Publications by authors named "Charles Sultan"

150 Publications

Prenatal Exposure to Diethylstilbestrol and Multigenerational Psychiatric Disorders: An Informative Family.

Int J Environ Res Public Health 2021 09 22;18(19). Epub 2021 Sep 22.

Service de Pédiatrie, Unité d'Endocrinologie-Gynécologie Pédiatrique, CHU Montpellier, University Montpellier, 34090 Montpellier, France.

Background: Psychiatric disorders in children exposed in utero to diethylstilbestrol (DES) are still debated. We report here the impact of DES prescribed to suppress lactation on the children born after such treatment and their progeny, focusing particularly on psychiatric disorders.

Case Presentation: We report here an informative family in which one or more psychiatric problems (e.g., bipolarity, suicide attempts and suicide, eating disorders) were detected in all children of second-generation (DES-exposed children; = 9), but for II-2 who died at the age of 26 years due to rupture of a congenital brain aneurysm, and were associated with non-psychiatric disorders (particularly, endometriosis and hypospadias). In the third generation, 10 out of 19 DES-exposed grandchildren had psychiatric disorders (autism spectrum disorder, bipolar disorder, dyspraxia and learning disabilities, mood and behavioral disorders, and eating disorders), often associated with comorbidities. In the fourth generation (7 DES-exposed great-grandchildren, aged between 0 and 18 years), one child had dyspraxia and autism spectrum disorder. The first daughter of the second generation (not exposed to DES) and her children and grandchildren did not have any psychiatric symptoms or comorbidities.

Conclusions: To our knowledge, the high prevalence of psychiatric disorders of various severities in two, and likely three generations, including DES-free pregnancies and DES-exposed pregnancies from the same family, has never been reported. This work strengthens the hypothesis that in utero exposure to DES contributes to the pathogenesis of psychiatric disorders. It also highlights a multigenerational, and possibly transgenerational, effect of DES in neurodevelopment and psychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18199965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507930PMC
September 2021

Multigenerational endometriosis : consequence of fetal exposure to diethylstilbestrol ?

Environ Health 2021 08 27;20(1):96. Epub 2021 Aug 27.

CHU Montpellier, Univ Montpellier, Unité d'Endocrinologie-Gynécologie Pédiatrique, Service de Pédiatrie, Montpellier, France.

Background: Endometriosis, which affects 10-15 % of women of reproductive age, is an estrogen-driven condition influenced by environmental and genetic factors. Exposition to estrogen-like endocrine-disrupting chemicals (EDCs) has been reported to contribute to the fetal origin of this disease.

Case Presentation: We report here an informative family in which all prenatally DES-exposed daughters and subsequent granddaughters presented endometriosis, whereas the unexposed first daughter and her progeny presented no gynecological disorders. Moreover, the only post-pubertal great-granddaughter, who presents chronic dysmenorrhea that remains resistant to conventional therapy, is at risk of developing endometriosis. The mother (I-2) was prescribed DES (30 mg/day for 3 months) to inhibit lactation after each delivery.

Conclusions: Although a direct causal link between the grandmother's treatment with DES and the development of endometriosis in possibly three exposed generations remains speculative, this report strengthens the suspicion that fetal exposition to DES contributes to the pathogenesis of adult diseases, such as endometriosis. It also highlights a multigenerational and likely transgenerational effect of EDCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12940-021-00780-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401160PMC
August 2021

Experimental Evidence of 2,3,7,8-Tetrachlordibenzo-p-Dioxin (TCDD) Transgenerational Effects on Reproductive Health.

Int J Mol Sci 2021 Aug 23;22(16). Epub 2021 Aug 23.

INSERM 1203, Développement Embryonnaire Fertilité Environnement, University of Montpellier, 34295 Montpellier, France.

Previous studies have demonstrated that endocrine disruptors (EDs) can promote the transgenerational inheritance of disease susceptibility. Among the many existing EDs, 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) affects reproductive health, including in humans, following direct occupational exposure or environmental disasters, for instance the Agent Orange sprayed during the Vietnam War. Conversely, few studies have focused on TCDD multigenerational and transgenerational effects on human reproductive health, despite the high amount of evidence in animal models of such effects on male and female reproductive health that mimic human reproductive system disorders. Importantly, these studies show that paternal ancestral TCDD exposure substantially contributes to pregnancy outcome and fetal health, although pregnancy outcome is considered tightly related to the woman's health. In this work, we conducted a systematic review of the literature and a knowledge synthesis in order (i) to describe the findings obtained in rodent models concerning TCDD transgenerational effects on reproductive health and (ii) to discuss the epigenetic molecular alterations that might be involved in this process. As ancestral toxicant exposure cannot be changed in humans, identifying the crucial reproductive functions that are negatively affected by such exposure may help clinicians to preserve male and female fertility and to avoid adverse pregnancy outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22169091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396488PMC
August 2021

Endocrine-Disrupting Chemicals and Disorders of Penile Development in Humans.

Sex Dev 2021 26;15(1-3):213-228. Epub 2021 Aug 26.

Centre de Référence Maladies Rares du Développement Génital DEVGEN, Constitutif Sud, Hôpital Lapeyronie, CHU Montpellier, Université Montpellier, Montpellier, France.

This paper reviews the current knowledge on the environmental effects on penile development in humans. The specific focus is on endocrine-disrupting chemicals (EDCs), a heterogeneous group of natural or manmade substances that interfere with endocrine function, and whether they can induce hypospadias and micropenis in male neonates. Epidemiological data and animal observations first raised suspicions about environmental effects, leading to the testis dysgenesis syndrome (TDS) hypothesis. More recent research has provided stronger indications that TDS may indeed be the result of the direct or indirect effects of EDCs. Drawing on epidemiological and toxicological studies, we also report on the effects of maternal diet and substances like pesticides, phthalates, bisphenol A, and polychlorinated biphenyls. Proximity to contamination hazards and occupational exposure are also suspected to contribute to the occurrence of hypospadias and micropenis. Lastly, the cumulative effects of EDCs and the possibility of transgenerational effects, with the penile development of subsequent generations being affected, raise concerns for long-term public health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000517157DOI Listing
August 2021

Poly(etheretherketone)/Poly(ethersulfone) Blends with Phenolphthalein: Miscibility, Thermomechanical Properties, Crystallization and Morphology.

