RESUMO
Premature ovarian insufficiency is a common form of female infertility affecting up to 4% of women and characterised by amenorrhea with elevated gonadotropin before the age of 40. Oocytes require controlled DNA breakage and repair for homologous recombination and the maintenance of oocyte integrity. Biallelic disruption of the DNA damage repair gene, Fanconi anemia complementation group A (FANCA), is a common cause of Fanconi anaemia, a syndrome characterised by bone marrow failure, cancer predisposition, physical anomalies and POI. There is ongoing dispute about the role of heterozygous FANCA variants in POI pathogenesis, with insufficient evidence supporting causation. Here, we have identified biallelic FANCA variants in French sisters presenting with POI, including a novel missense variant of uncertain significance and a likely pathogenic deletion that initially evaded detection. Functional studies indicated no discernible effect on DNA damage sensitivity in patient lymphoblasts. These novel FANCA variants add evidence that heterozygous loss of one allele is insufficient to cause DNA damage sensitivity and POI. We propose that intragenic deletions, that are relatively common in FANCA, may be missed without careful analysis, and could explain the presumed causation of heterozygous variants. Accurate variant curation is critical to optimise patient care and outcomes.
Assuntos
Alelos , Proteína do Grupo de Complementação A da Anemia de Fanconi , Insuficiência Ovariana Primária , Humanos , Insuficiência Ovariana Primária/genética , Feminino , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Adulto , Anemia de Fanconi/genética , Anemia de Fanconi/diagnóstico , Irmãos , Heterozigoto , Predisposição Genética para Doença , Linhagem , Mutação/genéticaRESUMO
Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.
Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Aminoacil-tRNA Sintetases/genética , Proteínas de Ligação a DNA/genética , Dimetilaliltranstransferase/genética , Endopeptidase Clp/genética , Farnesiltranstransferase/genética , Predisposição Genética para Doença , Geraniltranstransferase/genética , Disgenesia Gonadal 46 XX/genética , Perda Auditiva Neurossensorial/genética , Proteínas Mitocondriais/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Sequência de Bases , Criança , DNA Mitocondrial/genética , Feminino , Expressão Gênica , Disgenesia Gonadal 46 XX/diagnóstico , Disgenesia Gonadal 46 XX/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Ovário/metabolismo , Ovário/patologia , Linhagem , Peroxissomos/metabolismo , Peroxissomos/patologiaRESUMO
Premature ovarian insufficiency involves amenorrhea and elevated follicle-stimulating hormone before age 40, and its genetic basis is poorly understood. Here, we study 13 premature ovarian insufficiency (POI) patients using whole-exome sequencing. We identify PREPL and TP63 causative variants, and variants in other potentially novel POI genes. PREPL deficiency is a known cause of syndromic POI, matching the patients' phenotype. A role for TP63 in ovarian biology has previously been proposed but variants have been described in multiorgan syndromes, and not isolated POI. One patient with isolated POI harbored a de novo nonsense TP63 variant in the terminal exon and an unrelated patient had a different nonsense variant in the same exon. These variants interfere with the repression domain while leaving the activation domain intact. We expand the phenotypic spectrum of TP63-related disorders, provide a new genotype:phenotype correlation for TP63 and identify a new genetic cause of isolated POI.
