic illness, they remain with the pediatrician. In general, they are satisfied with the individualized educational plan at a local public school. When he was 6.5 years old, Jonny's school aid reported that he attempted to touch her in the genital area. The pediatrician attended the meeting to review this incident and successfully advocated for Jonny by pointing out that this was an isolated incident; it did not occur again. At 6 years old Jonny functioned in the 1.5-2.5 year old range with motor skills in the 6-12 month level according to the Bayley Scales of Infant Development and the Vineland Adaptive Behavior Scales. In the past a neurologist and a physiatrist saw Jonny, but both of these individuals moved from the community. He had prior evaluations at a children's orthopedic clinic at a small community hospital and at the local Shriner's hospital. He had a tonsillectomy and adenoidectomy at 7 years old. He is currently treated for constipation and receives dental care at a clinic for people with disabilities. His pediatrician has always respected the parents for their care and obvious love for their disabled child. However, parental resistance to addressing major issues such as obesity has frustrated his pediatrician. When the pediatrician suggested that Jonny was eligible for the state's managed care program, which would convert Medicaid coverage to a state sponsored program with more extensive services and case management, Jonny's mother repeatedly said that she would "think it over." At the current visit, the pediatrician recommended an adjustment of Jonny's wheelchair, a hip x-ray, a referral to Shriner's Hospital, and an appointment with a pediatric surgeon to address the undescended testicle and possible hernia. Jonny's mother mentioned that he had been to Shriner's Hospital for hip pain two years earlier but was told nothing could be done "because nothing was wrong with his bone." The hip x-ray was normal as well as a complete blood count and a C-reactive protein. The pediatric surgeon did not find a hernia and deferred treatment of the cryptorchid testicle. His parents contacted the wheelchair company to arrange adjustments. The pediatrician called the medical director at the Shriner's Hospital to discuss Jonny's case, but 2 months after the initial visit, the parents had not arranged for an appointment at the Shriner's Hospital. Jonny's hip pain persisted. The pediatrician now wonders how he can more effectively address Jonny's current problems and improve overall care for him and his family.

Gonadotrophin abnormalities in an infant with Lowe syndrome.

PubMed

Warner, Bronwen E; Inward, Carol D; Burren, Christine P

2017-01-01

This case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new insights on hypothalamic-pituitary-gonadal (HPG) axis and testicular function abnormalities in the multisystem disorder of Lowe syndrome. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare disorder characterised by eye abnormalities, central nervous system involvement and proximal renal tubular acidosis. There are a handful of reports of pubertal delay, infertility and cryptorchidism in Lowe syndrome. Biochemistry aged 72 h: testosterone 6.4 nmol/L, LH <0.5 IU/L and FSH <0.5 IU/L. Gonadotropin-releasing hormone stimulation test identified significantly raised baseline LH = 45.4 IU/L (contrasts with earlier undetectable LH), with a 20% increase on stimulation, while baseline FSH = 4.3 IU/L with no increase on stimulation. Day 14 HCG stimulation test produced an acceptable 50% increase in testosterone. The constellation of further abnormalities suggested Lowe syndrome: hypotonia, bilateral cataracts (surgical extraction and intraocular lens implantation) and renal tubular acidosis (microscopic haematuria, hypercalciuria, proteinuria, generalised aminoaciduria, hypophosphataemia and metabolic acidosis). DNA sequencing identified de novo hemizygous frameshift mutation OCRL c.2409_2410delCT in exon 22. Interpretation of initial and repeat GnRH and HCG testing indicates the likelihood of testicular failure. Partial testicular descent occurred but left orchidopexy was required. Improving long-term gonadal function in Lowe syndrome assumes increased importance for current cohorts as advances in renal replacement therapy have greatly improved life expectancy. Noting HPG axis abnormalities in Lowe syndrome in infancy can identify cases requiring increased surveillance of pubertal progress for earlier detection and management. Clinical endocrine problems in Lowe syndrome has been reported, but has focused on abnormalities in adolescence and young adulthood: pubertal delay and infertility.We present an infant with isolated LH elevation at baseline and on GnRH stimulation testing who also had bilateral impalpable testes.Early testing of the HPG axis in patients with Lowe syndrome may help predict gonadal abnormalities from a younger age, which will enhance the overall case management into adolescence.

Anthropometric and hormonal risk factors for male breast cancer: male breast cancer pooling project results.

PubMed

Brinton, Louise A; Cook, Michael B; McCormack, Valerie; Johnson, Kenneth C; Olsson, Håkan; Casagrande, John T; Cooke, Rosie; Falk, Roni T; Gapstur, Susan M; Gaudet, Mia M; Gaziano, J Michael; Gkiokas, Georgios; Guénel, Pascal; Henderson, Brian E; Hollenbeck, Albert; Hsing, Ann W; Kolonel, Laurence N; Isaacs, Claudine; Lubin, Jay H; Michels, Karin B; Negri, Eva; Parisi, Dominick; Petridou, Eleni Th; Pike, Malcolm C; Riboli, Elio; Sesso, Howard D; Snyder, Kirk; Swerdlow, Anthony J; Trichopoulos, Dimitrios; Ursin, Giske; van den Brandt, Piet A; Van Den Eeden, Stephen K; Weiderpass, Elisabete; Willett, Walter C; Ewertz, Marianne; Thomas, David B