Polymers (Basel) 2021 May 1;13(9). Epub 2021 May 1.

LGP-ENIT-INPT, Université de Toulouse, 47 Avenue d'Azereix, 65016 Tarbes, France.

Polyetheretherketone (PEEK)/polyethersulfone (PES) blends are initially not miscible, except when the blends are prepared by solvent mixing. We propose a route to elaborate PEEK/PES blends with partial miscibility by melt mixing at 375 °C with phenolphthalein. The miscibility of blends has been examined using differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMTA). When adding phenolphthalein to PEEK/PES blends, the glass transitions are shifted inward as an indication of miscibility. We suggest that phenolphthalein acts as a compatibilizer by creating cardo side groups on PEEK and PES chains by nucleophilic substitution in the melted state, although this condensation reaction was reported only in the solvent until now. In addition, phenolphthalein acts as a plasticizer for PES by decreasing its glass transition. As a consequence, the PEEK phase is softened which favors the crystallization as the increase of crystalline rate. Due to aromatic moieties in phenolphthalein, the storage modulus of blends in the glassy region is kept identical to pure PEEK. The morphological analysis by SEM pictures displays nano- to microsized PES spherical domains in the PEEK matrix with improved PEEK/PES interfacial adhesion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/polym13091466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124672PMC
May 2021

The evolving role of whole-exome sequencing in the management of disorders of sex development.

Endocr Connect 2021 Jun 16;10(6):620-629. Epub 2021 Jun 16.

Institute Pasteur, Rue Dr Roux, Paris, France.

Objective: Disorders of sex development (DSD) are defined as congenital conditions in which the development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients.

Methods: We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology.

Results: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two atients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A.

Conclusions: Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management - and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EC-21-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240709PMC
June 2021

How Far Should We Explore Hypospadias? Next-generation Sequencing Applied to a Large Cohort of Hypospadiac Patients.

Eur Urol 2021 04 16;79(4):507-515. Epub 2021 Jan 16.

Centre de Référence Maladies Rares DEVGEN Constitutif Sud, CHU de Montpellier, France; Laboratoire de Génétique de Maladies Rares, EA7402, Université de Montpellier, Montpellier, France; Chirurgie et Urologie Pédiatrique, Hôpital Lapeyronie, CHU de Montpellier, et Université de Montpellier, Montpellier, France. Electronic address:

Background: Next-generation sequencing (NGS) is generally used for patients with severe disorders of sex development (DSD). However, NGS has not been applied extensively for patients with hypospadias only, and most affected children do not benefit from an etiological diagnosis.

Objective: To evaluate the clinical usefulness of NGS for patients with hypospadias, regardless of severity.

Design, Setting, And Participants: Prospective multicenter research included 293 children with glandular to penoscrotal hypospadias (no undescended testis and no micropenis). After excluding likely pathogenic androgen receptor (AR) variants by Sanger sequencing, an NGS panel tested 336 genes including unexplored candidates in 284 patients.

Outcome Measurements And Statistical Analysis: The rate of pathogenic and likely pathogenic variants was assessed using REVEL, ClinVar, and in-house tools (Captain-ACHAB, MobiCNV, and MobiDetails).

Results And Limitations: Likely pathogenic variants were identified in 16 (5.5%) patients with both Sanger sequencing and NGS taken into account. Some genes were related to DSD (AR, NR5A1, HSD17B3, and MAMLD1), but reverse phenotyping revealed two syndromic disorders with midline defects (MID1) and alteration in the retinoic acid signaling pathway (RARA). Coverage analysis revealed an 18q deletion. Identification of likely pathogenic variants increased with hypospadias severity. Other variants of unknown significance (VUSs) in genes implicated in hypogonadotropic hypogonadism, Noonan syndrome, and genital tubercle development were also identified. Genetic study mainly focused on exonic variants, and most cases remain unexplained.

Conclusions: NGS reveals minor forms of DSD, undiagnosed syndromes, or candidate rare variants in new genes, indicating that even patients with mild hypospadias benefit from advanced sequencing techniques. Early molecular diagnosis would help improve follow-up at puberty and medical counseling for initially undiagnosed syndromes. Future studies will improve the diagnosis by investigating the contribution of VUSs.

Patient Summary: Next-generation sequencing enables simultaneous testing of numerous genes and should not be limited to disorders of sex development cases. Even patients with mild hypospadias would benefit from early diagnosis of a genetic defect implicated in sex development or other syndromes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2020.12.036DOI Listing
April 2021

The quantitative ultrasound method for assessing low bone mass in women with anorexia nervosa.

Arch Osteoporos 2021 01 14;16(1):13. Epub 2021 Jan 14.

Département de Médecine Nucléaire, Hôpital Lapeyronie, Centre Hospitalier Régional Universitaire (CHRU) Montpellier, 34295, Montpellier, France.

This study investigated the potential role of quantitative ultrasound (QUS) to assess low bone mass in anorexia nervosa patients (AN). Bone parameters from QUS and DXA were positively correlated and significantly reduced in AN compared with controls, suggesting that QUS is a pertinent technique to assess low bone mass in these patients.

Purpose: The aim of this study was to investigate the potential role of an alternative technique, quantitative ultrasound (QUS), to assess low bone mass in patients with anorexia nervosa (AN).

Methods: Two hundred seven young women (134 patients with AN and 73 healthy controls) with ages ranging from 14.4 to 38.4 years participated in this observational cross-sectional study. Bone mass was concomitantly evaluated by DXA to determine areal bone mineral density (aBMD; g/cm) at hip, lumbar spine, and radius and by QUS to determine broadband ultrasound attenuation (BUA; dB/MHz) at the heel.

Results: BUA (66.5 ± 4.6 dB/MHz vs 61.0 ± 5.0 dB/MHz) and aBMD at the hip (0.916 ± 0.013 g/cm vs 0.806 ± 0.010 g/cm), lumbar spine (0.966 ± 0.012 g/cm vs 0.886 ± 0.010 g/cm), and radius (0.545 ± 0.005 g/cm vs 0.526 ± 0.04 g/cm) were significantly decreased (p < 0.01) in patients with AN compared with controls. When patient and control data were pooled, BUA was significantly correlated with aBMD at the hip (r = 0.60, p < 0.001), lumbar spine (r = 0.48, p < 0.001), and radius (r = 0.40, p<0.001). In patients with AN, BUA and aBMD were mainly and positively correlated with weight, lean tissue mass, body mass index (BMI), and minimal BMI life and negatively with the duration of both disease and amenorrhea. Better concordance between the two techniques was obtained when absolute BUA and aBMD values were used according to the WHO T score classification.

