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Summary Low bone mass is a consequence of anorexia nervosa (AN). This study assessed the effects of energy deficiency on various bone and hormonal parameters. The interrelationships between energy deficiency and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit demineralisation and hormonal alterations in AN patients. Introduction Low areal bone mineral density (aBMD) is a well-known consequence of AN. However, the impact of reduced energy expenditure on bone metabolism is unknown. This study assessed the effects of energy deficiency on bone remodelling and its potential interactions with glucose homeostasis and adipose tissue-derived hormones in AN, a clinical model for reduced energy expenditure. Methods Fifty women with AN and 50 age-matched controls (mean age 18.1 ± 2.7 and 18.0 ± 2.1 years, respectively) were enrolled. aBMD was determined with DXA. Resting energy expenditure (REE m ), a marker of energy status, was indirectly assessed by calorimetry. Bone turnover markers, undercarboxylated osteocalcin (ucOC), parameters of glucose homeostasis, adipokines and growth factors were concomitantly evaluated. Results AN patients presented low aBMD at all bone sites. REE m , bone formation markers, ucOC, glucose, insulin, HOMA-IR, leptin and IGF-1 were significantly reduced, whereas the bone resorption marker, leptin receptor (sOB-R) and adiponectin were elevated in AN compared with CON. In AN patients, REE m was positively correlated with weight, BMI, whole body (WB) fat mass, WB fat-free soft tissue, markers of bone formation, glucose, insulin, HOMA-IR, leptin and IGF-1 and negatively correlated with the bone resorption marker and sOB-R. Biological parameters, aBMD excepted, appeared more affected by the weight variation in the last 6 months than by the disease duration. Conclusions The strong interrelationships between REE m and bone remodelling, glucose homeostasis and adipokines underscore the importance of preventing energy deficiency to limit short- and long-term bone demineralisation and hormonal alterations in AN patients.

Background:FOXL2 encodes a forkhead transcription factor whose mutations are responsible for the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), involving craniofacial/palpebral abnormalities often associated with premature ovarian failure (POF).Results:We describe a FOXL2 variant (p.Gly187Asp) in a case of POF without BPES. The subcellular localisation of FOXL2-G187D was normal but its transactivation capacity tested on two reporter promoters, one of which should be relevant to the ovary, was significantly lower than that of normal FOXL2. However, FOXL2-G187D was able to activate strongly a reporter construct driven by the promoter of Osr2 (odd-skipped related 2 transcription factor), which we have suggested to be a crucial target of FOXL2 in the craniofacial region. This is compatible with the absence of BPES in our patient.Conclusions:Our data provide evidence in favour of the implication of FOXL2 variants in non-syndromic POF and confirm the regulatory interaction between FOXL2 and OSR2 whose perturbation might contribute to the palpebral abnormalities observed in BPES patients.

Summary Peripubertal artistic gymnasts display elevated areal bone mineral density at various bone sites, despite delayed menarche and a high frequency of menstrual disorders, factors that may compromise bone health. The concomitant improvement in femoral bone geometry and strength suggested that this type of physical activity might have favourable clinical impact. Introduction The purpose of this study is to evaluate the effect of artistic gymnastics (GYM) on areal bone mineral density (aBMD), femoral bone geometry and bone markers and its relationship with the osteoprotegerin (OPG)/rank-ligand (RANKL) system in peripubertal girls. Methods Forty-six girls (age 10–17.2 years) were recruited for this study: 23 elite athletes in the GYM group (training 12–30 h/week, age at start of training 5.3 years) and 23 age-matched (±6 months; leisure physical activity ≤ 3 h/week) controls (CON). The aBMD at whole body, total proximal femur, lumbar spine, mid-radius and skull was determined using dual-X-ray absorptiometry. Hip structural analysis (HSA software) was applied at the femur to evaluate cross-sectional area (CSA, cm 2 ), cross-sectional moment of inertia (CSMI, cm 4 ), and the section modulus (Z, cm 3 ) and buckling ratio at neck, intertrochanteric region and shaft. Markers of bone turnover and OPG/RANKL levels were also analysed. Results GYM had higher (5.5–16.4%) non-adjusted aBMD and adjusted aBMD for age, fat-free soft tissue and fat mass at all bone sites, skull excepted and the difference increased with age. In the three femoral regions adjusted for body weight and height, CSA (12.5–18%), CSMI (14–18%), Z (15.5–18.6%) and mean cortical thickness (13.6–21%) were higher in GYM than CON, while the buckling ratio (21–27.1%) was lower. Bone markers decreased with age in both groups and GYM presented higher values than CON only in the postmenarchal period. A similar increase in RANKL with age without OPG variation was observed for both groups. Conclusion GYM is associated not only with an increase in aBMD but also an improvement in bone geometry associated with an increase in bone remodelling. These adaptations seem to be independent of the OPG/RANKL system.

