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Arhinia, or congenital absence of the nose, is an exceedingly rare anomaly caused by pathogenic variants in the gene SMCHD1 . Arhinia exhibits unique reconstructive challenges, as the midface is deficient in skeletal and soft tissue structures. The authors present 2 related patients with arhinia who harbor a novel SMCHD1 gene variant and illustrate their surgical midface and nasal construction. Targeted sequencing was carried out on DNA samples from the 2 affected patients, 1 anosmic and 1 healthy parent, to identify variants in exons 3 to 13 of SMCHD1 . The affected patients and anosmic parent were found to have a novel SMCHD1 gene variant p.E473V. A staged surgical approach was applied. First, both patients underwent a LeFort II osteotomy and distraction osteogenesis to improve the projection of the midfacial segment, followed by tissue expansion of the forehead, and nasal construction with a forehead flap that was placed over a costochondral framework derived from rib cartilage. The novel gene variant could guide future investigations on genetic pathways and molecular processes that underly the physiological and pathologic development of the nose. Further investigations on the variable expressivity ranging from anosmia to arhinia could improve clinical genetic screens for risk stratification of individuals with anosmia on passing on arhinia to their children. Due to the exceptional rarity and complexity of congenital arhinia, most surgical approaches are developed on a single-case basis. This case series, albeit limited to 2 cases, is the largest pedigree of such cases in the literature. It highlights key principles of a staged approach to nasal construction in arhinia and discusses nuances and improvements learned between both patients. It subsequently offers an optimized guide to this surgical strategy.
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Anosmia , Procedimentos de Cirurgia Plástica , Criança , Humanos , Nariz/cirurgia , Nariz/anormalidades , Linhagem , Proteínas Cromossômicas não Histona/genéticaRESUMO
BACKGROUND: Early life environmental exposures affect breast development and breast cancer risk in adulthood. The breast is particularly vulnerable during puberty when mammary epithelial cells proliferate exponentially. In overweight/obese (OB) women, inflammation increases breast aromatase expression and estrogen synthesis and promotes estrogen-receptor (ER)-positive breast cancer. In contrast, recent epidemiological studies suggest that obesity during childhood decreases future breast cancer risk. Studies on environmental exposures and breast cancer risk have thus far been limited to animal models. Here, we present the first interrogation of the human adolescent breast at the molecular level and investigate how obesity affects the immature breast. METHODS: We performed RNA-seq in 62 breast tissue samples from adolescent girls/young women (ADOL; mean age 17.8 years) who underwent reduction mammoplasty. Thirty-one subjects were non-overweight/obese (NOB; mean BMI 23.4 kg/m2) and 31 were overweight/obese (OB; BMI 32.1 kg/m2). We also compared our data to published mammary transcriptome datasets from women (mean age 39 years) and young adult mice, rats, and macaques. RESULTS: The ADOL breast transcriptome showed limited (30%) overlap with other species, but 88% overlap with adult women for the 500 most highly expressed genes in each dataset; only 43 genes were shared by all groups. In ADOL, there were 120 differentially expressed genes (DEG) in OB compared with NOB samples (padj < 0.05). Based on these DEG, Ingenuity Pathway Analysis (IPA) identified the cytokines CSF1 and IL-10 and the chemokine receptor CCR2 as among the most highly activated upstream regulators, suggesting increased inflammation in the OB breast. Classical ER targets (e.g., PR, AREG) were not differentially expressed, yet IPA identified the ER and PR and growth factors/receptors (VEGF, HGF, HER3) and kinases (AKT1) involved in hormone-independent ER activation as activated upstream regulators in OB breast tissue. CONCLUSIONS: These studies represent the first investigation of the human breast transcriptome during late puberty/young adulthood and demonstrate that obesity is associated with a transcriptional signature of inflammation which may augment estrogen action in the immature breast microenvironment. We anticipate that these studies will prompt more comprehensive cellular and molecular investigations of obesity and its effect on the breast during this critical developmental window.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Mama/patologia , Obesidade/fisiopatologia , Receptores de Estrogênio/metabolismo , Transcriptoma , Adolescente , Adulto , Mama/metabolismo , Neoplasias da Mama/genética , Feminino , Humanos , Inflamação , Fatores de Risco , Microambiente Tumoral , Adulto JovemRESUMO
BACKGROUND: Variants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 (SMCHD1) can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) and the unrelated Bosma arhinia microphthalmia syndrome (BAMS). In FSHD2, pathogenic variants are found anywhere in SMCHD1 while in BAMS, pathogenic variants are restricted to the extended ATPase domain. Irrespective of the phenotypic outcome, both FSHD2-associated and BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation. We compared FSHD2, BAMS and non-pathogenic SMCHD1 variants to derive genotype-phenotype relationships. METHODS: Examination of SMCHD1 variants and methylation of the SMCHD1-sensitive FSHD locus DUX4 in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a three-dimensional model of the ATPase domain of SMCHD1. RESULTS: DUX4 methylation analysis is essential to establish pathogenicity of SMCHD1 variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire SMCHD1 locus, missense variants are significantly enriched in the extended ATPase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1. CONCLUSIONS: The localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.
