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OBJECTIVE: Testicular samples obtained for fertility preservation often need to be transported between clinics. This study aimed to mimic this short-term hypothermic storage (4-8 °C) and explore the impact of these conditions and the transport medium composition on prepubertal rat testicular tissue samples. METHODS: Testicular tissue samples obtained from seven days post-partum rats were transferred to six compositionally different basal culture media and a balanced salt solution, which had been kept at 4-8 °C prior to transfer. The samples were preserved for either 12 or 24 hours in these hypothermic conditions. The potential effects of the short-term storage were evaluated by assessing the morphology, measuring the testosterone levels by radioimmunoassay and analysing 96 genes with TaqMan Low-Density Arrays. Summarizing results: Levels of gene expression related to energy, apoptosis and angiogenesis pathways were altered after hypothermic storage for 12 and especially 24 hours. We observed only minor differences in gene expression profiles for germ and testicular somatic cells, and no differences in tissue morphology and testosterone production levels. CONCLUSIONS: Short-term hypothermic storage of testicular tissue with a maximum duration of 24 hours does not affect the overall expression profile of testicular cell-specific genes; however, in a minor way, it affects the expression of specific cellular genes.
ABSTRACT
CONTEXT: Growth hormone (GH) is used to treat short children born small for gestational age (SGA); however, the effects of treatment on pubertal timing and adult height are rarely studied. OBJECTIVE: To evaluate adult height and peak height velocity in short GH-treated SGA children. METHODS: Prospective longitudinal multicenter study. Participants were short children born SGA treated with GH therapy (nâ =â 102). Adult height was reported in 47 children. A reference cohort of Danish children was used. Main outcome measures were adult height, peak height velocity, age at peak height, and pubertal onset. Pubertal onset was converted to SD score (SDS) using Danish reference data. RESULTS: Gain in height SDS from start of treatment until adult height was significant in both girls (0.94 [0.75; 1.53] SDS, Pâ =â .02) and boys (1.57 [1.13; 2.15] SDS, Pâ <â .001). No difference in adult height between GH dosage groups was observed. Peak height velocity was lower than a reference cohort for girls (6.5 [5.9; 7.6] cm/year vs 7.9 [7.4; 8.5] cm/year, Pâ <â .001) and boys (9.5 [8.4; 10.7] cm/year vs 10.1 [9.7; 10.7] cm/year, Pâ =â .002), but no difference in age at peak height velocity was seen. Puberty onset was earlier in SGA boys than a reference cohort (1.06 [-0.03; 1.96] SDS vs 0 SDS, Pâ =â .002) but not in girls (0.38 [-0.19; 1.05] SDS vs 0 SDS, Pâ =â .18). CONCLUSION: GH treatment improved adult height. Peak height velocity was reduced, but age at peak height velocity did not differ compared with the reference cohort. SGA boys had an earlier pubertal onset compared with the reference cohort.
Subject(s)
Body Height , Growth Disorders , Human Growth Hormone , Infant, Small for Gestational Age , Puberty , Adult , Body Height/drug effects , Body Height/physiology , Child , Female , Gestational Age , Growth Disorders/drug therapy , Human Growth Hormone/pharmacology , Human Growth Hormone/therapeutic use , Humans , Infant, Newborn , Infant, Small for Gestational Age/growth & development , Male , Prospective Studies , Puberty/drug effects , Puberty/physiology , Time FactorsABSTRACT
Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.