2014-03-01

The etiology of male breast cancer is poorly understood, partly because of its relative rarity. Although genetic factors are involved, less is known regarding the role of anthropometric and hormonally related risk factors. In the Male Breast Cancer Pooling Project, a consortium of 11 case-control and 10 cohort investigations involving 2405 case patients (n = 1190 from case-control and n = 1215 from cohort studies) and 52013 control subjects, individual participant data were harmonized and pooled. Unconditional logistic regression generated study design-specific (case-control/cohort) odds ratios (ORs) and 95% confidence intervals (CIs), with exposure estimates combined using fixed effects meta-analysis. All statistical tests were two-sided. Risk was statistically significantly associated with weight (highest/lowest tertile: OR = 1.36; 95% CI = 1.18 to 1.57), height (OR = 1.18; 95% CI = 1.01 to 1.38), and body mass index (BMI; OR = 1.30; 95% CI = 1.12 to 1.51), with evidence that recent rather than distant BMI was the strongest predictor. Klinefelter syndrome (OR = 24.7; 95% CI = 8.94 to 68.4) and gynecomastia (OR = 9.78; 95% CI = 7.52 to 12.7) were also statistically significantly associated with risk, relations that were independent of BMI. Diabetes also emerged as an independent risk factor (OR = 1.19; 95% CI = 1.04 to 1.37). There were also suggestive relations with cryptorchidism (OR = 2.18; 95% CI = 0.96 to 4.94) and orchitis (OR = 1.43; 95% CI = 1.02 to 1.99). Although age at onset of puberty and histories of infertility were unrelated to risk, never having had children was statistically significantly related (OR = 1.29; 95% CI = 1.01 to 1.66). Among individuals diagnosed at older ages, a history of fractures was statistically significantly related (OR = 1.41; 95% CI = 1.07 to 1.86). Consistent findings across case-control and cohort investigations, complemented by pooled analyses, indicated important roles for anthropometric and hormonal risk factors in the etiology of male breast cancer. Further investigation should focus on potential roles of endogenous hormones.

Dissecting the molecular pathways of (testicular) germ cell tumour pathogenesis; from initiation to treatment-resistance.

PubMed

Looijenga, L H J; Gillis, A J M; Stoop, H; Biermann, K; Oosterhuis, J W

2011-08-01

Human type II germ cell tumours (GCTs) originate from an embryonic germ cell, either as a primordial germ cell or gonocyte. This start determines the biological as well as clinical characteristics of this type of cancer, amongst others their totipotency as well as their overall (exceptional) sensitivity to DNA damaging agents. The histology of the precursor lesion, either carcinoma in situ or gonadoblastoma, depends on the level of testicularization (i.e. testis formation) of the gonad. The impact of either intrinsic (genetic) - and environmental factors involved in the pathogenesis is demonstrated by disorders of sex development as well as testicular dysgenesis syndrome as risk factors, including cryptorchidism, hypospadias and disturbed fertility as parameters. This knowledge allows identification of individuals at risk for development of this type of cancer, being a population of interest for screening. Factors known to regulate pluripotency during embryogenesis are proven to be of diagnostic value for type II GCTs, including OCT3/4, even applicable for non-invasive screening. In addition, presence of stem cell factor, also known as KITLG, allows distinction between delayed matured germ cells and the earliest stages of malignant transformation. This is of special interest because of the identified association between development of type II GCTs of the testis and a limited number of single nucleotide polymorphisms, including some likely related to KITL. Transition from the precursor lesion to an invasive cancer is associated with gain of the short arm of chromosome 12, in which multiple genes might be involved, including KRAS2 and possibly NANOG (pseudogenes). While most precursor lesions will progress to an invasive cancer, only a limited number of cancers will develop treatment resistance. Putative explanatory mechanisms are identified, including presence of microsatellite instability, BRAF mutations, apoptosis suppression and p21 sub-cellular localization. It remains to be investigated how these different pathways integrate to each other and how informative they are at the patient-individual level. Further understanding will allow development of more targeted treatment, which will benefit quality of life of these young cancer patients. © 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.

Protamine mRNA ratio in stallion spermatozoa correlates with mare fecundity.

PubMed

Paradowska-Dogan, A; Fernandez, A; Bergmann, M; Kretzer, K; Mallidis, C; Vieweg, M; Waliszewski, P; Zitzmann, M; Weidner, W; Steger, K; Kliesch, S

2014-07-01

Highly compacted sperm DNA in protamine toroids and a minor fraction of nucleohistones are prerequisites for the efficient transmission of the paternal genome into the oocyte at fertilization. The objective of this study was to evaluate whether protamines might serve as a prognostic factor for stallion fertility. In situ hybridization detected specific expression of P1 mRNA in the cytoplasm of stage I to VII spermatids, whereas comparable immunohistochemical stainings showed that protein expression was delayed till elongating spermatids in differentiation stages III to VIII. No staining was detectable in cryptorchid testis because of the lack of spermatids in the seminiferous tubules. Using quantitative real-time polymerase chain reaction, we identified mRNA transcripts of P1 and 2 variants of protamine- 2 (P2, P3) in ejaculated spermatozoa from 45 thoroughbred stallions. According to the mare fertility descriptor (i.e. the 'none-return-rate 28 percentage' or NRR28%), stallions were divided into three groups (i.e. high, reduced and low fertility). The P2/P1 mRNA ratio was found to be significantly reduced in the group with lower fertility (p = 0.016) and was slightly correlated with sperm concentration (correlation coefficient r = 0.263). Furthermore, morphologically abnormal sperm count negatively correlated with P2/P1 mRNA ratio, indicating that spermatozoa carrying head defects display a diminished protamine ratio (r = -0.348). Conversely, the P2/P1 ratio was positively correlated with mare fertility or NRR28% (r = 0.274). Interestingly, P3/P1 mRNA ratio remained unaltered in the investigated groups indicating that this variant plays a minor role in equine sperm chromatin compaction. Aberrant protamine transcripts content in equine spermatozoa was not associated with DNA defragmentation rate as measured by flow cytometric acridine orange test. On the basis of these results, we suggest that, similar to human, equine protamine expression constitutes a checkpoint of spermatogenesis and as a corollary the level of protamine mRNA may reflect the quality of spermatogenesis and spermatozoa's fertilizing capacity. © 2014 American Society of Andrology and European Academy of Andrology.

Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotropic hypogonadism? -a multicentre prospective study of hCG/rFSH treatment outcomes during adolescence.

