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Molecular Psychiatry Mar 2024Tachykinin receptor 3 (TACR3) is a member of the tachykinin receptor family and falls within the rhodopsin subfamily. As a G protein-coupled receptor, it responds to...
Tachykinin receptor 3 (TACR3) is a member of the tachykinin receptor family and falls within the rhodopsin subfamily. As a G protein-coupled receptor, it responds to neurokinin B (NKB), its high-affinity ligand. Dysfunctional TACR3 has been associated with pubertal failure and anxiety, yet the mechanisms underlying this remain unclear. Hence, we have investigated the relationship between TACR3 expression, anxiety, sex hormones, and synaptic plasticity in a rat model, which indicated that severe anxiety is linked to dampened TACR3 expression in the ventral hippocampus. TACR3 expression in female rats fluctuates during the estrous cycle, reflecting sensitivity to sex hormones. Indeed, in males, sexual development is associated with a substantial increase in hippocampal TACR3 expression, coinciding with elevated serum testosterone and a significant reduction in anxiety. TACR3 is predominantly expressed in the cell membrane, including the presynaptic compartment, and its modulation significantly influences synaptic activity. Inhibition of TACR3 activity provokes hyperactivation of CaMKII and enhanced AMPA receptor phosphorylation, associated with an increase in spine density. Using a multielectrode array, stronger cross-correlation of firing was evident among neurons following TACR3 inhibition, indicating enhanced connectivity. Deficient TACR3 activity in rats led to lower serum testosterone levels, as well as increased spine density and impaired long-term potentiation (LTP) in the dentate gyrus. Remarkably, aberrant expression of functional TACR3 in spines results in spine shrinkage and pruning, while expression of defective TACR3 increases spine density, size, and the magnitude of cross-correlation. The firing pattern in response to LTP induction was inadequate in neurons expressing defective TACR3, which could be rectified by treatment with testosterone. In conclusion, our study provides valuable insights into the intricate interplay between TACR3, sex hormones, anxiety, and synaptic plasticity. These findings highlight potential targets for therapeutic interventions to alleviate anxiety in individuals with TACR3 dysfunction and the implications of TACR3 in anxiety-related neural changes provide an avenue for future research in the field.
Topics: Animals; Testosterone; Neuronal Plasticity; Male; Rats; Female; Anxiety; Hippocampus; Receptors, Neurokinin-3; Neurons; Long-Term Potentiation; Receptors, Tachykinin; Rats, Sprague-Dawley
PubMed: 38135756
DOI: 10.1038/s41380-023-02361-z -
Orphanet Journal of Rare Diseases May 2023X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited...
BACKGROUND
X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited clinical and genetic characterization.
METHODS
The clinical, biochemical, genetic, therapeutic, and follow-up data of 42 patients diagnosed with X-linked AHC were retrospectively analysed.
RESULTS
Hyperpigmentation (38/42, 90%), vomiting/diarrhoea (20/42, 48%), failure to thrive (13/42, 31%), and convulsions (7/42, 17%) were the most common symptoms of X-linked AHC at onset. Increased adrenocorticotropic hormone (ACTH) (42/42, 100%) and decreased cortisol (37/42, 88%) were the most common laboratory findings, followed by hyponatremia (32/42, 76%) and hyperkalaemia (29/42, 69%). Thirty-one patients presented with PAI within the first year of life, and 11 presented after three years of age. Three of the thirteen patients over the age of 14 exhibited spontaneous pubertal development, and ten of them experienced delayed puberty due to HH. Six patients receiving human chorionic gonadotropin (hCG) therapy exhibited a slight increase in testicular size and had rising testosterone levels (both P < 0.05). The testicular volumes of the three patients with pulsatile gonadotropin-releasing hormone (GnRH) therapy were larger than those of the six patients undergoing hCG therapy (P < 0.05), and they also exhibited some growth in terms of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Of the 42 patients, three had an Xp21 deletion, and 39 had an isolated DAX1 defect. Most patients (9/10) with entire DAX1 deletion accounting for 23.8% (10/42) of the total variants had early onset age of less than one year.
CONCLUSIONS
This study details the clinical features and genetic spectra of X-linked AHC. Patients with X-linked AHC show a bimodal distribution of the age of onset, with approximately 70% presenting within the first year of life. Pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. The combination of clinical features and molecular tests provides information for an accurate diagnosis.