Subject(s)
Endocrine Disruptors/toxicity , Language Development Disorders/epidemiology , Neurodevelopmental Disorders/epidemiology , Prenatal Exposure Delayed Effects , Transcriptome/drug effects , Animals , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/genetics , Brain/drug effects , Brain/embryology , Child, Preschool , Estrogens/metabolism , Female , Fluorocarbons/analysis , Fluorocarbons/toxicity , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Humans , Locomotion/drug effects , Neural Stem Cells/drug effects , Neurodevelopmental Disorders/genetics , Organoids , Phenols/analysis , Phenols/toxicity , Phthalic Acids/analysis , Phthalic Acids/toxicity , Pregnancy , Risk Assessment , Thyroid Hormones/metabolism , Xenopus laevis , ZebrafishABSTRACT
INTRODUCTION: Obesity in women is often associated with hyperandrogenism, but the role of adipose tissue (AT) in androgen synthesis remains unclear. Therefore, we studied whether AT could be a source of androgens promoting hyperandrogenism. METHODS: Subcutaneous and visceral (visc) AT was collected from lean and obese women. Androgen levels were evaluated in serum, AT, and cell-culture supernatant. Gene and protein expression of steroidogenic enzymes were determined. RESULTS: Obese subjects had elevated serum androgen levels, which reduced after weight loss. Androgens were measurable in AT and in cell-culture supernatants of adipocytes. Steroids were higher in AT from obese women, with the highest difference for testosterone in visc AT (+7.9-fold, p = 0.032). Steroidogenic enzymes were expressed in human AT with depot-specific differences. Obese women showed a significantly higher expression of genes of the backdoor pathway and of CYP19 in visc AT. CONCLUSION: The whole steroidogenic machinery of the classical and backdoor pathways of steroidogenesis, and the capacity for androgen biosynthesis, were found in both AT depots and cultured adipocytes. Therefore, we hypothesize that AT is a de novo site of androgen production and the backdoor pathway of steroidogenesis might be a new pathomechanism for hyperandrogenism in women with obesity.
Subject(s)
Androgens , Hyperandrogenism , Adipocytes/metabolism , Adipose Tissue/metabolism , Androgens/metabolism , Female , Humans , Hyperandrogenism/complications , Hyperandrogenism/metabolism , Male , Obesity/complications , Obesity/metabolismABSTRACT
BACKGROUND: Potentially harmful effects of persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT) on prenatal development and the endocrine system have been controversially discussed. METHODS: Working with a German cohort of 324 pregnant women, we assessed POP levels and used robust linear regression models to determine potential associations between maternal POP concentrations and pre- and postnatal development in the children, as well as the thyroid hormone status of the mother and child. RESULTS: Maternal p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and most measured PCBs positively correlated with postnatal weight gain. We detected no correlation between newborn birth weight and head circumference, respectively, and maternal PCB and p,p'-DDE serum levels, while body length at birth was negatively associated with the maternal serum concentration of PCB 183. Maternal p,p'-DDE and nearly all PCB serum levels showed a negative correlation with maternal free triiodothyronine (FT3). p,p'-DDE and PCB 74 and 118 were negatively associated with maternal thyroid-stimulating hormone levels. In addition, we identified significant associations between maternal POP levels and thyroid hormone parameters of the child. CONCLUSIONS: These results indicate that POP exposure likely affects different aspects of pre- and postnatal development and impacts the thyroid hormone status of both mother and child. IMPACT: Pregnant women in a German cohort display a substantial accumulation of POPs. Body mass index and age influence maternal serum POP levels. Maternal POP levels show correlations with the child's length at birth and weight gain, and FT3 levels in the mother and child. Our data provide additional evidence for the potentially harmful influence of POPs. Our data indicate that POPs influence pre- and postnatal development.
Subject(s)
Environmental Pollutants , Polychlorinated Biphenyls , Child , Child Development , Dichlorodiphenyl Dichloroethylene/adverse effects , Environmental Pollutants/adverse effects , Female , Humans , Infant, Newborn , Maternal Exposure/adverse effects , Persistent Organic Pollutants , Polychlorinated Biphenyls/adverse effects , Pregnancy , Pregnant Women , Thyroid Hormones , Weight GainABSTRACT
BACKGROUND: Advances in three-dimensional culture technologies have led to progression in systems used to model the gonadal microenvironment in vitro. Despite demonstrating basic functionality, tissue organisation is often limited. We have previously detailed a three-dimensional culture model termed the three-layer gradient system to generate rat testicular organoids in vitro. Here we extend the model to human first-trimester embryonic gonadal tissue. RESULTS: Testicular cell suspensions reorganised into testis-like organoids with distinct seminiferous-like cords situated within an interstitial environment after 7 days. In contrast, tissue reorganisation failed to occur when mesonephros, which promotes testicular development in vivo, was included in the tissue digest. Organoids generated from dissociated female gonad cell suspensions formed loosely organised cords after 7 days. In addition to displaying testis-specific architecture, testis-like organoids demonstrated evidence of somatic cell differentiation. Within the 3-LGS, we observed the onset of AMH expression in the cytoplasm of SOX9-positive Sertoli cells within reorganised testicular cords. Leydig cell differentiation and onset of steroidogenic capacity was also revealed in the 3-LGS through the expression of key steroidogenic enzymes StAR and CYP17A1 within the interstitial compartment. While the 3-LGS generates a somatic cell environment capable of supporting germ cell survival in ovarian organoids germ cell loss was observed in testicular organoids. CONCLUSION: The 3-LGS can be used to generate organised whole gonadal organoids within 7 days. The 3-LGS brings a new opportunity to explore gonadal organogenesis and contributes to the development of more complex in vitro models in the field of developmental and regenerative medicine.
