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Annals of Pediatric Endocrinology &... Sep 2022Congenital hypogonadotropic hypogonadism (CHH) is characterized by complete or partial failure of pubertal development because of inadequate secretion of gonadotropic...
Congenital hypogonadotropic hypogonadism (CHH) is characterized by complete or partial failure of pubertal development because of inadequate secretion of gonadotropic hormones. CHH consists of hypogonadotropic hypogonadism with anosmia or hyposmia, Kallmann syndrome, and the normosmic variation normosmic idiopathic hypogonadotropic hypogonadism. CHH is one of the few treatable diseases of male infertility, although men with primary testicular dysfunction have irreversibly diminished spermatogenic capacity. The approach to CHH treatment is determined by goals such as developing virilization or inducing fertility. This review focuses on the current knowledge of therapeutic modalities for inducing puberty and fertility in men with CHH.
PubMed: 36203268
DOI: 10.6065/apem.2244208.104 -
Nature Communications Aug 2022Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital...
Kiss1 neurons, producing kisspeptins, are essential for puberty and fertility, but their molecular regulatory mechanisms remain unfolded. Here, we report that congenital ablation of the microRNA-synthesizing enzyme, Dicer, in Kiss1 cells, causes late-onset hypogonadotropic hypogonadism in both sexes, but is compatible with pubertal initiation and preserved Kiss1 neuronal populations at the infantile/juvenile period. Yet, failure to complete puberty and attain fertility is observed only in females. Kiss1-specific ablation of Dicer evokes disparate changes of Kiss1-cell numbers and Kiss1/kisspeptin expression between hypothalamic subpopulations during the pubertal-transition, with a predominant decline in arcuate-nucleus Kiss1 levels, linked to enhanced expression of its repressors, Mkrn3, Cbx7 and Eap1. Our data unveil that miRNA-biosynthesis in Kiss1 neurons is essential for pubertal completion and fertility, especially in females, but dispensable for initial reproductive maturation and neuronal survival in both sexes. Our results disclose a predominant miRNA-mediated inhibitory program of repressive signals that is key for precise regulation of Kiss1 expression and, thereby, reproductive function.
Topics: Animals; DEAD-box RNA Helicases; Female; Fertility; Kisspeptins; Male; Mice; MicroRNAs; Neurons; Ribonuclease III; Sexual Maturation
PubMed: 35945211
DOI: 10.1038/s41467-022-32347-4 -
Clinical Pediatric Endocrinology : Case... 2024Chronic inflammatory conditions, such as juvenile idiopathic arthritis, are associated with growth failure. Growth failure appears to be correlated with both the effects... (Review)
Review
Chronic inflammatory conditions, such as juvenile idiopathic arthritis, are associated with growth failure. Growth failure appears to be correlated with both the effects of inflammation and negative effects of glucocorticoids (used as therapeutic option) on the growth hormone axis and locally on the growth plate and bone metabolism. In the last decade, the introduction of biologics has changed the disease course regarding consequences and outcomes. Anyway in some cases, treatment with biologics has failed in restoring normal growth in patients with juvenile idiopathic arthritis; in contrast, several studies have reported improved height velocity and growth rate in patients with juvenile idiopathic arthritis treated with growth hormone. This study aimed to evaluate the impact of growth hormone treatment on the growth and pubertal development in juvenile idiopathic arthritis patients through a narrative review of the literature over the last four decades.
PubMed: 38299178
DOI: 10.1297/cpe.2023-0036 -
Frontiers in Pediatrics 2020Patients with anorexia nervosa (AN) experience medical complications including impaired bone metabolism, increased fracture rate, kidney stones and chronic renal...
Patients with anorexia nervosa (AN) experience medical complications including impaired bone metabolism, increased fracture rate, kidney stones and chronic renal failure. However, the mechanisms of such complications are not fully understood. Healthy adolescents have been shown to have higher PTH levels when compared with pre-pubertal children and adults. Given the importance of central measures of calcium and vitamin D metabolism in bone and kidney health, 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) have been extensively investigated in patients with AN, however none of the previous studies accounted for age-specific reference ranges for PTH. The aim of this study was to investigate central measures of calcium and vitamin D metabolism in adolescents with newly diagnosed AN using age-specific reference ranges and to determine whether any significant abnormalities required further study. This was a cross-sectional study of 61 adolescents (mean age = aged 15.2 ± 1.56 years) with newly diagnosed AN, referred to a tertiary center over a period of 2 years. Demographic, auxiological, and nutrient (vitamin D and calcium) intake data was obtained. Central measures of calcium and vitamin D metabolism in blood and urine were investigated. PTH results were compared with age-specific reference ranges from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER). Descriptive statistics and correlation analysis were performed. Low PTH levels were observed in 35% of the cohort. Overall, serum calcium, phosphate and 25OHD were within the reference range. Using loess curves, PTH had a significant negative and non-linear correlation with 25OHD with an inflection point at a 25OHD level of 100 nmol/l, above which the association was no longer present. Correlation analysis did not show a significant association between PTH and total or corrected serum calcium, urine calcium/creatinine (Ca/Cr) ratio, total dietary calcium intake, magnesium or Tanner staging. PTH levels were reduced in approximately a third of adolescents with AN. This observation has not been reported given the universal usage of reference ranges that covers all ages. This finding may unmask a potential role for reduced PTH levels in the pathogenesis of kidney stones and bone phenotype in patients with AN.