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Atresia das Cóanas/genética , Proteínas Cromossômicas não Histona/genética , Microftalmia/genética , Distrofia Muscular Facioescapuloumeral/genética , Nariz/anormalidades , Adenosina Trifosfatases/genética , Metilação de DNA , Feminino , Variação Genética , Humanos , Masculino , Mutação , Mutação de Sentido Incorreto , Domínios ProteicosRESUMO
BACKGROUND: Only a few small studies have previously reported episodes of hypoglycemia in children with neuromuscular diseases; however, there has been no broader investigation into the occurrence of hypoglycemia in children with congenital muscle disease (CMD). METHODS: Pediatric patients enrolled in the CMD International Registry (CMDIR) with a history of hypoglycemia were included in this retrospective review. Hypoglycemic episodes and associated clinical and biochemical characteristics were characterized. RESULTS: Ten patients with CMD (5 with LAMA2-related muscular dystrophy) reported at least one episode of hypoglycemia beginning at an average age of 3.5 years. Predominant symptoms included altered mental status and nausea/vomiting, and laboratory studies demonstrated metabolic acidosis and ketonuria, consistent with ketotic hypoglycemia. CONCLUSION: Patients with CMD may have an increased risk of hypoglycemia during fasting, illness, or stress due to their relatively low muscle mass and hence, paucity of gluconeogenic substrate. Clinicians should therefore maintain a high index of suspicion for hypoglycemia in this high-risk patient population and caregivers should routinely be trained to recognize and treat hypoglycemia.
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Hipoglicemia , Distrofias Musculares , Criança , Pré-Escolar , Jejum , Humanos , Hipoglicemia/complicações , Hipoglicemia/diagnóstico , Músculos/fisiopatologia , Distrofias Musculares/complicações , Estudos RetrospectivosRESUMO
BACKGROUND: Girls who are overweight/obese (OB) develop breast tissue but do not undergo menarche (the first menstrual period) significantly earlier than girls of normal weight (NW). It has been proposed that estrogen synthesized by adipose tissue may be contributory, yet OB do not have higher serum estrogen levels than NW matched on breast stage. We hypothesized that estrogen synthesized locally, in mammary fat, may contribute to breast development. This hypothesis would predict that breast development would be more advanced than other estrogen-sensitive tissues as a function of obesity and body fat. METHODS: Eighty premenarchal girls (26 OB, 54 NW), aged 8.2-14.7 years, underwent dual-energy x-ray absorptiometry to calculate percent body fat (%BF), Tanner staging of the breast, breast ultrasound for morphological staging, trans-abdominal pelvic ultrasound, hand x-ray (bone age, BA), a blood test for reproductive hormones, and urine collection to determine the vaginal maturation index (VMI), an index of estrogen exposure in urogenital epithelial cells. RESULTS: When controlling for breast morphological stage determined by ultrasound, %BF was not associated with serum estrogen or gonadotropin (LH and FSH) levels or with indices of systemic estrogen action (uterine volume, endometrial thickness, BA advancement, and VMI). Tanner breast stage did not correlate with breast morphological stage and led to misclassification of chest fatty tissue as breast tissue in some OB. CONCLUSIONS: These studies do not support the hypothesis that estrogen derived from total body fat or local (mammary) fat contributes to breast development in OB girls.