Conclusion: BUA measurement at the heel by QUS appears to be a pertinent nonionizing technique to assess low bone mass in patients with AN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11657-020-00870-wDOI Listing
January 2021

Diethylstilbestrol exposure during pregnancy with primary clear cell carcinoma of the cervix in an 8-year-old granddaughter: a multigenerational effect of endocrine disruptors?

Hum Reprod 2021 01;36(1):82-86

Unité d'Endocrinologie-Gynécologie Pédiatrique, Service de Pédiatrie, Hôpital Arnaud-de-Villeneuve, CHU Montpellier et Université Montpellier, Montpellier, France.

To date, vaginal/cervical clear cell adenocarcinoma (CCAC) has not been reported in the granddaughters of women treated with diethylstilbestrol (DES) during pregnancy. We present an 8-year-old girl with a history of severe vaginal bleeding who was diagnosed with cervical CCAC. She underwent fertility-sparing surgery and radiotherapy. No sign of recurrence was detected throughout a 10-year follow-up. Her grandmother had received DES therapy during pregnancy with the patient's mother. Although no direct causal link is demonstrated, this case raises for the first time, the hypothesis of multigenerational effects of DES in girls and strongly suggests the need to follow the granddaughters of DES-treated women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/humrep/deaa267DOI Listing
January 2021

Adolescent ovarian thecoma presenting as progressive hyperandrogenism: case report and review of the literature.

Gynecol Endocrinol 2020 Sep 16;36(9):839-842. Epub 2020 Mar 16.

Unité d'Endocrinologie-Gynécologie Pédiatrique, Département de Pédiatrie, Hôpital A.-de-Villeneuve, CHU Montpellier et Université Montpellier, Montpellier, France.

Hyperandrogenism is frequent and under investigated in adolescent girls. A 15-year-6-month-old French girl presented with oligomenorrhea and slowly progressing virilization 2 years post-menarche. Medical history revealed prenatal pesticide exposure through maternal professional activity and recurrent premature thelarche. Severe hirsutism, mild facial acne and clitoromegaly were noted. Serum androgens (testosterone: 94 ng/dL, 4-androstenedione: 8.23 ng/mL) were high and non-classic 21-hydroxylase deficiency was excluded. Pelvic ultrasonography showed a left ovarian mass, confirmed by computed tomography scan. Tumor markers were negative. Laparoscopic surgery was performed. The pathological diagnosis was benign luteinized thecoma. Postoperatively, the menstrual cycle and serum androgens became normal and hirsutism slowly improved. Hyperandrogenism 2 years after menarche should be systematically investigated, even if slowly progressive, since it may be a symptom of a rare virilizing ovarian tumor, like thecoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09513590.2020.1739265DOI Listing
September 2020

Specific Effects of Anorexia Nervosa and Obesity on Bone Mineral Density and Bone Turnover in Young Women.

J Clin Endocrinol Metab 2020 04;105(4)

Département de Médecine Nucléaire, Hôpital Lapeyronie, Centre Hospitalier Régional Universitaire (CHRU) Montpellier, Montpellier, France.

Objective: The threefold aim was to (1) compare areal bone mineral density (aBMD), bone turnover markers, and periostin levels in young women with either anorexia nervosa (AN) or obesity (OB) and controls (CON); (2) model the profiles according to age; and (3) determine the parameters associated with aBMD.

Subjects And Methods: One hundred and fifty-two young women with ages ranging from 16.0 to 27.0 years were subdivided into 3 groups (AN, OB, CON). The CON group was age-matched by ±6 months. aBMD, bone turnover markers, and periostin levels were evaluated.

Results: aBMD modeling showed that hip aBMD was higher in OB than in the other 2 groups from 19 years, and AN presented lower values than CON from 21 years. aBMD at the lumbar spine was higher in older OB and CON women, starting from 20 to 22 years, but in AN the difference with the other 2 groups increased with age. Periostin levels were lower in OB than in AN or CON, but no variation with age was observed. Compared with controls, OB and AN presented similarly lower markers of bone formation, although markers of bone resorption were lower in OB and higher in AN. A modeling approach showed that markers of bone formation and resorption were lower in older than in younger CON, whereas the values of these bone markers remained relatively constant in AN and OB. In all groups, lean body mass (LBM) was the parameter most positively correlated with aBMD.

Conclusion: This study demonstrated that weight extremes (AN or OB) influence aBMD, bone remodeling and periostin profiles. Moreover, factors related to aBMD were specific to each condition, but LBM was the parameter most consistently associated with aBMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgz259DOI Listing
April 2020

Oral contraceptives partially protect from bone loss in young women with anorexia nervosa.

Fertil Steril 2019 05 25;111(5):1020-1029.e2. Epub 2019 Mar 25.

Department of Emergency and Post-Emergency of Psychiatric, CHU Montpellier, University of Montpellier, INSERM, Montpellier, France.

Objective: To evaluate the potentially protective effects of oral contraceptives (OC) on bone loss in a large population of young women with anorexia nervosa (AN).

Design: Cross-sectional study.

Setting: University hospital.

Patient(s): Three hundred and five patients with AN (99 of them using OC) and 121 age-matched controls.

Intervention(s): None.

Main Outcome Measure(s): Areal bone mineral density (aBMD) evaluated by dual-energy X-ray absorptiometry and bone turnover markers, with leptin evaluated concomitantly.

Result(s): Although the AN patients taking OC presented lower aBMD compared with the controls at all bone sites, the whole body excepted, their aBMD values were systematically higher than those of AN patients who were not taking OC for the whole body and the lumbar spine, femoral neck, hip, and radius. These differences persisted after multiple adjustments. Preservation of aBMD improved with longer durations of OC use and shorter delays between disease onset and the start of OC. Moreover, patients with the lowest body mass index showed the best bone tissue responses to OC. Bone formation markers were systematically lower in the two groups of patients with AN compared with the controls. The markers of bone resorption were normalized in AN patients using OC.