PubMed: 32219087
DOI: 10.3389/fped.2020.00099 -
Frontiers in Cell and Developmental... 2023The mechanisms and aetiology underlying the development of premature ovarian insufficiency (POI) are poorly understood. However, the oocyte clearly has a role as...
The mechanisms and aetiology underlying the development of premature ovarian insufficiency (POI) are poorly understood. However, the oocyte clearly has a role as demonstrated by the Double Mutant (DM) mouse model where ovarian dysfunction (6 weeks) is followed by POI (3 months) due to oocyte-specific deletion of complex and hybrid N- and O-glycans. The ovaries of DM mice contain more primary follicles (3a stage) accompanied by fewer developing follicles, indicating a block in follicle development. To investigate this block, we first analysed early follicle development in postnatal (8-day), pre-pubertal (3-week) and post-pubertal (6-week and 3-month) DM ( :ZP3) and Control ( ) mice. Second, we investigated if transplantation of DM ovaries into a "normal" endocrine environment would restore follicle development. Third, we determined if replacing DM ovarian somatic cells would rescue development of DM oocytes. At 3-week, DM primary 3a follicles contain large oocytes accompanied by early development of a second GC layer and increased GC proliferation. At 6-week, DM primary 3a follicles contain abnormally large oocytes, accompanied with decreased GC proliferation. Transplantation of DM ovaries into a 'normal' endocrine environment did not restore normal follicle development. However, replacing somatic cells by generating reaggregated ovaries (ROs) did enable follicle development to progress and thus highlighted intra-ovarian factors were responsible for the onset of POI in DM females. Thus, these studies demonstrate oocyte-initiated altered communication between GCs and oocytes results in abnormal primary follicles which fail to progress and leads to POI.
PubMed: 37614224
DOI: 10.3389/fcell.2023.1202411 -
Translational Andrology and Urology Oct 2020The treatment modalities for testicular tumors (surgery, chemotherapy, and radiotherapy), have different associated gonadotoxic risks and the overall survival for most... (Review)
Review
The treatment modalities for testicular tumors (surgery, chemotherapy, and radiotherapy), have different associated gonadotoxic risks and the overall survival for most pediatric patients with testicular tumors is very good. However, necessary treatments may lead to the development of lasting gonadal dysfunction and subsequent negative health and quality of life impact. Research with long-term follow-up for patients who have undergone surgery as the sole treatment modality for testicular tumors in childhood are lacking. It is currently unclear if surgery leads to long-term negative functional outcomes. Alkylating agents (e.g., cyclophosphamide) have long been known to increase risk of infertility; platinum-based therapies used frequently for patients with germ-cell tumors (GCTs) also seem to carry some risk of gonadotoxicity, although they have not been as well studied. Radiotherapy to the gonads is toxic and Leydig cells are particularly sensitive to high doses of radiation (>12 Gy). Long-term fertility and hormonal impact vary based on the patient's age, as well as the type and intensity of the oncological treatment prescribed. Counselling regarding fertility risk and preservation options should ideally take place before initiating potentially gonadotoxic treatments. Hypogonadism in peri-pubertal boys can present as delayed onset or failure to progress through puberty. Sperm cryopreservation should be offered for post-pubertal boys who are able to provide a semen sample. For prepubertal boys or young males who cannot provide a semen sample, only experimental options are currently available. Much of the data reviewed here is extrapolated from research done on adult males whose reproductive and hormonal outcomes may not be comparable to younger patients who do not yet have fully developed reproductive systems. Currently, a lack of good quality evidence in this age range causes this restriction to be unavoidable. Patients and their families want to be informed of the risks and treatment options for preserving testicular function. As research continues in this field, it grows more important for urologists to be aware of the outcomes and options for their patients.