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Tecido Adiposo/metabolismo , Mama/metabolismo , Desenvolvimento Infantil/fisiologia , Estrogênios/metabolismo , Sobrepeso/metabolismo , Maturidade Sexual/fisiologia , Absorciometria de Fóton , Tecido Adiposo/crescimento & desenvolvimento , Adolescente , Mama/crescimento & desenvolvimento , Criança , Feminino , Inquéritos Epidemiológicos , Humanos , Menarca , North Carolina/epidemiologia , Sobrepeso/epidemiologia , Vagina/citologiaRESUMO
Despite their key role in the distribution of essential goods, seafarers were often overlooked in international COVID-19 responses. Border closures isolated them at sea, often for months beyond contract. Distributing vaccines to seafarers was inconsistent and often depended on the creativity of charities and industry and labour stakeholders. Even seafarers who received vaccinations often had them unrecognised in the ports they visited. These oversights should not be repeated in preparation for future pandemics. As a vulnerable population and as key international workers, seafarers' health should be prioritised by national and international health policy.
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COVID-19 , Navios , Humanos , COVID-19/prevenção & controle , PandemiasRESUMO
CONTEXT: Pubertal girls with higher total body fat (TBF) demonstrate higher androgen levels. The cause of this association is unknown but is hypothesized to relate to insulin resistance. OBJECTIVE: This work aimed to investigate the association between higher TBF and higher androgens in pubertal girls using untargeted metabolomics. METHODS: Serum androgens were determined using a quantitative mass spectrometry (MS)-based assay. Metabolomic samples were analyzed using liquid chromatography high-resolution MS. Associations between TBF or body mass index (BMI) z score (exposure) and metabolomic features (outcome) and between metabolomic features (exposure) and serum hormones (outcome) were examined using gaussian generalized estimating equation models with the outcome lagged by one study visit. Benjamini-Hochberg false discovery rate (FDR) adjusted P values were calculated to account for multiple testing. RaMP-DB (relational database of metabolomic pathways) was used to conduct enriched pathway analyses among features nominally associated with body composition or hormones. RESULTS: Sixty-six pubertal, premenarchal girls (aged 10.9 ± 1.39 SD years; 60% White, 24% Black, 16% other; 63% normal weight, 37% overweight/obese) contributed an average of 2.29 blood samples. BMI and TBF were negatively associated with most features including raffinose (a plant trisaccharide) and several bile acids. For BMI, RaMP-DB identified many enriched pathways related to bile acids. Androstenedione also showed strong negative associations with raffinose and bile acids. CONCLUSION: Metabolomic analyses of samples from pubertal girls did not identify an insulin resistance signature to explain the association between higher TBF and androgens. Instead, we identified potential novel signaling pathways that may involve raffinose or bile acid action at the adrenal gland.
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Anti-Black racism in K-12 education settings has long-term impacts on Black students, including negative academic and mental health outcomes. Limited interventions following experiences of racism shape Black students' expectations of K-12 education, accumulating over time into institutional distrust and these mental health outcomes. As such, it is necessary to understand how Black students experience racism within K-12 settings to better inform interventions that can be implemented at the school level. To that end, this study employed the participatory action research (PAR) method of photovoice to understand the impacts of racism in educational settings among 5 Black women undergraduate students. Results highlight the cumulative effects of racism on identity development and early coping. Implications inform future interventions to address the cumulative effects of anti-Black racism in K-12 education.