Assuntos
Códon sem Sentido , Insuficiência Ovariana Primária/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Feminino , Predisposição Genética para Doença , Humanos , Linhagem , Prolil Oligopeptidases , Domínios Proteicos , Serina Endopeptidases/genética , Fatores de Transcrição/química , Proteínas Supressoras de Tumor/química , Sequenciamento do Exoma/métodosRESUMO
CONTEXT: Spontaneous resumption of ovarian function is not a rare phenomenon in patients with premature ovarian insufficiency (POI). The outcome of this resumption is not known. OBJECTIVE: To describe the outcome following the resumption of ovarian function in POI patients. DESIGN: Cross-sectional study. SETTING: University medical centre. PATIENTS AND MAIN OUTCOME MEASURES: Cumulative incidence of ovarian function resumption and risk factors arresting this resumption during follow-up were determined in a large cohort of POI women. RESULTS: Five hundred and seven patients were included in the study, with a follow-up of 3·44 ± 4·05 years (0-29). Of these, 117 (23%) had features of ovarian function resumption. The cumulative incidence of pregnancy was 3·5% among the whole cohort and 15·3% among patients with resumption of ovarian function. Fifty-five patients (47%) experienced an arrest of their resumption during the follow-up period. In univariate analysis, high FSH and DHEA levels at initial evaluation were risk factors for the arrest of the resumption of ovarian function. In multivariate analysis, high FSH levels at the initial evaluation [1·89 (1·10-3·23), P = 0·03] and older age at diagnosis [1·53 (1·01-2·33), P = 0·04] were risk factors for the arrest of this resumption. CONCLUSION: Resumption of ovarian function is not a rare or brief phenomenon in POI women. The identification of predictive factors of this resumption, as well as its duration, increases our knowledge of the natural history of POI, and will improve the medical management, especially infertility counselling of these patients.
Assuntos
Ovário/fisiopatologia , Insuficiência Ovariana Primária/fisiopatologia , Adulto , Estudos Transversais , Desidroepiandrosterona/sangue , Feminino , Fertilidade , Hormônio Foliculoestimulante/sangue , Seguimentos , Humanos , Ovário/fisiologia , Gravidez , Prognóstico , Adulto JovemRESUMO
CONTEXT: Turner syndrome (TS) is characterized by short stature and premature ovarian insufficiency (POI). The main long-term complication of POI is osteoporosis, which can be prevented by hormone replacement therapy (HRT). OBJECTIVE: The objective of our study was to compare initial bone mineral density (BMD) and progression between TS and idiopathic POI patients under HRT. METHODS: A single-center retrospective study was conducted between 1998 and 2018. All women had undergone at least two bone densitometry assessments at least 2 years apart. RESULTS: 68 TS patients and 67 idiopathic POI patients were included. Mean age at initial assessment was 27 years (IQR, 21-35.5 years) in TS patients and 31.5 years (IQR, 23-37 years) in idiopathic POI patients (p=0.1). Lumbar and femoral neck BMD were lower in the TS group than in the idiopathic POI group (respectively 0.89g/cm² versus 0.95g/cm², p=0.03; 0.70g/cm² versus 0.77g/cm², p<0.0001). Mosaic karyotype was associated with better BMD in TS patients while history of growth hormone treatment had no impact on BMD. Over time, a significant gain in vertebral BMD was observed in TS patients versus a loss of BMD in idiopathic POI patients (p=0.0009). CONCLUSION: TS patients had a lower BMD at baseline than idiopathic POI patients, at both spinal and femoral levels. Over time, on HRT, a significant gain in vertebral BMD was observed in patients with TS, compared with a loss of BMD in patients with idiopathic POI. We hypothesized that earlier initiation and longer duration of HRT played an important role in this finding. Long-term prospective follow-up to assess the incidence of fractures in TS would be useful.
RESUMO
OBJECTIVE: The diagnosis of premature ovarian insufficiency (POI) is a traumatic event for many patients that involves poor fertility prognosis. After such diagnosis, spontaneous pregnancies are rare. The alternatives for building a family are oocyte donation, embryo donation, and adoption. However, we have few information on how many women with POI finally built a family after the diagnosis and which alternative they chose. DESIGN: We performed a cross-sectional, descriptive study. METHODS: We conducted a survey of all the women who consulted for POI in the department of endocrinology and reproductive medicine at la Pitié Salpêtrière between May 31, 1991, and January 12, 2021. We included patients who continued to be followed up regularly by our department or were contacted by mail or phone between June and September 2021. We excluded patients with Turner syndrome and POI secondary to oncological treatment and patients under 18 at the time of the survey. RESULTS: 985 patients were referred to the department for POI, and 324 patients were finally analyzed. 41% of the women who wanted to build a family had children after the diagnosis: 53.9% by oocyte donation, 1 woman by embryo donation, 5.6% after ovarian stimulation, 13.5% by adoption, and 25.8% who had spontaneous pregnancy after a mean time of 2.5 years. Spontaneous pregnancy rate was 8.6% in the whole cohort. CONCLUSIONS: Having children after a diagnosis of POI is not uncommon but more often results from oocyte donation. This study will provide enlightened information for newly diagnosed women on the possibilities to build a family after POI diagnosis.