PubMed

Rohayem, Julia; Hauffa, Berthold P; Zacharin, Margaret; Kliesch, Sabine; Zitzmann, Michael

2017-01-01

Testosterone treatment for pubertal induction in boys with hypogonadotropic hypogonadism (HH) provides virilization, but does not induce testicular growth or fertility. Larger studies evaluating the outcomes of gonadotropin replacement during adolescence have not been reported to date; whether previous testosterone substitution affects testicular responses is unresolved. We aimed to assess the effects of human chorionic gonadotropin (hCG) and recombinant FSH (rFSH) in boys and adolescents with HH with respect to a) testicular growth, b) spermatogenesis, c) quality of life (QoL) and to identify factors influencing therapeutic success. A prospective case study was conducted in 26 paediatric endocrine centres PATIENTS/INTERVENTIONS: HCG and rFSH were administered until cessation of testicular growth and plateauing of spermatogenesis to (1) prepubertal HH boys with absent or early arrested puberty (group A) and to (2) HH adolescents who had previously received full testosterone replacement (group B). Bi-testicular volumes (BTVs), sperm concentrations and QoL. Sixty (34 A/26 B) HH patients aged 14-22 years were enrolled. BTVs rose from 5 ± 5 to 34 ± 3 ml in group A vs 5 ± 3 to 32 ± 3 ml in group B, with normal final BTVs (≥24 ml) attained in 74%/70% after 25/23 months in A/B, respectively. Sperm in the ejaculate were found in 21/23(91%)/18/19(95%), with plateauing concentrations after 31/30 months of hCG and 25/25 months of combined treatment in A/B. Sperm concentrations were normal (≥15 mill/ml) in 61%/32%, with mean concentrations of 40 ± 73 vs 19 ± 38 mill/ml in A/B (n.s.). Outcomes were better in patients without bilateral cryptorchidism, with non-congenital HH causes, higher baseline BTVs, and higher baseline inhibin B and AMH levels. QoL increased in both groups. HCG/rFSH replacement during adolescence successfully induces testicular growth and spermatogenesis, irrespective of previous testosterone replacement, and enhances QoL. © 2016 John Wiley & Sons Ltd.

Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities.

PubMed

Mroske, Cameron; Rasmussen, Kristen; Shinde, Deepali N; Huether, Robert; Powis, Zoe; Lu, Hsiao-Mei; Baxter, Ruth M; McPherson, Elizabeth; Tang, Sha

2015-11-05

In humans, Mammalian Target of Rapamycin (MTOR) encodes a 300 kDa serine/ threonine protein kinase that is ubiquitously expressed, particularly at high levels in brain. MTOR functions as an integrator of multiple cellular processes, and in so doing either directly or indirectly regulates the phosphorylation of at least 800 proteins. While somatic MTOR mutations have been recognized in tumors for many years, and more recently in hemimegalencephaly, germline MTOR mutations have rarely been described. We report the successful application of family-trio Diagnostic Exome Sequencing (DES) to identify the underlying molecular etiology in two brothers with multiple neurological and developmental lesions, and for whom previous testing was non-diagnostic. The affected brothers, who were 6 and 23 years of age at the time of DES, presented symptoms including but not limited to mild Autism Spectrum Disorder (ASD), megalencephaly, gross motor skill delay, cryptorchidism and bilateral iris coloboma. Importantly, we determined that each affected brother harbored the MTOR missense alteration p.E1799K (c.5395G>A). This exact variant has been previously identified in multiple independent human somatic cancer samples and has been shown to result in increased MTOR activation. Further, recent independent reports describe two unrelated families in whom p.E1799K co-segregated with megalencephaly and intellectual disability (ID); in both cases, p.E1799K was shown to have originated due to germline mosaicism. In the case of the family reported herein, the absence of p.E1799K in genomic DNA extracted from the blood of either parent suggests that this alteration most likely arose due to gonadal mosaicism. Further, the p.E1799K variant exerts its effect by a gain-of-function (GOF), autosomal dominant mechanism. Herein, we describe the use of DES to uncover an activating MTOR missense alteration of gonadal mosaic origin that is likely to be the causative mutation in two brothers who present multiple neurological and developmental abnormalities. Our report brings the total number of families who harbor MTOR p.E1799K in association with megalencephaly and ID to three. In each case, evidence suggests that p.E1799K arose in the affected individuals due to gonadal mosaicism. Thus, MTOR p.E1799K can now be classified as a pathogenic GOF mutation that causes megalencephaly and cognitive impairment in humans.

Hemizygosity at the IGF1R locus correlates with growth delay in the ring chromosome 15 syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peoples, R.; Francke, U.

1994-09-01

The ring 15 syndrome is characterized by intrauterine growth retardation, mental retardation, postnatal growth failure, triangular facies, 5th finger clinodactyly, leg-length discrepancy, cafe-au-lait spots and cryptorchidism. The degree of short stature varies from mild to severe and is associated with normal growth hormone and IGF-1 levels, but a wide range of bone age delay. These children retain de novo rings with breakpoints in the short arm at 15p12-11 and in the long arm at 15q26, the region to which the insulin-like growth factor type 1 receptor (IGFIR) has been mapped. We investigated if the degree of growth failure correlates withmore » disruption loss of the IGF1R gene. Ring breakpoints for all patients were determined by typing of RFLP and microsatellite markers from distal 15q for patients and their parents. The order of the loci studied is cen-IVD-FES-D15S130-E15S107-D15S87-D15S86-D15S3. All breakpoints mapped distal to D15S100. Presence or absence of the IGF1R gene on the ring chromsomes of five patients was ascertained by in situ hybridization and gene dosage blots using probes for the more proximally located genes IVD and c-Fes as controls. Heterozygosity for one patient was also confirmed by typing of a polymorphism in the 3{prime} UTR of IGF1R. Two patients who retained the IGF1R were hemizygous at D15S87 while two lacking the IGF1R retained D15S107 indicating that the IGF1R maps between these two markers. Three of the patients with severe growth failure (more than 4 SDs below the mean) were hemizygous at the IGF1R locus while the patient with borderline short stature had two copies of the IGF1R; she was subsequently found to be growth hormone deficient and has demonstrated a response to therapy. Our finding of severe short stature correlating with loss of one copy of the IGF1R suggests a potential role for heterozygous IGF1R mutations in other cases of unexplained growth failure.« less

Local cluster of germ cell cancer in a cohort of male automotive workers in Germany not explained by previous or concurrent activities and exposures in farming and forestry.

