Transgenerational Transmission of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Effects in Human Granulosa Cells: The Role of MicroRNAs.

Endocrine-disrupting chemicals (EDCs) might contribute to the increase in female-specific cancers in Western countries. 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) is considered the "prototypical toxicant" to study EDCs' effects on reproductive health. Epigenetic regulation by small noncoding RNAs (sncRNAs), such as microRNAs (miRNA), is crucial for controlling cancer development. The aim of this study was to analyze transcriptional activity and sncRNA expression changes in the KGN cell line after acute (3 h) and chronic (72 h) exposure to 10 nM TCDD in order to determine whether sncRNAs' deregulation may contribute to transmitting TCDD effects to the subsequent cell generations (day 9 and day 14 after chronic exposure). Using Affymetrix GeneChip miRNA 4.0 arrays, 109 sncRNAs were found to be differentially expressed (fold change < -2 or >2; p-value < 0.05) between cells exposed or not (control) to TCDD for 3 h and 72 h and on day 9 and day 14 after chronic exposure. Ingenuity Pathway Analysis predicted that following the acute and chronic exposure of KGN cells, sncRNAs linked to cellular development, growth and proliferation were downregulated, and those linked to cancer promotion were upregulated on day 9 and day 14. These results indicated that TCDD-induced sncRNA dysregulation may have transgenerational cancer-promoting effects.

Early Female Transgender Identity after Prenatal Exposure to Diethylstilbestrol: Report from a French National Diethylstilbestrol (DES) Cohort.

Diagnostic of transsexualism and gender incongruence are terms to describe individuals whose self-identity does not match their sex assignment at birth. A transgender woman is an individual assigned male at birth (AMAB) on the basis of the external or internal genitalia who identifies and lives as a woman. In recent decades, a significant increase in the number of transgender people has been reported. Although, its etiology is unknown, biological, anatomical, genetic, environmental and cultural factors have been suggested to contribute to gender variation. In XY animals, it has been shown that environmental endocrine disruptors, through their anti-androgenic activity, induce a female identity. In this work, we described four XY individuals who were exposed in utero to the xenoestrogen diethylstilbesterol (DES) and were part of the French HHORAGES cohort. They all reported a female transgender identity starting from childhood and adolescence. This high prevalence of male to female transgenderism (1.58%) in our cohort of 253 DES sons suggests that exposure to chemicals with xenoestrogen activity during fetal life may affect the male sex identity and behavior.

Effects of prenatal exposure to synthetic sex hormones on neurodevelopment: a biological mechanism.

Since the middle of the 20th century, synthetic sex hormones (estrogens and progestins) have been administered to millions of pregnant or not women worldwide, mainly to avoid miscarriage or for comfort, although their mode of action and their effects on the mother and fetus were ignored. Despite the alerts and the description of somatic and psychiatric disorders in children exposed in utero, synthetic estrogens were prohibited for pregnant women only in the 1970s and 1980s, but some progestins are still authorized. In this review, we summarize the psychiatric disorders described in children exposed in utero to such hormones, focusing particularly on schizophrenia, bipolar disorders, severe depression, eating disorders, suicide and suicide attempts. Moreover, only in 2017 the mechanism of action of these xenohormones has started to be deciphered. Some studies showed that in the fetus exposed in utero, they alter the DNA methylation profile (mainly hypermethylation), and consequently the expression of genes implicated in neurodevelopment and in regulating the sexual organ morphogenesis and also of the promoter of estrogen receptors, located in the amygdala. These deleterious effects may be transmitted also to the next generations, thus affecting the children directly exposed and also the following generations.

Birth Outcomes in DES Children and Grandchildren: A Multigenerational National Cohort Study on Informative Families.

OBJECTIVE: Diethylstilbestrol (DES), a potent synthetic nonsteroidal estrogen belonging to the family of endocrine disrupting chemicals (EDCs), can cross the placenta and may cause permanent adverse health effects in the exposed mothers, their children (exposed in utero), and also their grandchildren through germline contribution to the zygote. This study evaluated pregnancy duration and birthweight (BW) variations in the children and grandchildren born before, during, and after maternal DES treatment in the same informative families, to rule out genetic, endocrine, and environmental factors. DESIGN AND SETTING: Nationwide retrospective observational study on 529 families of DES-treated women registered at the HHORAGES-France Association. The inclusion criteria were: (i) women with at least three pregnancies and three viable children among whom the first was not exposed in utero to DES, followed by one or more children with fetal exposure to DES, and then by one or more children born after DES treatment; (ii) women with at least one pre-DES or post-DES grandchild and one DES grandchild; (iii) confirmed data on total DES dose. Women with severe pathologies or whose illness status, habitat, lifestyle habits, profession, treatment changed between pregnancies, and all mothers who reported pregnancy-related problems, were excluded. RESULTS: In all, 74 women met all criteria. The preterm birth (PTB) rate was 2.7% in pre-DES, 14.9% in DES, and 10.8% in post-DES children (Cochran-Armitage test for trend, p = 0.0095). The mean BW was higher in DES than pre-DES full-term neonates (≥37 weeks of gestation) (p = 0.007). In grandchildren, BW was not different, whereas the PTB and low BW rates were slightly increased in children of DES women. CONCLUSIONS: These data within the same informative families show the DES impact on BW and PTB in DES and post-DES children and grandchildren. In particular, mean BW was higher in DES than pre-DES full-term neonates. This result may be in opposition to previous data from American cohorts, which reported lower BW in DES children, but is consistent with animal study. Our retrospective observational study highlights a multigenerational and likely transgenerational effect of this EDC in humans.