Conclusion(s): Although OC use does not provide total protection of aBMD, our data suggest that OC might be prescribed for young women with AN to limit their bone loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fertnstert.2019.01.008DOI Listing
May 2019

Torsion of otherwise healthy ovary Has a worse prognosis than torsion of pathologic ovary in children.

J Pediatr Surg 2019 Nov 1;54(11):2435-2438. Epub 2019 Mar 1.

Department of Pediatric Surgery and Urology, Lapeyronie Hospital, University Hospital of Montpellier and University of Montpellier, Montpellier, France; Rare Disease National Reference Center (Constitutive South) DEVGEN. Electronic address:

Introduction: To evaluate if torsion of an otherwise healthy ovary (THO) has a different prognosis than torsion with an underlying ovarian mass (TUOM) in children.

Material And Methods: Children with an ovarian torsion who were treated in our department from 1997 to 2016 were studied retrospectively. Patients with prenatal ovarian torsion and isolated oviduct torsion were excluded. Trophicity of the ovary was assessed by ultrasonography at the end of follow-up.

Results: Fifty-four girls were included. Twenty-seven presented a TUOM; the others had a THO. Beside the deleterious effect of late surgical management, another prognostic factor was identified. THO was more prone to an ovarian hypotrophy or atrophy than TUOM (n = 20 vs n = 5, p < 0.01). This was confirmed by logistic regression analysis (OR = 5.08, p = 0.01). To explain this finding, we further compared TUOM and THO. The diagnosis of TUOM was more frequently suspected on US at the first visit (p = 0.005). TUOM also occurred more often after puberty (>12 years, 52.9% vs 11.1%, p < 0.001) than THO.

Conclusion: THO is more frequently associated with an ovarian atrophy or hypotrophy than TUOM. A less obvious diagnosis at US and the early occurrence of THO before puberty with a less favorable hormonal climate may explain this finding.

Level Of Evidence: III.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpedsurg.2019.02.010DOI Listing
November 2019

Prenatal imaging of genital defects: clinical spectrum and predictive factors for severe forms.

BJU Int 2019 11 18;124(5):876-882. Epub 2019 Mar 18.

Unité de Chirurgie Viscérale et Urologique Pédiatrique, Hôpital Lapeyronie - CHU Montpellier, Montpellier, France.

Objectives: To report the clinical spectrum of genital defects diagnosed before birth, identify predictive factors for severe phenotypes at birth, and determine the rate of associated malformations.

Patients And Methods: A retrospective study (2008-2017) of 4580 fetuses, identified prenatally with abnormalities evaluated by our Reference Center for Fetal Medicine, included cases with fetal sonographic findings of abnormal genitalia or uncertainty of fetal sex determination. Familial, prenatal and postnatal data were collected via a standardised questionnaire.

Results: In all, 61 fetuses were included. The positive predictive value (PPV) of the prenatal diagnosis of genital defects was 90.1%. Most cases were 46,XY-undervirilized boys, 42 cases (68.8%), which included 29 with mid-penile or posterior hypospadias, nine with anterior hypospadias, and epispadias, micropenis, scrotal transposition, and buried penis (one each). In all, 46,XX-virilized girls were identified in seven cases (11.5%), which included four with congenital adrenal hyperplasia, two with isolated clitoromegaly, and one with ovotestis. Other defects included prune belly syndrome and persistent cloaca (six cases). Early detection during the second trimester (58.1% vs 18.8%, P = 0.03), intra-uterine growth restriction (IUGR) (45.2% vs 9.1%, P = 0.06), and curvature of the penis (38.7% vs 0%, P = 0.02), were more frequently related to severe defects in male newborns. Associated malformations (14 cases, 22.9%) and genetic defects (six) were frequent in undervirilized boys.

Conclusion: Prenatal imaging of genital defects leads to a wide range of phenotypes at birth. Its PPV is high and extra-urinary malformations are frequent. Early diagnosis during the second trimester, associated IUGR, and curvature of the genital tubercle, should raise suspicion of a severe phenotype and may justify delivery near a multidisciplinary disorders/differences of sex development team.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bju.14714DOI Listing
November 2019

Neurodevelopmental disorders in children exposed in utero to synthetic progestins: analysis from the national cohort of the Hhorages Association.

Gynecol Endocrinol 2019 Mar 9;35(3):247-250. Epub 2019 Jan 9.

c Service de Pédiatrie I , Unité d'endocrinologie et gynécologie pédiatrique , Université de Montpellier , France.

The medical and scientific communities have not yet fully acknowledged the undesirable effects of the synthetic hormones that have been administered to pregnant women for decades. The somatic effects of in utero exposure to diethylstilbestrol (DES), such as genital malformations, infertility, and cancer, have long been recognized but this has not been the case concerning psychiatric disorders. The progestins used in contraception and hormone replacement therapy are known to affect the adult brain, but no data exist on their effects due to in utero exposure of children. The Hhorages Association, a national patient support group, has assembled a cohort of 1200 women who took synthetic hormones during pregnancy. These women had a combined 1934 children. We obtained full questionnaire responses from 46 women treated with progestins only - and not an estrogenic cocktail - who gave birth to 115 children. Three groups were observed: Group 1 (n = 18): firstborn unexposed children, Group 2 (n = 62): children exposed in utero to synthetic progestins, and Group 3 (n = 35): children born after a previous pregnancy treated with progestins. No psychiatric disorders were reported in Group 1 and the incidence of psychiatric disorders was drastically elevated in Group 2. Our work shows a striking increase in psychiatric disorders among children exposed in utero to progestins and strongly suggests that prenatal exposure is associated with a high risk of psychiatric disorders in adolescence and adulthood, whether accompanied or not by disorders of sex development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09513590.2018.1512968DOI Listing
March 2019

Molecular genetics of hypospadias and cryptorchidism recent developments.

Clin Genet 2019 01 26;95(1):122-131. Epub 2018 Oct 26.

National Reference Center of Genital Development CRMR DEV-GEN Constitutif, Institut Universitaire de Recherche Clinique, Departement de Génétique, Université de Montpellier, Montpellier, France.

