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Mild Gestational Diabetes as a Risk Factor for Congenital Cryptorchidism
Abstract
Cryptorchidism is the most common malformation in newborn boys. Maternal diabetes has previously been suggested to be a risk factor for this disorder in one epidemiological study.
Evaluation of the prevalence of maternal glucose metabolism disorders during pregnancy in newborn boys having normal testicular descent or congenital cryptorchidism.
Postnatal analysis of maternal history concerning glucose metabolism abnormalities during pregnancy among cryptorchid and healthy Finnish boys.
The material of this case-control study comprises 1163 boys with normal testicular descent at birth and 125 boys with congenital cryptorchidism. All these singleton Finnish boys were born in Turku University Central Hospital (1997-2001) and were examined at birth and/or at the expected date of delivery.
Information about maternal diabetes diagnosis and abnormality of the result of a 2-h 75-g oral glucose tolerance test during pregnancy were obtained from the hospital records after delivery.
After adjustment for possible confounding factors, i.e. maternal smoking during pregnancy, maternal age at delivery, and risk factors of cryptorchidism, e.g. prematurity and weight for gestational age, abnormal maternal glucose metabolism was significantly more common in the group of cryptorchid boys [diet-treated gestational diabetes, P = 0.0001; odds ratio, 3.98 (95% confidence interval, 1.97-8.05); diet-treated gestational diabetes or only an abnormal result in oral glucose tolerance test, P = 0.0016; odds ratio, 2.44 (95% confidence interval, 1.40-4.25)] when compared with boys with normal testicular descent.
Mildly abnormal glucose metabolism during pregnancy was associated with an increased risk for congenital cryptorchidism. The mechanism remains to be elucidated.
... The effects of GDM on newborns appear during the neonatal period or early childhood [2]. Previous studies have shown that prolonged fetal exposure to hyperglycemia during pregnancy not only could change neonatal metabolic profile at birth [2,3] but also might increase the risk for cryptorchidism in male offspring [4]. The mechanism underlying the increased risk remains to be elucidated [4]. ...
... Previous studies have shown that prolonged fetal exposure to hyperglycemia during pregnancy not only could change neonatal metabolic profile at birth [2,3] but also might increase the risk for cryptorchidism in male offspring [4]. The mechanism underlying the increased risk remains to be elucidated [4]. ...
... A previous study showed that GDM might be associated with an increased risk for congenital cryptorchidism [4]. However, the exact mechanism was not explored. ...
The prevalence of Gestational diabetes mellitus (GDM) is increasing rapidly. In addition to the metabolic disease risks, GDM might increase the risks of cryptorchidism in children. However, its mechanism involved in abnormalities of the male reproductive system is still unclear. The purpose of this study was to study the effects of GDM on the development of mouse fetal Leydig and Sertoli cells. Pregnant mice were treated on gestational day (GD) 6.5 and 12.5 with streptozotocin (STZ, 100 mg/kg) or vehicle (sodium citrate buffer). Leydig and Sertoli cell development and functions were evaluated by investigating serum testosterone levels, cell number and distribution, genes, and protein expression. GDM decreased serum testosterone levels, the anogenital distance, and the level of DHH in Sertoli cells of testes of male offspring. Fetal Leydig cell number was also decreased in testes of GDM offspring by delaying the commitment of stem Leydig cells into the Leydig cell lineage. RNA-seq showed that FOXL2, RSPO1/β-Catenin signaling was activated and Gsk3β signaling was inhibited in GDM offspring testis. In conclusion, GDM disrupted reproductive tract and testis development in mouse male offspring via altering genes related to development.
... Considering the systemic impact of hypoglycemia and metabolic acidosis [Faiyaz-Ul-Haque et al., 2009], especially in fetuses, this gene is an excellent candidate for further target analysis to better comprehend cryptorchidism in pigs. According to research by Virtanen et al. [2006], abnormal glucose metabolism is likely to increase the risk for congenital cryptorchidism in humans. ...
... In previous research, the pentose phosphate pathway had greater activity in cryptorchid testes than in normal ones [Ahotupa and Huhtaniemi, 1992]. In addition, abnormal glucose metabolism during pregnancy was associated with an increased risk of cryptorchidism in humans [Virtanen et al., 2006[Virtanen et al., , 2007. The FBP2 gene was also identified to be altered in the fetal testis after phthalate exposure, which could cause testicular dysgenesis [Liu et al., 2005]. ...
Introduction:
Cryptorchidism is a hereditary anomaly characterized by the incomplete descent of one or both testicles to the scrotum. One of the challenges of this anomaly is that the retained testicle maintains its endocrine function. As a consequence, cryptorchid animals produce hormone-tainted meat in comparison to castrated animals and are likely to be more aggressive. Cryptorchidism can lead to reduced animal welfare outcomes and cause economic losses. Identifying genetic markers for cryptorchidism is an essential step toward mitigating these negative outcomes and may facilitate genome manipulation to reduce the occurrence of cryptorchidism. Attempts to identify such markers have used genome-wide association studies. Using whole-exome sequencing, we aimed to identify single nucleotide polymorphisms (SNPs) in the coding regions of cryptorchid pigs and to characterize functional pathways concerning these SNPs.
Methods:
DNA was extracted and sequenced from 5 healthy and 5 cryptorchid animals from the Landrace breed, using the Illumina HiSeq 2500 platform. Data were pre-processed using the SeqyClean tool and further mapped against the swine reference genome (Sus scrofa 11.1) using BWA software. GATK was used to identify polymorphisms (SNPs and InDels), which were annotated using the VEP tool. Network prediction and gene ontology enrichment analysis were conducted using the Cytoscape platform, and STRING software was used for visualization.
Results:
A total of 63 SNPs were identified across the genes PIGB, CCPG1, COMMD9, LDLRAD3, TRIM44, MYLPF, SEPTIN, ZNF48, TIA1, FAIM2, KRT18, FBP1, FBP2, CTSL, DAPK1, DHX8, GPR179, DEPDC1B, ENSSSCG00000049573, ENSSSCG00000016384, ENSSSCG00000022657, ENSSSCG00000038825, and ENSSSCG00000001229. Using pathway enrichment analyses and network prospection, we have identified the following significant adjusted p value threshold of 0.001 involved with the biological function pathways of estrogen signaling, cytoskeleton organization, and the pentose phosphate pathway.
Conclusion:
Our data suggest the involvement of new SNPs and genes in developing cryptorchidism in pigs. However, further studies are needed to validate our results in a larger cohort population. Variations in the GPR179 gene, with implications at the protein level, may be associated with the appearance of this anomaly in the swine. Finally, we are showing that the estrogen signaling pathway may be involved in the pathophysiological mechanisms of this congenital anomaly as previously reported in GWAS.
... Abnormal maternal glucose metabolism in pregnancy may be associated with an increased risk of genital malformation for the male offspring [8,43]. In women with gestational diabetes, the risk of delivering a male infant with cryptorchidism is increased by a factor of four compared to women without diabetes [43]. ...
... Abnormal maternal glucose metabolism in pregnancy may be associated with an increased risk of genital malformation for the male offspring [8,43]. In women with gestational diabetes, the risk of delivering a male infant with cryptorchidism is increased by a factor of four compared to women without diabetes [43]. It is postulated that early growth delay of the foetus in the first trimester might play a role. ...
... All these studies had provided pertinent statistical data on the association between maternal smoking during pregnancy and risk of cryptorchidism; the selection process and flow diagram are shown in detail in Fig. 1. These 20 studies comprised 5 cohort studies [11,14,25,33,42] and 15 case-control studies [1,2,5,7,9,10,12,30,32,34,41]. Case-control studies nested with cohort study were regarded as a case- control study here [6,28,36]. ...
... Both the pooled studies and subgroups were of low heterogeneity (pooled studies, I 2 = 30%, p = 0.10; cohort studies: I 2 = 36%, p = 0.18; case-control studies: I 2 = 28%, p = 0.15). By preparing a funnel plot, we could easily find the article (Virtanen et al. [41]) that contributed to the heterogeneity the most. We organized a sensitivity analysis, after eliminating the abovementioned article, and the pooled crude OR was 1.19, with 95% CI of 1.13-1.25 (p < 0.0001; and I 2 = 0%, p = 0.75) for the same outcome with perfect homogeneity. ...
The risk factors for undescended testes in male infants and the underlying pathogenesis still remain unclear. The aim of this study is to identify the relationship between maternal smoking during pregnancy and risk of cryptorchidism. A systematic review was conducted using appropriate search terms to identify articles pertaining to maternal smoking during pregnancy and risk of cryptorchidism. Entries up to December 23, 2017 were taken into consideration, without any language or regional restriction. The crude ORs and their 95% CIs were computed by using the fixed-effect model. Twenty studies involving 111,712 infants were included in our meta-analysis. The risk of having a male infant with cryptorchidism was significantly different between mothers who smoked during pregnancy and those who did not (pooled crude OR 1.18, 95% confidence interval [CI] 1.12–1.24, p < 0.00001).
Conclusion: Our findings suggest that smoking during pregnancy increased the risk of cryptorchidism by 1.18 times. Further investigations that are well-designed, multicentric studies measuring variables, such as the number of cigarettes smoked in a day and the stage of pregnancy during which the mothers smoked, are necessary to precisely determine the relationship between maternal smoking and risk of cryptorchidism.What is Known:
• Preterm and low birth weight have been definitively shown to be risk factors for cryptorchidism.
• The relationship between with maternal smoking during pregnancy and risk of cryptorchidism remains controversial all the time.
What is New:
• Mothers who smoked during pregnancy had a 1.18 times higher risk of having a child with cryptorchidism as compared to those who did not smoke.
• Evidence has been found that maternal smoking during pregnancy is a definitive risk factor for cryptorchidism.
... Smoking is thought to induce hypoxia in the fetus caused by the vasoconstrictive effects of nicotine 55 but contains thousands of other potentially toxic chemicals 56 and is also associated with deficient or altered androgen signaling. 57 Although the majority of existing literature does not support an association between smoking and cryptorchidism, 8,9,[12][13][14]17,19,[23][24][25][27][28][29][30][31]34,35 our results are consistent with five previous studies, 7,11,22,26 including those of a large Danish pregnancy cohort study by Jensen et al 22 that also found a higher risk among sons exposed to >10 cigarettes/day. Alcohol consumption during pregnancy is suspected to modify sex hormone levels in utero, which are essential for the descent of the testes. ...
... 62 In case of cryptorchidism, results have been mixed with some showing an association, whereas others not. 6,9,10,12,14,16,18,[23][24][25][26]31,33,34,63 A recent register-based Swedish study by Arendt et al, 63 including 1,055,705 boys, found results similar to ours regarding cryptorchidism and obesity. ...
Purpose
Cryptorchidism is the most frequent congenital malformation in boys and is associated with low sperm count, infertility and testicular cancer. Unhealthy maternal lifestyle during pregnancy such as smoking, high prepregnancy body mass index (BMI) as well as alcohol and caffeine intake may constitute possible risk factors for cryptorchidism, but results from the few previous studies are conflicting. We aimed to explore the association between maternal lifestyle factors and occurrence of cryptorchidism in sons.
Patients and methods
The Danish National Birth Cohort and the Aarhus Birth Cohort provided information on maternal lifestyle from early pregnancy. Data were linked to several Danish health registers, multiple imputation was used to handle missing data and Cox proportional hazards models were used to adjust for potential confounders.
Results
In total, 85,923 boys were included, and of them, 2.2% were diagnosed with cryptorchidism. We observed the strongest associations between maternal tobacco smoking and prepregnancy BMI and cryptorchidism. Sons of women who smoked 10–14 cigarettes/day had the highest hazard ratio (HR) for cryptorchidism (1.37; 95% CI: 1.06–1.76), and for maternal BMI ≥30 kg/m², the HR was 1.32 (95% CI: 1.06–1.65). Binge drinking was associated with an HR <1, if the women had one or two episodes in pregnancy (HR: 0.81; 95% CI: 0.67–0.98). Average maternal alcohol intake and caffeine intake during pregnancy were not significantly associated with a higher occurrence of cryptorchidism detected at birth or later in life.
Conclusion
Maternal tobacco smoking, overweight and obesity in pregnancy were associated with higher occurrence of cryptorchidism in boys in this study.
... Clinical examinations included the measurement of height, weight, and waist and hip circumference. Furthermore, testicular size and urogenital status was recorded, including testicular descent as GDM has been associated with an increased risk for abnormal testicular descent, i.e. cryptorchidism [16]. Twenty-five boys were exposed to metformin in utero, and 27 boys were born to mothers treated with insulin during pregnancy. ...
... Only one boy out of 52 (1.9%) had a history of congenital cryptorchidism, which is in line with the previously described prevalence of this condition in the Turku area in Finland (2.4% at birth and 1.0% at the age of three months) [29]. Mild, diet-treated GDM has been shown to be associated with an increased risk of congenital cryptorchidism [16]. There is no information concerning the association of metformin and cryptorchidism. ...
