Publications by authors named "Laura Gaspari"

48 Publications

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

Int J Environ Res Public Health 2021 Sep 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.
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http://dx.doi.org/10.3390/ijerph18199965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507930PMC
September 2021

[Impact of SARS-CoV-2 on fertility, gametes' quality and Assisted Reproduction Technology].

Gynecol Obstet Fertil Senol 2021 Sep 29. Epub 2021 Sep 29.

Inserm 1203, développement embryonnaire précoce humain et pluripotence, Embryopluripotency, université de Montpellier, Montpellier, France; Département de biologie de la reproduction, biologie de la reproduction/DPI et CECOS, CHU d'Arnaud de Villeneuve Montpellier, université de Montpellier, Montpellier, France. Electronic address:

The current pandemic context raises questions about COVID-19 consequences on Assisted Reproduction Technology (ART). Indeed, according to the first Biomedicine Agency recommendations, ART centers suspended their activities in March 2020 during the first wave of Covid-19. However, SARS-CoV-2 direct and indirect effects on gametes, fertility, pregnancy and neonatal health are still debated. The aim of this review is to assess the available data on this subject, to inform patients in care and adapt daily practice. Most recent studies are based on the effects of the infectious syndrome, on hormonal factors as well as on the expression of viral entry proteins (ACE2 and TMPRSS2) in cells involved in gametogenesis, to assess the impact of COVID-19. So far, no effect on female gametes was highlighted. More studies are needed to confirm this hypothesis. Mother to children transmission couldn't be proven, yet neonatal infection remains possible. However, men are more susceptible to be infected by SARS-CoV-2, to be symptomatic, and spermatogenesis is likely to be affected. Presence of the virus in semen is infrequently reported, but all of these parameters should be taken into account in ART.
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http://dx.doi.org/10.1016/j.gofs.2021.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423662PMC
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.
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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.
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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.
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http://dx.doi.org/10.1159/000517157DOI Listing
August 2021

[Impact of the lockdown on children and families: a survey of family pediatricians within a community.]

Recenti Prog Med 2021 03;112(3):207-215

Dipartimento Salute Donna, Infanzia e Adolescenza di Forlì-Cesena, AUSL Romagna.

Objectives: The recent lockdown, resulting from the SARS-CoV-2 pandemic, has had a strong social and psychological impact on the most fragile individuals and family structures. In the present work we investigated the experience of families without specific elements of social or health vulnerability during the quarantine period that occurred in the spring of 2020.

Materials And Methods: Between May and July 2020, 22 primary care pediatricians belonging to AUSL Romagna administered to a number of families a questionnaire to detect changes that occurred, during the lockdown, in family environment, school attendance and personal attitudes.

Results: A total of 721 questionnaires were collected, analyzing the associations between variables relating to home environment, daily rhythms, school and warning signs in relation to the age of children. As a result of the lockdown, family habits changed in 31% of cases, with a greater presence of the reference figure in 68% of these. Three out of four families reported they had sufficient domestic spaces, and nine out of ten had access to an outdoor, private or condominium space. Daily rhythms were preserved in 56.7% of cases; mood disorders appeared in 30% of adolescent children, followed by sleep, appetite and psychosomatic disorders. One in three children has made progress in terms of evolution and behavior, and one in 5 children has seen their relationships improve. The overall resilience of families during the lockdown period was considered good in 66.3%, sufficient in 31.3% and not satisfactory in only 2.4% of cases.

Conclusions: Our data show that, in the interviewed families, the simultaneous presence of adults and children at home has generally intensified. Families refer, on the whole, a positive and resilient behavior in the lockdown period, even if initial emotional problems are reported in one out of three children-adolescents. The ability to maintain a family organized structure seems to be partially compromised. Forced cohabitation leads to competition for the same resources of time and space and affects the entire family unit. The school institution emerges as a protective factor for children, young people and also for the well-being of families themselves.
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http://dx.doi.org/10.1701/3565.35460DOI Listing
March 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.
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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.
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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.
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http://dx.doi.org/10.1093/humrep/deaa267DOI Listing
January 2021

A cover flap reduces the rate of fistula after urethroplasty whatever the severity of hypospadias.