Diethylstilbestrol and autism.

It is acknowledged that diethylstilbestrol (DES), a synthetic diphenol with powerful estrogenic properties, causes structural anomalies of the reproductive tract and increases the risk of cancer and genital malformations in children and grandchildren of mothers treated during pregnancy. Conversely, data on DES effects on neurodevelopment and psychiatric disorders in in-utero exposed children and their descendants are rare, especially concerning Autism Spectrum Disorders (ASD). Recent studies presented in this review strengthen the hypothesis that in-utero exposure to DES and also other synthetic estrogens and progestogens, which all are endocrine disruptors, contributes to the pathogenesis of psychiatric disorders, especially ASD. A large epidemiological study in the USA in 2010 reported severe depression in in-utero exposed children (n=1,612), and a French cohort study (n=1,002 in-utero DES exposed children) in 2016 found mainly bipolar disorders, schizophrenia, major depression, suicide attempts, and suicide. Few publications described ASD in in-utero exposed children, mainly a Danish cohort study and a large Chinese epidemiological study. Molecular studies on endocrine disruptors demonstrated the transgenerational induction of diseases and DES epigenetic impact (DNA methylation changes) at two genes implicated in neurodevelopment (ZFP57 and ADAM TS9). We recently described in an informative family, somatic and psychiatric disorders in four generations, particularly ASD in boys of the third and fourth generation. These data show that the principle of precaution must be retained for the protection of future generations: women (pregnant or not) should be extremely vigilant about synthetic hormones.

[Impact of SARS-CoV-2 on fertility, gametes' quality and Assisted Reproduction Technology]. / Impact du SARS-CoV-2 sur la fertilité, les gamètes et l'Assistance médicale à la procréation.

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.

Biphasic (5-2%) oxygen concentration strategy significantly improves the usable blastocyst and cumulative live birth rates in in vitro fertilization.

Oxygen (O2) concentration is approximately 5% in the fallopian tube and 2% in the uterus in humans. A "back to nature" approach could increase in vitro fertilization (IVF) outcomes. This hypothesis was tested in this monocentric observational retrospective study that included 120 couples who underwent two IVF cycles between 2014 and 2019. Embryos were cultured at 5% from day 0 (D0) to D5/6 (monophasic O2 concentration strategy) in the first IVF cycle, and at 5% O2 from D0 to D3 and 2% O2 from D3 to D5/6 (biphasic O2 concentration strategy) in the second IVF cycle. The total and usable blastocyst rates (44.4% vs. 54.8%, p = 0.049 and 21.8% vs. 32.8%, p = 0.002, respectively) and the cumulative live birth rate (17.9% vs. 44.1%, p = 0.027) were significantly higher with the biphasic (5%-2%) O2 concentration strategy. Whole transcriptome analysis of blastocysts donated for research identified 707 RNAs that were differentially expressed in function of the O2 strategy (fold-change > 2, p value < 0.05). These genes are mainly involved in embryo development, DNA repair, embryonic stem cell pluripotency, and implantation potential. The biphasic (5-2%) O2 concentration strategy for preimplantation embryo culture could increase the "take home baby rate", thus improving IVF cost-effectiveness and infertility management.

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

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; n = 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.

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

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.

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

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.

Multigenerational endometriosis : consequence of fetal exposure to diethylstilbestrol ?

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.

[Impact of the lockdown on children and families: a survey of family pediatricians within a community.] / Impatto del lockdown sui bambini e sulle famiglie: un'indagine dei pediatri di famiglia all'interno di una comunità.

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.

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

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/cm2) 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/cm2 vs 0.806 ± 0.010 g/cm2), lumbar spine (0.966 ± 0.012 g/cm2 vs 0.886 ± 0.010 g/cm2), and radius (0.545 ± 0.005 g/cm2 vs 0.526 ± 0.04 g/cm2) 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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.