PubMed

Schmeisser, N; Behrens, T; Mester, B; Gottlieb, A; Langner, I; Ahrens, W

2011-02-01

To examine whether exposures or activities in farming, forestry and related occupations explain the excess incidence of germ cell cancer (GCC) observed among male employees in one of the six car-manufacturing plants that is located in a geographic area where farming is frequent. A cohort based case-control study was conducted among workers in six car-manufacturing plants located in areas with different industrial structure. The study involved 188 cases of germ cell cancer identified through active retrieval in 38 hospitals and 1000 controls, drawn from administrative accounting files, individually matched by year of birth (± 2 years). Information regarding tasks and exposures and potential confounding variables were obtained by face-to-face or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using a conditional logistic regression model adjusted for cryptorchidism and other potential confounders. In this case-control study 5.3% of cases and 6.3% of controls ever worked in agriculture or livestock farming. No increased risks were observed for working in agriculture (OR=0.8 95% CI: 0.4-1.6), livestock farming (OR=0.8 95% CI: 0.4-1.6) or for exposure to pesticides (OR=0.7 95% CI: 0.3-1.7), for exposure to fertilizers (OR=0.8 95% CI: 0.4-1.8) and disinfectants (OR=1.0 95% CI: 0.3-2.8). There were no statistically significant increases in risk associated with ever exposure to salt based wood protection agents (OR=2.3 95% CI: 0.6-9.1), working with plywood (OR=1.4 95% CI: 0.6-3.2), coated wood (OR=1.4 95% CI: 0.5-3.9) or working in forestry (OR=1.7 95% CI: 0.5-6.4). Lagging of exposures did not alter the results. The observed excess incidence in the cohort of automotive workers can be hardly explained by previous or concurrent work in farming or forestry. Because of the small numbers of subjects ever employed in farming the statistical power in assessing associations between agricultural work and agricultural exposures was limited and does not allow final conclusions about the association of farming related exposures and GCC risk. Copyright © 2010 Elsevier Ltd. All rights reserved.

Clinical analysis of anti-Ma2-associated encephalitis.

PubMed

Dalmau, Josep; Graus, Francesc; Villarejo, Alberto; Posner, Jerome B; Blumenthal, Deborah; Thiessen, Brian; Saiz, Albert; Meneses, Patricio; Rosenfeld, Myrna R

2004-08-01

Increasing experience indicates that anti-Ma2-associated encephalitis differs from classical paraneoplastic limbic or brainstem encephalitis, and therefore may be unrecognized. To facilitate its diagnosis we report a comprehensive clinical analysis of 38 patients with anti-Ma2 encephalitis. Thirty-four (89%) patients presented with isolated or combined limbic, diencephalic or brainstem dysfunction, and four with other syndromes. Considering the clinical and MRI follow-up, 95% of the patients developed limbic, diencephalic or brainstem encephalopathy. Only 26% had classical limbic encephalitis. Excessive daytime sleepiness affected 32% of the patients, sometimes with narcolepsy-cataplexy and low CSF hypocretin. Additional hormonal or MRI abnormalities indicated diencephalic-hypothalamic involvement in 34% of the patients. Eye movement abnormalities were prominent in 92% of the patients with brainstem dysfunction, but those with additional limbic or diencephalic deficits were most affected; 60% of these patients had vertical gaze paresis that sometimes evolved to total external ophthalmoplegia. Three patients developed atypical parkinsonism, and two a severe hypokinetic syndrome with a tendency to eye closure and dramatic reduction of verbal output. Neurological symptoms preceded the tumour diagnosis in 62% of the patients. Brain MRI abnormalities were present in 74% of all patients and 89% of those with limbic or diencephalic dysfunction. Among the 34 patients with cancer, 53% had testicular germ-cell tumours. Two patients without evidence of cancer had testicular microcalcification and one cryptorchidism, risk factors for testicular germ-cell tumours. After neurological syndrome development, 17 of 33 patients received oncological treatment (nine also immunotherapy), 10 immunotherapy alone, and six no treatment. Overall, 33% of the patients had neurological improvement, three with complete recovery; 21% had long-term stabilization, and 46% deteriorated. Features significantly associated with improvement or stabilization included, male gender, age <45 years, testicular tumour with complete response to treatment, absence of anti-Ma1 antibodies and limited CNS involvement. Immunosuppression was not found to be associated with improvement but was clearly effective in some patients. Fifteen patients (10 women, five men) had additional antibodies to Ma1. These patients were more likely to have tumours other than testicular cancer and to develop ataxia, and had a worse prognosis than patients with only anti-Ma2 antibodies (two women, 21 men); 67% of deceased patients had anti-Ma1 antibodies. Anti-Ma2 encephalitis (with or without anti-Ma1 antibodies) should be suspected in patients with limbic, diencephalic or brainstem dysfunction, MRI abnormalities in these regions, and inflammatory changes in the CSF. In young male patients, the primary tumour is usually in the testis, in other patients the leading neoplasm is lung cancer.

Psychopathological features in Noonan syndrome.

PubMed

Perrino, Francesca; Licchelli, Serena; Serra, Giulia; Piccini, Giorgia; Caciolo, Cristina; Pasqualetti, Patrizio; Cirillo, Flavia; Leoni, Chiara; Digilio, Maria Cristina; Zampino, Giuseppe; Tartaglia, Marco; Alfieri, Paolo; Vicari, Stefano