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Cranial neural crest cells (cNCC) are a multipotent embryonic cell population that give rise to a diverse set of cell types. These cells are particularly vulnerable to external metabolic stressors, as exemplified by the association between maternal hyperglycemia and congenital malformations. We were interested in studying the effect of various concentrations of glucose and pyruvate on cNCC metabolism, migration, and differentiation using an established murine neural crest cell model (O9-1). We unexpectedly observed a pattern of gene expression suggestive of cholesterol biosynthesis induction under glucose depletion conditions in O9-1 cells. We further showed that treatment with two different cholesterol synthesis inhibitors interfered with cell migration and differentiation, inhibiting chondrogenesis while enhancing smooth muscle cell differentiation. As congenital arhinia (absent external nose), a malformation caused by mutations in SMCHD1, appears to represent, in part, a defect in cNCC, we were also interested in investigating the effects of glucose and cholesterol availability on Smchd1 expression in O9-1 cells. Smchd1 expression was induced under high glucose conditions whereas cholesterol synthesis inhibitors decreased Smchd1 expression during chondrogenesis. These data highlight a novel role for cholesterol biosynthesis in cNCC physiology and demonstrate that human phenotypic variability in SMCHD1 mutation carriers may be related, in part, to SMCHD1's sensitivity to glucose or cholesterol dosage during development.
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Glucose , Crista Neural , Camundongos , Animais , Humanos , Diferenciação Celular , Glucose/metabolismo , Proteínas Cromossômicas não Histona/metabolismoRESUMO
SMCHD1 mutations cause congenital arhinia (absent nose) and a muscular dystrophy called FSHD2. In FSHD2, loss of SMCHD1 repressive activity causes expression of double homeobox 4 (DUX4) in muscle tissue, where it is toxic. Studies of arhinia patients suggest a primary defect in nasal placode cells (human nose progenitors). Here, we show that upon SMCHD1 ablation, DUX4 becomes derepressed in H9 human embryonic stem cells (hESCs) as they differentiate toward a placode cell fate, triggering cell death. Arhinia and FSHD2 patient-derived induced pluripotent stem cells (iPSCs) express DUX4 when converted to placode cells and demonstrate variable degrees of cell death, suggesting an environmental disease modifier. HSV-1 may be one such modifier as herpesvirus infection amplifies DUX4 expression in SMCHD1 KO hESC and patient iPSC. These studies suggest that arhinia, like FSHD2, is due to compromised SMCHD1 repressive activity in a cell-specific context and provide evidence for an environmental modifier.
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Anormalidades Congênitas , Proteínas de Homeodomínio , Distrofia Muscular Facioescapuloumeral , Nariz , Fatores de Transcrição , Humanos , Proteínas Cromossômicas não Histona/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/metabolismo , Fatores de Transcrição/metabolismo , Anormalidades Congênitas/genética , Nariz/anormalidadesRESUMO
Asbestos-contaminated vermiculite attic insulation (VAI) produced from a mine near Libby, Montana, may be present in millions of homes along with other commercial asbestos-containing materials (ACM). The primary goal of the research described here was to develop and test procedures that would allow for the safe and effective weatherization of low-income homes with asbestos. The presence of asbestos insulation was confirmed by bulk sampling of the suspect asbestos material. The homes were then tested for the presence of asbestos fibers in the living spaces. All 40 homes containing VAI revealed the presence of amphibole asbestos in bulk samples. Asbestos (primarily chrysotile) was confirmed in bulk samples of ACM collected from 18 homes. Amphibole asbestos was detected in the living space of 12 (26%) homes, while chrysotile asbestos was detected in the living space of 45 (98%) homes. These results suggest that asbestos sources in homes can contribute to living space contamination.
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Silicatos de Alumínio/análise , Amiantos Anfibólicos/análise , Asbestos Serpentinas/análise , Materiais de Construção/análise , Exposição Ambiental/análise , Habitação , Material Particulado/análise , Humanos , Montana , Estados UnidosRESUMO
Growth hormone (GH) is secreted by cells in the anterior pituitary on two time scales: discrete pulses over minutes that occur within a 24-hr pattern. Secretion reflects the balance of stimulatory and inhibitory inputs from the hypothalamus and is influenced by gonadal steroids, stress, nutrition, and sleep/wake states. We propose a novel approach for the analysis of GH data and use this approach to quantify (i) the timing, amplitude and the number of GH pulses and (ii) GH infusion, clearance and basal secretion (i.e., time invariant) rates, using serum GH sampled every 10 minutes during an 8-hour sleep study in 18 adolescents. In our method, we approximate hormonal secretory events by deconvolving GH data via a two-step coordinate descent approach. The first step utilizes a sparse-recovery approach to estimate the timing and amplitude of GH secretory events. The second step estimates physiological parameters. Our method identifies the timing and amplitude of GH pulses and system parameters from experimental and simulated data, with a median R2 of 0.93, among experimental data. Recovering GH pulses and model parameters using this approach may improve the quantification of GH parameters under different physiological and pathological conditions and the design and monitoring of interventions.