Objectives:
Studies in rodents suggest that metformin treatment during pregnancy may have harmful effects on testicular development in offspring. Our aim was to determine whether metformin treatment of gestational diabetes mellitus (GDM) affects testicular size in male offspring.
Methods:
We compared the testicular size in prepubertal boys born to mothers who participated in a randomized controlled trial (RCT) comparing metformin with insulin in the treatment of GDM. Twenty-five (42.4% of invited) and 27 (52.9% of invited) boys whose mothers had been treated with metformin or insulin, respectively, participated in the study. Testicular size was measured by a ruler, an orchidometer, and by ultrasonography at the age of 33 to 85 months.
Results:
The mean age of the boys was 60 months at the time of examination, and did not differ between the metformin and insulin group (p = 0.88). There was no difference in testicular size between the boys in the two groups (p always ≥ 0.40), and there were no significant differences in height, weight, BMI, BMI z-score, or waist-to-hip ratio (WHR) between the boys in the groups.
Conclusions:
Prepubertal testicular size did not differ between offspring born to metformin-treated mothers and those born to insulin-treated mothers.
... The causes of cryptorchidism are not well understood. In addition to genetic alterations [9] and exposure to endocrine-disrupting chemicals [10], maternal smoking [10][11][12][13], alcohol drinking [12][13][14], diabetes [15], and pre-pregnancy obesity [16] are considered potential risk factors for cryptorchidism. However, the mechanisms underlying these relationships remain unclear and the results of epidemiologic studies of associations between maternal exposure to specific risk factors and cryptorchidism are inconsistent. ...
... Thirteen studies including 15,373 cases investigated the relationship between maternal gestational diabetes and risk of cryptorchidism [2,13,15,16,22,27,30,32,33,39,40,45,48]. Two studies, [30,40] were published by same author in different years, we only used the data from [30]. ...
Background:
Maternal gestational smoking, diabetes, alcohol drinking, and pre-pregnancy obesity are thought to increase the risk of cryptorchidism in newborn males, but the evidence is inconsistent.
Method:
We conducted a systematic review and meta-analysis of studies on the association between maternal gestational smoking, diabetes, alcohol drinking, and pre-pregnancy obesity and the risk of cryptorchidism. Articles were retrieved by searching PubMed and ScienceDirect, and the meta-analysis was conducted using Stata/SE 12.0 software. Sensitivity analysis was used to evaluate the influence of confounding variables.
Results:
We selected 32 articles, including 12 case-control, five nested case-control, and 15 cohort studies. The meta-analysis showed that maternal smoking (OR = 1.17, 95% CI: 1.11-1.23) or diabetes (OR = 1.21, 95%CI: 1.00-1.46) during pregnancy were associated with increased risk of cryptorchidism. Overall, the association between maternal alcohol drinking (OR = 0.97, 95% CI: 0.87-1.07), pre-pregnancy body mass index (OR = 1.02, 95% CI: 0.95-1.09) and risk of cryptorchidism were not statistically significant. Additional analysis showed reduced risk (OR = 0.89, 95% CI: 0.82-0.96) of cryptorchidism with moderate alcohol drinking during pregnancy. No dose-response relationship was observed for increments in body mass index in the risk of cryptorchidism. Sensitivity analysis revealed an unstable result for the association between maternal diabetes, alcohol drinking and cryptorchidism. Moderate heterogeneity was detected in studies of the effect of maternal alcohol drinking and diabetes. No publication bias was detected.
Conclusion:
Maternal gestational smoking, but not maternal pre-pregnancy overweight or obesity, was associated with increased cryptorchidism risk in the offspring. Moderate alcohol drinking may reduce the risk of cryptorchidism while gestational diabetes may be a risk factor, but further studies are needed to verify this.
... Additional anomalies were frequently observed in male children with a diagnosis of UDT (Akre et al., 1999;Boisen et al., 2004). There are studies indicating that there seems to be an association between undescended testes with maternal diabetes, gestational diabetes and Rh incompatibility (Xiong et al., 2001;Virtanen et al., 2006). UDT may have long-term consequences on testicular function, including spermatogenesis, and on the risk of testicular cancer (Hadziselimovic and Huff, 2002;Kurahashi et al., 2005). ...
... Of the mothers, 18·8% smoked at least three cigarettes a day during pregnancy. We did not find a statistically significant relationship between smoking mothers and UDT, however, this ratio was close to that of Virtanen et al. (2006). We consider that an exact comparison cannot be made as they did not state number of cigarettes they daily smoked. ...
Undescended testis (UDT) is a very frequent clinical finding in boys. Despite its relatively high frequency, a uniform classification suitable for clinical setting is not available for the disorder. The purpose of this study is to investigate the anatomical localizations of non‐palpable testes and some potential aetiologic factors. We analysed the data for 133 patients with UDT. Physical examination and surgical outcomes of the patients were compared in terms of testicular localizations. Birth weight of the patients, gestational ages, presence of additional congenital anomalies, whether they were breastfed in infancy, age of the first diagnosis, maternal age during pregnancy, history of maternal diabetes and presence of Rh incompatibility. Using the described classification, the 101 right and 85 left impalpable testes were classified as follows: 15·8% Type I, 34·6% Type II, 17·3% Type III, 8·3% Type IV, 24·1% normal testes on the right side when manually examined. Left impalpable testes were classified as follows when manually examined as follows: 13·5% Type I, 26·3% Type II, 9·0% Type III, 15·0% Type IV and 36·1% normal testes. When we compared these results with surgical results, we found a statistically significant difference. Being familiar with anatomic localizations of undescended testes is of (vital) importance in terms of surgical approach and for possible postoperative complications. Although manual examination is an indispensable part of diagnosis, it may be insufficient to determine its localization, and thus further tests may be required. Further studies are required to investigate the aetiologic factors for UDT.
... 18 The most consistently reported risk factor is being small for gestational age (SGA), [19][20][21] but maternal lifestyle factors may also play an important role. 22,23 We identified 20 epidemiological studies investigating the association between maternal cigarette smoking during pregnancy and cryptorchidism 20,21,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] published from 1984 to 2011. A meta-analysis 42 was published in 2011, summarizing the findings of the majority of the mentioned studies. ...
... However, the majority of the existing literature does not support an association between maternal cigarette smoking during pregnancy and cryptorchidism. 21,24,25,[27][28][29][30][32][33][34]36,37,[39][40][41] These studies differed in several ways. Most of the studies that did not find associations were case-control studies with data on maternal smoking obtained postpartum, thus liable to recall bias. ...
Maternal cigarette smoking may affect the intrauterine hormonal environment during pregnancy and this early fetal exposure may have detrimental effects on the future trajectory of reproductive health. In this review, we discuss the epidemiological literature on the association between prenatal exposure to maternal cigarette smoking and several aspects of reproductive health. The literature points towards an increased risk of the urogenital malformation cryptorchidism, but a potential protective effect on the risk of hypospadias in sons following prenatal cigarette smoking exposure. Studies on sexual maturation find a tendency towards accelerated pubertal development in exposed boys and girls. In adult life, prenatally exposed men have impaired semen quality compared with unexposed individuals, but an influence on fecundability, that is, the biological ability to reproduce, is less evident. We found no evidence to support an association between prenatal cigarette smoking exposure and testicular cancer. Among adult daughters, research is sparse and inconsistent, but exposure to cigarette smoking in utero may decrease fecundability. In conclusion, prenatal exposure to cigarette smoking may cause some long-term adverse effects on the reproductive health.
... However, in one study heavy smoking was associated with an increased risk of bilateral cryptorchidism (Thorup, Cortes and Petersen, 2006). Diettreated gestational diabetes was also found to increase the risk, possibly by altering the hormone balance of the developing fetus (Virtanen et al., 2006). Occupational risk factors include gardening and farming, putatively due to pesticide exposure (Weidner et al., 1998), (Kristensen et al., 1997). ...
... According to a study by Kjersgaard et al., mothers with overweight and obesity in pregnancy were associated with higher occurrence of cryptorchidism in boys, but a meta-analysis performed by Zhang et al. did not prove this observation [33,34]. Some studies found an association between cryptorchidism and maternal diabetes [35]. The same meta-analysis by Zhang mentioned before found moderate heterogeneity in studies of the effect of maternal diabetes and cryptorchidism [34]. ...
... Afecta a un 15% de las parejas. El factor masculino se encuentra en el 45-50% de los casos, un 30% sólo relacionado con el hombre y el 20% asociado tanto a factores femeninos y masculinos 89,91,92 . ...
La diabetes mellitus (DM) es una de las mayores amenazas para la salud pública en las sociedades modernas. Si bien durante varios años se sugirió que la DM no tenía efecto significativo en la función reproductiva masculina, esta visión fue cambiando. La creciente incidencia de la DM a nivel mundial afectará a cada vez más hombres y de menor edad, y por lo tanto podría afectar su potencial reproductivo.
... Afecta a un 15% de las parejas. El factor masculino se encuentra en el 45-50% de los casos, un 30% sólo relacionado con el hombre y el 20% asociado tanto a factores femeninos y masculinos 89,91,92 . ...
... Grossesse naissance prématurée [85] augmentation de la prévalence faible poids à la naissance [85] insémination artificielle [108] Etat de santé de la mère lors de la gestation hypertension maternelle [108] augmentation de la prévalence diabète gestationnel [109] consommation importante de caféine durant la grossesse [108] utilisation de patches de nicotine durant la grossesse [108] Exposition environnementale foetale à des composés chimiques consommation d'alcool durant la grossesse [110] augmentation de la prévalence exposition à un cocktail de pesticides [111] exposition prénatale aux composés organochlorés [112] exposition in utero aux analgésiques durant le second trimestre de la grossesse [96] exposition foetale aux perturbateurs endocriniens environnementaux oestrogéniques ou antiandrogénique [113] altération de le production d'INSL3 entrainant la cryptorchidie Tableau 2: Quelques éléments pouvant favoriser les risques de cryptorchidie selon la bibliographie ...
L'exposition durant la vie périnatale à des perturbateurs endocriniens (PE) anti-androgéniques, induit des altérations durables du système reproducteur mâle. Si leur action a été objectivée chez l’homme et l’animal, la question du seuil de toxicité reste entière, car l’exposition environnementale correspond à de faibles doses. Ici, nous exposons in utero des rats mâles à de faibles doses de flutamide: 10 mg/kg/j ; 1; 3 doses faibles selon la définition de l'OMS 0.1; 0.01; 0.001 et 0. L'exposition fœtale induit chez l’adulte (1) des altérations morphologiques à la dose 10 mg/kg/j (diminution du poids des organes du tractus génital et une diminution du compte spermatique); (2) des altérations cellulaires à partir de 1mg (augmentation de l'apoptose des cellules germinales) et (3) des altérations moléculaires à toutes les doses testées pour MCL1, BCL2, XIAP, HSPA2, ELAVL1 et MOV10L1. Ces altérations s’intègrent dans la dérégulation de 2 voies de signalisation expliquant l’apoptose des cellules germinalesLorsque l’exposition a lieu à l’âge l’adulte dans les mêmes conditions, les effets morphologiques et cellulaires sont observés uniquement à 10mg, les effets moléculaires uniquement aux doses 10 et 1 mg. Ces effets ne sont plus observés 2 mois après l’arrêt de l’exposition. En conclusion : Nous avons (i) identifié des voies de signalisation impliquées dans le phénotype d’infertilité induite par une exposition à de faibles doses d’anti-androgène ; (ii) montré que ces voies étaient actives aux plus faibles doses testées prédisposant à une infertilité masculine programmée in utero
... Parallèlement, les mères d'enfants cryptorchides sont significativement plus souvent traitées pour un diabète gestationnel que les mères de garçons normaux (Virtanen et al., 2006). Ces données suggèrent un lien entre le métabolisme du glucose et de l'insuline et la balance hormonale du foetus en développement. ...
Au cours de cette thèse, nous nous sommes intéressés à la différenciation normale et pathologique des cellules germinales (CGs). Dans une première partie, la différenciation normale a été étudiée chez l'amphibien urodèle Pleurodeles waltl. L'acide rétinoïque (AcR) est impliqué dans l'induction de l'entrée en méiose des cellules germinales (CGs) chez les amniotes (Bowles et al., 2006 ; Smith et al., 2008). Nous avons voulu savoir si l'AcR était aussi impliqué dans ce processus chez le pleurodèle. Nous avons montré que l'expression de PwDmc1 (marqueur de méiose), survient plus précocement dans les gonades femelles (avant la métamorphose) que dans les gonades mâles (après la métamorphose). In vitro, l'application d'AcR sur des gonades mâles et femelles en culture organotypique ainsi que l'inhibition de la dégradation de l'AcR endogène induisent l'entrée en méiose des CGs. Nous avons également montré que la balance synthèse/dégradation l'AcR endogène est modulée par les hormones stéroïdes. Les mécanismes de différenciation des CGs décrits chez les mammifères semblent donc conservés chez les urodèles. La seconde partie de la thèse s'inscrit dans le contexte de la différenciation pathologique des CGs.De nombreuses études ont montré qu'une exposition in utero à des xénobiotiques pouvait provoquer des altérations de la différenciation des CGs. Ces cellules altérées restent en dormance pendant l'enfance. A la puberté, elles prolifèrent et donnent naissance aux tumeurs testiculaires, suggérant que le développement de ces tumeurs est hormono-sensible (McIntyre et al., 2008). Nous avons étudié les effets des hormones stéroïdes sur la prolifération des cellules séminomateuses humaines TCam2. L'oestradiol et la testostérone stimulent leur prolifération ainsi que l'expression d'une isoforme tronquée du récepteur alpha des oestrogènes ER[alpha]36. Ce récepteur est induit par la voie GPER-AMPc/PKA et semble nécessaire à l'expression du récepteur à l'EGF. Il pourrait donc constituer une cible thérapeutique potentielle.
