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Molecular and Cellular Endocrinology Dec 2020Prenatal testosterone (T)- treated female sheep manifest juvenile insulin resistance, post-pubertal increase in insulin sensitivity and return to insulin resistance...
Prenatal testosterone (T)- treated female sheep manifest juvenile insulin resistance, post-pubertal increase in insulin sensitivity and return to insulin resistance during adulthood. Since compensatory hyperinsulinemia is associated with insulin resistance, altered pancreatic islet ontogeny may contribute towards metabolic defects. To test this, pregnant sheep were treated with or without T propionate from days 30-90 of gestation and pancreas collected from female fetuses at gestational day 90 and female offspring at 21 months-of-age. Uterine (maternal) and umbilical (fetal) arterial blood insulin/glucose ratios were determined at gestational day 90. The morphological and functional changes in pancreatic islet were assessed through detection of 1) islet hormones (insulin, glucagon) and apoptotic beta cells at fetal day 90 and 2) islet hormones (insulin, glucagon and somatostatin), and pancreatic lipid and collagen accumulation in adults. At gestational day 90, T-treatment led to maternal but not fetal hyperinsulinemia, decrease in pancreatic/fetal weight ratio and alpha cells, and a trend for increase in beta cell apoptosis in fetal pancreas. Adult prenatal T-treated female sheep manifested 1) significant increase in beta cell size and a tendency for increase in insulin and somatostatin stained area and proportion of beta cells in the islet; and 2) significant increase in pancreatic islet collagen and a tendency towards increased lipid accumulation. Gestational T-treatment induced changes in pancreatic islet endocrine cells during both fetal and adult ages track the trajectory of hyperinsulinemic status with the increase in adult pancreatic collagen accumulation indicative of impending beta cell failure with chronic insulin resistance.
Topics: Animals; Animals, Newborn; Apoptosis; Embryonic Development; Female; Fetus; Hyperandrogenism; Hyperinsulinism; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Sheep; Testosterone
PubMed: 32726642
DOI: 10.1016/j.mce.2020.110950 -
Italian Journal of Pediatrics May 2021The sweat chloride test (ST) is the gold standard for cystic fibrosis (CF) diagnosis in symptomatic patients, within the newborn screening and in the follow-up of CF...
BACKGROUND
The sweat chloride test (ST) is the gold standard for cystic fibrosis (CF) diagnosis in symptomatic patients, within the newborn screening and in the follow-up of CF patients during molecular therapies. However, false positives have been reported in patients with different diseases. We describe and discuss 4 cases due to different clinical conditions in which we recorded false positive ST, and the test remained altered for a period of varying length.
CASES PRESENTATION
Case 1: Eight months old female child suffering from constipation, recurrent vomiting and failure to thrive, family history of recurrent pancreatitis without mutations in the PRSS1 and SPINK1 genes. Both ST and fecal elastase were altered although no CFTR gene mutations were found. Due to rapid clinical deterioration, celiac disease was suspected and diagnosed by laboratory tests and intestinal biopsy. After 2 weeks of gluten-free diet ST and fecal elastase normalized. Case 2: 14 months old male suffering from bilateral renal dysplasia, episodes of metabolic alkalosis, recurrent respiratory infections and recurrent vomiting. The child had more ST positives, but no CFTR mutations were found. During follow-up, he developed sensorineural hearing loss and an atrial septic defect was found. Finally, a diagnosis of Klinefelter was made, but the ST normalized several years later. Case 3 and 4: Two boys with stubborn constipation and fecal occlusion treated with Poly Ethylene Glycol (PEG) with salts showed pathological ST. The test returned normal a few days after stopping treatment.
CONCLUSIONS
We hypotesized the possible causes of ST alteration in these conditions: in celiac disease it could be due to a transient dysregulation of the aquaporins, rapidly reversed by the diet; in Klinefelter, it may be due to stable pubertal hypoandrogenism; while, the PEG formulation itself contains salts that can temporarily alter ST.
Topics: Celiac Disease; Chlorides; Constipation; Cystic Fibrosis; Diagnosis, Differential; Female; Humans; Infant; Klinefelter Syndrome; Male; Sweat
PubMed: 33990208
DOI: 10.1186/s13052-021-01060-1 -
Medicina (Kaunas, Lithuania) Jun 2023: The ubiquitin proteosome system (UPS) is a non-lysosomal pathway that functions in all eukaryotes. The transport of polyubiquitinated proteins to proteosomes takes...