Assuntos
Infertilidade Feminina , Menopausa Precoce , Insuficiência Ovariana Primária , Gravidez , Feminino , Humanos , Estudos Transversais , Destinação do Embrião , Infertilidade Feminina/terapia , Insuficiência Ovariana Primária/complicaçõesRESUMO
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.
Assuntos
Hiperplasia Suprarrenal Congênita , Gonadotrofos , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/genética , Androgênios , Feminino , Fertilidade , Humanos , Gravidez , Progesterona , Esteroide 21-Hidroxilase/genéticaRESUMO
Complete androgen insensitivity syndrome (CAIS), where 46,XY individuals present as female, is caused by variants in the androgen receptor gene (AR). We analyzed the DNA of a patient with suspected CAIS using a targeted gene sequencing panel and whole exome sequencing (WES) but did not detect any small nucleotide variants in AR. Analysis of WES data using our bioinformatics pipeline designed to detect copy number variations (CNV) uncovered a rare duplication of exon 2 of AR. Using array comparative genomic hybridization, the duplication was found to span 43.6 kb and is predicted to cause a frameshift and loss of AR protein. We confirmed the power of our WES-CNV detection protocol by identifying pathogenic CNVs in FSHR and NR5A1 in previously undiagnosed patients with disorders of sex development. Our findings illustrate the usefulness of CNV analysis in WES data to detect pathogenic genomic changes that may go undetected using only standard analysis protocols.
Assuntos
Síndrome de Resistência a Andrógenos , Variações do Número de Cópias de DNA , Síndrome de Resistência a Andrógenos/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA/genética , Exoma/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Sequenciamento do Exoma/métodosRESUMO
The mitochondrial ribosome is critical to mitochondrial protein synthesis. Defects in both the large and small subunits of the mitochondrial ribosome can cause human disease, including, but not limited to, cardiomyopathy, hypoglycaemia, neurological dysfunction, sensorineural hearing loss and premature ovarian insufficiency (POI). POI is a common cause of infertility, characterised by elevated follicle-stimulating hormone and amenorrhea in women under the age of 40. Here we describe a patient with POI, sensorineural hearing loss and Hashimoto's disease. The co-occurrence of POI with sensorineural hearing loss indicates Perrault syndrome. Whole exome sequencing identified two compound heterozygous variants in mitochondrial ribosomal protein 7 (MRPS7), c.373A>T/p.(Lys125*) and c.536G>A/p.(Arg179His). Both novel variants are predicted to be pathogenic via in-silico algorithms. Variants in MRPS7 have been described only once in the literature and were identified in sisters, one of whom presented with congenital sensorineural hearing loss and POI, consistent with our patient phenotype. The other affected sister had a more severe disease course and died in early adolescence due to liver and renal failure before the reproductive phenotype was known. This second independent report validates that variants in MRPS7 are a cause of syndromic POI/Perrault syndrome. We present this case and review the current evidence supporting the integral role of the mitochondrial ribosome in supporting ovarian function.
Assuntos
Disgenesia Gonadal 46 XX , Perda Auditiva Neurossensorial , Insuficiência Ovariana Primária , Adolescente , Feminino , Humanos , Ribossomos Mitocondriais/patologia , Disgenesia Gonadal 46 XX/genética , Disgenesia Gonadal 46 XX/patologia , Insuficiência Ovariana Primária/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Proteínas Ribossômicas/genética , Proteínas Mitocondriais/genéticaRESUMO
Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis.