Subject(s)
Sertoli Cells , Testis , Animals , Collagen , Drug Combinations , Female , Gonads , Humans , Laminin , Male , Proteoglycans , Rats , SuspensionsABSTRACT
In recent years, there has been an increased incidence in several of the most common reproductive disorders, including hypospadias and cryptorchidism in newborns, and testicular cancer and lower sperm quality in young adult males. In addition, the timing of puberty has also changed over time. Although the cause of these reproductive effects is a matter of intense debate, a link with the presence of ubiquitous compounds in the environment, or the exposure to specific groups of medications during foetal life, has been suggested. Results from epidemiological and experimental studies, as well as clinical observations in humans indicate that endocrine-disrupting chemicals may be associated with those disorders. In this review, we will summarize the results of epidemiological studies and experimental studies utilising human testicular cells or tissue. Due to increasing public interest and the recently published data, the main focus will be on the effects of prenatal exposure to mild analgesics.
Subject(s)
Cryptorchidism , Endocrine Disruptors , Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Cryptorchidism/chemically induced , Cryptorchidism/epidemiology , Endocrine Disruptors/adverse effects , Endocrine Disruptors/toxicity , Female , Genitalia, Male , Humans , Infant, Newborn , Male , Pregnancy , Testicular Neoplasms/chemically induced , Testicular Neoplasms/epidemiologyABSTRACT
INTRODUCTION: Sexual development in females and males are routinely measured according to the Tanner Stages. Sparse data exist on the timing of pubertal milestones in Pakistan. To fill this gap, the age of attainment of pubertal milestones and their relationship with nutritional status was explored among children and adolescents living in the rural district of Matiari, Pakistan. METHODS: Anthropometry, nutrition biomarkers and Tanner Stage were assessed among girls aged 9.0-14.9 years (n = 723) and boys aged 10.0-15.9 years (n = 662) who were free from known disease in the rural District of Matiari, Pakistan. Median age was calculated for all Tanner Stages and menarche. Multivariable linear regressions were undertaken to determine covariates associated with the timing (age) of pubertal milestones. RESULTS: Among participants living in this rural community, the median age of puberty onset for girls was 11.9 years (95%CI:10.9; 12.5) and boys was 12.3 years (95%CI:11.5; 12.9). Age at first menarche was 12.9 years (95%CI:12.1; 13.3). Undernutrition was widespread among adolescents in this community. Thirty-seven percent of females and 27.0% of males were stunted while 20.5% of females and 31.3% of males were thin. Only 8% (n = 58) of females and 12% (n = 78) of males were free from any nutrient deficiency with most adolescents having two or three nutrient deficiencies. CONCLUSIONS: Undernutrition (stunting or thinness) was associated with relatively older ages for early puberty stages but not puberty completion. This may decrease the duration of the pubertal growth spurt and curtail potential catch-up growth that may occur during puberty. Efforts to decrease nutrient deficiencies, stunting and thinness beyond childhood should be made in rural Pakistan.
Subject(s)
Malnutrition , Rural Population , Adolescent , Aged , Child , Female , Humans , Male , Malnutrition/epidemiology , Menarche , Middle Aged , Nutritional Status , Pakistan/epidemiology , PubertyABSTRACT
Fertility preservation for male childhood cancer survivors not yet capable of producing mature spermatozoa, relies on experimental approaches such as testicular explant culture. Although the first steps in somatic maturation can be observed in human testicular explant cultures, germ cell depletion is a common obstacle. Hence, understanding the spermatogonial stem cell (SSC) niche environment and in particular, specific components such as the seminiferous basement membrane (BM) will allow progression of testicular explant cultures. Here, we revealed that the seminiferous BM is established from 6 weeks post conception with the expression of laminin alpha 1 (LAMA 1) and type IV collagen, which persist as key components throughout development. With prepubertal testicular explant culture we found that seminiferous LAMA 1 expression is disrupted and depleted with culture time correlating with germ cell loss. These findings highlight the importance of LAMA 1 for the human SSC niche and its sensitivity to culture conditions.