2018-01-01

Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, skeletal and haematological/lymphatic defects, distinctive facies, cryptorchidism, and a wide spectrum of congenital heart defects. Recurrent features also include variable cognitive deficits and behavioural problems. Recent research has been focused on the assessment of prevalence, age of onset and characterization of psychiatric features in this disorder. Herein, we evaluated the prevalence of attention deficit and hyperactivity disorder (ADHD), anxiety and depressive symptoms and syndromes in a cohort of individuals with clinical and molecular diagnosis of NS. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS PL) has been used for the assessment of psychiatric disorders according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Multidimensional Anxiety Scale for Children (MASC) and the Children's Depression Inventory (CDI) have been assessed for the evaluation of anxiety and depressive symptoms and syndromes, whereas Conners Teacher and Parent Rating Scales-long version (CRS-R) have been used to evaluate ADHD. The study included 27 individuals (67% males) with an average age of 10.4 years (range 6-18 years) receiving molecular diagnosis of NS or a clinically related condition, evaluated and treated at the Neuropsychiatric Unit of Children's Hospital Bambino Gesù and at the Center for Rare Diseases of Fondazione Policlinico Universitario Agostino Gemelli, in Rome. Twenty individuals showed mutations in PTPN11, five in SOS1 and two in SHOC2. The mean IQ was 94 (Standard Deviation = 17, min = 56, max = 130). Seventy percent of the individuals (n = 19; 95% Confidence Interval = 52-85%) showed ADHD features, with six individuals reaching DSM-IV-TR criteria for ADHD disorder, and thirteen showing subsyndromal traits. Symptoms or syndrome of anxiety were present in 37% of the cohort (n = 10; 95% Confidence Interval = 19-56%), with two individuals showing anxiety disorder and eight cases exhibiting subsyndromal traits. Our results show individuals with NS do present a very high risk to develop psychiatric disorders or symptoms during paediatric age. Based on these findings, preschool assessment of inattentive, hyperactivity/impulsivity and anxiety/depressive symptoms is recommended in order to plan a personalized treatment for psychological/psychiatric issues in affected individuals. Dedicated prospective studies are required to confirm the present data and better characterize the psychopathological profile in NS. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Transition in endocrinology: induction of puberty.

PubMed

Dunkel, Leo; Quinton, Richard

2014-06-01

Puberty is the period during which we attain adult secondary sexual characteristics and reproductive capability. Its onset depends upon reactivation of pulsative GNRH, secretion from its relative quiescence during childhood, on the background of intact potential for pituitary-gonadal function. This review is intended: to highlight those current practices in diagnosis and management that are evidence based and those that are not; to help clinicians deal with areas of uncertainty with reference to physiologic first principles; by sign-posting relevant data arising from other patient groups with shared issues; to illustrate how recent scientific advances are (or should be) altering clinician perceptions of pubertal delay; and finally, to emphasise that the management of men and women presenting in advanced adult life with absent puberty cannot simply be extrapolated from paediatric practice. There is a broad spectrum of pubertal timing that varies among different populations, separated in time and space. Delayed puberty usually represents an extreme of the normal, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP), but organic defects of the hypothalamo-pituitary-gonadal axis predisposing to hypogonadism may not always be initially distinguishable from it. CDGP and organic, or congenital hypogonadotrophic hypogonadism are both significantly more common in boys than girls. Moreover, around 1/3 of adults with organic hypogonadotrophic hypogonadism had evidence of partial puberty at presentation and, confusingly, some 5-10% of these subsequently may exhibit recovery of endogenous gonadotrophin secretion, including men with Kallmann syndrome. However, the distinction is crucial as expectative ('watch-and-wait') management is inappropriate in the context of hypogonadism. The probability of pubertal delay being caused by organic hypogonadism rises exponentially both with increasing age at presentation and the presence of associated 'red flag' clinical features. These 'red flags' comprise findings indicating lack of prior 'mini-puberty' (such as cryptorchidism or micropenis), or the presence of non-reproductive congenital defects known to be associated with specific hypogonadal syndromes, e.g. anosmia, deafness, mirror movements, renal agenesis, dental/digital anomalies, clefting or coloboma would be compatible with Kallmann (or perhaps CHARGE) syndrome. In children, interventions (whether in the form or treatment or simple reassurance) have been historically directed at maximising height potential and minimising psychosocial morbidity, though issues of future fertility and bone density potential are now increasingly 'in the mix'. Apubertal adults almost invariably harbour organic hypogonadism, requiring sensitive acknowledgement of underlying personal issues and the timely introduction of sex hormone replacement therapy at more physiological doses. © 2014 European Society of Endocrinology.

[Bernard Schapiro--an orthodox Jew as an early andrologist in the 20th century].

PubMed

Borgwardt, Götz

2002-01-01

The unusual history and professional background of one of the first andrologists is reported. Bernhard Schapiro, born in 1888 in Dvinsk in Latvia, then a city in the Russian Pale of Settlements for Jews, grew up as an orthodox (hassidic) Jew receiving exclusively talmudic lessons until he was 18 years old. During the final years of this period of life he was educated at the famous Slobodka Talmud Academy Kenesset Israel in Kovno where he absorbed the ideals of Musar-doctrines, thus being influenced for the rest of his life. The Rogachover Gaon J. Rozin supported his desire to study medicine. After a brief stay in Frankfurt/Main he acquired by own efforts the necessary general knowledge to matriculate for access to university. Medical studies at Zurich University (1913-1919) were followed by a one-year-internship at a dermatologic department in Breslau/Silesia. The thesis for his doctorate at Zurich University in 1920 was on, Relations between Nodular Erythema and Tuberculosis'. He spent two years training in dermatology at Breslau University under Jadassohn. Back in Berlin, he married and had four children, while he worked at Magnus Hirschfeld's Institute for Sexual Sciences. After initial clinical studies in venerology he more and more turned to andrological problems, including treatment of underdeveloped male genitals, premature ejaculation and impotence in general. In this context he tested the new drug Praehormon and developed the two remedies Testifortan and Praejaculin. He was the first to describe the effect of anterior pituitary lobe hormone on the descent of cryptorchid testicles, thus initiating a treatment modality still in motion today. When Hitler came to power he and his family were spared as Swiss citizens, but he lost his base for working after the Institute was looted. He established an andrologic practice at Zurich. What he had witnessed in Germany caused him to set up a Swiss branch of Mizrachi, the spiritually based center of Zionism in Switzerland. He left Europe in 1940 for New York/USA. After compulsory repetition of medical exams in a new language he managed to establish a new existence as andrologist. His practice flourished, the more as he was trusted to treat Jewish patients according to Jewish Law. The decisive step brought him to Jerusalem, in 1951, where he founded and headed an Endocrinologic Department of the University, pursuing andrologic questions, until his death on December 31, 1966. What actually controlled his life can be read on his tombstone: 'He remained a pupil of Slobodka all the days of his life'.