Assuntos
Insuficiência Ovariana Primária , Animais , Proteínas de Ciclo Celular/genética , Cromossomos , DNA Helicases/genética , Proteínas de Ligação a DNA , Feminino , Humanos , Meiose/genética , Camundongos , Fenótipo , Insuficiência Ovariana Primária/genética , Insuficiência Ovariana Primária/patologia , Sequenciamento do ExomaRESUMO
We conducted a retrospective study on the long-term effect of mitotane treatment on testicular adrenal rest tumors (TARTs) in five adult patients with classic 21-hydroxylase deficiency. After 60 months of mitotane treatment, a decrease in adrenal steroids was observed in four patients. Testicular ultrasonography showed complete disappearance of TART in two patients, stabilization in two patients and a halving of TART volume in the remaining patient. Sperm count improved notably in two patients who had normal baseline inhibin B levels and small inclusions, thus enabling cryopreservation of the subjects' semen. Four years of follow-up of these two patients after the withdrawal of mitotane showed no recurrence of TART and persistent normal testicular function. In conclusion, mitotane could be used as a last resort in CAH patients in the cases of azoospermia associated with TARTs but normal inhibin B levels, as it can improve long-term endocrine and exocrine testicular function.
Assuntos
Hiperplasia Suprarrenal Congênita/complicações , Tumor de Resto Suprarrenal/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Mitotano/uso terapêutico , Neoplasias Testiculares/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/patologia , Tumor de Resto Suprarrenal/etiologia , Tumor de Resto Suprarrenal/patologia , Adulto , Humanos , Masculino , Estudos Retrospectivos , Neoplasias Testiculares/etiologia , Neoplasias Testiculares/patologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient's age, but diagnosis is often late. OBJECTIVE: To evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development. PATIENTS AND METHODS: This observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases-non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)-included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening. RESULTS: Median age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8-10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD. CONCLUSION: The early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.
Assuntos
Síndrome de Resistência a Andrógenos , Doenças do Sistema Endócrino , Disgenesia Gonadal , Adulto , Pré-Escolar , Estudos de Coortes , Doenças do Sistema Endócrino/diagnóstico , Humanos , Recém-Nascido , Masculino , Doenças Raras/diagnósticoRESUMO
CONTEXT: Controversial data exist on cardiovascular damages in patients with congenital adrenal hyperplasia (CAH). OBJECTIVE: To assess blood pressure and early cardiovascular damages on a large cohort of adult CAH patients and control individuals. DESIGN: Case-control study. SETTING: Referral Center for Rare Disease, Pitié Salpêtrière Hospital, Paris, France. PATIENTS OR OTHER PARTICIPANTS: Fifty-eight women and 26 men with CAH diagnosed in childhood and 85 controls matched-paired for sex, age and smoking status were prospectively included. INTERVENTION: Measurement of large arteries and microcirculatory anatomical and functional indices as well as hormonal status and cardiovascular risk factors evaluation. MAIN OUTCOME MEASURE: The primary objective was to compare carotid intima-media thickness (cIMT) in CAH patients and controls. The secondary objectives were to compare blood pressure (BP), radial augmentation index (rAI), central BP, carotid-femoral pulse wave velocity (PWV), skin microcirculation indices and inflammation parameters in CAH patients and controls. RESULTS: Although PWV and cIMT were identical in patients and controls, higher rAI (64.6â±â1.7 vs. 59.9â±â1.6%, Pâ=â0.02) and higher central SBP (101.8â±â1.5 vs. 95.1â±â1.5âmmHg, Pâ<â0.001) were observed in CAH patients. Regarding microcirculatory indices, there was a higher functional resting capacity and a lower anatomical capillary density in CAH patients. In multivariate analysis, we found an independant association between CAH and central SBP elevation. CONCLUSION: We found an early rise in central SBP in CAH patients whereas sublinical arterial damages markers were normal. Our study suggest that vascular damages and increased cardiovascular risk could be mainly BP-driven.