... In view of the nature of our subcohort (case-control study of cryptorchidism) and a possible association between GDM and congenital cryptorchidism (34), we additionally used logistic regression to model the odds of GDM in relation to cryptorchidism at birth, and multiple linear regression to assess the relationship between cryptorchidism and HOMA2-B, HOMA2-IR, fasting/ stimulated plasma glucose, and disposition index in women who did not have GDM, adjusting all analyses for the above covariates as well as prematurity (gestation <37 vs. ≥37 weeks) and small for gestational age (birth weight SD score <−1.5 vs. ≥−1.5), which are both risk factors for cryptorchidism (34). Finally, we used logistic regression to remodel the odds of GDM in relation to serum phthalate/phenol concentrations after excluding mothers of sons with congenital cryptorchidism. ...
Certain phthalates and bisphenol A (BPA) have been associated with insulin resistance and type 2 diabetes in non-pregnant adults, but studies of gestational diabetes mellitus (GDM) have reported conflicting results for phthalates and no associations with BPA. Our aim was to investigate the relationship between maternal serum levels of phthalate metabolites and phenols at 10–17 weeks of gestation and glucose homeostasis at 28 weeks of gestation. 232 women aged ≥16 years without type 1 or 2 diabetes with singleton male pregnancies were recruited from a single UK maternity centre between 2001 and 2009 as part of a prospective observational study (Cambridge Baby Growth Study). Serum levels of 16 phthalate metabolites and 9 phenols (including BPA) were measured using liquid chromatography/tandem mass spectrometry. Oral glucose tolerance tests were performed at 28 weeks. 47/232 (20.3%) women had GDM. First-trimester triclosan (TCS) was inversely associated with incident GDM (adjusted odds ratio per log increase in concentration 0.54, 95% confidence interval 0.34–0.86, p = 0.010). Amongst women without GDM, first-trimester mono-(2-ethylhexyl) phthalate and mono(carboxyisooctyl) phthalate levels were positively associated with 120-min plasma glucose (adjusted β 0.268 and 0.183, p = 0.0002 and 0.010, respectively) in mid-pregnancy. No other monotonic associations were detected between phthalate or phenol levels and fasting or stimulated plasma glucose, β-cell function, insulin resistance, or 60-min disposition index. Our results support a glycaemia-raising effect of phthalates during pregnancy, consistent with findings in non-pregnant populations and suggest a possible protective effect of exposure to TCS against GDM.
... We considered additional models that adjusted for pregnancyrelated factors-despite some of them possibly arising after onset of the male reproductive disorders-to evaluate whether any association between these disorders and ASD is independent of these conditions, under the assumption that if they weren't, the adjusted association would likely be reduced. Fertility treatments, preeclampsia, diabetes, and in-utero growth restriction have been suggested to relate to risk of ASD and male reproductive tract disorders, possibly through shared risk factors acting prior to conception or in early gestation (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). ...
Androgens have an extensive influence on brain development in regions of the brain that are relevant for autism spectrum disorder (ASD), yet their etiological involvement remains unclear. Hypospadias (abnormal positioning of the urethral opening) and cryptorchidism (undescended testes) are 2 relatively common male birth defects that are strongly associated with prenatal androgen deficiencies. Having either disorder is a proxy indicator of atypical gestational androgen exposure, yet the association between these disorders and autism has not been extensively studied. We analyzed male singleton live births (n = 224,598) occurring from January 1, 1999, through December 31, 2013, in a large Israeli health-care organization. Boys with autism, cryptorchidism, and hypospadias were identified via International Classification of Diseases, Ninth Revision, codes, with further verification of autism case status by review of medical records. In multivariable-adjusted analyses, the odds ratio for ASD among boys with either condition was 1.62 (95% confidence interval (CI): 1.44, 1.82). The odds ratio for boys with cryptorchidism only was 1.55 (95% CI: 1.34, 1.78), and that for boys with hypospadias only was 1.65 (95% CI: 1.38, 1.98). ASD risk was not elevated among unaffected brothers of hypospadias or cryptorchidism cases, despite familial aggregation of all 3 conditions, providing some indication for the possibility of pregnancy-specific risk factors driving the observed associations. Results suggest that in-utero hypoandrogenicity could play a role in ASD etiology.
... It has been reported that GDM is associated with an increased risk of congenital cryptorchidism (Virtanen et al., 2006), delayed onset of puberty, reduced body weight as well as decreased absolute weights of testes, epididymides and sexual accessory glands after post-natal day 40 (Amorim et al., 2011). However, Jelodar et al. (2009) have reported that GDM causes increases in body weights of 1-, 30-and 60-day-old offspring as well as an increase in absolute testicular weight on postnatal day 90. ...
The purpose of this study was to determine the effect of gestational diabetes mellitus (GDM) on some reproductive characteristics, testicular and pancreatic oxidative status and pancreatic endocrine receptor densities of male offspring at post-pubertal stage. A total of 36 1-day-old Wistar Albino male offspring including 12 pups of nontreated mothers (control group), 14 pups of 40 mg/kg STZ-injected mothers (STZ-40 group) and 10 pups of 60 mg/kg STZ-injected mothers (STZ-60 group) were used. The offspring were euthanised on post-natal day 60, their blood, reproductive organs and pancreatic tissues were obtained and examined. When compared with the control group, there was a significant decrease in body and absolute reproductive organ weights, serum testosterone level, testicular and pancreatic catalase activities, pancreatic glutathione level, epididymal sperm concentration of both STZ-40 and STZ-60 groups as well as in testicular glutathione level of only STZ-60 group. Significant increases were determined in testicular and pancreatic malondialdehyde level and glutathione peroxidase activity in both groups and in fasting serum glucose of only STZ-60 group in comparison with the control group. Although some histopathological damages were observed in testes of both STZ-40 and STZ-60 groups, there were no detectable differences between the groups in density of insulin, glucagon and somatostatin receptors in pancreas. In conclusion, GDM has negative effects on reproductive efficiency and testicular–pancreatic tissue oxidant/antioxidant balance of male offspring at post-pubertal stage.
... Thus, testicular descent may be vulnerable to adverse lifestyle and environmental factors throughout pregnancy [44]. Although an increased risk in undescended testis in infants born to mothers with diabetes and gestational diabetes have been reported [45,46], the increased risk in our study remained after we adjusted for both of these factors. We cannot determine whether exposure in the first trimester was the critical time for two of these cases, who were both also exposed in trimester two and one in trimester three. ...
Background: The direct effects of angiotensin converting enzyme inhibitor (ACEI) medications on the fetus are difficult to determine since these medicines are usually administered to women presenting with high-risk pregnancies. The aim of this study was to provide an overview of the dispensing patterns, demographic characteristics and pregnancy outcomes of women dispensed an ACEI during pregnancy. Methods: Exposed pregnancies were all births in Western Australia, 2002-2005 where the mother was dispensed an ACEI under the Australian Pharmaceutical Benefits Scheme, compared with all other births during the same period. Result: From 2002 to 2005, there were 96,698 births in Western Australia. At least one form of ACEI was dispensed to 95 pregnant women (0.1%) and a further 677 pregnant women (0.7%) were dispensed an antihypertensive medication that was not an ACEI. Women dispensed an ACEI in the first trimester were more likely to be obese (aOR 33.4; 95% CI: 19.5-57.2), to have gestational diabetes (aOR 2.6; 1.3-5.4), to have a preterm delivery (aOR 2.8; 1.4-5.6), and to have smoked during their pregnancy (aOR 1.9; 1.2-3.0). The children of women dispensed an ACEI were more likely to have a major birth defect (aOR 2.6; 1.3-5.2). The risk of a major uro-genital birth defect (aOR 4.8; 2.0-11.7) was increased. Conclusion: Although ACEIs are contraindicated, pregnant women continue to be dispensed these medications. This study provides a profile of these women and their pregnancy outcomes. A clear change in the pattern of dispensing ACEIs later in pregnancy was apparent for these women. A greater number of women were dispensed ACEIs during trimester 1, followed by a marked reduction in dispenses in trimester 2 and trimester 3. Although the number of children affected is small, our data suggests that an increased risk of uro-genital defects may arise with maternal ACEI use in the first trimester.
... Pravi uzrok pojave nespuštenih testisa do danas nije poznat, premda je očito da je za poremećaj odgovorno više čimbenika. Kao glavni čimbenici rizika navode se porođajna masa <2,5 kg, nedonošenost, blizanačka trudnoća, te obiteljska anamneza, insuficijencija placente sa smanjenom sekrecijom HCG, niske vrijednosti majčinih estrogena, dijabetes majke, uključujući i gestacijski dijabetes (15)(16)(17). Hormoni imaju ključnu ulogu u obje faze spuštanja testisa, pa je za to nužna očuvana hipotalamo-hipofiznotestikularna osovina (18). Stoga malfor-macije središnjeg živčanog sustava i kongenitalni hipogonadotropni hipogonadizam mogu biti udruženi s nespuštenim testisima (19). ...
Objective: The late descent of a testicle into the scrotum can cause infertility in later life, even in boys who are treated early on time and with an appropriate method, which leads to an increased risk of testicular malignancy regardless of the implemented treatment procedure. Today's experience suggests that the treatment for undescended testes are generally delayed, hormonal and surgical treatment, as complementary methods of treatment in everyday practice are rarely used, problems of malignant disease development is under-emphasised and clinically poorly monitored. Methods: Selective literature search in PubMed from the last 10 years based on the keywords: "cryptorchidism", "maldescenzus testis", "etiology of undescended testes", "treatment of undescended testicles", "testicular cancer". Results and conclusions: Undescended testicles are the most common genital disorders in boys. Every newborn with the problem of undescended testes should be monitored until their sixth month of life, and then if the problem still persists, hormonal treatment and/or operating have to be considered with treatment being completed by one year of age. The success of the treatment depends of the testis position and time when the treatment will be completed. Successful treatment of undescended testicles until the age of twelve does not reduce the risk of malignancy, but facilitates clinical examination of the testicles.
... Gestational diabetes has become more frequent due to the increasing trends in obesity. In women with gestational diabetes, the risk of delivering a cryptorchid son is increased fourfold compared with non-diabetics (447). The underlying mechanism is not known, although early growth delay of the fetus in the first trimester might play a role. ...
Introduction:
Kartagener's syndrome (KS) is characterized by the classic triad of chronic sinusitis, bronchiectasis and situs inversus.
This is caused by dynein arm defects in axonemal microtubules in ciliary and flagellar structures. Male patients are invariably
infertile because of the immotility of spermatozoa. We report a healthy birth that was achieved by intracytoplasmic sperm
injection (ICSI) using ejaculated spermatozoa from a patient with KS.
Case report:
The wife of the patient was a 33-year-old woman with infertility of one-year duration.Her diagnostic infertility work-ups
were normal. Her husband was 33 years old. He had normal secondary sex characteristics and both testicular volumes were normal.
His serum FSH, LH, testosterone and prolactin levels were all within normal limits. He had dextrocardia and dysosmia as well
as a history of chronic bronchitis and sinusitis, the classic triad disorders of KS, and was therefore diagnosed with KS.
Several semen analyses showed sperm concentration of 77-87 × 10 6 /ml and ejaculated volume of 3.5-4.0 ml. However, only 2-28 motile spermatozoa were observed in the whole field with a Makler
Counting Chamber. After eosin staining, 30% of the sperm were viable with unremarkable morphology. Transmission electron microscopy
(TEM) of the sperm tail showed the absence of both inner and outer dynein arms. After counseling for this condition and suitability
for ICSI, the couple proceeded with ICSI using ejaculated spermatozoa.
In August 2005, after ovarian stimulation by a long protocol using GnRHa / hMG, twenty-one oocytes were obtained, and 18 metaphase
II oocytes were retrieved. Fresh semen samples were obtained after masturbation. The sperm concentration was 57.2 × 10 6 /ml and the volume was 3.5 ml. Total motility was 0.3%, and no spermatozoa showed straight progressive motility. After swim-up
preparation, we observed a few motile spermatozoa that appeared morphologically normal, and these motile spermatozoa were
selected for ICSI. Thirteen oocytes were fertilized. All embryos were cryopreserved in the cleavage stage to prevent development
of ovarian hyperstimulation syndrome.