Topics: Child; Humans; Male; East Asian People; Gonadotropin-Releasing Hormone; Hypoadrenocorticism, Familial; Hypogonadism; Mutation; Retrospective Studies; Testosterone
PubMed: 37237297
DOI: 10.1186/s13023-023-02737-y -
Arquivos Brasileiros de Endocrinologia... Mar 2009Type 2 diabetes mellitus (T2DM) in children and adolescents is an important Public Health problem against the backdrop of the epidemic of childhood obesity. The clinical... (Review)
Review
Type 2 diabetes mellitus (T2DM) in children and adolescents is an important Public Health problem against the backdrop of the epidemic of childhood obesity. The clinical presentation of T2DM in youth is heterogeneous from minimal symptomatology to diabetic ketoacidosis. The increasing rates of youth T2DM have paralleled the escalating rates of obesity, which is the major risk factor impacting insulin sensitivity. Additional risk factors include minority race, family history of diabetes mellitus, maternal diabetes during pregnancy, pubertal age group and conditions associated with insulin resistance (IR) - such as polycystic ovary syndrome (PCOS). The pathophysiology of T2DM has been studied extensively in adults, and it is widely accepted that IR together with beta-cell failure are necessary for the development of clinical diabetes mellitus in adulthood. However, pathophysiologic studies in youth are limited and in some cases conflicting. Similar to adults, IR is a prerequisite, but beta-cell failure is necessary for progression from normal glucose tolerance to prediabetes and frank diabetes in youth. Even though rates of T2DM in youth are increasing, the overall prevalence remains low if compared with type 1 diabetes mellitus (T1DM). However, as youth with T1DM are becoming obese, the clinical distinction between T2DM and obese T1DM has become difficult, because of the overlapping clinical picture with evidence of islet cell autoimmunity in a significant proportion of clinically diagnosed youth with T2DM. The latter are most likely obese children with autoimmune T1DM who carry a misdiagnosis of T2DM. Further research is needed to probe the pathophysiological, immunological, and metabolic differences between these two groups in the hopes of assigning appropriate therapeutic regimens. These challenges combined with the evolving picture of youth T2DM and its future complications provide unending opportunities for acquisition of new knowledge in the field of childhood diabetes.
Topics: Adolescent; Adult; Child; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Progression; Female; Glucose; Glucose Intolerance; Humans; Insulin; Insulin Resistance; Insulin Secretion; Obesity; Polycystic Ovary Syndrome; Young Adult
PubMed: 19466209
DOI: 10.1590/s0004-27302009000200008 -
Animals : An Open Access Journal From... Oct 2019Poor sow retention due to reproductive failure is a common reproductive inefficiency amongst piggeries. This shows that traditional methods of gilt selection are...
Poor sow retention due to reproductive failure is a common reproductive inefficiency amongst piggeries. This shows that traditional methods of gilt selection are inadequate and a marker of reproductive success is needed. The aim of this study was to determine whether circulating levels of AMH and E2 at D80 and D160 are associated with uterine and ovarian traits at D160. Uterine weight, horn length and horn diameter were measured, and ovarian follicle counts were determined histologically. There was a negative relationship between both D80 and D160 AMH levels and D160 ovarian follicle populations. There was also a positive relationship between D80 E2 levels and uterine capacity in gilts that were pubertal at D160. The findings indicate that D80 and D160 AMH could be used to predict ovarian reserve and that D80 E2 levels may be indicative of uterine capacity in precocial gilts.
PubMed: 31619004
DOI: 10.3390/ani9100811 -
Nature Neuroscience Mar 2013The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism...
The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats. We identify silencers of the Polycomb group (PcG) as principal contributors to this mechanism and show that PcG proteins repress Kiss1, a puberty-activating gene. Hypothalamic expression of two key PcG genes, Eed and Cbx7, decreased and methylation of their promoters increased before puberty. Inhibiting DNA methylation blocked both events and resulted in pubertal failure. The pubertal increase in Kiss1 expression was accompanied by EED loss from the Kiss1 promoter and enrichment of histone H3 modifications associated with gene activation. Preventing the eviction of EED from the Kiss1 promoter disrupted pulsatile gonadotropin-releasing hormone release, delayed puberty and compromised fecundity. Our results identify epigenetic silencing as a mechanism underlying the neuroendocrine control of female puberty.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Estradiol; Female; Gonadotropin-Releasing Hormone; Histones; Hypothalamus; Kisspeptins; Polycomb-Group Proteins; Rats; Rats, Sprague-Dawley; Sexual Maturation
PubMed: 23354331
DOI: 10.1038/nn.3319 -
Fertility and Sterility Jun 2016To evaluate the hypothalamus-hypophysis-gonad axis in a cohort of children and adolescents with nonmosaic triple X syndrome.