Subject(s)
Fertility Preservation , Laminin/metabolism , Puberty/metabolism , Spermatogonia/metabolism , Basement Membrane/metabolism , Collagen Type IV/metabolism , Fibronectins/metabolism , Humans , Male , Models, Biological , Seminiferous Tubules/metabolism , Spermatozoa/metabolism , Testis/metabolism , Transcription, GeneticABSTRACT
Type 1 diabetes mellitus (T1DM) is associated with impaired spermatogenesis and lower testosterone levels and epididymal weight. However, the underlying processes in the testis are unknown and remain to be elucidated. Therefore, the present study focused on the effects of T1DM on testicular function in a spontaneously diabetic rat model. BB/OKL rats after diabetes manifestation were divided into 3 groups: those without insulin treatment and insulin treatment for a duration of 2 and of 6 weeks. Anthropometrical data, circulating levels of gonadotrophins, testosterone, and inhibin B were measured. Intratesticular testosterone, oxidative stress, inflammation, and apoptosis were analyzed. Key enzymes of steroidogenesis were evaluated in the testis. Untreated diabetic rats had significantly lower serum follicle-stimulating hormone and luteinizing hormone levels. Serum and intratesticular testosterone levels significantly decreased in untreated diabetic rats compared to healthy controls. Key markers of Leydig cell function were significantly downregulated at the RNA level: insulin-like factor 3 (Insl3) by 53% (Pâ =â .006), Star by 51% (Pâ =â .004), Cyp11A1 by 80% (Pâ =â .003), 3Beta-Hsd2 by 61% (Pâ =â .005), and Pbr by 52% (Pâ =â .002). In the insulin-treated group, only Cyp11A1 and 3Beta-Hsd2 transcripts were significantly lower. Interestingly, the long-term insulin-treated group showed significant upregulation of most steroidogenic enzymes without affecting testosterone levels. Tumor necrosis factor α and apoptosis were significantly increased in the long-term insulin-treated rats. In conclusion T1DM, with a severe lack of insulin, has an adverse action on Leydig cell function. This is partially reversible with well-compensated blood glucose control. Long-term T1DM adversely affects Leydig cell function because of the process of inflammation and apoptosis.
Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Insulin/administration & dosage , Leydig Cells/drug effects , Leydig Cells/metabolism , Animals , Apoptosis/drug effects , Cholesterol Side-Chain Cleavage Enzyme/genetics , Cholesterol Side-Chain Cleavage Enzyme/metabolism , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/physiopathology , Follicle Stimulating Hormone/metabolism , Humans , Insulin/genetics , Insulin/metabolism , Leydig Cells/cytology , Luteinizing Hormone/metabolism , Male , Proteins/genetics , Proteins/metabolism , Rats , Spermatogenesis/drug effects , Testis/cytology , Testis/drug effects , Testis/metabolism , Testosterone/metabolismABSTRACT
Over the last 50 years, there has been a steady decline in fertility rates in humans, which has occurred in parallel with an increasing incidence of obesity and metabolic disorders. The potential impact of these disorders and plausible mechanisms by which they negatively influence male reproduction are only partly understood and published data are often controversial. Obesity is one of the most important health challenges worldwide and is becoming more prevalent in children and adolescents. Obesity, the metabolic syndrome and related co-morbidities can lead to impaired male reproductive function, including adverse effects on spermatogenesis and steroidogenesis as illustrated by reduced sperm number and quality, decreased testosterone levels and elevated inflammatory markers. The incidence of diabetes mellitus type I is also dramatically increasing and may negatively impact spermatogenesis and testicular function, resulting in decreased serum testosterone and epididymal weight. In this review, we summarize and discuss the effects of metabolic diseases that typically develop during childhood and adolescence on later reproductive function and fertility. While impact on reproductive health is likely observed in both sexes, we have chosen to focus on the male in the current review. Specifically, we illustrate adverse effects of obesity, type 1 diabetes, the metabolic syndrome and insulin resistance on sperm function and testosterone metabolism. Identification of pathophysiological mechanisms during childhood may open up new avenues for early prevention and treatment resulting in better reproductive outcomes and improved fertility rates during adulthood.