In October 2005, two--step embryo transfer was performed in the hormone replacement (HR) cycle. A twin pregnancy was achieved,
one resulting in missed abortion but the other being uneventful. A healthy female infant was delivered in June 2006 at a gestation
age of 37 weeks and weighing 2675 g.
In April 2008, the couple was referred to our clinic for a second pregnancy. Four cycles of single blastocyst transfer using
a cryopreserved-thawed blastocyst were repeatedly performed. Pregnancy tests were positive in three cycles, but all of the
three pregnancies resulted in chemical abortion.
In January 2009, after using an ovarian stimulation protocol similar to that used in the first cycle, five metaphase II oocytes
were retrieved. Sperm concentration and total motility were 68.1 × 10 6 /ml and 0.1%, respectively, and a few progressive motile sperm were observed. The intracytoplasmic morphologically selected
sperm injection (IMSI) procedure was performed with the progressive motile sperm. All oocytes were fertilized. One embryo
was cryopreserved in the cleavage stage and the other four embryos were cultured for three more days, but no blastocyst was
obtained. In March 2009, cryopreserved-thawed embryo transfer was performed in the HR cycle, but pregnancy was not achieved.
Conclusion:
This case report demonstrates that successful pregnancy after ICSI in couples with Kartagener's syndrome is possible with
ejaculated spermatozoa. Our results suggest that even for KS patients, if motile sperm are observed, a fertilization rate
comparable to that with ICSI of the other male factor can be expected. KS is a heterogeneous group of disorders with similar
clinical presentations, and treatment should be individualized depending on sperm motility.
... Gestational diabetes has become more frequent due to the increasing trends in obesity. In women with gestational diabetes, the risk of delivering a cryptorchid son is increased fourfold compared with non-diabetics (447). The underlying mechanism is not known, although early growth delay of the fetus in the first trimester might play a role. ...
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.
... Previous studies suggest that gestational diabetes and preterm birth may independently increase the risk of cryptorchidism [41][42][43], and may be related to the level of the exposure at or before birth. Thus, the analyses were repeated excluding those children (11 cases, 12 controls), who were born before gestational week 37 + 0, whose mothers had gestational diabetes, or who were older than 5 years old. ...
Background:
Congenital cryptorchidism, i.e. failure of the testicular descent to the bottom of the scrotum, is a common birth defect. The evidence from epidemiological, wildlife, and animal studies suggests that exposure to mixtures of endocrine disrupting chemicals during fetal development may play a role in its pathogenesis. We aimed to assess the association between cryptorchidism and prenatal exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs), and polybrominated diphenyl ethers (PBDEs).
Methods:
We conducted a case-control study consisting of 44 cryptorchid cases, and 38 controls operated for inguinal hernia, umbilical hernia, or hydrocele at the Turku University Hospital or Rigshospitalet, Copenhagen in 2002-2006. During the operation a subcutaneous adipose tissue biopsy was taken. Samples were analysed for 37 PCBs, 17 PCDD/Fs and 14 PBDEs by gas chromatography-high-resolution mass spectrometry. Chemical concentrations were adjusted for postnatal variation introduced by differences in duration of breastfeeding, age at the operation, and country of origin with a multiple linear regression. Association between adjusted and unadjusted chemical concentrations and the risk of cryptorchidism were analysed with logistic regression to get an estimate for odds ratio (OR) of cryptorchidism per multiplication of chemical concentrations with ca. 2.71 (Napier's constant).
Results:
Total-TEq i.e. the WHO-recommended 2,3,7,8-TCDD equivalent quantity of 17 dioxins and 12 dioxin-like PCBs and sum of PCDD/Fs were positively associated with cryptorchidism [OR 3.21 (95 % CI 1.29-9.09), OR 3.69 (95 % CI 1.45-10.9), respectively], when adjusting for country of origin, the duration the child was breastfed, and age at operation. The association between the sum of PCBs and cryptorchidism was close to significant [OR 1.92 (95 % CI 0.98-4.01)], whereas the association between the sum of PBDEs and cryptorchidism was not [OR 0.86 (95 % CI 0.47-1.54)]. There were no associations between unadjusted chemical concentrations and the risk of cryptorchidism.
Conclusions:
Prenatal exposure to PCDD/Fs and PCDD/F-like PCBs may be associated with increased risk for cryptorchidism. Our finding does not exclude the possibility of an association between the exposure to PBDEs and cryptorchidism.
... 76 A maternal medical history of pre-eclampsia, d iabetes, infertility treatment, breech delivery or caesarean section is also associated with an increased risk of genital malformation. [77][78][79] In addition, maternal lifestyle during pregnancy (in particular smoking and the use of nicotine pat ches, alcohol consumption and a vegetarian diet) has, in some studies, been found to be associated with cryptorchidism and hypospadias. 77,80,81 Evaluation of the effect of maternal smoking during pregnancy in 3,486 young Danish men revealed that prenatal exposure to smoking is associated with impaired testicular function and the effect is even more pronounced than that of a man's own smoking. ...
Although common reproductive problems, such as male infertility and testicular cancer, present in adult life, strong evidence exists that these reproductive disorders might have a fetal origin. The evidence is derived not only from large epidemiological studies that show birth‑cohort effects with regard to testicular cancer, levels of testosterone and semen quality, but also from histopathological observations. Many infertile men have histological signs of testicular dysgenesis, including Sertoli‑cell‑only tubules, immature undifferentiated Sertoli cells, microliths and Leydig cell nodules. The most severe gonadal symptoms occur in patients with disorders of sexual development (DSDs) who have genetic mutations, in whom even sex reversal of individuals with a 46,XY DSD can occur. However, patients with severe DSDs might represent only a small proportion of DSD cases, with milder forms of testicular dysgenesis potentially induced by exposure to environmental and lifestyle factors. Interestingly, maternal smoking during pregnancy has a stronger effect on spermatogenesis than a man's own smoking. Other lifestyle factors such as alcohol consumption and obesity might also have a role. However, increasing indirect evidence exists that exposure to ubiquitous endocrine disrupting chemicals, present at measurable concentrations in individuals, might affect development of human fetal testis. If confirmed, health policies to prevent male reproductive problems should not only target adult men, but also pregnant women and their children.
... It has also been reported that lesser than diabetes hyperglycemia in pregnancy is related to perinatal mortality [16]. Mildly abnormal glucose metabolism during pregnancy was associated with an increased risk for certain congenital abnormalities [17]. The HAPO (Hyperglycemia and Adverse Pregnancy Outcomes) study results showed a linear relationship between plasma glucose and adverse outcomes-there is a continuum of risk with no clear threshold which could divide women into those with gestational diabetes and those without it [9,18]. ...
... It has also been reported that lesser than diabetes hyperglycemia in pregnancy is related to perinatal mortality [16]. Mildly abnormal glucose metabolism during pregnancy was associated with an increased risk for certain congenital abnormalities [17]. The HAPO (Hyperglycemia and Adverse Pregnancy Outcomes) study results showed a linear relationship between plasma glucose and adverse outcomes-there is a continuum of risk with no clear threshold which could divide women into those with gestational diabetes and those without it [9,18]. ...
Association between conventionally identified hyperglycemias and rates of congenital abnormalities is known; however there is less information about role of HbA1c in determining gestational hyperglycemias and associated risks. This study tried to explore the association between HbA1c in women without known diabetes at first antenatal visit and risk of congenital malformations (CM) among Saudi women living at Al-Madinah Al-Monawarah.
Eleven hundred and eighty (1180), healthy, first-trimester pregnant Saudi females without known diabetes, were selected from various antenatal care clinics of Al-Madinah Al-Monawarah city. General clinical and biochemical data was collected for this study by researchers at first visit and the time of delivery.
Nearly one fifth (19.6%) of mothers had above normal HbA1c (>5.7) at first visit. Rates of CM had significant positive association with level of HbA1c. Rate of CM among those who had HbA1c in diabetes range, pre-diabetes range or normal range was 27.8%, 9.8% and 3.0%, respectively. The difference was significant between normal and pre-diabetes at the level P=0.000 and between pre-diabetes and diabetes at level P=0.038.
In this study HbA1c is found to be a valuable predictor of risk of congenital malformations. This observation calls for further studies and establishment of policies for care of pregnant mothers having higher than normal HbA1c at first visit.
Copyright © 2015. Published by Elsevier Ltd.
... Previous studies on risk factors for testicular cancer did not stress this 'Western' lifestyle/nutritional pattern and focused primarily on dietary patterns during early life and adulthood but not on maternal diet . Studies investigating the risk of congenital anomalies related to TGCT, (cryptorchidism and hypospadias), in association with maternal diet and gestational diabetes have provided contradictory results (Pierik et al., 2004;Virtanen et al., 2006;Giordano et al., 2008;Trabert et al., 2014). Furthermore, it remains unclear how epigenetic events in male germ cells triggered by maternal diet and gestational diabetes would influence the etiology of TGCT (Godmann et al., 2009). ...
Basic research results can provide new ideas and hypotheses to be examined in epidemiological studies. We conducted a survey among testicular cancer researchers on hypotheses concerning the etiology of this malignancy. All researchers on the mailing list of Copenhagen Testis Cancer Workshops and corresponding authors of PubMed-indexed articles identified by the search term 'testicular cancer' and published within 10 years (in total 2750 recipients) were invited to respond to an e-mail-based survey. Participants of the 8th Copenhagen Testis Cancer Workshop in May 2014 were subsequently asked to rate the plausibility of the suggested etiologic hypotheses on a scale of 1 (very implausible) to 10 (very plausible). This report describes the methodology of the survey, the score distributions by individual hypotheses, hypothesis group, and the participants' major research fields, and discuss the hypotheses that scored as most plausible. We also present plans for improving the survey that may be repeated at a next international meeting of experts in testicular cancer. Overall 52 of 99 (53%) registered participants of the 8th Copenhagen Testis Cancer Workshop submitted the plausibility rating form. Fourteen of 27 hypotheses were related to exposures during pregnancy. Hypotheses with the highest mean plausibility ratings were either related to pre-natal exposures or exposures that might have an effect during pregnancy and in post-natal life. The results of the survey may be helpful for triggering more specific etiologic hypotheses that include factors related to endocrine disruption, DNA damage, inflammation, and nutrition during pregnancy. The survey results may stimulate a multidisciplinary discussion about new etiologic hypotheses of testicular cancer.
Published 2014. This article is a U. S. Government work and is in the public domain in the USA.
... However, it has been reported that some specific malformations are more frequent among women with GDM, such as specific cardiac defects, oesophageal/intestinal atresia and spinal deformations (81). A Finnish study reveals that GDM may increase the risk of congenital cryptorchidism (82). A randomized clinical trial investigating whether treatment of women with GDM would reduce the risk of perinatal complications demonstrates significantly lower rates of serious perinatal complications (defined as perinatal death, shoulder dystocia, bone fracture and nerve palsy) in the intervention group. ...
... 76 A maternal medical history of pre-eclampsia, d iabetes, infertility treatment, breech delivery or caesarean section is also associated with an increased risk of genital malformation. [77][78][79] In addition, maternal lifestyle during pregnancy (in particular smoking and the use of nicotine pat ches, alcohol consumption and a vegetarian diet) has, in some studies, been found to be associated with cryptorchidism and hypospadias. 77,80,81 Evaluation of the effect of maternal smoking during pregnancy in 3,486 young Danish men revealed that prenatal exposure to smoking is associated with impaired testicular function and the effect is even more pronounced than that of a man's own smoking. ...
Although common reproductive problems, such as male infertility and testicular cancer, present in adult life, strong evidence exists that these reproductive disorders might have a fetal origin. The evidence is derived not only from large epidemiological studies that show birth-cohort effects with regard to testicular cancer, levels of testosterone and semen quality, but also from histopathological observations. Many infertile men have histological signs of testicular dysgenesis, including Sertoli-cell-only tubules, immature undifferentiated Sertoli cells, microliths and Leydig cell nodules. The most severe gonadal symptoms occur in patients with disorders of sexual development (DSDs) who have genetic mutations, in whom even sex reversal of individuals with a 46,XY DSD can occur. However, patients with severe DSDs might represent only a small proportion of DSD cases, with milder forms of testicular dysgenesis potentially induced by exposure to environmental and lifestyle factors. Interestingly, maternal smoking during pregnancy has a stronger effect on spermatogenesis than a man's own smoking. Other lifestyle factors such as alcohol consumption and obesity might also have a role. However, increasing indirect evidence exists that exposure to ubiquitous endocrine disrupting chemicals, present at measurable concentrations in individuals, might affect development of human fetal testis. If confirmed, health policies to prevent male reproductive problems should not only target adult men, but also pregnant women and their children.
Background
Investigations regarding the association between maternal smoking and specific urogenital teratogenesis exist. However, an integrated systematic review and meta-analysis studying the relationship by encompassing the whole urogenital system is essential.