: The ubiquitin proteosome system (UPS) is a non-lysosomal pathway that functions in all eukaryotes. The transport of polyubiquitinated proteins to proteosomes takes place via the p97/Valosin-containing protein (VCP) chaperone protein. The p97/VCP binds to polyubiquitinated proteins, allowing these proteins to reach the proteasome and, thus, their destruction. In the case of p97/VCP deficiency, ubiquitinated proteins accumulate in the cell cytoplasm, and their subsequent failure to break down produces various pathological conditions. Small VCP interacting protein (SVIP) and p97/VCP proteins have not been studied in human testicular tissues from different postnatal periods. Therefore, in our study, we aimed to examine the expression of SVIP and p97/VCP in postnatal human testicular tissues. Our study aimed to contribute to further studies on the use of these proteins as testicular cell biomarkers in cases of unexplained male infertility. : Immunohistochemical studies with the aim of determining the expression of p97/VCP and SVIP proteins in neonatal, prepubertal, pubertal, adult, and geriatric human testis tissues were performed. : In testicular sections obtained from a neonatal group, p97/VCP and SVIP were localized in different testicular and interstitial cells, and the lowest expression was observed in this group. While the expressions of these proteins were low in the neonatal period, they increased gradually in the prepubertal, pubertal and adult periods. The expression of p97/VCP and SVIP, which peaked in adulthood, showed a significant decrease in the geriatric period. : As a result, the expression of p97/VCP and SVIP correlated with the increase in age, but it decreased significantly in older groups.
Topics: Aged; Humans; Infant, Newborn; Male; Adenosine Triphosphatases; Cell Cycle Proteins; Membrane Proteins; Phosphate-Binding Proteins; Testis; Valosin Containing Protein; Child; Adolescent; Adult
PubMed: 37374283
DOI: 10.3390/medicina59061079 -
Frontiers in Endocrinology 2021The prevalence of idiopathic oligozoospermia has been esteemed as high as 75%. An Italian survey has reported bilateral testicular hypotrophy in 14% of final-year high...
The prevalence of idiopathic oligozoospermia has been esteemed as high as 75%. An Italian survey has reported bilateral testicular hypotrophy in 14% of final-year high school students. The search for determinants of testicular growth in childhood is important for the primary prevention of spermatogenic failure. Therefore, this retrospective study aimed to evaluate the testicular growth and pubertal onset in deficient children treated recombinant human growth hormone (rhGH). To accomplish this, the clinical charts of 93 patients with GH deficiency (GHD) were carefully reviewed. Their mean age at the time of diagnosis was 11.2 ± 2.4 years. rhGH was administered for 44.0 ± 22.4 months, and the onset of puberty was recorded after a mean of 25.8 ± 22.4 months from the first rhGH administration. As expected, serum insulin-like growth factor 1 (IGF1) levels increased significantly after treatment. Before rhGH therapy, the Tanner stage was I in 59 out of 70 boys (84.3%), II in 8/70 (11.4%), III in 3/70 (4.3%). No one was on stage IV or V. The mean Tanner stage was 1.19 ± 0.51. At the last visit, the Tanner stage was I in 8/72 boys (11.1%), II in 6/72 (8.3%), III in 6/72 (8.3%), IV in 16/72 (22.2%), and V in 36/72 (50.0%). After a mean of 44.0 ± 22.4 months of rhGH treatment, the mean Tanner stage was 4.05 ± 1.30. Patients treated with rhGH showed a significant testicular volume (TV) growth over time, whereas no growth was observed in age-matched but not yet treated patients, even when the age was compatible with a spontaneous start of puberty. The multivariate regression analysis showed that the duration of treatment and the mean rhGH dose significantly predicted the percentage of TV increase. In contrast, age, serum FSH, and IGF1 levels, and final rhGH dose did not impact TV growth over time. In conclusion, these findings suggest that GH may play a role in testicular growth and pubertal onset, despite the descriptive nature of this study. Further properly designed studies are needed to confirm these findings. This knowledge may be useful to implement the diagnostic-therapeutic algorithm in case of a lack of testicular growth in childhood.
Topics: Adolescent; Child; Growth Disorders; Hormone Replacement Therapy; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Puberty; Recombinant Proteins; Retrospective Studies; Testis
PubMed: 33868165
DOI: 10.3389/fendo.2021.619895 -
Frontiers in Physiology 2019Gonadotoxic treatment of malignant diseases as well as some non-malignant conditions such as cryptorchidism in young boys may result in infertility and failure to father...