Regulatory Mechanism of Muscle Disuse Atrophy in Adult Rats

NASA Technical Reports Server (NTRS)

1993-01-01

During the last phase of NAG 2-386 we completed three studies. The effects of 14 days of weightlessness; the vastus medialis (VM) from flight rats in COSMOS 2044 was compared with the VM from tail suspended rats and other controls. The type I and II fibers in the mixed fiber portion of the VM were significantly reduced in flight rats and capillary densities paralleled the fiber density changes. The results of this project compared favorably with those in the extensor digitorum longus following seven days of flight in SL 3. The cardiovascular projects focused on the blood pressure changes in head down tilted rats (HDT) and non-head down tilted (N-HDT) rats. Blood pressures (MAP, SP and DP) were significantly elevated through seven days of HDT and rapidly returned to control levels within one day after removal from the HDT position. The N-HDT showed some slight rise in blood pressure but these were not as great and they were not as rapid. The HDT rats were characterized as exhibiting transient hypertension. These results led to some of the microvascular and vascular graduate student projects of Dr. Bernhard Stepke. Also our results refute or, at least, do not agree with previous reports from other laboratories. Each animal, in our blood pressure projects, served as its own control thereby providing more accurate results. Also, our experiments focused on recovery studies which can, in and of themselves, provide guidelines for flight experiments concerned with blood pressure changes. Another experiment was conducted to examine the role of testicular atrophy in whole body suspended (WBS) and tail suspended (TS) rats. We worked in conjunction with Dr. D.R. Deaver's laboratory at Pennsylvania State University and Dr. R. P. Amann at Colorado State University. In the TS rats the testes are retracted into the abdominal cavity, unless a ligature is placed to maintain them in the external scrotal sac. The cryptorchid condition in TS rats results in atrophy of the testes and lowered levels of spermatid formation. Hormonal changes due to testes atrophy must be considered in future experiments where related effects may modify muscle, bone or other tissue changes. Also, some new assessments of past results (published by many researchers) may warrant revised interpretations. The blood pressure studies and the testicular function results were presented and reviewed during an invited lecture at the University of Bordeaux II during the Animals in Space Symposium in March 1993. In summary, each of these three projects complied with the objectives of the proposal and serve to demonstrate the utility of animal models in preparations and interpretations of space flight results. All funding has been expended in accordance with the approved budget.

Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants.

PubMed

Fisher, B G; Thankamony, A; Hughes, I A; Ong, K K; Dunger, D B; Acerini, C L

2016-11-01

What is the relationship between maternal paracetamol intake during the masculinisation programming window (MPW, 8-14 weeks of gestation) and male infant anogenital distance (AGD), a biomarker for androgen action during the MPW? Intrauterine paracetamol exposure during 8-14 weeks of gestation is associated with shorter AGD from birth to 24 months of age. The increasing prevalence of male reproductive disorders may reflect environmental influences on foetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces foetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism. Prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 676 delivered male infants and completed a medicine consumption questionnaire. Mothers self-reported medicine consumption during pregnancy by a questionnaire administered during the perinatal period. Infant AGD (measured from 2006 onwards), penile length and testicular descent were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between paracetamol intake during three gestational periods (<8 weeks, 8-14 weeks and >14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of six hundred and eighty-one male infants were exposed to paracetamol during pregnancy, of whom sixty-eight were reported to be exposed during 8-14 weeks. AGD measurements were available for 434 male infants. Paracetamol exposure during 8-14 weeks of gestation, but not any other period, was associated with shorter AGD (by 0.27 SD, 95% CI 0.06-0.48, P = 0.014) from birth to 24 months of age. This reduction was independent of body size. Paracetamol exposure was not related to penile length or testicular descent. Confounding by other drugs or endocrine-disrupting chemicals cannot be discounted. The cohort was not fully representative of pregnant women in the UK, particularly in terms of maternal ethnicity and smoking prevalence. There is likely to have been misclassification of paracetamol exposure due to recall error. Our observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development. This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation for Disabled Children, the Evelyn Trust, the Mothercare Group Foundation, Mead Johnson Nutrition, and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. The authors declare no conflict of interest. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants

PubMed Central

Fisher, B.G.; Thankamony, A.; Hughes, I.A.; Ong, K.K.; Dunger, D.B.; Acerini, C.L.

2016-01-01

STUDY QUESTION What is the relationship between maternal paracetamol intake during the masculinisation programming window (MPW, 8–14 weeks of gestation) and male infant anogenital distance (AGD), a biomarker for androgen action during the MPW? SUMMARY ANSWER Intrauterine paracetamol exposure during 8–14 weeks of gestation is associated with shorter AGD from birth to 24 months of age. WHAT IS ALREADY KNOWN The increasing prevalence of male reproductive disorders may reflect environmental influences on foetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces foetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism. STUDY DESIGN, SIZE, DURATION Prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 676 delivered male infants and completed a medicine consumption questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHOD Mothers self-reported medicine consumption during pregnancy by a questionnaire administered during the perinatal period. Infant AGD (measured from 2006 onwards), penile length and testicular descent were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between paracetamol intake during three gestational periods (<8 weeks, 8–14 weeks and >14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of six hundred and eighty-one male infants were exposed to paracetamol during pregnancy, of whom sixty-eight were reported to be exposed during 8–14 weeks. AGD measurements were available for 434 male infants. MAIN RESULTS AND THE ROLE OF CHANCE Paracetamol exposure during 8–14 weeks of gestation, but not any other period, was associated with shorter AGD (by 0.27 SD, 95% CI 0.06–0.48, P = 0.014) from birth to 24 months of age. This reduction was independent of body size. Paracetamol exposure was not related to penile length or testicular descent. LIMITATIONS, REASONS FOR CAUTION Confounding by other drugs or endocrine-disrupting chemicals cannot be discounted. The cohort was not fully representative of pregnant women in the UK, particularly in terms of maternal ethnicity and smoking prevalence. There is likely to have been misclassification of paracetamol exposure due to recall error. WIDER IMPLICATIONS OF THE FINDINGS Our observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development. STUDY FUNDING/COMPETING INTERESTS This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation for Disabled Children, the Evelyn Trust, the Mothercare Group Foundation, Mead Johnson Nutrition, and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. The authors declare no conflict of interest. PMID:27609981

Causes of male infertility: a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts.