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Hormônio do Crescimento Humano , Adolescente , Hormônio do Crescimento , HumanosRESUMO
BACKGROUND: TGF-ß superfamily members are important biomarkers of reproductive health in women desiring fertility and during pregnancy. TGF-ß proteins derived from the ovary and/or placenta have been detected in serum in women, but there have been very few attempts to measure them non-invasively, such as in urinary samples, and to compare them to serum concentrations. METHODS: We measured inhibin A, inhibin B, total inhibin, AMH, activin A, activin B, activin AB, follistatin, the GDF-9/BMP-15 complex, and GDF-15 in paired serum and urine samples from healthy reproductive aged women and in pregnant (second trimester) women. RESULTS: We detected all hormones in serum in both pregnant and non-pregnant women. Inhibin A, total inhibin, activin A, activin AB, follistatin, and GDF-15 were significantly higher in pregnant than in non-pregnant women. GDF-15 was the only hormone consistently detected in urine. We also measured, for the first time, the GDF-9/BMP-15 functional heterodimer and the GDF-15 protein harboring the H202D polymorphism. CONCLUSIONS: We report the successful measurement of the GDF-9/BMP-15 heterodimer (its native form) in serum and the ability to measure GDF-15 non-invasively, in urinary samples. This novel GDF-15 assay also captures the antigen in the presence of a common genetic variant.
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Fator de Crescimento Transformador beta , Adulto , HumanosRESUMO
Context: In children, growth hormone (GH) pulses occur after sleep onset in association with slow-wave sleep (SWS). There have been no studies in children to quantify the effect of disrupted sleep on GH secretion. Objective: This study aimed to investigate the effect of acute sleep disruption on GH secretion in pubertal children. Methods: Fourteen healthy individuals (aged 11.3-14.1 years) were randomly assigned to 2 overnight polysomnographic studies, 1 with and 1 without SWS disruption via auditory stimuli, with frequent blood sampling to measure GH. Results: Auditory stimuli delivered during the disrupted sleep night caused a 40.0 ± 7.8% decrease in SWS. On SWS-disrupted sleep nights, the rate of GH pulses during N2 sleep was significantly lower than during SWS (IRR = 0.56; 95% CI, 0.32-0.97). There were no differences in GH pulse rates during the various sleep stages or wakefulness in disrupted compared with undisrupted sleep nights. SWS disruption had no effect on GH pulse amplitude and frequency or basal GH secretion. Conclusion: In pubertal children, GH pulses were temporally associated with episodes of SWS. Acute disruption of sleep via auditory tones during SWS did not alter GH secretion. These results indicate that SWS may not be a direct stimulus of GH secretion.
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Limited data exist on the reproductive hormone dynamics that govern the transition from menarche to the establishment of the mature ovulatory cycles of a fertile young woman. It is also unclear how environmental and lifestyle factors could modulate this transition in contemporary girls. Here, we introduce A Girl's First Period Study, an ambitious longitudinal study aimed at charting the early post-menarchal course of a cohort of healthy girls in the Triangle region of North Carolina.
