Shifting the landscape: Dominant C-terminal rare missense FOXL2 variants in non-syndromic primary ovarian failure etiology.

Pathogenic germline variants in the FOXL2 gene are associated with Blepharophimosis, Ptosis, and Epicanthus Inversus syndrome (BPES) in humans, an autosomal dominant condition. Two forms of BPES have emerged: (i) type I (BPES-I), characterized by ocular signs and primary ovarian failure (POI), and (ii) type II (BPES-II) with no systemic associations. This study aimed to compare the distribution of FOXL2 variants in idiopathic POI/DOR (diminished ovarian reserve) and both types of BPES, and to determine the involvement of FOXL2 in non-syndromic forms of POI/DOR. We studied the whole coding region of the FOXL2 gene using next-generation sequencing in 1282 patients with non-syndromic POI/DOR. Each identified FOXL2 variant was compared to its frequency in the general population, considering ethnicity. Screening of the entire coding region of the FOXL2 gene allowed us to identify 10 different variants, including nine missense variants. Of the patients with POI/DOR, 14 (1%) carried a FOXL2 variant. Significantly, six out of nine missense variants (67%) were overrepresented in our POI/DOR cohort compared to the general or specific ethnic subgroups. Our findings strongly suggest that five rare missense variants, mainly located in the C-terminal region of FOXL2 are high-risk factors for non-syndromic POI/DOR, though FOXL2 gene implication accounts for approximately 0.54% of non-syndromic POI/DOR cases. These results support the implementation of routine genetic screening for patients with POI/DOR in clinical settings.

Fertility and pregnancy outcomes in women with nonclassic 21-hydroxylase deficiency.

INTRODUCTION: Overall fertility and pregnancy outcomes in patients with nonclassic congenital adrenal hyperplasia (NCCAH) have been poorly studied. It has been suggested that hydrocortisone (HC) may decrease the time to conceive (TTC) and the rate of miscarriage in these patients. OBJECTIVES: To describe fertility and pregnancy outcomes in a large cohort of NCCAH women. The secondary objective was to identify factors that could impact reproductive outcomes, with a particular focus on HC dose and genetic status. DESIGN: Retrospective study in a referral center for congenital adrenal hyperplasia. PATIENTS AND MEASUREMENTS: One hundred seventy-three female patients with NCCAH confirmed by genetic testing, followed in our center between 2010 and 2019. RESULTS: Among the 173 patients, 95 women had a parental project, 86 of whom presented 176 pregnancies, 56% under glucocorticoid (GC) treatment and 44% without, and 76 women obtained 128 live births. Two-thirds of the patients regularized their cycle under GC treatment, with significant decrease of androgens and progesterone levels. This treatment was associated with a shortening of TTC (coef ß = -.196, information coefficient [IC] = [-10.7; -0.91], p = .021). Androgen levels and TTC were positively correlated to the rate of miscarriage (OR = 4.8, IC = [1.15; 20.34], p = .021 for testosterone, OR = 1.4, IC = [1.05; 1.81], p = .02 for androstenedione, and OR = 1.03, IC = [1.01; 1.06], p = .015 for TTC). There was no difference in terms of obstetric outcomes between patients with or without GC treatment. CYP21A2 genotype had no impact on pregnancy outcome or TTC. CONCLUSIONS: Infertility is relative in patients with NCCAH. HC seems beneficial for fertility and pregnancy outcomes, especially for patients with menstrual disorders and high preconceptional androgen levels.

Classical and non-classical congenital adrenal hyperplasia: What is the difference in subsequent fertility?

21-Hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia. Increased production of adrenal-derived androgens and progesterone in 21OHD women interfere with their reproductive function and their fertility in many different ways, depending on the severity of the disease. Sexuality and fertility in women with classic 21OHD is impaired, due to several issues such as disrupted gonadotropic axis due to androgen and progesterone overproduction, and mechanical, psychological factors related to genital surgery. Fertility and fecundity in these women get better over the years. Subfertility seems contrariwise to be relative in non-classic 21OHD women. Before pregnancy, genotyping the partner and genetic counselling is mandatory.