PubMed

Punab, M; Poolamets, O; Paju, P; Vihljajev, V; Pomm, K; Ladva, R; Korrovits, P; Laan, M

2017-01-01

What are the primary causes of severe male factor infertility? Although 40% of all patients showed primary causes of infertility, which could be subdivided into three groups based on the severity of their effect, ~75% of oligozoospermia cases remained idiopathic. There are few large-scale epidemiological studies analyzing the causes of male factor infertility. A prospective clinical-epidemiological study was conducted at the Andrology Centre, Tartu University Hospital between 2005 and 2013, recruiting male partners of couples failing to conceive a child for over ≥12 months. Among 8518 patients, 1737 (20.4%) were diagnosed with severe male factor infertility. A reference group of fertile controls was comprised of 325 partners of pregnant women. The mean age of infertility patients and fertile controls was 33.2 ± 7.3 and 31.7 ± 6.3 years, respectively. All participants were examined using a standardized andrology workup, accompanied by a structured medical interview. Hormonal analysis included serum FSH, LH and testosterone. Semen quality was determined in accordance to the World Health Organization recommendations. Cases with spermatozoa concentrations of ≤5 million/ml were screened for chromosomal aberrations and Y-chromosomal microdeletions. The primary cause of infertility was defined for 695 of 1737 patients (~40%). The analyzed causal factors could be divided into absolute (secondary hypogonadism, genetic causes, seminal tract obstruction), severe (oncological diseases, severe sexual dysfunction) and plausible causal factors (congenital anomalies in uro-genital tract, acquired or secondary testicular damage). The latter were also detected for 11 (3.4%) men with proven fertility (diagnoses: unilateral cryptorchidism, testis cancer, orchitis, mumps orchitis). The causal factors behind the most severe forms of impaired spermatogenesis were relatively well understood; causes were assigned: for aspermia in 46/46 cases (100%), for azoospermia in 321/388 cases (82.7%), and for cryptozoospermia in 54/130 cases (41.5%). In contrast, 75% of oligozoospermia cases remained unexplained. The main cause of aspermia was severe sexual dysfunction (71.7% of aspermia patients). Azoospermia patients accounted for 86.4% of all cases diagnosed with secondary hypogonadism and 97.1% of patients with seminal tract obstruction. Of patients with a known genetic factor, 87.4% had extreme infertility (azoo-, crypto- or aspermia). The prevalence of congenital anomalies in the uro-genital tract was not clearly correlated with the severity of impaired sperm production. Previously defined 'potential contributing factors' varicocele and leukocytospermia were excluded as the primary causes of male infertility. However, their incidence was >2-fold higher (31.0 vs 13.5% and 16.1 vs 7.4%; P < 0.001) in the idiopathic infertility group compared to controls. In addition, the proportions of overweight (or obese) patients and patients suffering from a chronic disease were significantly increased in almost all of the patient subgroups. The study included only subjects with reduced total spermatozoa counts. Thus, these findings cannot be automatically applied to all male factor infertility cases. The novel insights and improved clarity achieved in the comprehensive analysis regarding the absolute, causative and plausible factors behind male infertility, as well as the 'potential contributing factors', will be valuable tools in updating the current clinical guidelines. The study highlights knowledge gaps and reiterates an urgent need to uncover the causes and mechanisms behind, and potential treatments of, oligozoospermic cases, representing the majority of idiopathic infertility patients (86.3%). The project was financed by the EU through the ERDF, project HAPPY PREGNANCY, no. 3.2.0701.12-004 (M.P., M.L.) and the Estonian Research Council: grants PUT181 (M.P.) and IUT34-12 (M.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We have no competing interests to declare. TRAIL  REGISTRATION NUMBER: Not applicable. ©The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Maternal use of mild analgesics during pregnancy associated with reduced anogenital distance in sons: a cohort study of 1027 mother-child pairs.

PubMed

Lind, Dorte Vesterholm; Main, Katharina M; Kyhl, Henriette Boye; Kristensen, David Møbjerg; Toppari, Jorma; Andersen, Helle Raun; Andersen, Marianne Skovsager; Skakkebæk, Niels E; Jensen, Tina Kold