Objective
Even though many studies about inborn urogenital malformations have been conducted, its etiologic factors and exact pathogenesis are still unclear. Our aim is to assess the risk of congenital urogenital malformations in offspring of smoking pregnant women.
Results
The meta-analysis, covering 41 case-control and 11 cohort studies, suggested that maternal smoking was associated with an increased risk of urogenital teratogenesis (odds ratio [OR] = 1.13, 95% confidence interval [CI]: 1.04–1.23, p = 0.005), cryptorchidism (OR = 1.18, 95%CI: 1.12-1.24, p = 0.0001), hypospadias (OR = 1.16, 95%CI: 1.01-1.33, p = 0.039), and kidney malformations (OR = 1.30, 95%CI: 1.14-1.48, p = 0.0001). Moreover, paternal smoking during the mother’s pregnancy was also significantly associated (OR = 1.26, 95%CI: 1.03-1.55, p = 0.028). The association between smoking > 10 cigarettes/day was evident but was not significant (OR = 1.24, 95%CI:0.81-1.88, p = 0.323).
Conclusion
Our results showed that maternal smoking during pregnancy increased the risk of congenital urogenital malformations. In numerous epidemiological studies, maternal smoking during pregnancy has a significant role in fetal development. Therefore, quitting tobacco use may be an effective method for reducing the risk of congenital urogenital malformation in pregnant women.
Cryptorchidism, i.e., undescended testis, is one of the most common genital malformations in newborn male babies. The birth rate of cryptorchidism varies from 1.6 – 9.0 %. Etiology of disrupted testicular descent is complex and predisposing causes include genetic, hormonal, environmental, lifestyle and maternal factors. Testicular descent occurs in two major steps and testicular hormones and normal function of hypothalamic-pituitary-testicular axis are important for normal descent. Several gene mutations are associated with syndromic cryptorchidism but they are rarely found in boys with isolated undescended testis.
Testicular regression can also cause an empty scrotum. Normal male genital phenotype indicates that the boy has had functioning testis during development. Torsion of the testis can cause testicular regression but in many cases the reason for vanishing testis remains elusive.
In this narrative review we discuss genetics of cryptorchidism and testicular regression.
Im Rahmen einer retrospektiven Datenanalyse über einen Zeitraum von 6 Jahren wurde an Hand von 814 operierten Hoden die Koinzidenz eines Maldescensus testis mit einer Morgagni-Hydatide untersucht. Dabei ergab sich eine Hydatidengesamtprävalenz bei erfolgter Hodenhülleneröffnung nicht-deszendierter Hoden von 62,66 %. Zusätzlich konnten wir eine Korrelation zwischen Patientenalter und Größenausprägung der Hydatiden feststellen. Entsprechend der Studienergebnisse kann die Vermutung geäußert werden, dass von einer Größenwachstumsdynamik der Hydatiden – am ehesten unter Hormoneinfluss – in Bezug zum Patientenalter ausgegangen werden kann.
Cryptorchidism is one of the most frequent congenital anomalies in boys. Multiple factors influence the physiological descent of testes, including mechanical, genetic and also hormonal processes, so that conversely the causality of the pathological mechanism of undescended testes can be attributed to a multifactorial origin. The present paper attempts to explain the multifactorial-related pathological mechanism of cryptorchidism and to provide a contribution to the clinical work with respect to the diagnostic and treatment measures to be initiated. The article includes a current epidemiological overview with respect to the pathophysiology, diagnostics and guideline-based therapeutic measures of cryptorchidism.
Der Hodenhochstand ist die häufigste kongenitale Anomalie des männlichen Urogenitaltraktes und steht in Zusammenhang mit einer verminderten Fertilität sowie einer erhöhten Malignität. Seit dem Jahr 2009 liegt das definierte Behandlungsziel der AWMF-Leitlinie für Hodenhochstand bei einer abgeschlossenen Therapie innerhalb der ersten zwölf Lebensmonate. Nationale sowie internationale Studien zeigen bisher eine mangelnde Umsetzung der Therapievorgaben. Die vorliegende retrospektive Studie untersucht die Umsetzung der Therapieleitlinie an der kinderchirurgischen Abteilung des Uniklinikum Würzburgs im Zeitraum von 2010 bis 2015. Von den insgesamt 578 Patienten, die aufgrund eines uni- bzw. bilateralem Hodenhochstandes operativ versorgt wurden, sind 21,1 % leitliniengerecht therapiert worden. Das durchschnittliche Operationsalter lag bei 40 Monaten, wobei kein Trend zu einer früheren Operation in dem betrachteten Zeitraum festzustellen ist. Die Erstvorstellung aufgrund eines Hodenhochstandes erfolgte in 30 % der Fälle innerhalb des ersten Lebensjahres in der kinderchirurgischen Abteilung, womit 70 % der Patienten den Zeitpunkt einer empfohlenen Therapie nicht erfüllt haben. Neben dem später resultierenden Operationszeitpunkt bei sekundär aszendierten Hoden zeigte eine Analyse der behandlungsbeeinflussenden Faktoren, dass sich das Vorliegen chronischer Begleiterkrankungen ebenfalls negativ auf den Zeitpunkt der Therapie auswirkt. Vor allem die engmaschige Betreuung verschiedener Fachdisziplinen wirkt sich positiv auf den Therapiezeitpunkt aus. Zusammenfassend ist festzustellen, dass der grundlegende Baustein einer frühzeitigen Diagnose und Therapie in der fortlaufenden Kontrolle der Hodenlokalisation, der Aufklärung der Eltern bezüglich des Krankheitsbildes und möglicher Spätkomplikation sowie der Anleitung zur Selbstuntersuchung besteht.
Aim of the study:
Endocrine-disrupting chemicals (EDCs) are exogenous agents that are capable of altering the endocrine system functions, including the regulation of developmental processes. The aim of this study was to investigate the association between EDC exposure and other parental factors in the etiology of hypospadias and cryptorchidism.
Methods:
A case-control study was conducted. Cases (n = 210) were infants aged between 6 months and 14 years diagnosed with hypospadias or cryptorchidism who attended the authors' hospital over a period of 18 months, and controls (n = 210) were infants within the same range of age and without any urological disorders who attended the outpatient clinic of the same hospital during the same time period. Their selection was independent of exposures. Data on parental occupational exposure to EDCs and other sociodemographic variables were collected through face-to-face interviews and systematically for both cases and controls. Crude and adjusted odds ratios (ORs) were estimated to control for confounding with their 95% confidence interval (CI) by means of logistic regressions. Specifically, three final models of a dichotomous outcome were constructed: one for cryptorchidism, one for hypospadias, and the third considering both malformations together. The Hosmer-Lemeshow test was used to assess the goodness of fit of the models. Their discriminatory accuracy (DA) was ascertained by estimating their areas under the receiver operating characteristic curves area under the curve (AUC) along with their 95% CI.
Results:
Associations were found between advanced maternal age (OR adjusted = 1.82; 95% CI: 1.14-2.92), mother's consumption of anti-abortives (OR = 5.40; 95% CI: 1.40-38.5) and other drugs (OR = 2.02; 95% CI: 1.31-3.16) during pregnancy, maternal and paternal occupational exposure to EDCs (OR = 4.08; 95% CI: 2.03-8.96 and OR = 3.90; 95% CI: 2.41-6.48, respectively), fathers smoking (OR = 2.0; 95% CI: 1.33-2.99), and fathers with urological disorders (OR = 2.31; 95% CI: 1.15-4.90). Maternal and paternal high educational level could be protective of cryptorchidism (OR = 0.47; 95% CI: 0.28-0.76 and OR = 0.63; 95% CI: 0.42-0.93, respectively). The DA of the models for the whole sample (AUC = 0.75; 95% CI: 0.70-0.79) for cryptorchidism (AUC = 0.76; 95% CI: 0.71-0.82) and for hypospadias (AUC = 0.75; 95% CI: 0.69-0.81) was moderately high.
Conclusions:
Advanced age, some parental occupational exposure to EDCs, some drug consumption, smoking, and the father's history of urological disorders may increase risk and predict the developments of these malformations. Studies with higher samples sizes are needed to assess associations between individual EDC occupational exposures and drugs and these malformations.
Background:
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).
Methods:
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.
Results:
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.
Conclusions:
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.
Background:
Diabetes in pregnancy has been associated with an increased risk of congenital malformations overall, but studies on genital anomalies in boys are conflicting and possible causal mechanisms are not well understood. Previous studies have mainly assessed pre-gestational and gestational diabetes in combination. Yet considering the vulnerable time windows for the genital anomalies, associations could well differ between types of diabetes and between the two genital anomalies and we therefore aimed to study this further.
Methods:
A population-based cohort study of 2,416,248 singleton live-born boys from Denmark (1978-2012) and Sweden (1987-2012) was carried out using Danish and Swedish register-based data. Using Cox regression models, we estimated hazard ratios for hypospadias and cryptorchidism according to maternal diabetes. We considered type and severity of diabetes, as well as timing of diagnosis in relation to birth.
Results:
Pre-gestational type 1 diabetes was associated with a higher risk of both genital anomalies. The highest risks were seen for boys of mothers with diabetic complications (hazard ratio for hypospadias = 2.33, [95% confidence interval: 1.48, 3.66] and hazard ratio for cryptorchidism = 1.92, [95% confidence interval: 1.39, 2.65]). Gestational diabetes was associated with slightly increased risks of both genital anomalies.
Conclusions:
These results are consistent with the hypothesis that poor glycemic control may interfere with fetal genital development in the critical early period of organogenesis. Given the widespread and increasing occurrence of diabetes, these results are of public health importance.
Undescended testis - known as cryptorchidism - is one of the most common congenital abnormalities observed in boys, and is one of the few known risk factors for testicular cancer. The key factors that contribute to the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases in fetal development - between 8-15 weeks (the first phase of decent) and 25-35 weeks gestation (the second phase of descent); the failure of a testis to descend permanently is probably caused by disruptions to one or both of these phases, but the causes and mechanisms of such disruptions are still unclear. A broad range of putative risk factors have been evaluated in relation to the development of cryptorchidism but their plausibility is still in question. Consistent evidence of an association with cryptorchidism exists for only a few factors, and in those cases in which evidence seems unequivocal the factor is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor could vary considerably between mother-son pairs depending on an array of genetic, maternal, placental and fetal factors - all of which could vary between regions. Thus, the role of causative factors in aetiology of cryptorchidism requires further research.
This paper reports a case of a male infant born to a 32-year-old multiparous mother with overweight (BMI 28.5kg/m²) and gestational diabetes mellitus (GDM). The mother had fasting hyperglycaemia (range 5.7-6.0mmol/L) noted at 24 weeks of pregnancy and was managed with diet alone. There is no family history of diabetes mellitus and the mother did not have pre-eclampsia. Physical examination of the infant revealed macrosomia (birthweight, 4600g) and bilateral congenital cryptorchidism. The baby suffered severe hypoglycaemia (blood glucose 1.7mmol/L) and hypocalcaemia (total serum calcium 1.03mmol/L), manifesting with seizures. He was successfully managed with 10% dextrose water and calcium gluconate infusion, using standard protocol. His karyotype is 46 XY. The patient was discharged from admission at the age of 10 days and was referred to the paediatric endocrinologist at the tertiary hospital. By 8 weeks of age, the right testis was noticed to have descended into the right scrotum. At the age of 3 months, the left testis was still not palpable either in the inguinal canal or the scrotal sac. The patient was lost to follow up. Conclusion: Diet-treated maternal overweight in association with GDM could potentially increase the risk for hypocalcaemia, hypoglycaemia, macrosomia and congenital cryptorchidism in the offspring, highlighting the need for physicians to assess for the presence of these morbidities in such infants.