BACKGROUND
Gonadotoxic treatment of malignant diseases as well as some non-malignant conditions such as cryptorchidism in young boys may result in infertility and failure to father children later in life. As a fertility preserving strategy, several centers collect testicular biopsies to cryopreserve spermatogonial stem cells (SSCs) world-wide. One of the most promising therapeutic strategies is to transplant SSCs back into the seminiferous tubules to initiate endogenous spermatogenesis. However, to obtain sufficient numbers of SSC to warrant transplantation, propagation of cells is needed together with proper validation of their stem cell identity.
MATERIALS AND METHODS
A minute amount of testicular biopsies (between 5 mg and 10 mg) were processed by mechanical and enzymatic digestion. SSCs were enriched by differential plating method in StemPro-34 medium supplemented with several growth factors. SSC-like cell clusters (SSCLCs) were passaged five times. SSCLCs were identified by immunohistochemical and immunofluorescence staining, using protein expression patterns in testis biopsies as reference. Quantitative polymerase chain reaction analysis of SSC markers LIN-28 homolog A (LIN28A), G antigen 1 (GAGE1), promyelocytic leukemia zinc finger protein (PLZF), integrin alpha 6 (ITGA6), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and integrin beta 1 (ITGB1) were also used to validate the SSC-like cell identity.
RESULTS
Proliferation of SSCLCs was achieved. The presence of SSCs in SSCLCs was confirmed by positive immunostaining of LIN28, UCHL1 and quantitative polymerase chain reaction for LIN28A, UCHL1, PLZF, ITGA6, and ITGB1, respectively.
CONCLUSION
This study has demonstrated that SSCs from infant boys possess the capacity for proliferation and advance a fertility preservation strategy for pre-pubertal boys who may otherwise lose their fertility.
PubMed: 31607938
DOI: 10.3389/fphys.2019.01155 -
Hormone Research in Paediatrics 2021In the randomized "Toddler Turner" study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up... (Observational Study)
Observational Study Randomized Controlled Trial
INTRODUCTION
In the randomized "Toddler Turner" study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters.
METHODS
Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups.
RESULTS
The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>-2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = -0.30; p = 0.016]). No new safety concerns arose.
CONCLUSION
Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood.
Topics: Adolescent; Body Height; Child, Preschool; Female; Growth Disorders; Human Growth Hormone; Humans; Infant; Puberty; Turner Syndrome
PubMed: 34111870
DOI: 10.1159/000513788 -
Orphanet Journal of Rare Diseases Nov 2021For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are... (Observational Study)
Observational Study
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.
Topics: Adult; Androgen-Insensitivity Syndrome; Child, Preschool; Cohort Studies; Endocrine System Diseases; Gonadal Dysgenesis; Humans; Infant, Newborn; Male; Rare Diseases
PubMed: 34736502
DOI: 10.1186/s13023-021-02099-3 -
Journal of Animal Science Jan 2023Successful development of replacement gilts determines their reproductive longevity and lifetime productivity. Selection for reproductive longevity is challenging due to...
Successful development of replacement gilts determines their reproductive longevity and lifetime productivity. Selection for reproductive longevity is challenging due to low heritability and expression late in life. In pigs, age at puberty is the earliest known indicator for reproductive longevity and gilts that reach puberty earlier have a greater probability of producing more lifetime litters. Failure of gilts to reach puberty and display a pubertal estrus is a major reason for early removal of replacement gilts. To identify genomic sources of variation in age at puberty for improving genetic selection for early age at puberty and related traits, gilts (n = 4,986) from a multigeneration population representing commercially available maternal genetic lines were used for a genomic best linear unbiased prediction-based genome-wide association. Twenty-one genome-wide significant single nucleotide polymorphisms (SNP) located on Sus scrofa chromosomes (SSC) 1, 2, 9, and 14 were identified with additive effects ranging from -1.61 to 1.92 d (P < 0.0001 to 0.0671). Novel candidate genes and signaling pathways were identified for age at puberty. The locus on SSC9 (83.7 to 86.7 Mb) was characterized by long range linkage disequilibrium and harbors the AHR transcription factor gene. A second candidate gene on SSC2 (82.7 Mb), ANKRA2, is a corepressor for AHR, suggesting a possible involvement of AHR signaling in regulating pubertal onset in pigs. Putative functional SNP associated with age at puberty in the AHR and ANKRA2 genes were identified. Combined analysis of these SNP showed that an increase in the number of favorable alleles reduced pubertal age by 5.84 ± 1.65 d (P < 0.001). Candidate genes for age at puberty showed pleiotropic effects with other fertility functions such as gonadotropin secretion (FOXD1), follicular development (BMP4), pregnancy (LIF), and litter size (MEF2C). Several candidate genes and signaling pathways identified in this study play a physiological role in the hypothalamic-pituitary-gonadal axis and mechanisms permitting puberty onset. Variants located in or near these genes require further characterization to identify their impact on pubertal onset in gilts. Because age at puberty is an indicator of future reproductive success, these SNP are expected to improve genomic predictions for component traits of sow fertility and lifetime productivity expressed later in life.