During the last decade, a tremendous amount of work has been devoted to the study of the molecular genetics of isolated hypospadias and cryptorchidism, two minor forms of disorders of sex development (DSD). Beyond the genes involved in gonadal determination and sex differentiation, including those underlying androgen biosynthesis and signaling, new genes have been identified through genome-wide association study and familial clustering. Even if no single genetic defect can explain the whole spectrum of DSD, these recent studies reinforce the strong role of the genetic background in the occurrence of these defects. The timing of signaling disruption may explain the different phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13432DOI Listing
January 2019

Functional and Structural Study of the Amino Acid Substitution in a Novel Familial Androgen Receptor Mutation (W752G) Responsible for Complete Androgen Insensitivity Syndrome.

Sex Dev 2018 Aug 1. Epub 2018 Aug 1.

Mutations of the androgen receptor (AR) gene are the most frequent cause of 46,XY disorders of sex development. They are associated with a variety of phenotypes, ranging from phenotypic women (complete androgen insensitivity syndrome, CAIS) to milder degrees of undervirilization (partial forms) or men with only infertility (mild form). We identified a new W752G AR mutation responsible for a familial case of CAIS and performed an in vitro study and structural analysis of this mutation and the only other reported substitution affecting the same amino acid (W752R). Although sex assignment is not discussed in cases of CAIS, we show how the phenotype-genotype correlation can be refined by in vitro and structural studies according to the nature of the amino acid substitution, which in turn may have interesting impacts on the follow-up of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000491114DOI Listing
August 2018

Family History is Underestimated in Children with Isolated Hypospadias: A French Multicenter Report of 88 Families.

J Urol 2018 10 30;200(4):890-894. Epub 2018 Apr 30.

Department of Pediatric Surgery and Urology, Lapeyronie Hospital, CHU Montpellier, Montpellier University, Montpellier, France; National Reference Center of Genital Development (Constitutive South), Arnaud de Villeneuve Hospital, CHU Montpellier, Montpellier University, Montpellier, France; Pediatric Endocrinology and Gynecology Unit, Department of Pediatrics, Arnaud de Villeneuve Hospital, CHU Montpellier, Montpellier University, Montpellier, France; Genetic Genital Development Unit, University Institute of Clinical Research, CHU Montpellier, Montpellier University, Montpellier, France. Electronic address:

Purpose: While familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed to determine the frequency of hypospadias in families of boys with hypospadias, to establish whether these familial forms exhibit a particular phenotype and to evaluate the prevalence of genetic defects of the main candidate genes.

Materials And Methods: A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1.

Results: Family history of hypospadias was more frequent than expected (88 patients, 22.3%). In 17 instances (19.3%) familial hypospadias cases were multiple. Familial hypospadias was related to the paternal side in 59.1% of cases, consisting of the father himself (30.7%) as well as paternal uncles and cousins. Premature birth, assisted reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of genetic analysis combined with previous data on androgen receptor sequencing revealed that familial cases more frequently tend to demonstrate genetic defects than sporadic cases (5.68% vs 1.63%, p = 0.048).

Conclusions: Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated forms justify a full clinical investigation of the family history. Detecting these hereditary forms may help to determine the underlying genetic defects, and may improve followup and counseling of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.juro.2018.04.072DOI Listing
October 2018

Effects of the two types of anorexia nervosa (binge eating/purging and restrictive) on bone metabolism in female patients.

Clin Endocrinol (Oxf) 2018 06 25;88(6):863-872. Epub 2018 Apr 25.

Unité d'Endocrinologie et Gynécologie Pédiatrique, Département de Pédiatrie, Hôpital Arnaud de Villeneuve, CHRU Montpellier et UMI, Montpellier, France.

Objective: This study compared the profiles of the two types of anorexia nervosa (AN; restrictive: AN-R, and binge eating/purging: AN-BP) in terms of body composition, gynaecological status, disease history and the potential effects on bone metabolism.

Design: Two hundred and eighty-six women with AN (21.8 ± 6.5 years; 204 AN-R and 82 AN-BP) and 130 age-matched controls (CON; 22.6 ± 6.8 years) were enrolled. Areal bone mineral density (aBMD) was determined using DXA and resting energy expenditure (REE) was indirectly assessed using calorimetry. Markers of bone formation (osteocalcin [OC], procollagen type I N-terminal propeptide [PINP] and resorption (type I-C telopeptide breakdown products [CTX]) and leptin were concomitantly evaluated.

Results: Anorexia nervosa patients presented an alteration in aBMD and bone turnover. When compared according to type, AN-BP were older than AN-R and showed less severe undernutrition, lower CTx levels, longer duration of AN, and higher REE levels and aBMD at radius and lumbar spine. After adjustment for age, weight and hormonal contraceptive use, the aBMD and CTx differences disappeared. In both AN groups, aBMD was positively correlated with anthropometric parameters and negatively correlated with durations of AN and amenorrhoea, the bone formation markers (OC and PINP) and the leptin/fat mass ratio. REE was positively correlated with aBMD in AN-R patients only.

Conclusions: This study shows the profiles of AN patients according to AN type. However, the impact of the profile characteristics on bone status, although significant, was minor and disappeared after multiple adjustments. The positive correlation between REE and aBMD reinforces the concept that energy disposal and bone metabolism are strongly interdependent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cen.13610DOI Listing
June 2018

Disorders of puberty.

Best Pract Res Clin Obstet Gynaecol 2018 Apr 14;48:62-89. Epub 2017 Nov 14.

Unité d'Endocrinologie et Gynécologie Pédiatrique, Département de Pédiatrie, Hôpital A. de Villeneuve, Centre Hospitalo Universitaire de Montpellier et Université de Montpellier, France.

Over the past 20 years, a clear secular trend toward the earlier onset of puberty has been described. A better knowledge should help clinicians attempting to define both precocious and delayed puberty (PP and DP, respectively). The definition of PP for girls is the appearance of secondary sex characteristics development before the age of 8 years, while DP is based on the absence of thelarche at the age of 13 years. Regarding PP, one should clinically distinguish between true precocious puberty, i.e., complete or central PP, and incomplete PP, which refers to premature thelarche, premature pubarche, and isolated menarche. Evaluation of girls of PP requires careful examination of the clinical expression, a GnRH test, and imaging of the central neurosystem. GnRH analog is considered the gold standard treatment of central precocious puberty. Peripheral PP should be managed according to the underlying causes. DP is suspected in girls with no breast development by the age of 13 years, or absence of menarche at 15 years with secondary sex characteristics. The clinical examination along with endocrine, radiological, and genetic investigation should be able to identify girls with permanent hypogonadism as opposed to those with transitory hypogonadism, who undergo spontaneous but DP. Estrogen therapy should be discussed according to the causes of DP. In all cases, emotional and psychosocial disorders should be considered for these girls with disorders of puberty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpobgyn.2017.11.004DOI Listing
April 2018

A novel variant of DHH in a familial case of 46,XY disorder of sex development: Insights from molecular dynamics simulations.