Objectifs : La majorité des études effectuées au cours des dernièresdécennies ont mis en évidence une augmentation du nombre decas de cryptorchidie et d’hypospadias entre 1970 et 1990. De plus,l’importante variabilité géographique de ces anomalies est biendécrite. Cette étude vise à mesurer la prévalence à la naissancede la cryptorchidie et de l’hypospadias au Québec, à vérifier sices anomalies sont en augmentation et à en évaluer la répartitioninterrégionale.Méthode : Une étude épidémiologique descriptive a été réalisée àpartir du nombre de garçons de cinq ans et moins hospitalisés pourune cryptorchidie ou un hypospadias au Québec de 1989 à 2004selon les données du fichier administratif d’hospitalisation MEDÉCHO.Les données sur les naissances provenaient de l’Institut dela statistique du Québec.Résultats : La prévalence annuelle moyenne pour 1000 naissancesvivantes de sexe masculin est de 19,1 (IC à 95 % : 18,8-19,4) pourla cryptorchidie et 11,4 (IC à 95 % 11,1-11,6) pour l’hypospadiasau Québec. Au cours de la période étudiée, la prévalence de cryptorchidiea légèrement diminué, alors que celle de l’hypospadiasest demeurée stable. Comparativement à la province du Québec,des régions présentent une prévalence significativement différentede cryptorchidie et/ou d’hypospadias. .Conclusion : Au Québec, la prévalence de cryptorchidie est enlégère diminution alors que celle de l’hypospadias est stable.Des variations régionales significatives sont observables. D’autresétudes sont nécessaires afin d’évaluer l’hypothèse d’un lien avecles contaminants environnementaux en émergence. L’implantationd’un système de surveillance des anomalies congénitales permettraitune représentation plus valide de la situation.Objectives: Previous research has shown evidence of an increasein the number of cases of cryptorchidism and hypospadias between1970 and 1990. Geographical disparities of these anomalies arewidely described. This study aims to measure the prevalence ofcryptorchidism and hypospadias at birth in the province of Quebec,to investigate if there is an increasing trend and to assess the interregionaldistribution of these anomalies. Method: A descriptive epidemiological study was undertaken toinvestigate the number of newborn males up to five years of age,hospitalized for cryptorchidism or hypospadias in Quebec between1989 and 2004 based on data collected from MED-ECHO, a databasecompiling hospitalizations and used for administrative purposes.Birth rates were provided by the Statistical Institute of Quebec. Results: Mean yearly prevalence per 1000 male live births was19.1 (95% CI 18.8-19.4) for cryptorchidism and 11.4 (95% CI11.1-11.6) for hypospadias for the province of Quebec. Within theperiod of study, the prevalence of cryptorchidism decreased slightlywhile that of hypospadias remained stable. Significant variationsin prevalence were observed in some regions compared to theprovince, for both pathologies. Conclusion: In Quebec, the prevalence of cryptorchidism isdecreasing while that of hypospadias is stable. There is significantregional variation among the province. More studies are neededto assess the potential link with environmental contaminants asan emerging explanation. The implementation of an adequate surveillancesystem for congenital anomalies would allow for a moreaccurate representation of the situation.
The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community abouthow environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, andepigeneticchanges, therebyproducingeffects inexposedindividuals as well as theirdescendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in arange that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings canbemuchbetter translated tohumanhealth. Armedwith this information, researchers, physicians, andother healthcare providers can guide regulators and policymakers as they make responsible decisions.
This systematic review aimed to investigate the association between maternal smoking during pregnancy and birth defects in children. We performed an electronic search of observational studies in the databases ovid MEDLINE (1950 to April 2010), LILACS and SciELO. We included 188 studies with a total of 13,564,914 participants (192,655 cases). Significant positive associations were found between maternal smoking and birth defects in the following body systems: cardiovascular (OR: 1.11; 95%CI: 1.03-1.19), digestive (OR: 1.18; 95%CI: 1.07-1.30), musculoskeletal (OR: 1.27; 95%CI: 1.16-1.39) and face and neck (OR: 1.28; 95%CI: 1.19-1.37). The strength of association between maternal smoking and birth defects measured by the OR (95%CI) is significantly related to the amount of cigarettes smoked daily (χ2 = 12.1; df = 2; p = 0.002). In conclusion, maternal smoking during pregnancy is associated with congenital malformations in children and this association is dose-dependent.
To examine the epidemiological characteristics of boys with cryptorchidism.
Cohort survey using the Swedish personal identification code and Medical Birth Registry to link cryptorchid boys with their pregnancy and delivery data. They were compared with the total population of male births during the same period.
2861 cryptorchid boys born in Sweden between 1973 and 1982 were identified. Of these 437 could not be linked with their Medical Birth Registry information for various reasons, or were excluded because they were under 1 year of age at the end of 1982, leaving 2424 cases for study. The reference population comprised all boys born in Sweden during the same period (n = 458,601).
For each study variable, the observed number of cases among boys with cryptorchidism was compared with the expected number calculated from the whole population. A significant increase in intensity ratio for cryptorchidism was found with the first birth, caesarean section, toxaemia of pregnancy, and certain congenital abnormalities (hypospadias and subluxation of the hip). It was also more common in small for dates infants. There was a seasonal variation in cryptorchidism, with increased incidence in January-March.
Cryptorchidism may be caused by hormonal influences during pregnancy, which could be affected by utero-placental factors involving placental dysfunction or by daylight hours, through pineal activity.
Impaired testicular descent (cryptorchidism) is one of the most frequent congenital abnormalities in humans, involving 2% of male births. Cryptorchidism can result in infertility and increases risk for development of germ-cell tumours. Testicular descent from abdomen to scrotum occurs in two distinct phases: the trans-abdominal phase and the inguino-scrotal phase. Currently, little is known about the factors that regulate the trans-abdominal phase of testicular descent. Leydig insulin-like hormone (Insl3) is a member of the insulin hormone superfamily expressed in the developing testis. We show here that mice mutant for Insl3 are viable, but exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, resulting in abnormal spermatogenesis and infertility. Female homozygotes have impaired fertility associated with deregulation of the oestrus cycle. These findings reveal roles for Insl3 in the development of the urogenital tract and in female fertility. Insl3 may act as a hormone to regulate the growth and differentiation of the gubernaculum, thereby mediating intra-abdominal testicular descent.
Results of in vitro experiments indicate that with increasing concentrations of SHBG, testosterone (T) is preferentially bound to SHBG in comparison with estradiol (E2). In these studies, the ratio of non-SHBG-bound E2 (non-SHBG-E2) to non-SHBG-T increased with increasing levels of SHBG. SHBG has consequently been regarded as an estrogen amplifier. In this cross-sectional study in 399 men aged between 40 and 80 yr we tested whether higher levels of SHBG are associated with a higher estrogen/androgen ratio in vivo. The mean T level of these men was in the eugonadal range [536 +/- 152 ng/dl (18.6 +/- 5.26 nmol/liter), mean +/- sd]. With increasing SHBG levels the non-SHBG-bound fraction of T decreased from 80 to 36% and that of E2 from 89 to 53%. Higher levels of SHBG were associated with higher levels of both total T [regression coefficient (beta) after adjustment for age and body mass index, 286 +/- 15.8; P < 0.001] and total E2 (beta = 4.47 +/- 0.90; P < 0.001). However, SHBG levels were negatively related with levels of non-SHBG-E2 (beta = -1.78 +/- 0.69; P < 0.001), whereas there was a positive association between levels of SHBG and non-SHBG-T (beta = 32.0 +/- 9.78; P = 0.001). Furthermore, we observed a negative relationship between SHBG levels and the E2/T ratio of either total (beta = -0.016 +/- 0.002; P < 0.001) or non-SHBG-bound (beta = -0.011 +/- 0.002; P < 0.001) hormone. Therefore, we conclude that in eugonadal men, higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.
Gestational diabetes mellitus has been associated with adverse maternal and infant outcomes, including preeclampsia and fetal macrosomia. Although cigarette smoking has been associated with increased insulin resistance, its effect on gestational diabetes mellitus risk is uncertain. The authors evaluated the effects of smoking on glucose tolerance in a cohort of pregnant women who participated in the Calcium for Preeclampsia Prevention trial, a randomized study of nulliparous women conducted in five US medical centers from 1992 to 1995. Results of screening and diagnostic testing for gestational diabetes mellitus were analyzed. For 3,774 of the 4,589 women enrolled, plasma glucose concentration 1 hour after a 50-g oral glucose challenge and complete information on pregnancy outcome were available; for 3,602 of the women, gestational diabetes mellitus status was known. Adjusted mean 1-hour plasma glucose concentration (mg/dl) was elevated in women who smoked at study enrollment (112.6, 95% confidence interval: 110.0, 115.3) compared with women who had never smoked (108.3, 95% confidence interval: 106.7, 109.8; p < 0.01). Women who smoked were at increased risk of gestational diabetes mellitus when criteria proposed by the National Diabetes Data Group were used (adjusted odds ratio = 1.9, 95% confidence interval: 1.0, 3.6). These findings support an association between smoking and gestational diabetes mellitus.
While an abnormal oral glucose tolerance test (GTT) is known to be associated with an increased risk of pregnancy complications, the impact of one abnormal value is not clear. In 1986 we screened 4618 pregnant women for gestational diabetes at 24-28 weeks' gestation. Eighty-seven percent had normal results; of the 13% with abnormal screening tests, 139 had one abnormal value on the subsequent 3-hour oral GTT. These women were then compared with 725 randomly selected patients with a normal screening test. The frequency of chronic hypertension, cesarean section, 5-minute Apgar score below 7, preterm delivery, shoulder dystocia, congenital malformations, and perinatal mortality did not differ significantly between the groups. The incidence of macrosomia (birth weight above 4000 g) was significantly greater in the study group (18.0%) than in the control group (6.6%) (odds ratio 2.18; 95% confidence interval 1.77-5.37), a relationship that persisted after controlling for confounding risk factors by logistic regression modeling (odds ratio 2.55; 95% confidence interval 1.44-4.52). The incidence of preeclampsia/eclampsia was significantly greater in the study group (7.9%) than in the control group (3.3%) (odds ratio 2.51; 95% confidence interval 1.14-5.52), which also persisted after controlling for confounding risk factors using logistic regression modeling (odds ratio 2.81; 95% confidence interval 1.26-6.28). Our results suggest that patients with one abnormal value on an oral GTT during pregnancy are at risk for delivering macrosomic infants and developing preeclampsia/eclampsia.
Insulin concentration correlates negatively with sex hormone-binding globulin (SHBG) in adults, although the age at which this relationship develops is unknown. The present study assesses this relationship in a cohort of European, Maori, South Asian, and Pacific Islands neonates from 125 normal and 35 pregnancies complicated by diabetes. Maternal glycemia was assessed with a 3-h 100-g oral glucose tolerance test with fasting glucose and fructosamine concentrations determined at 36-38 weeks. Umbilical cord blood was taken for insulin, C peptide, fructosamine, SHBG, sex hormone, and insulin-like growth factor I (IGF-I) measurements, and neonatal anthropometry was measured 24 h after delivery. Babies from pregnancies complicated by diabetes were heavier, fatter, hyperinsulinemic (90.4 vs. 130.6 pmol/L, respectively; P < 0.01), with similar SHBG (44.0 +/- 6.5 vs. 44.2 +/- 12.0) and sex hormone levels and higher IGF-I concentrations (57.1 +/- 24.2 vs. 70.1 +/- 37.1; P < 0.05). There were no ethnic differences in cord SHBG, sex hormones, or IGF-I. SHBG correlated negatively with cord insulin concentrations [males, -0.31 (P < 0.01); females, -0.35 (P < 0.001)], birth weight [males, -0.25 (P < 0.05); females, -0.36 (P < 0.001)] and other measures of neonatal size. In both normal pregnancies and those complicated by diabetes, cord IGF-I correlated with cord C peptide levels [0.32 (0.32 (P < 0.001) and 0.42 (P < 0.05), respectively] and neonatal size, but only in normal babies was there a correlation between IGF-I and insulin [0.43 (P < 0.001) and 0.10] or SHBG [-0.28 (P < 0.01) and -0.01]. These data confirm that relationships between insulin concentration and SHBG are present at birth and are likely to be physiological.
A prospective hospital-based cohort study was conducted to determine the prevalence rates of cryptorchidism at birth, 3 months, and 1 year of age.
A total of 6935 consecutive male neonates delivered at Mount Sinai Hospital in New York City between October 1987 and October 1990 were examined at birth for cryptorchidism. Standardized examination and classification criteria were used. Infants classified as cryptorchid at birth were reexamined at 3 months and 1 year after the expected date of delivery.
Of 6935 neonates assessed at birth, 255 (3.7%) were found to be cryptorchid at birth. The rates were significantly elevated for low birth weight, preterm, small-for-gestational age, and twin neonates. The overall rate had declined to 1.0% by the 3-month assessment and 1.1% at the 1-year assessment. Although the rates at the 1-year assessment tended to be higher for low birth weight and preterm infants, no significant group differences were observed.
Since the prevalence rates in this study are similar to those reported several decades ago, these data provide no evidence that the rate of cryptorchidism has increased either at birth or by 1 year of age. Furthermore, most testes that descend spontaneously do so within the first 3 months after the expected date of delivery.
To determine the incidence of gestational diabetes and its associated maternal and infant morbidity by two sets of 3-hour glucose tolerance test criteria, those recommended by the National Diabetes Data Group or the lower, modified criteria of Carpenter and Coustan.
Prospective, observational outcome cohort study.
Prepaid health maintenance organization.
A total of 2019 pregnant women preregistered in a health maintenance organization were screened for a plasma glucose of 7.77 mmol/L (140 mg/dL) or greater, 1 hour after ingestion of a 50-g glucose drink administered after an overnight fast. Positive subjects received a 3-hour glucose tolerance test interpreted by the two criteria. Data are presented for 521 randomly selected negative screenees; 264 positive screen, negative glucose tolerance test subjects; and 101 subjects with gestational diabetes mellitus.
Maternal risk factors for diabetes, infant birth weight corrected for gestational age (birth-weight ratio), umbilical cord serum insulin levels, and 33 maternal and infant perinatal morbidities assessed from chart review.