World J Urol 2021 Jul 27;39(7):2691-2695. Epub 2020 Oct 27.

Département de Chirurgie et Urologie Pédiatrique, Hopital Lapeyronie, CHU Montpellier et Université de Montpellier, 371 Av Giraud, 34295, Montpellier cedex 5, France.

Objective: To determine which patients should benefit from the interposition of a well-vascularized flap between the neourethra and the penile skin and if it should be performed even in mild hypospadias.

Patients And Methods: A retrospective study on patients with a primary hypospadias repair was performed (2003-2017). Only patients undergoing urethroplasty based on the principle of a tubularization were selected to ensure comparable groups. Patients were assigned in two groups according to the use or not of a cover flap. Univariate analysis and adjusted logistic regression were used to evaluate the relation between postoperative complications, the severity of hypospadias, the use of flap and patients' characteristics.

Results: Three-hundred and seventy-six patients were included with anterior (59.3%), midshaft (27.4%) and posterior hypospadias (13.3%). The median follow-up was 54 months (24 months-17 years). The overall rate of fistula was 11.7% (n = 44). Comparing the outcome in children with flap (n = 217) to controls (n = 159) showed that the use of a flap reduces the rate of fistula (6.5 vs 18.9%, p < 0.001). Stratification of the study according to the phenotype reveals that the more severe the hypospadias, the more protective was the flap (OR = 2.6 for anterior, 5.5 for midpenile, 7.1 for posterior hypospadias). The flap remains nevertheless significantly effective whatever the phenotype (p < 0.05 for anterior, p = 0.01 for midpenile, p = 0.02 for posterior hypospadias).

Conclusions: The more severe the hypospadias, the more effective is the cover flap to avoid fistula. It remains nevertheless suitable even in anterior hypospadias and the use of a cover flap should not be limited to the surgery of severe phenotypes.
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http://dx.doi.org/10.1007/s00345-020-03489-1DOI Listing
July 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.
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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.
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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.
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http://dx.doi.org/10.1016/j.fertnstert.2019.01.008DOI Listing
May 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.
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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.
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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.
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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.
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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.
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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.
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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.
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http://dx.doi.org/10.1016/j.bpobgyn.2017.11.004DOI Listing
April 2018

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

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

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

Role of sclerostin and dickkopf-1 in the dramatic alteration in bone mass acquisition in adolescents and young women with recent anorexia nervosa.

J Clin Endocrinol Metab 2014 Apr 28;99(4):E582-90. Epub 2014 Jan 28.

Service de Médecine Nucléaire (L.M., D.M.-G.), Hôpital Lapeyronie, Centre Hospitalier Regional Universitaire (CHRU) Montpellier et Université Montpellier 1 (UMI); Service d'Hormonologie (L.M., P.P., F.P., C.S.) et Service de Rhumatologie (E.T.), Departement d'Endocrinologie, Diabète, Nutrition (P.L., J.B., E.R.), and Unité de Recherche Clinique et Epidémiologie (H.B., M.-C.P.), Hôpital Lapeyronie, CHRU Montpellier; Département d'Urgence et Post-Urgence Psychiatrique (S.G., P.C.), Hôpital Lapeyronie, CHRU Montpellier and UM1, Inserm Unité (U) 1061; Physiologie et Médecine Expérimentale du Cœur et des Muscles (L.M.), Inserm U1046, UM1 and UM2; Centre d'Investigation Clinique (CIC) Inserm 1411 (M.-C.P., E.R.), Hôpital Gui de Chauliac, CHRU Montpellier; Unité d'Endocrinologie et Gynécologie Pédiatrique (F.P., C.S.), Département de Pédiatrie, Hôpital Arnaud de Villeneuve, CHRU Montpellier et UM1; and Institut de Génomique Fonctionnelle (E.R.), Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203/Inserm U661/UM1 and UM2, 34295 Montpellier, France; and Département de Pédiatrie (L.G.), Hôpital Caremeau, CHRU Nîmes, 30000 Nîmes, France.