Positive association between progestins and the evolution of multiple fibroadenomas in 72 women.

OBJECTIVE: Multiple fibroadenomas (MFA) of the breast is a rare benign disease, thus its natural history is poorly understood. The aim of our study was to describe the radiological evolution of MFA and to evaluate the influence of different factors on this evolution. METHODS: This was a longitudinal cohort study. All patients included had two clinical and radiological assessments (breast ultrasound (US) and/or MRI) at least 5 years apart. RESULTS: Seventy-two women were followed for 7.6 ± 2.1 years. The radiological evolution showed a decrease or stability in the number of fibroadenomas (FA) in 26/44 cases on the MRI and in 38/64 cases on the US. There was a decrease of size in 35/44 cases on the MRI and in 53/64 cases on the US. An increase in the number of FAs was found in 18/44 cases in the MRI and 26/64 cases in the US with, for the majority, a decrease of size (19/26 by MRI and 16/18 by MRI). Older age at the first FA (P < 0.0001) and at the diagnosis of MFA (P < 0.0001), pregnancy (P = 0.003) and progestin use (P < 0.001), particularly lynestrenol (P < 0.0001), had a beneficial effect on the evolution of MFA. CONCLUSION: This is the first longitudinal study describing women with MFA. The radiological evolution of MFA seamed favorable and similar to that expected for a single FA. We identified factors influencing the evolution of the disease, including progestin treatments such as lynestrenol, which could have a beneficial effect. Our cohort should be followed further in order to expand our knowledge of MFA, especially concerning the risk of breast cancer.

Just the tip of the iceberg: difficulties in assessing and managing extreme obesity in routine clinical care.

As obesity prevalence increases worldwide, healthcare professionals are often faced with challenging cases associated with massive obesity. A 33-year-old woman (weight 342 kg, body mass index = 100 kg/m²) presented with respiratory failure, limb edema and ascites. Abdominal CT scan became feasible after initial weight loss and showed a large pelvic mass in contact with the left ovary. The surgical removal performed despite a high-risk profile led to the diagnosis of a giant mucinous borderline tumor whose growth was due to delayed care and responsible for multiple severe complications: sepsis, anemia, esophagitis, constipation, anorexia due to mechanical compression, undernutrition, sarcopenia and lower limb edema contributing to a severe disability. After 7 months under specialized care, her weight decreased to 180 kg, complications were treated and disability improved. This case, showing that, despite barriers, a multidisciplinary approach makes quality of care possible even in massively obese patients, is an educational example to reduce stigma.

Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk.

CONTEXT: In a cohort of 95 women with multiple breast fibroadenomas (MFAs), we recently identified patients harboring germline heterozygous variants of the prolactin receptor (PRLR) exhibiting constitutive activity (PRLRI146L and PRLRI176V). OBJECTIVE: This study sought to better delineate the potential role of PRLR gain-of-function variants in benign and malignant mammary tumorigenesis. DESIGN: This was an observational study and transgenic mouse model analysis. SETTING: The study took place at the Department of Endocrinology, Reproductive Disorders and Rare Gynecologic Diseases, Pitié Salpêtrière, Paris, and Inserm Unit 1151, Paris. PATIENTS OR OTHER PARTICIPANTS: We generated a second MFA cohort (n = 71) as well as a group of control subjects (n = 496) and a cohort of women with breast cancer (n = 119). We also generated two transgenic mouse models carrying the coding sequences of human PRLRI146L or PRLRWT. INTERVENTION: We aimed to determine the prevalence of PRLR variants in these three populations and to uncover any association of the latter with specific tumor pattern, especially in patients with breast cancer. RESULTS: This study did not highlight a higher prevalence of PRLR variants in the MFA group and in the breast cancer group compared with control subjects. Transgenic mice expressing PRLRI146L exhibited very mild histological mammary phenotype but tumors were never observed. CONCLUSION: PRLRI146L and PRLRI176V variants are not associated with breast cancer or MFA risk. However, one cannot exclude that low but sustained PRLR signaling may facilitate or contribute to pathological development driven by oncogenic pathways. Long-term patient follow-up should help to address this issue.