Gestational diabetes incidence was 5.0% overall based on the modified criteria and 3.2% by the recommended criteria. Maternal age and family history of diabetes were higher in both modified and recommended groups. Birthweight ratio was 1.05 in negative screenees, 1.09 in gestational diabetes overall (P < .05 when only diet-treated subjects were considered), and 1.11 in modified and 1.08 in recommended criteria groups. Cord serum insulin levels in infants of gestational diabetic mothers by both criteria were 40% above those of negative screenees (P < .001). The average percentage incidence of 33 possible perinatal morbidities was 41% higher in gestational diabetic pregnancies by the modified criteria. The cumulative number of morbidities was higher in both modified and recommended criteria groups (P < .01 in both instances). In contrast, subjects having a positive glucose screening test but a negative glucose tolerance test by modified criteria had none of the characteristics of gestational diabetes with the single exception of greater age.
Fifty percent more cases of gestational diabetes were identified using the more inclusive, modified criteria. These cases had as much excess in maternal diabetes risk factors, infant macrosomia, and cord hyperinsulinemia and nearly as much increase in perinatal morbidity as subjects diagnosed by the recommended criteria. The incidence and perinatal impact of gestational diabetes may be greater than previously appreciated. The modified criteria deserve wider verification and use.
A nested case-control study of cryptorchidism (i.e. undescended testicles) was undertaken as part of a hospital-based cohort study of 6699 singleton male neonates in New York City. Since some of the cryptorchid infants experienced spontaneous descent of their testes, separate analysis was performed for this third group of 'late descenders' (n=140). Cases (n=63) represented infants whose testes remained undescended at the one year assessment. Controls (n=219) represented the next male infant who was delivered immediately after an infant who was cryptorchid at birth. The only independent risk factors for cryptorchidism were Asian ethnic group (adjusted odds ratio (OR) = 3.90, 95% confidence interval (CI) = 1.22-12.41), swollen legs or feet during pregnancy (adjusted OR = 2.16, 95% CI = 1.15-4.04), a family history of cryptorchidism (adjusted OR = 4.32, 95% CI = 1.91-9.80), low birthweight (adjusted OR = 4.10, 95% CI = 1.39-12.08), and use of analgesics during pregnancy (adjusted OR = 1.93, 95% CI = 1.03-3.62). Multiple logistic regression analysis was also performed to identify those factors that were associated with late testicular descent. In this analysis the independent risk factors were black or Hispanic ethnicity (adjusted OR = 2.05, 95% CI = 1.09-3.83), a family history of cryptorchidism (adjusted OR = 4.25, 95% CI = 1.84-9.78), consumption of cola-containing drinks during the pregnancy (adjusted OR = 2.09, 95% CI = 1.10-3.99), a low birthweight delivery (adjusted OR = 9.78, 95% CI = 3.39-28.20), and preterm birth (adjusted OR = 4.01, 95% CI = 1.66-9.70).
We aimed to evaluate gestational impaired glucose tolerance (GIGT) in untreated patients using umbilical cord blood insulin and connecting peptide (C-peptide) concentrations to indicate fetal hyperinsulinemia. A 75 g, 2-hour oral glucose tolerance test, evaluated using WHO criteria, was performed in 722 antenatal patients. Cord C-peptide (p = 0.001) and insulin (p = 0.008) concentrations were significantly higher in patients with GIGT in comparison to those with normal glucose tolerance. The WHO test failed to identify abnormal C-peptide concentrations (p = 0.057), but did identify abnormal insulin concentrations (p = 0.006) and cases where either or both were raised (p = 0.002), with a low Youden's index (range 8.1-11.3) in all 3 cases. A significant biochemical difference exists in patients with GIGT. The WHO criteria for GIGT predict abnormal biochemical outcomes, but they do so poorly.
Several groups have reported a risk of fetal macrosomia in pregnancies with maternal glucose intolerance which is intermediate between gestational diabetes (GDM) and normal glucose tolerance. The present study was designed to determine whether these pregnancies are also at risk for fetal obesity, hyperinsulinism and placental villous immaturity. 325 women with risk factors for GDM underwent a 75 g OGTT interpreted according to the O'Sullivan criteria. All women who met the criteria for GDM were managed with diet therapy. Insulin therapy was added for women with a mean serum glucose value > 100 mg/dl on a 24 hour glucose profile. Patients not meeting the GDM criteria were managed without special intervention. Primary outcome variables were measures of neonatal weight and skinfold thickness, fetal and neonatal insulin and glucose concentration, and placental villous maturation. Outcome parameters were compared among three groups: pregnancies with normal OGTT (control, n = 95), 1 abnormal value in the OGTT (1 abnl, n = 76) and GDM (n = 154). The outcome of pregnancies with 1 abnormal value in the OGTT was different from those with normal OGTT. Regarding fetal growth, rates of LGA were approximately twice as high in groups with one abnormal value and GDM (21% and 24%) compared to women with normal OGTTs (11%: p < 0.05 vs GDM and p = 0.07 vs 1 abnormal value). The percent of infants with skinfold thickness > 90th percentile was also greater in the 1 abnormal value and GDM groups (31.1 and 31.6% respectively) compared to controls (19.2%; p < 0.05 for GDM vs control only). Regarding fetal hyperinsulinism, AFI concentrations were similar in control and GDM groups (3.1 +/- 0.4 and 3.4 +/- 0.8 microU/ml, respectively), but were higher in the group with one abnormal OGTT value (4.3 +/- 1.2 microU/ml, p < 0.05 vs controls). Cord blood insulin: glucose ratios were elevated in both the 1 abnormal value and GDM groups (0.22 +/- 0.05 and 0.20 +/- 0.02 microU/ml per mg/dl), compared to controls (0.12 +/- 0.01 microU/ml per mg/dl, p < 0.05 vs 1 abnormal value). Neonatal glycemia < 30 mg/dl was significantly more common in the one abnormal value than in the control group (49% vs 34% of infants) and intermediate in the GDM group (40%). Severe placental villous immaturity was more than twice as frequent in the 1 abnormal value group compared to controls (24% vs 9%, p < 0.05) and the most frequent in the GDM group (33%; p < 0.001 vs controls). Pregnancies with glucose intolerance below the thresholds for diagnosis of GDM have an increased risk for fetal obesity, hyperinsulinism, postpartum hypoglycemia and placental immaturity. These findings indicate the continuum of risk for fetal morbidity associated with increasing maternal glucose intolerance in pregnancy.
The sexual dimorphic position of the gonads in mammals is dependent on differential development of two ligaments, the cranial suspensory ligament (CSL) and the gubernaculum. During male embryogenesis, outgrowth of the gubernaculum and regression of the CSL result in transabdominal descent of the testes, whereas in the female, development of the CSL in conjunction with failure of the gubernaculum development holds the ovaries in a position lateral to the kidneys. Several lines of evidence suggest that regression of the CSL and induction of gubernaculum development are mediated by testosterone and a yet unidentified testicular factor, respectively. The Insl3 gene (originally designated Ley I-L), a member of the insulin-like superfamily, is specifically expressed in Leydig cells of the fetal and postnatal testis and in theca cells of the postnatal ovary. Here we show that male mice homozygous for a targeted deletion of the Insl3 locus exhibit bilateral cryptorchidism with free moving testes and genital ducts. These malformations are due to failure of gubernaculum development during embryogenesis. In double-mutant male mice for Insl3 and androgen receptor genes, testes are positioned adjacent to the kidneys and steadied in the abdomen by the CSL. These findings demonstrate, that the Insl3 induces gubernaculum development in an androgen-independent way, while androgen-mediated regression of the CSL occurs independently from Insl3.
Male sexual differentiation relies upon testicular secretion of the hormones testosterone, Mullerian inhibiting substance, and insulin-3 (Insl3). Insl3 is responsible for testicular descent through virilization and outgrowth of the embryonic gubernaculum. In mouse, prenatal exposure to 17beta-estradiol and the nonsteroidal synthetic estrogen diethylstilbestrol (DES) disturbs the endocrine balance, causing demasculinizing and feminizing effects in the male embryo, including impaired testicular descent (cryptorchidism). In the current study, we show that maternal exposure to estrogens, including 17alpha- and beta-estradiol, as well as DES, specifically down regulates Insl3 expression in embryonic Leydig cells, thereby providing a mechanism for cryptorchidism. These experiments may have implications for the widespread use of estrogenic substances in agriculture and the environment.
Insulin is an important regulator of serum sex hormone-binding globulin (SHBG) concentration which works by inhibiting its production in hepatocytes. Low SHBG level is associated with increased insulin resistance and hyperinsulinemia. Our purpose was to compare maternal serum SHBG level between normal and gestational diabetic pregnant women and to study the relationships between SHBG, SHBG/insulin and SHBG/glucose ratio and several endocrine, metabolic and clinical parameters.
Serum SHBG concentrations were measured in 34 women with gestational diabetes and in 32 matched controls. Glucose, insulin, C-peptide, fructosamine, beta-HCG, cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, apolipoprotein A, apolipoprotein B, total and free T4, total and free estriol, T3 and IGF-1 were measured. Insulin sensitivity was estimated using the short insulin tolerance test.
SHBG, SHBG/insulinemia ratio and SHBG/glucose ratio were significantly lower in the diabetic group (309.54 +/- 112.22 vs 460.54 +/- 144.54, p = 0.00001), (33.55 +/- 16.62 vs 72.56 +/- 66.50, p = 0.0006 using log-transformed values), (5.88 +/- 1.87 vs 3.39 +/- 1.23, p < 0.00001). SHBG was negatively correlated with insulinemia (r = -0.40, p = 0.001), C-peptide (r = -0.41, p = 0.001), glycemia (r = -0.27, p = 0.02), diastolic blood pressure (r = -0.41, p = 0.001) and beta-HCG (r = -0.41, p = 0.001) and positively correlated with LDL-c (r = 0.25, p = 0.04) and apolipoprotein B (r = 0.33, p = 0.007).
SHBG concentrations are lower in gestational diabetic pregnant women and are related to insulin levels but not to peripheral insulin sensitivity. Since insulinemia was similar in normal and gestational diabetic pregnant women, we speculate that gestational diabetes is characterized by a higher peripheral insulin resistance, a fasting normal insulinemia and a higher hepatic insulin sensitivity, at least in other actions than on carbohydrate metabolism. The role of sex steroids, T4 and IGF-1 in regulating SHBG appears to be limited during pregnancy.
Low Sex-Hormone-Binding Globulin (SHBG) levels--indicating a state of hyperandrogenicity--are associated with a higher risk for the development of non-insulin dependent diabetes (NIDDM) in women and are accepted as a marker of muscular insulin resistance. To analyze whether low SHBG values are also present in patients with gestational diabetes, we investigated levels of SHBG in 42 patients with gestational diabetes mellitus (GDM) in comparison with 48 pregnant women with normal glucose tolerance (NGT). Beside maternal parameters like body-mass index (BMI), HbA1c, fasting, 1- and 2-hour blood glucose and insulin concentrations, parameters of the new-borns (head-circumference, body weight, height and sex) were recorded. Maternal and neonatal variables were then related to SHBG levels. Both groups showed no differences in BMI, height, weight or age of gestation. Patients with GDM revealed significantly lower levels of SHBG than pregnant women with NGT(512 +/- 249 nmol/l vs. 643 +/- 137 nmol/l; p < 0.01). In patients with severe GDM and insulin therapy significantly lower levels of SHBG than in those with dietary treatment only were found (223 +/- 210 nmol/l vs. 592 +/- 102 nmol/l; p < 0.001). SHBG was inversely correlated to BMI (r = - 0.30; p < 0.01), 1-hour (r = - 0.20; p < 0.05) and 2-hour blood glucose levels (r = - 0.30; p <0.01). In summary, we found significantly lower levels of SHBG in patients with GDM, especially in those who developed severe GDM and required insulin therapy during the last months of pregnancy.
To study prevalence, risk factors, and maternal and infant outcomes of women with gestational diabetes mellitus (GDM).
A retrospective cohort study was performed based on 111563 pregnancies delivered between 1991 through 1997 in 39 hospitals in northern and central Alberta, Canada. Multivariate logistic regression was used to estimate the odds ratios with 95% confidence intervals, and to control for confounding variables.
The prevalence of GDM was 2.5%. Risk factors for GDM included age >35 years, obesity, history of prior neonatal death, and prior cesarean section. Teenage mothers and women who drank alcohol were less likely to have GDM. Mothers with GDM were at increased risk of presenting with pre-eclampsia, premature rupture of membranes, cesarean section, and preterm delivery. Infants born to mothers with GDM were at higher risk of being macrosomic or large-for-gestational-age.
Specific conditions predispose to GDM which itself is associated with a significantly increased risk of maternal and fetal morbidity.