Background: The nutritional deprivation of adolescent girls with anorexia nervosa (AN) reduces bone mass acquisition. A better understanding of this process would improve the medical treatment of bone alteration and its long-term consequences.

Objective: The first aim was to model the bone mass acquisition in young women with AN. The second aim was to identify the clinical and biological factors associated with bone demineralization and investigate the potential role of sclerostin and dickkopf-1 protein (DKK-1).

Population And Methods: Ninety-eight AN patients (mean age 18.2 ± 2.6 years) and 63 age-matched controls were enrolled in this study. Areal bone mineral density (aBMD) was determined by dual-energy x-ray absorptiometry. Calciotropic hormones, bone turnover markers, sclerostin, DKK-1, and growth factors were concomitantly evaluated.

Results: The aBMD was significantly reduced at all bone sites in AN patients vs controls (range, -3.3% at the radius to -12.1% for total proximal femur). Bone formation markers IGF-1 and DKK-1 were significantly decreased in AN patients, whereas PTH, sclerostin, and the bone resorption markers were increased. In patients, the AN duration, amenorrhea, weight, body mass index, fat mass, and fat-free soft tissue were negatively correlated with aBMD, whereas the age of AN onset was positively correlated. Multiple regression analysis revealed that the duration of amenorrhea was the independent factor most negatively associated with aBMD at all bone sites except the radius.

Conclusion: This case-control study demonstrated a dramatic reduction in aBMD, reinforced for the first time by our models, and indicates the need for early, systematic, and adapted bone mass monitoring. Moreover, appropriate treatment should be started early in patients with AN. Increased secretion of sclerostin suggests that it may be a target for pharmacological action.
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http://dx.doi.org/10.1210/jc.2013-2565DOI Listing
April 2014

Salivary adiponectin levels are associated with training intensity but not with bone mass or reproductive function in elite Rhythmic Gymnasts.

Peptides 2014 Jan 15;51:80-5. Epub 2013 Nov 15.

Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Patras Medical School, University Hospital, Patras, Greece; Federation Internationale de Gymnastique (FIG) Medical Committee, Lausanne, Switzerland. Electronic address:

Elite Rhythmic Gymnasts (RGs) constitute a unique metabolic model and they are prone to developing Anorexia Athletica. The aim of the present study was to evaluate the effect of training intensity on salivary adiponectin levels and assess a possible role of salivary adiponectin levels as a predictive factor of reproductive dysfunction and bone mass acquisition in elite RGs. The study included 80 elite female RGs participating in the World Rhythmic Gymnastics Championship tournament held in Montpellier, France on September 2011. Anthropometric values were assessed, training data and menstrual pattern were recorded, bone mass was measured with Broadband ultrasound attenuation (dB/Mhz) and baseline salivary adiponectin levels were determined. The athletes were classified as intensely and very intensely trained, considering the mean training intensity (40.84h/week). Moreover, considering their reproductive status, they were divided into RG's with normal menstruation, primary amenorrhea and oligomenorrhea. All comparisons were adjusted to age, BMI and body fat percentage differences. Very intensely trained RGs showed higher salivary adiponectin levels (p=0.05). Moreover, salivary adiponectin levels showed significant correlation with training intensity (r=0.409, p=0.003). On the other hand, no association of salivary adiponectin levels was documented with either reproductive function or bone mass acquisition. The results of the present study suggest that, in elite RGs, salivary adiponectin levels are associated with the intensity of training, possibly reflecting the deterioration of energy balance rather than the training stress. On the other hand, a predictive role of salivary adiponectin levels in reproductive dysfunction or bone mass acquisition could not be supported.
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http://dx.doi.org/10.1016/j.peptides.2013.11.003DOI Listing
January 2014

Despite a high prevalence of menstrual disorders, bone health is improved at a weight-bearing bone site in world-class female rhythmic gymnasts.

J Clin Endocrinol Metab 2013 Dec 8;98(12):4961-9. Epub 2013 Oct 8.