Subject(s)
Infertility, Male/etiology , Metabolic Syndrome/complications , Reproduction , Adolescent , Child , Humans , Infertility, Male/pathology , MaleABSTRACT
Objectives Staging sexual maturation is an integral component of adolescent research. The Pubertal Development Scale (PDS) is commonly used as a puberty self-assessment tool because it avoids the use of images. Among the youth living in rural Pakistan, we determined the accuracy of self-reported pubertal assessments using a modified PDS compared to the 'gold standard' of physically assessed Tanner stages by a physician. Methods The strength of agreement between self-assessed puberty using a modified PDS and the 'gold' standard of physician-assessed Tanner stages was reported using weighted kappa (κ w) for girls (n = 723) of 9.0-14.9 years of age or boys (n = 662) of 10.0-15.9 years of age living in the rural District of Matiari. Results Agreement between the gold standard and self-assessment for puberty was substantial, with a κ w of 0.73 (95% confidence interval [CI]: 0.67; 0.79) for girls and a κ w of 0.61 (95% CI: 0.55; 0.66) for boys. Substantial agreement was observed for both boys and girls classified as thinness but only for girls with a normal body mass index. Those who were classified as severely thin had moderate agreement. The prevalence of overestimation was 18.5% (95% CI: 15.9-21.5) for girls and 2.7% (95% CI: 1.7-4.3) for boys, while the prevalence of underestimation estimation was 8.0% (95% CI: 6.2-10.2) for girls and 29.0% (95% CI: 25.8-32.6) for boys. Conclusions Most girls and boys assessed their pubertal development with substantial agreement with physician assessment. Girls were better able to assess their puberty, but they were more likely to overestimate. Agreement for boys was also substantial, but they were more likely to underestimate their pubertal development. In this rural Pakistan population, the PDS seems to be a promising tool for self-assessed puberty.
Subject(s)
Genitalia, Female/growth & development , Genitalia, Male/growth & development , Physical Examination/statistics & numerical data , Puberty/physiology , Self-Assessment , Sexual Maturation , Adolescent , Child , Cross-Sectional Studies , Developing Countries , Female , Follow-Up Studies , Humans , Male , Pakistan , Prognosis , Rural Population , Surveys and QuestionnairesABSTRACT
BACKGROUND: Some children born small for gestational age (SGA) experience supra-physiological insulin-like growth factor-I (IGF-I) concentrations during GH treatment. However, measurements of total IGF-I concentrations may not reflect the bioactive fraction of IGF-I which reaches the IGF-I receptor at target organs. We examined endogenous IGF-bioactivity using an IGF-I kinase receptor activation (KIRA) assay that measures the ability of IGF-I to activate the IGF-IR in vitro. AIM: To compare responses of bioactive IGF and total IGF-I concentrations in short GH treated SGA children in the North European Small for Gestational Age Study (NESGAS). MATERIAL AND METHOD: In NESGAS, short SGA children (n = 101, 61 males) received GH at 67 µg/kg/day for 1 year. IGF-I concentrations were measured by Immulite immunoassay and bioactive IGF by in-house KIRA assay. RESULTS: Bioactive IGF increased with age in healthy pre-pubertal children (n = 94). SGA children had low-normal bioactive IGF levels at baseline (-0.12 (1.8 SD), increasing significantly after one year of high-dose GH treatment to 1.1 (1.4) SD, P < 0.01. Following high-dose GH, 68% (n = 65) of SGA children had a total IGF-I concentration >2SD (mean IGF-I 2.8 SDS), whereas only 15% (n = 15) had levels of bioactive IGF slightly above normal reference values. At baseline, bioactive IGF (SDS) was significantly correlated to height (SDS) (r = 0.29, P = 0.005), in contrast to IGF-I (SDS) (r = 0.17, P = 0.10). IGF-I (SDS) was inversely correlated to delta height (SDS) after one year of high-dose GH treatment (r = -0.22, P = 0.02). CONCLUSION: In contrast to total IGF-I concentrations, bioactive IGF stayed within the normal reference ranges for most SGA children during the first year of GH treatment.