[Therapeutic education programme for patients with chronic endocrine conditions: Transition from paediatric to adult services]. / Un programme d'éducation thérapeutique centré sur la transition des patients, avec endocrinopathie chronique, entre les services d'endocrinologie pédiatrique et adulte.

UNLABELLED: The purpose of this study is to contribute to better identifying the transition of patients with chronic endocrine conditions from paediatric to adult department. The aim was to specify the means and the competences that must be used by patients and health care teams and which could be help to the best quality care. METHOD: We propose group sessions and individual interviews. A thematic analysis of the sessions and the responses to questionnaires have enabled the development of individual educational diagnosis and assess the autonomy of young adolescents. RESULTS: Fifty of 214 patients from paediatric services participated to therapeutic education program (TEP) in the last four years. This program is based on the psychic movements of adolescence. One year after the therapeutic education program session, 48 patients came to all the medical consultations and we observed a greater autonomy in adolescent patients. CONCLUSION: However, we must improve the modalities for including patients in this "transition program".

Gynecologic follow up of 129 women on dialysis and after kidney transplantation: a retrospective cohort study.

OBJECTIVE: To describe the gynecologic issues and follow-up in our referral center of women on dialysis and after kidney transplantation. STUDY DESIGN: This retrospective cohort study included 129 dialysed women among whom 102 had had transplants. Data on menstrual pattern, pregnancies, contraception, and cervical cytology were retrieved from patients' files. RESULTS: The follow-up started at age 41.6±14.2 years and lasted for 9.5±10.2 years. Of the women, 78.7% had regular menses before dialysis, decreasing to 30.6% on dialysis (p<0.001), when 43.1% were amenorrheic (p<0.001). After transplantation, more patients had regular menstruation and fewer were amenorrheic (respectively 57.1% and 23.1%, p<0.001). On dialysis and after transplantation, 25% and 30.5% of patients suffered from metrorrhagia (compared to 17.1% before, p<0.01). Concerning pregnancies, rates of spontaneous abortions (33.3%, p=0.01), intrauterine growth retardation (28.5%, p<0.001) and prematurity (23.8%, p=0.008) were significantly higher after transplantation than before dialysis. Prescriptions for the combined contraceptive pill and intrauterine device decreased whereas chlormadinone acetate was widely used: it treated metrorrhagia and relieved mastodynia in 80% and 12% of the cases. Smear tests showed more inflammation (33% vs 0.8%, p<0.05), condylomas (13.6% vs 3.1%, p=0.005) and intraepithelial neoplasias (12.6% vs 2.3%, p=0.003) among patients after renal graft than before dialysis. CONCLUSION: Women on dialysis and after kidney transplantation suffered more from irregular menses and metrorrhagia which was improved by chlormadinone acetate. We noted high rates of obstetrical complications and abnormal smear tests. Consequently, this population must have close follow-up to identify and treat gynecologic issues.

Increased risk of high grade cervical squamous intraepithelial lesions in systemic lupus erythematosus: A meta-analysis of the literature.

Conflicting data have been published regarding the risk of cervical lesions among women with systemic lupus erythematosus (SLE). We systematically reviewed the evidence for an association of SLE with cervical precancerous lesions (high-grade squamous intraepithelial lesions, HSIL), and performed a meta-analysis to determine the risk of HSIL in SLE patients. Observational studies identified up to February 2013 from the Medline, Embase and Cochrane databases were selected if they assessed the prevalence of HSIL in female SLE patients versus healthy female controls and included in a meta-analysis with pooled effect estimates obtained using a random-effects model. Of 235 citations retrieved, 7 studies met inclusion criteria. The pooled odds ratio for the risk of HSIL in SLE patients (n=416) versus female controls (n=11,408) was 8.66 (95% CI: 3.75-20.00), without significant heterogeneity across studies. Cumulative meta-analysis according to year of study publication revealed a slight increase in the risk of HSIL in the 2001-2011 period and then a stabilization afterwards. This meta-analysis shows that the risk of HSIL is significantly increased in SLE patients, compared to healthy female controls. This suggests that women with SLE may benefit from HPV vaccines and specific cervical cancer screening.