Assuntos
Hiperplasia Suprarrenal Congênita , Pressão Sanguínea/fisiologia , Hiperplasia Suprarrenal Congênita/epidemiologia , Hiperplasia Suprarrenal Congênita/fisiopatologia , Adulto , Espessura Intima-Media Carotídea , Criança , Feminino , Humanos , Estudos Prospectivos , Análise de Onda de PulsoRESUMO
During childhood, the main aims of the medical treatment of congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase are to prevent salt loss and virilization and to attain normal stature and normal puberty. As such, there is a narrow therapeutic window through which the intended results can be achieved. In adulthood, the clinical management has received little attention, but recent studies have shown the relevance of long-term follow-up of these patients. The aims here are to review the multiple clinical, hormonal and metabolic abnormalities that could be found in adult CAH patients as such a decrease in bone mineral density, overweight and disturbed reproductive functions. In women with classic CAH, a low fertility rate is reported, and is probably the consequence of multiple factors including neuroendocrine and hormonal factors, feminizing surgery, and psychological factors. Men with CAH may present hypogonadism either through the effect of adrenal rests or from suppression of gonadotropins resulting in infertility. Therefore a multidisciplinary team with knowledge of CAH should carefully follow up these patients, from childhood through to adulthood, to avoid these complications and to ensure treatment compliance and tight control of the adrenal androgens.
Assuntos
Hiperplasia Suprarrenal Congênita/etiologia , Erros Inatos do Metabolismo/complicações , Esteroide 21-Hidroxilase/metabolismo , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/terapia , Adulto , Humanos , Infertilidade/etiologia , Obesidade/etiologia , Osteoporose/etiologiaRESUMO
Folliculogenesis requires communication between granulosa cells and oocytes, mediated by connexin-based gap junctions. Connexin 37 (Cx37)-deficient female mice are infertile. The present study assessed Cx37 deficiency in patients with primary ovarian insufficiency (POI). A candidate gene study was performed in patients and controls from the National Genotyping Center (Evry, France) including 58 Caucasian patients with idiopathic isolated POI and 142 Caucasian controls. Direct genomic sequencing of the coding regions of the GJA4 gene (encoding Cx37) was performed with the aim to identify a deleterious variant associated with POI and absent in ethnically matched controls. A single Cx37 variant absent in the control population was identified, namely a c.946G>A heterozygous substitution leading to a p.Gly316Ser variant that was present in two POI patients. This variant was absent in all Caucasian controls from various databases, and has been observed exclusively in African populations. This variant was identified to have a dominant negative effect in HeLa cells in vitro to alter connexon function (by 67.2±7.17%), as determined by Gap-fluorescence recovery after photobleaching. The alteration principally resulted from a decrease of cell surface connexons due to altered trafficking (by 47.73±8.59%). In marked contrast to this observation, a p.Pro258Ser variant frequent in all ethnic populations in databases had no functional effect in vitro. In conclusion, the present study reported on a Cx37 variant in two Caucasian POI patients, which was absent in control Caucasian populations, and which had a deleterious effect in vitro. It is therefore suggested that in the genetic context of the Caucasian population, this variant may contribute to POI.
Assuntos
Comunicação Celular/genética , Conexinas/genética , Junções Comunicantes/genética , Insuficiência Ovariana Primária/genética , Animais , População Negra/genética , Membrana Celular/genética , Membrana Celular/metabolismo , Feminino , Junções Comunicantes/metabolismo , Células da Granulosa/metabolismo , Células da Granulosa/patologia , Células HeLa , Heterozigoto , Humanos , Camundongos , Oócitos/crescimento & desenvolvimento , Oócitos/patologia , Insuficiência Ovariana Primária/patologia , Ratos , População Branca/genética , Proteína alfa-4 de Junções ComunicantesRESUMO
Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and in some cases aldosterone deficiency associated with androgen excess. Goals of treatment are to replace deficient hormones and control androgen excess, while avoiding the adverse effects of exogenous glucocorticoid. Over the last 5 years, cohorts of adults with CAH due to 21-hydroxylase deficiency from Europe and the United States have been described, allowing us to have a better knowledge of long-term complications of the disease and its treatment. Patients with CAH have increased mortality, morbidity and risk for infertility and metabolic disorders. These comorbidities are due in part to the drawbacks of the currently available glucocorticoid therapy. Consequently, novel therapies are being developed and studied in an attempt to improve patient outcomes. New management strategies in the care of pregnancies at risk for congenital adrenal hyperplasia using fetal sex determination and dexamethasone have also been described, but remain a subject of debate. We focused the present overview on the data published in the last 5 years, concentrating on studies dealing with cardiovascular risk, fertility, treatment and prenatal management in adults with classic CAH to provide the reader with an updated review on this rapidly evolving field of knowledge.