Of the 10,730 neonates born in the period 1978-1997 and examined for cryptorchidism (C) at birth, 1387 were pre-term (gestational age <37 wk), and 9343 were full-term. At birth, a total of 737 neonates (6.9%) were cryptorchid, 487 had bilateral C and 250 unilateral C. The C rate of pre-terms was 10 times higher than that of the full-terms (30.1 and 3.4%, respectively). Comparing the two studied decades, a significant decrease of C rate was found in the second decade in full-term neonates. The rates of C at birth were significantly elevated for low birth weight, babies born from mothers with an age <20 or >35 yr, newborns from mothers with A Rh positive and B Rh positive blood group. Of the 737 cryptorchid newborns at birth, 613 (83%) were re-examined after 12 months from the expected date of delivery, and those born in the period 1988-1997 were also re-evaluated at 6 months of life. Late spontaneous descent occurred in 464 cases (75.7%), while 149 (24.3%) were still cryptorchid. The incidence of C at 12 months from the expected date of delivery, after survival curve calculation, in term and pre-term infants, was 1.53 and 7.31%, respectively, in the period 1978-1987, and 1.22 and 3.13% respectively, in the 2nd decade (1988-1997). In the groups also examined at 6 months of life, spontaneous descent occurred almost completely within the first 6 months of life in term infants, but not in pre-terms. No evidence of seasonal cyclicity was found. Medical and/or surgical treatment was generally started within 2-4 yr of age earlier in the second decade of the study. In conclusion, the main risk factor for C at birth and at 12 months of life seems to be pre-term birth and low birth weight. If this is associated itself to a higher risk of infertility too, it remains to be defined.
To investigate the effects of pregestational, as opposed to gestational, diabetes on infant malformations.
All women delivering infants at Parkland Hospital between January 1, 1991, and December 31, 2000, were ascertained. Screening for gestational diabetes was methodically employed throughout the study period using National Diabetes Data Group criteria for diagnosis of pregestational and gestational diabetes. Standardized definitions of major infant malformations were specified before data analysis and subdivided according to the organ systems involved.
A total of 145,196 women were delivered during the study period, and 2687 (1.9%) were diagnosed to have diabetes mellitus. Gestational diabetes was diagnosed in 2277 (1.6%) of whom 230 (10%) had fasting hyperglycemia diagnosed, and the remainder consistently demonstrated fasting serum levels less than 105 mg/dL. Pregestational diabetes was diagnosed in 410 (0.3%) women. Infant malformations occurred in 1.5% of nondiabetic women compared with 1.2% of women with normal fasting glucose gestational diabetes, 4.8% in women with gestational diabetes plus fasting hyperglycemia, and 6.1% in those with pregestational diabetes (P <.001, for comparison of the latter two groups with the nondiabetic population).
Women with pregestational diabetes or gestational diabetes plus fasting hyperglycemia have a three- to four-fold increased risk of infant malformations, whereas women with mild gestational diabetes have malformation rates no different than the general nondiabetic obstetric population.
The original 'oestrogen hypothesis' postulated that the apparent increase in human male reproductive developmental disorders (testis cancer, cryptorchidism, hypospadias, low sperm counts) might have occurred because of increased oestrogen exposure of the human foetus/neonate; five potential routes of exposure were considered. This review revisits this hypothesis in the light of the data to have emerged since 1993. It addresses whether there is a secular increasing trend in the listed disorders and highlights the limitations of available data and how these are being addressed. It considers whether new data has emerged to support the suggestion that increased oestrogen exposure could cause these abnormalities and reviews new data on potential routes via which such increased exposure could have occurred. Secular trends: The disorders listed above are now considered to represent a syndrome of disorders (testicular dysgenesis syndrome, TDS) with a common origin in foetal life. Testicular cancer has increased in incidence in Caucasian men worldwide and lifetime risk is 0.3-0.8%. Secular trends in cryptorchidism are unclear but it is by far the commonest (2-4% at birth) congenital abnormality in either sex. Secular trends for hypospadias are not robust, although most studies suggest a progressive increase; registry data probably under-estimates incidence, but based on this data hypospadias is the second most common (0.3-0.7% at birth) congenital malformation. Retrospective analyses of sperm count data show a global downward trend but this is inconclusive - prospective studies using standardized methodology show significant differences between countries and very low sperm counts in the youngest cohort of men. For all disorders, other then testis cancer, standardized prospective studies are the best way forward and are in progress across Europe. Oestrogen effects: Evidence that foetal exposure to oestrogens can induce the above disorders has strengthened. New pathways via which such changes could be induced have been identified, including suppression of testosterone production by the foetal testis, suppression of androgen receptor expression and suppression of insulin-like factor-3 (InsL3) production by foetal Leydig cells. Other evidence suggests that the balance between androgen and oestrogen action may be important in induction of reproductive tract abnormalities. Oestrogen exposure: Although many new environmental oestrogens have been identified, their uniformly weak oestrogenicity excludes the possibility that they could induce the above disorders. However, emerging data implicates various environmental chemicals in being able to alter endogenous levels of androgens (certain phthalates) and oestrogens (polychlorinated biphenyls, polyhalogenated hydrocarbons), and the former have been shown to induce a similar collection of disorders to TDS. Other mechanisms via which increased fetal exposure to pregnancy oestrogens might occur (increasing trend in obesity, dietary changes) are also discussed.
We sought to examine the association between early pregnancy levels of sex hormone binding globulin and subsequent gestational diabetes mellitus, an association that has not been studied previously.
We conducted a nested case-control study of 44 patients with gestational diabetes mellitus and 94 women with negative third-trimester screening for gestational diabetes mellitus. Sex hormone binding globulin levels were measured from serum samples that had been collected in the first trimester, and clinical data were ascertained from prospectively collected electronic medical records.
Compared with women without gestational diabetes mellitus, first-trimester sex hormone binding globulin levels were lower among women in whom gestational diabetes mellitus subsequently developed (187 +/- 82 nmol/L vs 233 +/- 92 nmol/L, P <.01). In logistic regression analysis that was adjusted for body mass index, age, race, smoking, blood pressure, serum testosterone and estradiol levels, and gestational age at serum collection, sex hormone binding globulin levels remained independently associated with subsequent gestational diabetes mellitus. For every 50-nmol/L increase in sex hormone binding globulin, the odds of gestational diabetes mellitus fell by 31% (odds ratio, 0.69; 95% CI: 0.48, 0.99).
Sex hormone binding globulin offers a potential early marker to target women who are at risk for gestational diabetes mellitus.
To investigate whether different degrees of maternal glucose intolerance are associated with the risk of spontaneous preterm birth.
We performed a cohort study of 46,230 pregnancies screened by a 50-g, 1-hour oral glucose tolerance test between 24 and 28 gestation weeks at the Northern California Kaiser Permanente Medical Care Program. Spontaneous preterm birth was defined as an infant born at less than 37 gestation weeks with at least one of the following: spontaneous labor, preterm premature rupture of membranes, or incompetent cervix. Glucose tolerance status was categorized as normal screening (1-hour plasma glucose less than 140 mg/dL), abnormal screening (1-hour plasma glucose of at least 140 mg/dL with a normal diagnostic 100-g, 3-hour oral glucose tolerance test result), Carpenter-Coustan (plasma glucose measurements during the diagnostic oral glucose tolerance test met the thresholds but were lower than the National Diabetes Data Group thresholds), and gestational diabetes mellitus (GDM) by the National Diabetes Data Group criteria.
One thousand nine hundred fifty-six spontaneous preterm births occurred. Age-adjusted incidences of spontaneous preterm birth were 4.0% in normal screening, 5.0% in abnormal screening, 6.7% in Carpenter-Coustan, and 6.7% in GDM. In a logistic regression model adjusted for age, race-ethnicity, preeclampsia-eclampsia-pregnancy-induced hypertension, chronic hypertension, polyhydramnios, and birth weight for gestational age, pregnancies with abnormal screening, Carpenter-Coustan, and GDM had a significantly higher risk of spontaneous preterm birth than pregnancies with normal screening (relative risk [95% confidence interval]: 1.23 [1.08, 1.41], 1.53 [1.16, 2.03], and 1.42 [1.15-1.77], respectively).
The risk of spontaneous preterm birth increased with increasing levels of pregnancy glycemia. This association was independent of perinatal complications that could have triggered early delivery.
Women with gestational diabetes mellitus (GDM) and their offspring are at increased risk of developing diabetes. Although increases in diabetes prevalence have been reported in the United States, it is unknown whether this trend is also occurring for GDM. We examined trends in the yearly cumulative incidence of GDM between the years 1991 and 2000.
A cohort study of 267,051 pregnancies screened for GDM that occurred among members of the Northern California Kaiser Permanente Medical Care Program, representing 86.8% of all eligible pregnancies, was undertaken.
GDM was identified in 14,175 pregnancies according to the diagnostic plasma glucose thresholds of the American Diabetes Association (96.5%) or the World Health Organization (3.5%). An additional 2,743 pregnant women with GDM were identified by a hospital discharge diagnosis. The women screened in 2000 were slightly older (mean [standard deviation] age 28.8 [6.0] years) than were those screened in 1991 (28.2 [5.7] years) and more likely to be from minority ethnic groups (51.4% versus 37.3% identified as African American, Asian, Hispanic, and other). The age- and ethnicity-adjusted yearly cumulative incidence of GDM increased steadily from 5.1% in 1991 to 7.4% in 1997 and leveled off through 2000 (6.9%).
The observed increase in yearly cumulative incidence of GDM was independent of changes in age and ethnicity of the study population. A true increase in GDM incidence might reflect or contribute to the increases in the prevalence of diabetes and obesity. Coordinated efforts are needed to alter this trend and to prevent chronic diabetes in GDM patients and their offspring.
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Several investigators have shown striking differences in semen quality and testicular cancer rate between Denmark and Finland. Since maldescent of the testis is a shared risk factor for these conditions we undertook a joint prospective study for the prevalence of congenital cryptorchidism.
1068 Danish (1997-2001) and 1494 Finnish boys (1997-99) were consecutively recruited prenatally. We also established prevalence data for all newborns at Turku University Central Hospital, Finland (1997-99, n=5798). Testicular position was assessed by a standardised technique. All subtypes of congenital cryptorchidism were included, but retractile testes were considered normal.
Prevalence of cryptorchidism at birth was 9.0% (95% CI 7.3-10.8) in Denmark and 2.4% (1.7-3.3) in Finland. At 3 months of age, prevalence rates were 1.9% (1.2-3.0) and 1.0% (0.5-1.7), respectively. Significant geographic differences were still present after adjustment for confounding factors (birthweight, gestational age, being small for gestational age, maternal age, parity, mode of delivery); odds ratio (Denmark vs Finland) was 4.4 (2.9-6.7, p<0.0001) at birth and 2.2 (1.0-4.5, p=0.039) at three months. The rate in Denmark was significantly higher than that reported 40 years ago.
Our findings of increasing and much higher prevalence of congenital cryptorchidism in Denmark than in Finland contribute evidence to the pattern of high frequency of reproductive problems such as testicular cancer and impaired semen quality in Danish men. Although genetic factors could account for the geographic difference, the increase in reproductive health problems in Denmark is more likely explained by environmental factors, including endocrine disrupters and lifestyle.
Undescended testis is one of the most common congenital defects in the newborn boys and the common cause of cryptorchidism. If left untreated, this condition is strongly associated with infertility and drastically increased risk of testicular cancer in adulthood. Testis position in developing males is defined by sexual dimorphic differentiation of two gonadal ligaments, gubernaculum and cranial suspensory ligament. Recent transgenic mouse studies identified testicular hormone insulin-like 3 (INSL3), and its receptor, GREAT/LGR8, as the critical regulators of the gubernacular differentiation. Mutation analysis of the two genes in patients with undescended testis revealed functionally deleterious mutations, which may be responsible for the abnormal phenotype in some of the patients.
Cryptorchidism is a common ailment of new-born boys, affecting 1-9% of full term boys at birth. Cryptorchidism has been associated with an increased risk of testicular cancer and reduced fertility. Aetiology of cryptorchidism remains obscure in most cases. Familial occurrence suggests a heritable susceptibility to cryptorchidism; however, seasonal variation in the incidence of cryptorchidism suggests that environmental factors also contribute. Testicular descent is characterised by androgen-dependent regression of cranial suspensory ligament and androgen + insulin-like hormone 3 (Ins l3)-dependent gubernacular outgrowth. Even though hormonal defects are rarely detected in patients, both hypo-and hypergonadotropic hormonal patterns have been associated with cryptorchidism. Moreover, cryptorchid boys have significantly reduced serum androgen bioactivity at 3 months of age when normal boys have a strong surge of reproductive hormones. Defects in Ins l3 action cause cryptorchidism in male mice, and over-expression in female mice causes ovarian descent. Defects in leucine-rich repeat-containing G-protein-coupled receptor 8/G-protein-coupled receptor affecting testis descent (LGR8/GREAT), the receptor for Ins l3, manifest the same phenotype as Ins l3 knockout mutants. Even though mutations found in Ins l3 and LGR8/GREAT genes are not a common cause of cryptorchidism in patients, it remains to be resolved whether low Ins l3 levels during development are associated with cryptorchidism. Cryptorchidism may reflect foetal testicular dysgenesis that may later manifest as subfertility or testicular cancer.
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