[Fertility on women with Turner syndrome]. / Fertilité chez les femmes ayant un syndrome de Turner.

Spontaneous pregnancies occur in 1.8 to 7.6% among women with Turner syndrome. A genetic counseling is required before conception because only 30 to 40% of these pregnancies lead to the birth of a healthy child. A check-up has to be done before pregnancy, and if authorized, it will be tightly followed-up. Pregnancy is contraindicated if cardiac or aortic malformations exist, except for bicuspid aortic valve. Teams advice single embryo transfer. Rates of pregnancies of 45 to 60% after oocyte donation, but 40 to 60% of spontaneous abortions are noted, due to uterine factors. A study is trying to define patients who could postulate to cryopreservation of ovarian tissue.

Study of anti-Müllerian hormone and its relation to the subsequent probability of pregnancy in 112 patients with systemic lupus erythematosus, exposed or not to cyclophosphamide.

CONTEXT: Cyclophosphamide is used for renal and major extrarenal involvement in systemic lupus erythematosus (SLE) and is associated with a risk of premature ovarian failure. There are no data available about the relation between anti-Müllerian hormone (AMH) serum levels and the probability of subsequent pregnancy in SLE patients. OBJECTIVE: We analyzed AMH levels and the probability of pregnancy in SLE women exposed to cyclophosphamide. DESIGN AND SETTING: We conducted a matched cohort study in referral centers for SLE. PATIENTS: Fifty-six cyclophosphamide-exposed SLE women younger than 40 years of age and 56 control SLE women matched for age within 6 months participated in the study. MAIN OUTCOME MEASURES: AMH was measured in samples from the PLUS study (ClinicalTrials.gov no. NCT00413361). All patients were interviewed in May 2012 regarding their obstetric status. RESULTS: The mean age ± SD of the 112 patients was 31.6 ± 5.8 years. The mean AMH level was low (1.21 ± 1.01 ng/mL) and was significantly lower in patients exposed to cyclophosphamide (P = .03) and in patients older than 30 years (P = .02). During a median follow-up (interval between sampling and the interview) period of 4.2 (range, 2.5-4.8) years, 38 patients sought to become pregnant, and 32 (84.2%) succeeded. In the univariate analysis, the risk of failure was associated with cumulative cyclophosphamide dose (P = .007) and older age (P = .02), but not with AMH. CONCLUSION: We confirmed that AMH levels are low in SLE patients and decrease significantly with age and cyclophosphamide exposure. Nonetheless, the risk of failure to conceive was low and was predicted by cyclophosphamide exposure and age, but not by AMH levels.

Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia.

OBJECTIVE: Women with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility. DESIGN: Case/control study. METHODS: Sixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28 ± 3 days), were included. LH pulse patterns over 6 h were determined in patients and controls. RESULTS: No differences were observed between patients and controls in terms of mean LH levels, LH pulse amplitude, or LH frequency. In CAH patients, LH pulsatility patterns were heterogeneous, leading us to perform a clustering analysis of LH data, resulting in a two-cluster partition. Patients in cluster 1 had similar LH pulsatility patterns to the controls. Patients in cluster 2 had: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels. CONCLUSIONS: LH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.

Progestogen-only contraceptives and the risk of acute myocardial infarction: a meta-analysis.