Assuntos
Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Terapia de Reposição Hormonal/métodos , Gerenciamento Clínico , Humanos , Fatores de RiscoRESUMO
Objective: To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI). Design: MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants. Setting: Academic research institution. Participants: All were diagnosed with POI prior to age 40 years and presented with elevated follicle-stimulating hormone levels. Interventions: None. Main Outcome Measures: We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging. Results: MCM8 was sequenced in 155 POI participants, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551*, in MCM9, which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway. Conclusions: We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.
Assuntos
Envelhecimento/genética , Dano ao DNA/genética , Reparo do DNA/genética , Proteínas de Manutenção de Minicromossomo/genética , Insuficiência Ovariana Primária/genética , Adulto , Feminino , Humanos , Análise de Sequência de DNARESUMO
Premature ovarian insufficiency leads to through infertility and estrogen deficiency. Optimal management encompasses estrogen replacement therapy. Long-term outcome of women with POI is not known. We design a study to evaluate the medical care, hormone replacement therapy compliance and bone mineral density (BMD) in POI women with at least a five-year follow-up after the first evaluation. One hundred and sixty-two patients (37.3±8.0 years) were evaluated (follow-up 7.9±2.8 years). Sixty-nine patients (42.6%) had stopped their hormone replacement therapy (HRT) for at least one year during the follow up period. BMD determination at initial evaluation and at follow-up visit was completed in 92 patients. At first evaluation, 28 patients (30%) had osteopenia and 7 (8%) had osteoporosis. At follow up, 31 women (34%) had BMD impairment with osteopenia in 61% and osteoporosis in 5%. In univariate analysis and multivariate analysis, there was a significant loss of femoral BMD in women who had stopped their HRT for over a year. In conclusion, this first study concerning long-term follow-up of POI patients shows the poor compliance to their HRT, despite its importance in the prevention of bone demineralization. This study reinforces the need for follow up and specific care for POI women.
Assuntos
Terapia de Reposição de Estrogênios , Osteoporose Pós-Menopausa/tratamento farmacológico , Insuficiência Ovariana Primária/tratamento farmacológico , Adulto , Densidade Óssea/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Menopausa Precoce/efeitos dos fármacos , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/fisiopatologia , Insuficiência Ovariana Primária/complicações , Insuficiência Ovariana Primária/fisiopatologia , Síndrome de Turner/tratamento farmacológico , Síndrome de Turner/patologiaRESUMO
AIM: Adverse outcomes in adult congenital adrenal hyperplasia (CAH) patients are frequent. The determinants of them have not yet been established. OBJECTIVE: To establish the prevalence of adverse outcomes and to find determining factors for each of them. DESIGN, PATIENTS, AND METHODS: Cross-sectional monocentric study of 104 patients with childhood onset of CAH (71 women, 33 men). Analysis established first the determinants of clinical, hormonal, genetic variables and second a composite criterion for some of the outcomes and determinants. RESULTS: BMI was above 25 kg/m(2) in 44% of the cohort, adrenal hyperplasia and/or nodules were present in 45% of the patients, and irregular menstrual cycles and hyperandrogenism were found in 50 and 35% of the women respectively. In univariate analysis, the determinants of these outcomes were all linked to disease control, especially 17-hydroxyprogesterone (17OHP) and androstenedione concentrations. Low weight was a determinant of abnormal bone mineral density (BMD) (60% of the cohort). Multivariate analysis confirmed these data. A classic form (CF) of CAH was a determinant of testicular adrenal rest tumors (TARTs) (36% of the men). Total cumulative glucocorticoid dose was a determinant of BMI and TART, whereas fludrocortisone dose was a determinant of TART (P=0.03). In men, the composite criterion was associated with androstenedione concentration and CF. In women, the composite criterion was associated with total testosterone concentration. CONCLUSION: The present study confirms the high prevalence of adverse outcomes in CAH patients. These are, most often, related to disease control. The impaired health status of adults with CAH could therefore be improved through the modification of treatment.