Topics: Pregnancy; Female; Animals; Swine; Genome-Wide Association Study; Sexual Maturation; Reproduction; Phenotype; Polymorphism, Single Nucleotide; Signal Transduction
PubMed: 36848325
DOI: 10.1093/jas/skad063 -
Journal of Clinical Medicine Jan 2024Paediatric and adolescent shoulder instability is caused by a unique combination of traumatic factors, ligamentous laxity, and pattern of muscle contractility. The... (Review)
Review
Paediatric and adolescent shoulder instability is caused by a unique combination of traumatic factors, ligamentous laxity, and pattern of muscle contractility. The multifactorial nature of its aetiology makes interpretation of the literature difficult as nomenclature is also highly variable. The purpose of this review is to summarize the existing literature and shed light on the nuances of paediatric and adolescent shoulder instability. The epidemiology, clinical features, imaging, and management of all forms of paediatric shoulder instability are presented. The main findings of this review are that structural abnormalities following a dislocation are uncommon in pre-pubertal paediatric patients. Young post-pubertal adolescents are at the highest risk of failure of non-operative management in the setting of traumatic instability with structural abnormality, and early stabilisation should be considered for these patients. Remplissage and the Latarjet procedure are safe treatment options for adolescents at high risk of recurrence, but the side-effect profile should be carefully considered. Patients who suffer from instability due to generalized ligamentous laxity benefit from a structured, long-term physiotherapy regimen, with surgery in the form of arthroscopic plication as a viable last resort. Those who suffer from a predominantly muscle patterning pathology do not benefit from surgery and require focus on regaining neuromuscular control.
PubMed: 38337418
DOI: 10.3390/jcm13030724 -
Journal of Ovarian Research Jan 2020Acute myeloid leukemia (AML) in monozygotic twins is a rare event and, until now, only a few cases have been reported. Due to improved oncological treatment and cancer... (Review)
Review
BACKGROUND
Acute myeloid leukemia (AML) in monozygotic twins is a rare event and, until now, only a few cases have been reported. Due to improved oncological treatment and cancer survival rates, quality of life considerations post-treatment have become an important aspect in the treatment regime. The ability to have their own biological children is considered one of the most important indicators of quality of life by cancer survivors. As fertility following oncological treatment is often impaired, fertility preservation methods should be offered to these patients prior to the treatment. Here, we present a very rare case in which we can in vivo observe the impact of oncological treatment on female fertility when applied before and after puberty.
CASE PRESENTATION
This is a very rare case of concordant AML in monozygotic twin sisters. Twin A became sick at the age of 21 months. She was treated with cytostatic medications and then underwent bone marrow transplantation (BMT), the donor being her twin sister B. After 27 years, she is disease free and has regular periods. After trying to conceive for 4 years, she was seen by an infertility specialist. She underwent hysteroscopic uterine septum removal and laparoscopic enucleation of bilateral paraovarian cysts. Following those procedures, she immediately conceived naturally. Twin B became sick at 15 years of age. She was treated with chemotherapy and cranial radiation and relapsed after 10 years. She then received chemotherapy and had a BMT. Until relapse, she had normal menstrual cycles. After the second treatment she became amenorrhoeic and is now part of an oocyte donation program.
CONCLUSIONS
This is a case of AML in monozygotic twins who, after treatment, have completely different reproductive potential. They both received oncological treatment, and one of them conceived conceived naturally while the other suffered premature ovarian failure and is not able to have a biological child. Based on the outcome of this case, it appears that the pre-pubertal state truly serves as protection against ovarian failure.
Topics: Acute Disease; Adolescent; Adult; Bone Marrow Transplantation; Female; Fertility; Humans; Infertility, Female; Leukemia, Myeloid; Oocyte Donation; Pregnancy; Primary Ovarian Insufficiency; Quality of Life; Reproduction; Siblings; Twins, Monozygotic
PubMed: 31900235
DOI: 10.1186/s13048-019-0607-0