CONTEXT: The association between combined oral contraceptives (OC) and the risk of myocardial infarction (MI) has been intensively studied, and conclusions are controversial. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular diseases is poorly investigated and remains unclear. OBJECTIVE: We carried out a meta-analysis based on EMBASE- and MEDLINE-referenced literature corresponding to OC marketed since 1960. METHODS: Eligible articles published in English language describing OC or POC use and MI outcome were reviewed, and relevant ones were extracted. All types of POC and route of administration were considered. RESULTS: Six case-control studies were identified. The combined odds ratio showed no increase in the MI risk with POC use (odds ratio = 1.07; 95% confidence interval, 0.62-1.84). This result was similar according to the route of administration, including implant, injectable, and oral POC. CONCLUSION: Data from observational studies suggest no increase in risk of MI with POC use. However, these results are based on limited data. Further investigations are needed, especially among women at high MI risk.

Bone health should be an important concern in the care of patients affected by 21 hydroxylase deficiency.

Osteoporosis has been an understandable concern for children and adult patients with congenital adrenal hyperplasia (CAH) who may receive or have received supraphysiological doses of glucocorticoids. Some previous reports on bone mineral density (BMD) in adult CAH patients showed no significant differences in BMD between patients with CAH and controls, but others have found lower BMD in CAH patients. In reports documenting the BMD reduction, this outcome has been attributed to an accumulated effect of prolonged exposure to excess glucocorticoids during infancy and childhood. We recently conducted a trial to establish the role of the total cumulative glucocorticoid dose on BMD. We established for the first time that there was a negative relationship between total cumulative glucocorticoid dose and lumbar and femoral BMD. Women might benefit from the preserving effect of estrogens compared to men. BMI (Body Mass Index) also appeared to protect patients from bone loss. In light of this, physicians should bear in mind the potential consequences of glucocorticoids on bone and therefore adjust the treatment and improve clinical and biological surveillance from infancy. Furthermore, preventive measures against corticosteroid-induced osteoporosis should be discussed right from the beginning of glucocorticoid therapy.

Characterization of two constitutively active prolactin receptor variants in a cohort of 95 women with multiple breast fibroadenomas.

BACKGROUND: The role of prolactin (PRL) and its receptor (hPRLR) in promoting breast tumors is debated. We recently identified a gain-of-function hPRLR variant (I146L) in four women with multiple breast fibroadenomas (MFA) and no control subject. OBJECTIVES: The specific aims were to describe this cohort of women presenting with MFA to identify and functionally characterize germline variants of hPRL/hPRLR genes and compare phenotypes of all patients. DESIGN: Ninety-five patients prospectively underwent clinical examination, breast ultrasonography, magnetic resonance imaging, and hormonal evaluation of gonadal and lactotrope functions. We analyzed hPRL/hPRLR coding sequences and made comparisons with a control population of 194 women. Functional characterization of hPRLR variants was performed. Pathology and immunochemistry were systematically carried out after surgical removal of tumors. RESULTS: One third of patients had a family history of breast disease. No hormonal imbalance was observed, except 30.7% of explosive stimulated PRL. Prolactin receptor variants were identified in exon 5 (I76V: 10 patients, eight controls) and exon 10 (one patient, no control). Both I146L and I76V variants exhibited constitutive activity. Pathology showed common fibroadenomas and identified six benign phyllodes tumors. Estrogen and progesterone receptors were detected in 85 and 98% of samples, respectively. Ki-67 median staining was less than 5%. No phenotypic difference was observed between carriers and noncarriers of either hPRLR variant. CONCLUSION: We present the largest population with MFA ever described, 15% of which had a hPRLR exhibiting basal activity in vitro. This questions the involvement of the hPRLR in MFA etiology and the potential relevance of therapeutic inhibition of PRLR signaling in patients.

Progestogen-only contraceptives and the risk of stroke: a meta-analysis.