OBJECTIVE
To evaluate the hypothalamus-hypophysis-gonad axis in a cohort of children and adolescents with nonmosaic triple X syndrome.
DESIGN
Cross-sectional study with retrospective analysis.
SETTING
University pediatric hospital.
PATIENT(S)
Fifteen prepubertal subjects (median age 9.0 years, range 6.9-11.9 years) with nonmosaic triple X syndrome and age- and pubertal-matched control group (30 girls, median age 9.1 y, range 6.9-11.6 years).
INTERVENTION(S)
None.
MAIN OUTCOME MEASURE(S)
We evaluated FSH, LH, and E2 levels and performed an autoimmunity screening as well as a pelvic ultrasonography and an LH-releasing hormone stimulation test.
RESULT(S)
All triple X patients (with and without pubertal signs) showed a pubertal LH peak level that was significantly different from controls. Triple X patients showed increased basal and peak FSH and LH values compared with control subjects. However, the mean E2 level was significantly lower than control subjects. However, triple X patients showed reduced DHEAS levels and reduced inhibin levels compared with control subjects. Finally, triple X patients had a significantly reduced ovarian volume compared with control subjects, in both prepubertal and pubertal patients.
CONCLUSION(S)
Triple X patients showed premature activation of the GnRH pulse generator, even without puberty signs. Both basal and peak LH and FSH levels were higher than in control subjects, and E2 and inhibin levels and ovarian volume were reduced, which led to a reduced gonadal function. Other studies and a longitudinal evaluation is necessary to better understand the endocrinologic features of these subjects.
Topics: Child; Chromosomes, Human, X; Cross-Sectional Studies; Female; Follicle Stimulating Hormone; Gonadal Hormones; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Luteinizing Hormone; Male; Puberty; Puberty, Precocious; Retrospective Studies; Sex Chromosome Aberrations; Sex Chromosome Disorders of Sex Development; Trisomy
PubMed: 26952785
DOI: 10.1016/j.fertnstert.2016.02.019 -
The Journal of Pediatrics Mar 2019To examine the associations of in utero exposure to maternal diabetes with surrogate measures of offspring pubertal timing (age at peak height velocity [APHV]) and speed... (Observational Study)
Observational Study
OBJECTIVE
To examine the associations of in utero exposure to maternal diabetes with surrogate measures of offspring pubertal timing (age at peak height velocity [APHV]) and speed of pubertal growth (peak height velocity [PHV]).
STUDY DESIGN
Data from 77 exposed and 340 unexposed youth followed from age 2 to 19 years (51% non-Hispanic white, 50% female) were analyzed using the Exploring Perinatal Outcomes among Children study, a historical prospective cohort. Maternal diabetes status was collected from obstetric records, and child heights from 2 years to current age from pediatric records. Other covariates were collected during research visits. The superimposition by translation and rotation method, using height measurements (4-52 per participant), modeled APHV and PHV. Accelerated failure time analyses were used to test whether exposure to maternal diabetes was associated with younger APHV and faster PHV.
RESULTS
Adjusting for child's sex, race/ethnicity, and socioeconomic status, median APHV was reached ~3 months earlier in youth exposed to maternal diabetes compared with unexposed youth (P < .03). Youth exposed to maternal diabetes had a faster PHV than unexposed youth: exposed girls had 10.5% greater median PHV compared with unexposed girls and exposed boys had a 4.0% greater median PHV compared with unexposed boys (P < .001 for exposure by sex interaction).
CONCLUSIONS
Our findings provide evidence that exposure to maternal diabetes in utero is associated with earlier pubertal timing and faster pubertal growth. Whether earlier puberty or faster speed of pubertal growth mediates the association between maternal diabetes exposure and later chronic disease risk remains to be studied.