Simplified treatment regimens for HIV-1 may have advantages. In this open-label, randomized, controlled trial, patients with HIV-1 infection who had not previously received antiretroviral therapy were given oral induction therapy, then treated with either monthly injections of long-acting cabotegravir and rilpivirine or standard treatment. At 48 weeks, similar viral suppression was observed with the two regimens.

Background Aim According to literature, the incidence of complete androgen insensitivity syndrome (CAIS) revealed by inguinal hernia in “girls” is variable due to the clinical heterogeneity of the series. The aim of this study is to estimate the percentage of CAIS in children with female phenotype who presented with various forms of hernias. Material and Methods This is a retrospective study based on a population of 129 “girls” treated for bilateral hernia repair. The gonads were assessed either by preoperative US or by intra operative direct examination. In case of CAIS suspicion, gonadic tissue was sampled, karyotyping and hormonal analysis were performed. Diagnosis of CAIS was confirmed by direct AR gene sequencing (exons 1–8). Results We identified 2 cases of CAIS (mutations pS204N+delR615 and del F584). The percentage of CAIS depends on the population involved. On the entire series (including simple permeability of the peritoneo-vaginal channel, n=129), the rate of CAIS is low, 1.6%. In case of clinical bilateral hernia whatever the content, digestive or gonadal, the rate of CAIS climbs at 6.9%. For the bilateral gonadic hernias (n=7), the rate of CAIS is 28.6%. Conclusions The incidence of CAIS among “girls” undergoing bilateral hernia repair is low and varies according to the involved population. The simple permeability of the contralateral channel is not a significant risk factor for CAIS. Systematic research of CAIS may be justified in a small number of patients, especially those with bilateral gonadal content. Visualization of the gonads remains mandatory in these particular patients.

Background and Aims Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen-receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome. The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR. Methods 292 Caucasian children presenting with isolated hypospadias (no micropenis, no cryptorchidism) and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1–8) was performed. Results Five missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n=5), penile midshaft (n=2) and penile posterior (n=2) hypospadias, i.e., 3%: p.Q58L (c.1288 A>T), 4 cases of p.P392S (c.2289 C>T), 2 cases of p.A475V (c.2539 C>T), p.D551H (c.1651 G>C) and p.Q799E (c.3510 C>G). None of these mutations was present in the control group. Four mutations are novel findings since 1 has never been reported to date (p.D551H) and 3 have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patients. Conclusion AR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration is important for proper diagnosis and may significantly improve the follow-up of these patients during puberty, especially regarding future fertility.

Background The prostaglandin D2 (PGD2) pathway is involved in numerous biological processes and while it has been identified as a partner of the embryonic sex determining male cascade, the roles it plays in ovarian function remain largely unknown. PGD2 is secreted by two prostaglandin D synthases (Pgds); the male-specific lipocalin (L)-Pgds and the hematopoietic (H)-Pgds. Methods To study the expression of the Pgds in the adult ovary, in situ hybridization were performed. Then, to evaluate the role of H-Pgds produced PGD2 in the ovarian physiology, adult female mice were treated with HQL-79, a specific inhibitor of H-Pgds enzymatic activity. The effects on expression of the gonadotrophin receptors FshR and LhR , steroidogenic genes Cyp11A1 , StAR and on circulating progesterone and estradiol, were observed. Results We report the localization of H-Pgds mRNA in the granulosa cells from the primary to pre-ovulatory follicles. We provide evidence of the role of H-Pgds-produced PGD2 signaling in the FSH signaling through increased FshR and LhR receptor expression. This leads to the activation of steroidogenic Cyp11A1 and StAR gene expression leading to progesterone secretion, independently on other prostanoid-synthetizing mechanisms. We also identify a role whereby H-Pgds-produced PGD2 is involved in the regulation of follicular growth through inhibition of granulosa cell proliferation in the growing follicles. Conclusions Together, these results show PGD2 signaling to interfere with FSH action within granulosa cells, thus identifying an important and unappreciated role for PGD2 signaling in modulating the balance of proliferation, differentiation and steroidogenic activity of granulosa cells.