BACKGROUND AND PURPOSE: The association between combined oral contraceptives (OC) use and increased risk of stroke has been reported. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular disease remains unclear. METHODS: A meta-analysis based on EMBASE and MEDLINE referenced literature corresponding to OCs marketed since 1960 was carried out. Eligible articles assessing the risk of stroke in relation to OC or POC were reviewed, and relevant studies were extracted. All types of POC and routes of administration were taken into account in the meta-analysis. RESULTS: Six case-control studies were identified. The combined odd ratio (OR) showed no increase in the risk of stroke among POC users (OR=0.96; 95% confidence interval: 0.70 to 1.31). This result was similar according to the route of administration (either implant or injectable or oral POC). CONCLUSIONS: Data from observational studies show that POC use is not associated with an increased risk of stroke. However, these results are based on limited data. Further investigations are needed in women with risk factors of stroke.

Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members.

CONTEXT: Nonclassical congenital adrenal hyperplasia (NC-CAH) due to partial 21-hydroxylase deficiency is one of the most frequent autosomal recessive diseases. OBJECTIVE: The aim of this study was to determine the genotype/phenotype relationship in probands and family members. PATIENTS AND METHODS: A total of 161 NC-CAH unrelated women diagnosed on late-onset symptoms, mainly hirsutism, and post-ACTH 17-hydroxyprogesterone more than 10 ng/ml, and 330 of their relatives was explored. CYP21A2 was genotyped in 124 probands. RESULTS: The most frequent mutation was V281L. One severe mutation was found in 63.7% of probands, and surprisingly two severe mutations in four probands. Contrasting with the absence of clinical differences, basal testosterone, and androstenedione, basal and post-ACTH 17-hydroxyprogesterone were significantly higher in probands carrying at least one severe mutation than in those with two mild mutations (P < 0.01). Among the 330 family members, 51 were homozygotes or compound heterozygotes, and 42 were clinically asymptomatic; 242 were heterozygotes and 37 unaffected. Post-ACTH 21-deoxycortisol (21dF) was significantly higher in heterozygotes than in unaffected, however, an overlap existed. In 12 heterozygotes, post-ACTH 21dF was below 0.55 ng/ml, the cutoff value usually accepted for suggesting heterozygosity. CONCLUSIONS: The study of family members underlines the variable expression of NC-CAH even within a family, suggesting that modifier factors may modulate phenotype expression. Post-ACTH 21dF cannot reliably detect heterozygous subjects. Considering the high frequency of heterozygotes in the general population, it is essential to genotype the partner(s) of the patients with one severe mutation to offer genetic counseling.

Impact of total cumulative glucocorticoid dose on bone mineral density in patients with 21-hydroxylase deficiency.

OBJECTIVE: It remains controversial whether long-term glucocorticoids are charged of bone demineralization in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The aim of this study was to know whether cumulative glucocorticoid dose from the diagnosis in childhood to adulthood in patients with CAH had a negative impact on bone mineral density (BMD). DESIGN: This was a retrospective study. METHODS: Thirty-eight adult patients with classical and non-classical CAH were included. BMD was measured in the lumbar spine and femoral neck. Total cumulative glucocorticoid (TCG) and total average glucocorticoid (TAG) doses were calculated from pediatric and adult files. RESULTS: We showed a difference between final and target heights (-0.82+/-0.92 s.d. for women and -1.31+/-0.84 s.d. for men; P<0.001). Seventeen patients (44.7%) had bone demineralization (35.7% of women and 70% of men). The 28 women had higher BMD than the 10 men for lumbar (-0.26+/-1.20 vs -1.25+/-1.33 s.d.; P=0.02) and femoral T-scores (0.21+/-1.30 s.d. versus -1.08+/-1.10 s.d.; P=0.007). In the salt-wasting group, women were almost significantly endowed with a better BMD than men (P=0.053). We found negative effects of TCG, TAG on lumbar (P<0.001, P=0.002) and femoral T-scores (P=0.006, P<0.001), predominantly during puberty. BMI was protective on BMD (P=0.006). CONCLUSION: The TCG is an important factor especially during puberty for a bone demineralization in patients with 21-hydroxylase deficiency. The glucocorticoid treatment should be adapted particularly at this life period and preventive measures should be discussed in order to limit this effect.