Subject(s)
Biomarkers/blood , Body Height/drug effects , Growth Disorders/blood , Human Growth Hormone/administration & dosage , Infant, Small for Gestational Age/growth & development , Insulin-Like Growth Factor I/analysis , Case-Control Studies , Child , Female , Follow-Up Studies , Growth Disorders/drug therapy , Growth Disorders/pathology , Humans , Infant, Small for Gestational Age/blood , Insulin-Like Growth Factor Binding Protein 3/blood , Male , PrognosisABSTRACT
AIM: To assess factors associated with the timing of puberty onset (Tanner Stage Breast 2/Genital 2) among adolescents living in an urban slum in Karachi, Pakistan. METHODS: Girls enrolled at 8-10 years (n = 1009) and boys 9-11 years (n = 863) were followed every 6 months from 2006 to 2010. Parametric survival analysis for interval-censored data was used to estimate median age at puberty onset and assess the association between exposures and timing of puberty onset. RESULTS: The overall median age at Tanner Stage Breast 2 (AAB2) was 10.1 years (95% CI: 10.1; 10.5), and the median age at Tanner Stage Genital 2 (AAG2) was 10.1 years (95% CI: 10.1; 10.6). Stunting delayed AAB2 1 year and AAG2 about 6 months when compared to non-stunted peers. In the multivariable model, after adjusting for age at enrolment, stunting, thinness and vitamin A deficiency (VAD) were significantly associated with delayed AAB2, while stunting and anaemia were significantly associated with delayed AAG2. CONCLUSION: Among adolescents living in the Karachi slum, stunting and highly prevalent anaemia delayed AAG2, while stunting, thinness and VAD delayed AAG2. Parental and household factors were not significantly associated with the timing of puberty onset.
Subject(s)
Poverty Areas , Puberty , Adolescent , Cross-Sectional Studies , Female , Humans , Male , Pakistan/epidemiology , ThinnessSubject(s)
Transsexualism , Adolescent , Age of Onset , Autism Spectrum Disorder/epidemiology , Child , Comorbidity , Disorders of Sex Development/diagnosis , Disorders of Sex Development/epidemiology , Disorders of Sex Development/psychology , Feeding and Eating Disorders/epidemiology , Gender Dysphoria/diagnosis , Gender Dysphoria/epidemiology , Gender Dysphoria/psychology , Humans , Interdisciplinary Communication , Legislation, Medical , Patient Care Team , Sex Reassignment Surgery/psychology , Sweden , Transsexualism/diagnosis , Transsexualism/epidemiology , Transsexualism/psychology , Young AdultSubject(s)
Gender Dysphoria , Transsexualism , Adolescent , Child , Fertility Preservation , Gender Dysphoria/diagnosis , Gender Dysphoria/drug therapy , Gender Dysphoria/metabolism , Gender Dysphoria/psychology , Gonadotropin-Releasing Hormone/adverse effects , Gonadotropin-Releasing Hormone/therapeutic use , Humans , Mental Health , Parents/psychology , Puberty/metabolism , Quality of Life , Transsexualism/diagnosis , Transsexualism/drug therapy , Transsexualism/metabolism , Transsexualism/psychology , Young AdultABSTRACT
Hypogonadotrophic hypogonadism (HH) is a rare disorder that manifests absent puberty and infertility. Genetic syndromes with hypogonadism, such as Klinefelter syndrome, are associated with an increased risk of neurodevelopmental disorders (NDDs). However, it is not clear whether patients with HH or transient delayed puberty in general, have an increased risk of NDDs. We performed a register-based study on a national cohort of 264 patients with HH and 7447 patients diagnosed with delayed puberty that was matched with 2640 and 74 470 controls, respectively. The outcome was defined as having any of the following NDD diagnoses: (i) autism spectrum disorder (ASD); (ii) attention deficit hyperactivity disorder (ADHD); or (iii) intellectual disability (ID). Additional sensitivity analyses were performed to control for different parental and birth variables, as well as diagnosed malformation syndromes and chromosomal anomalies (ie, Down's and Turner syndromes). Patients with HH had increased risk for being diagnosed with ASD (odds ratio [OR] = 5.7; 95% confidence interval [CI] = 2.6-12.6), ADHD (OR = 3.0; 95% CI = 1.8-5.1) and ID (OR = 18.0; 95% CI = 8.9-36.3) compared to controls. Patients with delayed puberty also had a significantly increased risk of being diagnosed with an NDD. These associations remained significant after adjustments. This is the first study to demonstrate a significant association between HH, delayed puberty and NDDs in a population-based cohort. Clinicians should be aware of the overlap between these disorders. Further studies should explore the mechanisms behind these associations.