Clin Endocrinol (Oxf) 2017 Nov 13;87(5):539-544. Epub 2017 Aug 13.

Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Objective: Disorders of sex development (DSD) are a heterogeneous group of conditions affecting the differentiation and development of the internal and external genitalia. Here, we aimed at identifying the genetic cause of DSD in two 46,XY sisters from a consanguineous family.

Design: We performed a whole-exome sequencing of two 46,XY female individuals. Sanger sequencing was used to validate the most likely candidate variant, affecting the desert hedgehog (DHH) gene. Molecular dynamics simulations were performed to get insights into the impact of the variant on protein structure and on its interaction with the protein partner BOC (brother of CDO/cell adhesion molecule, downregulated by oncogenes).

Patients: The index patient presented with a female phenotype, primary amenorrhoea (low oestradiol and testosterone and high FSH and LH). She also had an apparent absence of intra-abdominal gonads and uterus, facial dysmorphy, psychomotor retardation and neuropathy. Her sister displayed a similar gonadal and endocrinological picture, without dysmorphy or psychomotor retardation.

Results: Whole-exome sequencing revealed a homozygous variant in DHH leading to the p.Trp173Cys substitution. The relevant Trp residue is conserved, and its alteration was predicted to be deleterious. Molecular dynamics simulations showed that the mutation increases the conformational flexibility of the protein and potentially alters its interaction with BOC, a positive regulator of Hedgehog signalling. We do not exclude an interference of the mutation with DHH-intein-mediated auto-processing.

Conclusions: This report increases the number of described homozygous DHH variants and highlights the importance of advanced bioinformatic tools to better understand the pathogenicity of human variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cen.13420DOI Listing
November 2017

Late surgical correction of hypospadias increases the risk of complications: a series of 501 consecutive patients.

BJU Int 2017 06 1;119(6):942-947. Epub 2017 Feb 1.

Department of Paediatric Surgery and Urology, Lapeyronie Hospital, CHU Montpellier, Montpellier, France.

Objectives: To evaluate the outcomes of hypospadias surgery according to age and to determine if some complications are age-related.

Patients And Methods: This retrospective study was based on 722 boys with hypospadias undergoing primary repair. A total of 501 boys underwent urethroplasty and were included in the study. Complications requiring an additional procedure (stenosis, fistula, dehiscence, relapse of curvature, urethrocele) were included in the analysis, as well as healing problems, infections, haematomas and detrusor-sphincter dyssynergy. Logistic regression analysis was performed.

Results: Hypospadias was anterior in 63.1%, mid-penile in 20.5%, posterior in 8.4% and scrotal in 7.9% of the boys. The median (range) age was 4 (1-16) years. The overall rates of re-intervention and complications were 22.8% and 36.2%, respectively. Age >2 years was a significant predictor of complications (P = 0.002, odds ratio 1.98 [95% confidence interval 1.26-3.13]). Some periods of time appeared to be associated with a specific complication: dyssynergy was more common between the ages of 24 and 36 months (12.5 vs 3.6%; P = 0.01) and healing problems were more common in boys aged >13 years (1.5 vs 28.5%; P = 0.06).

Conclusion: Delayed surgery may be detrimental for patients. Factors related to age may influence the rate of complications. After the age of 2 years, urethral surgery may interfere with the normal toilet-training process. During puberty, endogenous testosterone may alter healing. Even if no specific data exist for severe hypospadias, it may be prudent to continue to advocate early surgery in patients with disorders of sex development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bju.13771DOI Listing
June 2017

Reversible growth failure and complete GH deficiency in a 4-year-old girl with very early Hashimoto's thyroiditis and subsequent hyperplasia of pituitary thyrotroph cells.

Eur J Pediatr 2016 Aug 2;175(8):1119-22. Epub 2016 Feb 2.

Unité d'Endocrinologie-Gynécologie Pédiatriques, Departement de Pédiatrie, Hôpital Arnaud-de-Villeneuve, CHU Montpellier et Université Montpellier 1, Montpellier, France.

Unlabelled: Hashimoto's thyroiditis is a well-known cause of growth retardation in adolescence. It is less frequently seen in children and rarely seen in infants. A 4-year-old girl was referred to our clinic for a second opinion before starting growth hormone (GH) treatment. Linear growth had markedly declined in the past 2 years, with height -3.4 standard deviations. GH deficiency was complete. She had dry, gray-sallow skin and bloated abdomen, but no goiter. The parents reported fatigue and constipation. Hormonal evaluation revealed TSH 629.5 mIU/ml, free T4 0.08 ng/dl, and prolactin 17.2 ng/ml. Bone age was 2 years. Antibodies to thyroglobulin and thyroid peroxidase were positive, suggesting Hashimoto's thyroiditis. Brain magnetic resonance imaging showed anterior pituitary hyperplasia. After 3 years of L-thyroxine therapy, she was symptomless, her height was -0.6 standard deviations, and the TSH level was normal. Brain magnetic resonance imaging showed regression of the pituitary hyperplasia.

Conclusions: This report describes a patient with Hashimoto's thyroiditis and pituitary hyperplasia, both quite rare in very young children. Acquired hypothyroidism may appear after neonatal screening and therefore should not be overlooked in investigations of short stature, even when clinical signs of hypothyroidism are absent.

What Is Known: • Hashimoto's thyroiditis and pituitary hyperplasia are rare in very young children. • Acquired hypothyroidism can appear after negative neonatal screening and should not be overlooked. What is New: • Short children should be evaluated for growth hormone deficiency but only after excluding other causes, particularly hypothyroidism, as we report a child with this disease but no clinical signs of it.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00431-016-2698-6DOI Listing
August 2016

Molecular analyses of juvenile granulosa cell tumors bearing AKT1 mutations provide insights into tumor biology and therapeutic leads.

Hum Mol Genet 2015 Dec 11;24(23):6687-98. Epub 2015 Sep 11.

Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France, Faculty of Biological Sciences, Université Paris Diderot-Paris VII, 75205 Paris, France,

Juvenile granulosa cell tumors (JGCTs) of the ovary are pediatric neoplasms representing 5% of all granulosa cell tumors (GCTs). Most GCTs are of adult type (AGCTs) and bear a mutation in the FOXL2 gene. The molecular basis of JGCTs is poorly understood, although mutations in the GNAS gene have been reported. We have detected in-frame duplications within the oncogene AKT1 in >60% of the JGCTs studied. Here, to evaluate the functional impact of these duplications and the existence of potential co-driver alterations, we have sequenced the transcriptome of four JGCTs and compared them with control transcriptomes. A search for gene variants detected only private alterations probably unrelated with tumorigenesis, suggesting that tandem duplications are the best candidates to underlie tumor formation in the absence of GNAS alterations. We previously showed that the duplications were specific to JGCTs. However, the screening of eight AGCTs samples without FOXL2 mutation showed the existence of an AKT1 duplication in one case, also having a stromal luteoma. The analysis of RNA-Seq data pinpointed a series of differentially expressed genes, involved in cytokine and hormone signaling and cell division-related processes. Further analyses pointed to the existence of a possible dedifferentiation process and suggested that most of the transcriptomic dysregulation might be mediated by a limited set of transcription factors perturbed by AKT1 activation. Finally, we show that commercially available AKT inhibitors can modulate the in vitro activity of various mutated forms. These results shed light on the pathogenesis of JGCTs and provide therapeutic leads for a targeted treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddv373DOI Listing
December 2015

Postpubertal Persistent Hyperestrogenemia in McCune-Albright Syndrome: Unilateral Oophorectomy Improved Fertility but Detected an Unexpected Borderline Epithelial Ovarian Tumor.

J Pediatr Adolesc Gynecol 2015 Dec 7;28(6):e169-72. Epub 2015 Apr 7.

Department of Endocrinology and Reproductive Medicine, University Hospital of Nice, INSERM U1065/C3M, Nice, France. Electronic address:

Background: McCune-Albright syndrome (MAS), due to a somatic mutation of the GNAS1 gene, begins usually in girls with peripheral precocious puberty. Ovarian autonomy may persist in adulthood with acyclic hyperestrogenemia, infertility, and a potential risk of estrogen-dependent cancer.

Case: A 22-year-old woman, with MAS, was referred for infertility with left macropolycystic ovary, hyperestrogenemia, and chronic anovulation unsuccessfully treated by controlled hyperstimulation. Once ovarian cyst punctures and cDNA analysis verified that GNAS1 mutation was restricted to the left ovary, unilateral ovariectomy was performed. It improved right ovarian function, allowed an in vitro fertilization-induced pregnancy, but revealed an unexpected borderline epithelial ovarian tumor.

Summary And Conclusion: Several breast cancers have already been reported in young MAS patients but not a borderline epithelial ovarian tumor. In this context, we would recommend that persistent hyperestrogenemia in an adult be corrected and gynecological follow-up of the breasts, ovaries, and endometrium be implemented.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpag.2015.04.001DOI Listing
December 2015

Association between fetal DES-exposure and psychiatric disorders in adolescence/adulthood: evidence from a French cohort of 1002 prenatally exposed children.

Gynecol Endocrinol 2016 14;32(1):25-9. Epub 2015 Jul 14.

b Unité d'Endocrinologie-Gynécologie Pédiatrique , Service de Pédiatrie, Hôpital Arnaud de Villeneuve, CHU Montpellier and Université Montpellier , Montpellier , France , and.

In utero diethylstilbestrol (DES) exposure has been demonstrated to be associated with somatic abnormalities in adult men and women. Conversely, the data are contradictory regarding the association with psychological or psychiatric disorders during adolescence and adulthood. This work was designed to determine whether prenatal exposure to DES affects brain development and whether it is associated with psychiatric disorders in male and female adolescents and young adults. HHORAGES Association, a national patient support group, has assembled a cohort of 1280 women who took DES during pregnancy. We obtained questionnaire responses from 529 families, corresponding to 1182 children divided into three groups: Group 1 (n = 180): firstborn children without DES treatment, Group 2 (n = 740): exposed children, and Group 3 (n = 262): children born after a previous pregnancy treated by DES. No psychiatric disorders were reported in Group 1. In Group 2, the incidence of disorders was drastically elevated (83.8%), and in Group 3, the incidence was still elevated (6.1%) compared with the general population. This work demonstrates that prenatal exposure to DES is associated with a high risk of psychiatric disorders in adolescence and adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/09513590.2015.1063604DOI Listing
December 2016

A Hot-spot of In-frame Duplications Activates the Oncoprotein AKT1 in Juvenile Granulosa Cell Tumors.

EBioMedicine 2015 May 6;2(5):421-31. Epub 2015 Mar 6.

Institut Jacques Monod, Université Paris Diderot, CNRS UMR7592, Paris 75013, France ; Université Paris Diderot-Paris VII, 75205 Paris Cedex 13, France.

Background: Ovarian granulosa cell tumors are the most common sex-cord stromal tumors and have juvenile (JGCTs) and adult forms. In a previous study we reported the occurrence of activating somatic mutations of Gαs, which transduces mitogenic signals, in 30% of the analyzed JGCTs.

Methods: We have searched for alterations in other proteins involved in ovarian mitogenic signaling. We focused on the PI3K-AKT axis. As we found mutations in AKT1, we analyzed the subcellular localization of the mutated proteins and performed functional explorations using Western-blot and luciferase assays.

Findings: We detected in-frame duplications affecting the pleckstrin-homology domain of AKT1 in more than 60% of the tumors occurring in girls under 15 years of age. The somatic status of the mutations was confirmed when peritumoral DNA was available. The JGCTs without duplications carried point mutations affecting highly conserved residues. Several of these substitutions were somatic lesions. The mutated proteins carrying the duplications had a non-wild-type subcellular distribution, with a marked enrichment at the plasma membrane. This led to a striking degree of AKT1 activation demonstrated by a strong phosphorylation level and by reporter assays.

Interpretation: Our study incriminates somatic mutations of AKT1 as a major event in the pathogenesis of JGCTs. The existence of AKT inhibitors currently tested in clinical trials opens new perspectives for targeted therapies for these tumors, which are currently treated with standard non-specific chemotherapy protocols.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2015.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485906PMC
May 2015

Is Hypospadias Associated with Prenatal Exposure to Endocrine Disruptors? A French Collaborative Controlled Study of a Cohort of 300 Consecutive Children Without Genetic Defect.