Topics: Adolescent; Anthropometry; Body Height; Body Mass Index; Child; Child, Preschool; Colorado; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Humans; Male; Menarche; Pregnancy; Pregnancy in Diabetics; Prenatal Exposure Delayed Effects; Prospective Studies; Puberty; Puberty, Precocious; Sexual Maturation; Social Class; Young Adult
PubMed: 30528762
DOI: 10.1016/j.jpeds.2018.10.053 -
Frontiers in Endocrinology 2024We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST).
INTRODUCTION
We present the evolution of GHD in adolescent males with persistent growth failure, in whom the diagnosis was established after a second GH stimulation test (GST).
METHODS
We performed a retrospective chart review of children who presented for short stature (height less < 2SD for mean/mid-parental height) and/or growth failure (sustained growth velocity < 0 SD) to pediatric endocrinology at Mount Sinai Kravis Children's Hospital, New York and who had 2 GSTs. Data collected from electronic medical records were analyzed using SPSS v28.0.
RESULTS
Of 53 patients included, 42 were males. Average GH peak on initial GST was 15.48 ± 4.92 ng/ml, at 10.07 ± 2.65 years, mean height -1.68 ± 0.56SD(28% had <2SD), IGF-1 -1.00 ± 0.88SD. After 2.23 ± 1.22 years, at 12.04 ± 2.41years, height SDs decreased to -1.82 ± 0.63SD and IGF-1 was -1.08 ± 0.84SD. At repeat GST, average GH peak was 7.59 ± 2.12 ng/dL, with 36% ≤7 ng/dl and 32% in puberty. 12 males reached adult height of 0.08 ± 0.69 SD with a mean height gain of 1.83 ± 0.56SD(p<0.005), IGF-1 of -1.15 ± 0.81SD after 4.64 ± 1.4 years of GH.
CONCLUSION
We offer evidence for Evolving Growth Hormone Deficiency (EGHD) through repeat GST in children with persistent growth slowdown, even with pubertal progression; emphasizing the need for careful longitudinal follow-up to make accurate diagnosis.
Topics: Humans; Male; Human Growth Hormone; Adolescent; Retrospective Studies; Child; Growth Disorders; Female; Body Height; Insulin-Like Growth Factor I; Proof of Concept Study; Dwarfism, Pituitary
PubMed: 38752175
DOI: 10.3389/fendo.2024.1398171 -
Neurology Oct 2012Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children...
OBJECTIVES
Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes.
METHODS
A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Student's t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression.
RESULTS
Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X).
CONCLUSIONS
RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations.
Topics: Adolescent; Age of Onset; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Female; Genotype; Growth Charts; Growth Disorders; Humans; Infant; Male; Methyl-CpG-Binding Protein 2; Mutation; Phenotype; Puberty; Quality Control; Reference Standards; Rett Syndrome; Young Adult
PubMed: 23035069
DOI: 10.1212/WNL.0b013e31826e9a70 -
Biochimica Et Biophysica Acta Dec 2012The purpose of this review is to summarize science-based new treatments for human reproductive failure and future developments. (Review)
Review
PURPOSE
The purpose of this review is to summarize science-based new treatments for human reproductive failure and future developments.
RESULTS
First will be discussed popular but erroneous myths of current non-science based treatments. Then will be discussed new treatments and their scientific base, including ovary and egg freezing, and transplantation to preserve fertility in young women undergoing gonadotoxic chemotherapy and radiation for cancer; new perspectives on human epididymal sperm maturation based on a comparison between ICSI (intracytoplasmic sperm injection) with testis sperm versus epididymal sperm; simplifying IVF and reducing cost by more intelligent and milder ovarian stimulation; improving pregnancy rate in older women; searching the genome to find genes which control spermatogenesis and whose deletion or mutation causes spermatogenic failure; and human spermatogenic stem cell culture to treat azoospermia, and to preserve fertility in pre-pubertal boys undergoing cancer treatment.
CONCLUSION
With stem cell biology and molecular understanding of reproductive failure, new therapies for previously untreatable infertility are currently on the near horizon. Conversely our clinical results with new therapeutic approaches are adding to our understanding of the basic science of reproduction. This article is part of a Special Issue entitled: Molecular Genetics of Human Reproductive Failure.
Topics: Female; Humans; Infertility, Female; Infertility, Male; Male; Pregnancy; Reproduction; Reproductive Techniques, Assisted
PubMed: 23046814
DOI: 10.1016/j.bbadis.2012.10.004