Subject(s)
Hypogonadism/epidemiology , Neurodevelopmental Disorders/epidemiology , Neurodevelopmental Disorders/etiology , Puberty, Delayed/epidemiology , Attention Deficit Disorder with Hyperactivity/complications , Attention Deficit Disorder with Hyperactivity/epidemiology , Autism Spectrum Disorder/complications , Autism Spectrum Disorder/epidemiology , Case-Control Studies , Child , Cohort Studies , Comorbidity , Female , Humans , Hypogonadism/complications , Klinefelter Syndrome/complications , Klinefelter Syndrome/epidemiology , Male , Puberty, Delayed/etiology , Registries/statistics & numerical data , Risk FactorsABSTRACT
Chronic diseases are known to cause premature aging and frailty. Data about telomere length and telomere length-regulating proteins after pediatric KTx are scarce. Leukocyte telomere length and gene expression level of eight telomere-binding proteins were analyzed in 20 KTx recipients, eight childhood NBL survivors, and nine healthy controls. The influence of key clinical parameters on telomere length and on regulators of telomere length was evaluated. The telomere length in the KTx recipients tended to be shorter (0.53 AU) than in the healthy controls (0.64 AU) but longer than in the NBL survivors (0.38 AU). There was no significant difference in telomere length between the NBL survivors and the KTx recipients (P = .110). The gene expression level of telomere length-preserving protein RPA1 was significantly higher in the KTx recipients than among the NBL survivors or healthy controls, while the expression of TRF2 and the tumor suppressor gene p16 was significantly higher in the KTX recipients when compared to the controls. TRF2 and TIN2 correlated significantly with hsCRP; additionally, TRF2 showed significant correlation with plasma creatinine and eGFR. KTx recipients have near to normal telomere length, but they have significantly higher gene expression levels of telomere regulatory proteins compared with healthy controls, suggesting activation of mechanisms preserving telomere length among KTx recipients. Our results suggest that declined graft function and consequent inflammatory response may have influence on telomerase activity.
Subject(s)
Cancer Survivors , Kidney Transplantation , Telomere Shortening , Telomere-Binding Proteins/metabolism , Adolescent , Adult , Biomarkers/metabolism , Case-Control Studies , Cross-Sectional Studies , Humans , Male , Young AdultABSTRACT
INTRODUCTION: Adolescence is a time of significant physical and emotional change, and there is emerging concern that adolescents living in low- and middle-income countries (LMIC) may face substantial challenges in relation to linear growth and mental health. Data on the global burden of stunting after 5 years of age are limited, but estimates suggest up to 50 per cent of all adolescents in some LMIC are stunted. Additionally, many LMIC lack robust mental health care delivery systems. Pakistan has one of the world's largest populations of adolescents (10 to 19 years) at approximately 40 million. The Nash-wo-Numa study's primary objective is to assess the prevalence and risk factors for stunting among early adolescents in rural Pakistan. The study also aims to determine the prevalence of poor mental health and identify factors associated with common mental health concerns during the childhood to adulthood transition. METHODS: This cross-sectional study will include girls (n= 738) 9.0 to 14.9 years of age and boys (n=687) 10.0 to 15.9 years of age who live in the rural district of Matiari, Pakistan. Participants will be assessed for anthropometrical measures, puberty development, nutritional biomarkers as well as symptoms of depression, anxiety and trauma using validated scales. ETHICS AND DISSEMINATION: The proposed study aims to complete the picture of child and adolescent health concerning linear growth and mental health by including puberty indicators. Ethics approval has been granted by the Ethics Review Committee at the Aga Khan University, Karachi, Pakistan, #5251-WCH-ERC-18 and Research Ethics Board at SickKids Hospital, Toronto, Canada, #:1000060684. Study results will be presented at relevant conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03647553; Pre-results.