Eur Urol 2015 Dec 23;68(6):1023-30. Epub 2015 May 23.

Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France; Unité d'Endocrinologie et Gynécologie Pédiatriques, Service de Pédiatrie, Hôpital Arnaud de Villeneuve et Université Montpellier 1, CHU de Montpellier, Montpellier, France.

Background: Numerous studies have focused on the association between endocrine-disrupting chemicals (EDCs) and hypospadias. Phenotype variability, the absence of representative comparison groups and concomitant genetic testing prevent any definitive conclusions.

Objective: To identify the role of occupational and environmental exposures to EDCs in nongenetic isolated hypospadias.

Design, Setting, And Participants: A total of 408 consecutive children with isolated hypospadias and 302 normal boys were prospectively included (2009-2014) in a multi-institutional study in the south of France, the area of the country with the highest prevalence of hypospadias surgery.

Outcome Measurements And Statistical Analysis: In patients without AR, SRD5A2, and MAMLD1 mutations, parental occupational and professional exposures to EDCs were evaluated based on European questionnaire QLK4-1999-01422 and a validated job-exposure matrix for EDCs. Environmental exposure was estimated using the zip code, the type of surrounding hazards, and distance from these hazards. Multivariate analysis was performed.

Results: Fetal exposure to EDCs around the window of genital differentiation was more frequent in the case of hypospadias (40.00% vs 17.55%, odds ratio 3.13, 95% confidence interval 2.11-4.65). The substances were paints/solvents/adhesives (16.0%), detergents (11.0%), pesticides (9.0%), cosmetics (5.6%), and industrial chemicals (4.0%). Jobs with exposure were more frequent in mothers of hypospadiac boys (19.73% vs 10.26%, p=0.0019), especially cleaners, hairdressers, beauticians, and laboratory workers. Paternal job exposure was more frequent in the cases of hypospadias (40.13% vs 27.48%, p=0.02). Industrial areas, incinerators, and waste areas were more frequent within a 3-km radius for mothers of hypospadiac boys (13.29% vs. 6.64%, p<0.00005). Association of occupational and environmental exposures increases this risk.

Conclusions: This multicenter prospective controlled study with a homogeneous cohort of hypospadiac boys without genetic defects strongly suggests that EDCs are a risk factor for hypospadias through occupational and environmental exposure during fetal life. The association of various types of exposures may increase this risk.

Patient Summary: Our multi-institutional study showed that parental professional, occupational, and environmental exposures to chemical products increase the risk of hypospadias in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2015.05.008DOI Listing
December 2015

Molecular action of norgestimate: new developments.

Gynecol Endocrinol 2015 Jun 13;31(6):487-90. Epub 2015 May 13.

INSERM U896, Institut de Recherche en Cancérologie de Montpellier (IRCM) Parc Euromédecine - ICM F-34298 , Montpellier , France .

Background: Acne occurs because the sebaceous glands are overstimulated by high levels of androgens or are hypersensitive to normal levels of testosterone. In women with mild or moderate acne, the association of norgestimate (NG), and ethinyl estradiol (EE) is an effective treatment. This is related to the effect of oral contraceptives on androgen production and transport and the antiandrogenic properties of NG itself.

Design: The present work was undertaken to find out whether NG and its derivative, 17-deacetylnorgestimate(dNG), present steroid activities other than antiandrogen activities, using human progesterone receptor(PR), estrogen receptor α(ERα) and β(ERβ), glucocorticoid receptor(GR) and mineralocorticoid receptor(MR)-responsive cell lines.

Results: We confirmed that NG and its metabolite were progestogen partial agonists (EC50 of 13 and 11.1 nM) and ERα selective agonists (EC50 of 30.4 and 43.4 nM), as well as full antagonists of low affinity for GR (IC50 of 325 and 255 nM) and moderate affinity for MR (IC50 of 81.2 and 83.7).

Conclusion: We demonstrated that NG and dNG have full progestogen and weak estrogenic (through ERα) properties, which could explain in part the efficacy of NG in association with EE for the treatment of moderate acne in women. Moreover, their antagonist MR activity might have a favorable impact on cardiovascular risk, atherosclerosis and lipid profiles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/09513590.2015.1016904DOI Listing
June 2015

Evidence of ERalpha and ERbeta selectivity and partial estrogen agonism in traditional Chinese medicine.

Reprod Biol Endocrinol 2014 Oct 10;12:97. Epub 2014 Oct 10.

Unité d'Endocrinologie Pédiatrique, CHU Arnaud de Villeneuve, Montpellier, France.

The use of complementary and alternative medicine and herbal products, especially traditional Chinese medicines, is progressively rising for both adults and children. This increased use is based on the popular belief that these medicines are safe and harmless. In this report, we describe the results of a bedside-to-bench study that involved a short-statured 4-year-old boy with deficiencies in growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone due to an ectopic posterior pituitary gland and invisible pituitary stalk. Although the boy was given replacement therapy with hydrocortisone and L-thyroxin, the parents refused to treat him with growth hormone and consulted a naturopath who prescribed a traditional Chinese medicine (TCM) to stimulate the boy's growth. From the age of 20 months, the child's growth was regularly monitored while he was being treated with hydrocortisone, thyroxin, and the TCM. Over a 36-month period, the child's growth velocity accelerated (3 cm/year to 8 cm/year), his height increment substantially increased (-2 SD to -0.8 SD), and his bones matured. In the laboratory investigation, estrogen receptor (ER)alpha and ERbeta reporter cell lines were used to characterize the estrogenic activity of the TCM medicine and its 18 components, and the results established that the medicine and some of its components have estrogen receptor ERalpha and ERbeta selectivity and partial estrogen agonism. Partial estrogenic activity of the TCM was confirmed using whole-cell competitive binding, cell proliferation, and endogenous gene expression assays in the ERalpha-positive breast cancer cell lines. Although the presence of evidence is not always evidence of causality, we have concluded that this traditional Chinese medicine contains ingredients with estrogenic activity that can sustain bone growth and maturation without affecting other estrogen-dependent tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1477-7827-12-97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201695PMC
October 2014
-->