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Ciclo Menstrual , Ovulação , Adolescente , Feminino , Humanos , Estudos Longitudinais , Hormônio Luteinizante , Menarca , Distúrbios MenstruaisRESUMO
BACKGROUND AND OBJECTIVES: Facioscapulohumeral muscular dystrophy type 2 (FSHD2) and arhinia are 2 distinct disorders caused by pathogenic variants in the same gene: SMCHD1. The mechanism underlying this phenotypic divergence remains unclear. In this study, we characterize the neuromuscular phenotype of individuals with arhinia caused by SMCHD1 variants and analyze their complex genetic and epigenetic criteria to assess their risk for FSHD2. METHODS: Eleven individuals with congenital nasal anomalies, including arhinia, nasal hypoplasia, or anosmia, underwent a neuromuscular examination, genetic testing, muscle ultrasound, and muscle MRI. Risk for FSHD2 was determined by combined genetic and epigenetic analysis of 4q35 haplotype, D4Z4 repeat length, and methylation profile. We also compared expression levels of pathogenic DUX4 mRNA in primary myoblasts or dermal fibroblasts (upon myogenic differentiation or epigenetic transdifferentiation, respectively) in these individuals vs those with confirmed FSHD2. RESULTS: Among the 11 individuals with rare, pathogenic, heterozygous missense variants in exons 3-11 of SMCHD1, only a subset (n = 3/11; 1 male, 2 female; age 25-51 years) met the strict genetic and epigenetic criteria for FSHD2 (D4Z4 repeat unit length <21 in cis with a 4qA haplotype and D4Z4 methylation <30%). None of the 3 individuals had typical clinical manifestations or muscle imaging findings consistent with FSHD2. However, the patients with arhinia meeting the permissive genetic and epigenetic criteria for FSHD2 displayed some DUX4 expression in dermal fibroblasts under the epigenetic de-repression by drug treatment and in the primary myoblasts undergoing myogenic differentiation. DISCUSSION: In this cross-sectional study, we identified patients with arhinia who meet the full genetic and epigenetic criteria for FSHD2 and display the molecular hallmark of FSHD-DUX4 de-repression and expression in vitro-but who do not manifest with the typical clinicopathologic phenotype of FSHD2. The distinct dichotomy between FSHD2 and arhinia phenotypes despite an otherwise poised DUX4 locus implies the presence of novel disease-modifying factors that seem to operate as a switch, resulting in one phenotype and not the other. Identification and further understanding of these disease-modifying factors will provide valuable insight with therapeutic implications for both diseases.
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Proteínas Cromossômicas não Histona , Distrofia Muscular Facioescapuloumeral , Proteínas Cromossômicas não Histona/genética , Estudos Transversais , Feminino , Proteínas de Homeodomínio/genética , Humanos , Masculino , Distrofia Muscular Facioescapuloumeral/diagnóstico por imagem , Distrofia Muscular Facioescapuloumeral/genética , FenótipoRESUMO
In the 1970's, Boyar and colleagues made the seminal observation that during the early stages of puberty, there is a sleep-specific augmentation of pulsatile luteinizing hormone (LH) secretion. Building on this tantalizing association between sleep and the re-awakening of the neuro-reproductive axis, a number of investigators have since mapped the dynamic relationship between sleep and reproductive hormones across the pubertal transition. In this review, we focus on the complex, reciprocal relationship between sleep and reproductive hormones during adolescence as well as the potential effects of melatonin and orexin on gonadotropin-releasing hormone (GnRH) activity in children with chronic insomnia and narcolepsy, respectively. Given the important interaction between the reproductive and somatotropic axes during puberty, we end with a discussion of sleep and growth hormone (GH) secretion in children.