Unité d'Endocrinologie et Gynécologique Pédiatrique, Hôpital Arnaud de Villeneuve, Centre Hospitalier Universtaire de Montpellier et Université Montpellier I, 191 Avenue Doyen Gaston Giraud, 34295 Montpellier, Cedex 5, France.

Context: Regular physical activity during puberty improves bone mass acquisition. However, it is unknown whether extreme intense training has the same favorable effect on the skeleton.

Objective: We evaluated the bone mass acquisition in a unique cohort of world-class rhythmic gymnasts.

Study Participants: A total of 133 adolescent girls and young women with a mean age of 18.7 ± 2.7 (14.4-26.7) years participated in this study: 82 elite rhythmic gymnasts (RGs) and 51 controls (CONs).

Main Outcome Measures: Anthropometric variables and body composition were assessed, and all participants completed questionnaires on their general medical, menstrual, and training histories. Broadband ultrasound attenuation (BUA in decibels per megahertz) was determined by quantitative ultrasound at the heel.

Results: RGs presented lower weight (-8.5%, P < .001), body mass index (-11.7%, P < .001), and body fat mass (-43%, P < .001) and higher muscle mass (6.3%, P < .01) and height (+2.8 cm, P < .01). RGs presented an age of menarche significantly delayed compared with CONs (15.6 ± 1.6 vs 12.7 ± 1.7 years; P < .001) and a high prevalence of menstrual disorders (64%). BUA values were higher in RGs vs CONs (68.6 ± 4.6 and 65.4 ± 3.3 dB/Mhz, respectively; P < .001). This difference was exacerbated when BUA was adjusted for age and body weight. BUA values in RGs were not affected by menstrual or training status. Among RGs with menarche, BUA was higher (71.5 ± 4.1 and 67.9 ± 3.5 dB/Mhz) for delayed (14.4 ± 0.8 years) vs severely delayed (17.3 ± 1.4 years) menarcheal age. BUA was positively correlated with body weight and body mass index and tended to be correlated with age.

Conclusion: Conversely to expectations for adolescents and young women with a high prevalence of menstrual disorders and/or delayed menarche, intense training in rhythmic gymnastics appeared to have a beneficial effect on the bone health of a weight-bearing site. This effect was nevertheless modulated by the age of menarche. The high mechanical loading generated by this activity may counterbalance the negative effect of menstrual disorders.
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http://dx.doi.org/10.1210/jc.2013-2794DOI Listing
December 2013

Increased serum estrogenic bioactivity in girls with premature thelarche: a marker of environmental pollutant exposure?

Gynecol Endocrinol 2013 Aug 14;29(8):788-92. Epub 2013 Jun 14.

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

The aim of the work was to investigate the pathophysiology of isolated premature thelarche (IPT) by determining the impact of pre/postnatal exposure to endocrine disrupting chemicals (EDCs) through evaluation of total serum estrogenic bioactivity (EBA). The pathophysiology remains elusive, although recent investigations suggested the role of EDCs in premature female breast development. We investigated 15 girls with IPT. Plasma estradiol, follicle-stimulating hormone, and luteinizing hormone were measured in basal state and after gonadotropin-releasing hormone testing; bone age and uterine length were also assessed for all patients. Total EBA of patient serum was analyzed with an ultrasensitive bioassay that we previously developed and compared with that of 18 age-matched control girls. Parents were interviewed about their environmental/occupational exposure to EDCs during the patient's prenatal/postnatal life. Nine families reported parental occupational/environmental EDCs exposure during prenatal/postnatal patient life; the mean total EBA found in these 9 IPT girls was significantly elevated (12.31 ± 6.64 pg/mL) in comparison with that of the 6 patients without exposure (2.53 ± 0.73 pg/mL) and the 18 age-matched controls (3.53 ± 2.23 pg/mL; p < 0.01). The significant increase in total EBA in these 9 girls with IPT suggests that premature female breast development may be related in some cases to higher pre/postnatal contamination by EDCs.
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http://dx.doi.org/10.3109/09513590.2013.801448DOI Listing
August 2013
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