2017-01-01

Is maternal use of mild analgesics in pregnancy associated with anogenital distance (AGD)-the distance from the anus to the genitals-in the offspring? Maternal use of mild analgesics [especially simultaneous use of paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs)] during pregnancy was associated with a shorter AGD in boys whereas no effect was found in girls. Mild analgesics including paracetamol (acetaminophen) and NSAIDs (e.g. ibuprofen and acetyl salicylic acid) have endocrine disrupting properties and in utero exposure reduces AGD in male rats. In humans, maternal exposure has been associated with cryptorchidism and hypospadias in male offspring but no studies have examined AGD. A prospective birth cohort study. Between 2010 and 2012, 2500 pregnant women were recruited from the Odense Child Cohort. Children were examined 3 months after the expected date of birth. Pregnant women were asked about use of medication including mild analgesics (paracetamol and NSAID) during pregnancy at recruitment (gestational age (GA) week 10-27) and at GA week 28. AGD and penile width were measured 3 months after expected date of birth by trained personnel. A total of 1027 women answered both questionnaires and their children were examined. Associations between prenatal exposure to mild analgesics and AGD and penile width were estimated using multivariable linear regression adjusting for age and weight-for-age SD score. A total of 40% of the women reported use of paracetamol and/or NSAIDs (4.4%) during the first 28 weeks of pregnancy. Exposure to analgesics during pregnancy was associated with a reduced AGD in boys, although statistically significant only for NSAIDs. The association was significant among 20 boys exposed to both paracetamol and NSAIDs (AGD -4.1 mm; CI 95%: -6.4; -1.7). Maternal intake of analgesics did not show any clear association with AGD in female offspring. No effect on penile width was found. Only 27 boys and 18 girls were exposed to NSAIDs and most of them were also exposed to paracetamol. This makes it impossible to distinguish between exposures to NSAIDs alone and a potential mixture effect. Moreover, use of mild analgesics was self-reported up to 2 months after intake, which could have caused misclassification of exposure but is probably not associated with AGD as this was unknown to the women at time of reply to the questionnaire thereby underestimating the association. Confounding by indication may also explain our findings, as the condition for which the analgesic was taken may be associated with a reduction in AGD, rather than the use of the analgesic medication. This is the first study to report such an association in humans and further studies are needed to confirm our findings. A negative association was observed between exposure to analgesics during pregnancy and AGD in boys, suggesting disruption of androgen action. The health implications of a shorter AGD are still uncertain, but in cross-sectional studies among adult men a shorter AGD is associated with poorer semen quality and lower testosterone. As 41% of the women used these painkillers the finding are of public health importance and pregnant women should be advised about the potentially harmful effects of painkiller use. The study was funded by the Danish Environmental Protection Agency by way of the Center on Endocrine Disruptors Danish Center for Hormone Disrupting Chemicals, the Danish Foundation for Scientific Innovation and Technology (09-067180), the Danish Research Council (4004-00352B_FSS), Novo Nordic Foundation (NNF15OC0017734), Ronald McDonald Children Foundation, K.A. Rohde's and wife's Foundation, Odense University Hospital and Region of Southern Denmark, Municipality of Odense, the Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense University Hospital Research Foundation and Odense Patient data Exploratory Network (OPEN). The authors declare they have no competing interests. Not applicable. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Causes of male infertility: a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts

PubMed Central

Punab, M.; Poolamets, O.; Paju, P.; Vihljajev, V.; Pomm, K.; Ladva, R.; Korrovits, P.; Laan, M.

2017-01-01

STUDY QUESTION What are the primary causes of severe male factor infertility? SUMMARY ANSWER Although 40% of all patients showed primary causes of infertility, which could be subdivided into three groups based on the severity of their effect, ~75% of oligozoospermia cases remained idiopathic. WHAT IS KNOWN ALREADY There are few large-scale epidemiological studies analyzing the causes of male factor infertility. STUDY DESIGN, SIZE, DURATION A prospective clinical-epidemiological study was conducted at the Andrology Centre, Tartu University Hospital between 2005 and 2013, recruiting male partners of couples failing to conceive a child for over ≥12 months. Among 8518 patients, 1737 (20.4%) were diagnosed with severe male factor infertility. A reference group of fertile controls was comprised of 325 partners of pregnant women. PARTICIPANTS/MATERIALS, SETTING, METHODS The mean age of infertility patients and fertile controls was 33.2 ± 7.3 and 31.7 ± 6.3 years, respectively. All participants were examined using a standardized andrology workup, accompanied by a structured medical interview. Hormonal analysis included serum FSH, LH and testosterone. Semen quality was determined in accordance to the World Health Organization recommendations. Cases with spermatozoa concentrations of ≤5 million/ml were screened for chromosomal aberrations and Y-chromosomal microdeletions. MAIN RESULTS AND THE ROLE OF CHANCE The primary cause of infertility was defined for 695 of 1737 patients (~40%). The analyzed causal factors could be divided into absolute (secondary hypogonadism, genetic causes, seminal tract obstruction), severe (oncological diseases, severe sexual dysfunction) and plausible causal factors (congenital anomalies in uro-genital tract, acquired or secondary testicular damage). The latter were also detected for 11 (3.4%) men with proven fertility (diagnoses: unilateral cryptorchidism, testis cancer, orchitis, mumps orchitis). The causal factors behind the most severe forms of impaired spermatogenesis were relatively well understood; causes were assigned: for aspermia in 46/46 cases (100%), for azoospermia in 321/388 cases (82.7%), and for cryptozoospermia in 54/130 cases (41.5%). In contrast, 75% of oligozoospermia cases remained unexplained. The main cause of aspermia was severe sexual dysfunction (71.7% of aspermia patients). Azoospermia patients accounted for 86.4% of all cases diagnosed with secondary hypogonadism and 97.1% of patients with seminal tract obstruction. Of patients with a known genetic factor, 87.4% had extreme infertility (azoo-, crypto- or aspermia). The prevalence of congenital anomalies in the uro-genital tract was not clearly correlated with the severity of impaired sperm production. Previously defined ‘potential contributing factors’ varicocele and leukocytospermia were excluded as the primary causes of male infertility. However, their incidence was >2-fold higher (31.0 vs 13.5% and 16.1 vs 7.4%; P < 0.001) in the idiopathic infertility group compared to controls. In addition, the proportions of overweight (or obese) patients and patients suffering from a chronic disease were significantly increased in almost all of the patient subgroups. LIMITATIONS REASONS FOR CAUTION The study included only subjects with reduced total spermatozoa counts. Thus, these findings cannot be automatically applied to all male factor infertility cases. WIDER IMPLICATIONS OF THE FINDINGS The novel insights and improved clarity achieved in the comprehensive analysis regarding the absolute, causative and plausible factors behind male infertility, as well as the ‘potential contributing factors’, will be valuable tools in updating the current clinical guidelines. The study highlights knowledge gaps and reiterates an urgent need to uncover the causes and mechanisms behind, and potential treatments of, oligozoospermic cases, representing the majority of idiopathic infertility patients (86.3%). STUDY FUNDING/COMPETING INTEREST(S) The project was financed by the EU through the ERDF, project HAPPY PREGNANCY, no. 3.2.0701.12-004 (M.P., M.L.) and the Estonian Research Council: grants PUT181 (M.P.) and IUT34-12 (M.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We have no competing interests to declare. TRAIL  REGISTRATION NUMBER Not applicable PMID:27864361