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CONTEXT: Epidemiologic studies have demonstrated that overweight/obese girls (OW/OB) undergo thelarche and menarche earlier than normal weight girls (NW). There have been no longitudinal studies to specifically investigate how body weight/fat affects both clinical and biochemical pubertal markers in girls. OBJECTIVE: To investigate the effect of total body fat on reproductive hormones and on the maturation of estrogen-sensitive tissues during puberty in girls. METHODS: Ninety girls (36 OW/OB, 54 NW), aged 8.2 to 14.7 years, completed 2.8â ±â 1.7 study visits over 4 years. Visits included dual-energy x-ray absorptiometry to calculate total body fat (TBF), Tanner staging, breast ultrasound for morphological staging (BMORPH; A-E), pelvic ultrasound, hormone tests, and assessment of menarchal status. The effect of TBF on pubertal markers was determined using a mixed, multistate, or Cox proportional hazards model, controlling for baseline BMORPH. RESULTS: NW were older than OW/OB (11.3 vs 10.2 years, Pâ <â .01) at baseline and had more advanced BMORPH (Pâ <â .01). Luteinizing hormone, estradiol, and ovarian and uterine volumes increased with time with no effect of TBF. There was a timeâ ×â TBF interaction for follicle-stimulating hormone, inhibin B, estrone, total and free testosterone, and androstenedione: Levels were initially similar, but after 1 year, levels increased in girls with higher TBF, plateaued in girls with midrange TBF, and decreased in girls with lower TBF. Girls with higher TBF progressed through BMORPH stage D more slowly but achieved menarche earlier than girls with lower TBF. CONCLUSION: In late puberty, girls with higher TBF demonstrate differences in standard hormonal and clinical markers of puberty. Investigation of the underlying causes and clinical consequences of these differences in girls with higher TBF deserves further study.
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Tecido Adiposo/fisiologia , Composição Corporal/fisiologia , Puberdade/fisiologia , Absorciometria de Fóton , Adolescente , Desenvolvimento do Adolescente/fisiologia , Criança , Feminino , Humanos , Estudos Longitudinais , Menarca/fisiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Estados Unidos/epidemiologiaRESUMO
CONTEXT: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. OBJECTIVE: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. DESIGN: We compared patients with HA to control women. SETTING: The study was conducted at secondary referral centers. PATIENTS AND OTHER PARTICIPANTS: Women with HA (nâ =â 106) and control women (ClinSeq study; nâ =â 468). INTERVENTIONS: We performed exome sequencing in all patients and controls. MAIN OUTCOME MEASURE(S): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. RESULTS: RSVs were overrepresented in women with HA compared with controls (Pâ =â .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). CONCLUSIONS: Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.
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Amenorreia/genética , Hormônio Liberador de Gonadotropina/metabolismo , Doenças Hipotalâmicas/genética , Adolescente , Adulto , Idoso , Amenorreia/epidemiologia , Amenorreia/etiologia , Estudos de Casos e Controles , Criança , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hipogonadismo/epidemiologia , Hipogonadismo/etiologia , Hipogonadismo/genética , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/epidemiologia , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Sequenciamento do Exoma , Adulto JovemRESUMO
CONTEXT: Adolescents have more small, growing follicles and larger ovaries than normal women and are prone to anovulatory cycles (ANOV). It is unknown if a higher antral follicle count (AFC) per se contributes to ANOV in early postmenarchal girls. OBJECTIVE: To determine the relationship between AMH (an AFC biomarker), other reproductive hormones, and ANOV in postmenarchal girls and to compare AMH in girls and regularly cycling adults. METHODS: A total of 23 girls (1.7 ± 0.2 years postmenarche) and 32 historic adult controls (≤34 years) underwent serial hormone measurements during 1 to 2 menstrual cycles. Girls also had pelvic ultrasounds. AMH was measured 5 times/subject using the Ansh ultrasensitive ELISA. RESULTS: Girls had higher AMH than women (5.2 ± 0.3 vs. 3.3 ± 0.4 ng/mL; P < 0.01) and girls with more ovulatory (OV) cycles tended to have lower AMH than those with ANOV (2 OV 4.5 ± 0.2, 1 OV 5.7 ± 1.1, 0 OV 6.8 ± 1.1 ng/mL; P = 0.1). In girls, AMH correlated with natural-log (ln) transformed LH (r = 0.5, P = 0.01), ln_androstenedione (r = 0.6, P = 0.003), ln_testosterone (r = 0.5, P = 0.02), and ovarian volume (r = 0.7, P < 0.01) but not with FSH, estradiol, P4, or body mass index. In women, AMH correlated with estradiol and P4 (both r = -0.4, P ≤ 0.03) but not with ln_LH or body mass index. CONCLUSIONS: In postmenarchal girls, AMH is higher than in ovulatory women and is associated with LH, androgens, and a propensity for anovulatory cycles. The cause of the transient increase in AMH and AFC during late puberty and the steps underlying the transition to a mature ovary deserve further study.