PubMed: 33209712
DOI: 10.21037/tau-19-923 -
Endocrine Reviews Feb 2016Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease, and cystic... (Review)
Review
Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt are often seen during adolescence. The underlying inflammatory state mediated by proinflammatory cytokines, prolonged use of glucocorticoid, and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the GH-IGF axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biological therapy may lead to improvement of growth in some of these children, but approximately one-third continue to grow slowly. There is increasing evidence that the use of relatively high-dose recombinant human GH may lead to partial catch-up growth in chronic inflammatory conditions, although long-term follow-up data are currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease, and cystic fibrosis, systemic abnormalities of the GH-IGF axis, and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human GH in these conditions and discussed the role of recombinant human IGF-1.
Topics: Adolescent; Animals; Arthritis, Juvenile; Child; Combined Modality Therapy; Cystic Fibrosis; Drug Therapy, Combination; Evidence-Based Medicine; Growth Disorders; Growth Plate; Growth Substances; Human Growth Hormone; Humans; Inflammatory Bowel Diseases; Insulin-Like Growth Factor I; Practice Guidelines as Topic; Puberty, Delayed; Recombinant Proteins
PubMed: 26720129
DOI: 10.1210/er.2015-1026 -
Hormone Research in Paediatrics 2024Recombinant human growth hormone (rhGH) therapy effectively increases height in various disorders of childhood growth. However, whether rhGH affects pubertal timing is... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Recombinant human growth hormone (rhGH) therapy effectively increases height in various disorders of childhood growth. However, whether rhGH affects pubertal timing is unclear. We aimed to review systematically published evidence on the effect of rhGH on pubertal timing.
METHODS
Embase, MEDLINE, and Cochrane Library databases were searched until December 2021 on randomized and non-randomized controlled studies of rhGH in children.
RESULTS
Twenty-five articles (n = 1,433 children) were identified, describing 12 randomized and 13 non-randomized controlled studies in children with idiopathic short stature (ISS; 15 studies), small for gestational age (n = 6 studies), chronic renal failure (n = 3), Noonan syndrome (n = 1), and growth hormone deficiency (n = 1). Significant differences in the effects of rhGH on pubertal timing were found by clinical indication. Only among children with ISS, rhGH promoted earlier age at pubertal timing (mean difference = -0.46 years; 95% CI, -0.90 to -0.03; 9 studies; n total = 397) or higher relative risk for pubertal onset during study follow-up (1.26; 95% CI, 1.03 to 1.54; 6 studies; n total = 284).
CONCLUSIONS
Treatment with rhGH appears to promote earlier pubertal timing among children with ISS. Evidence was lacking in children with growth hormone deficiency due to the absence of studies with untreated controls.
Topics: Child; Humans; Human Growth Hormone; Growth Hormone; Body Height; Growth Disorders; Dwarfism, Pituitary; Recombinant Proteins
PubMed: 37075730
DOI: 10.1159/000530578 -
Environmental Health Perspectives Sep 2018Animal studies suggest that phthalates and bisphenol A (BPA), endocrine-disrupting chemicals found in many consumer products, may impact the timing of puberty.
BACKGROUND
Animal studies suggest that phthalates and bisphenol A (BPA), endocrine-disrupting chemicals found in many consumer products, may impact the timing of puberty.
OBJECTIVES
We aimed to determine the association of prenatal exposure to high-molecular-weight phthalates and BPA with pubertal timing in boys and girls participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) longitudinal cohort study.
METHODS
We quantified urinary concentrations of eight phthalate metabolites and BPA at two time points during pregnancy among participating mothers ([Formula: see text]) and conducted clinical Tanner staging of puberty on their children every 9 months between 9 and 13 y of age. We conducted accelerated failure time models and examined the role of child overweight/obese status in this association.
RESULTS
The sum of urinary metabolites of di(2-ethylhexyl) phthalate [Formula: see text], monobenzyl phthalate (MBzP), and BPA were associated with later onset of at least one of the three outcomes assessed in girls (thelarche, pubarche, or menarche) and with earlier onset of at least one of the two outcomes assessed in boys (gondarche and pubarche). We found that monocarboxynonyl phthalate, monocarboxyoctyl phthalate, mono(3-carboxypropyl) phthalate, and BPA were associated with later pubarche and menarche mostly among normal-weight girls but not overweight/obese girls. MBzP was associated with later thelarche in all girls, and [Formula: see text] was associated with later thelarche and menarche in all girls. BPA and all phthalate biomarkers were associated with earlier gonadarche and pubarche in all boys as well as in overweight/obese boys when stratified by weight. Among normal-weight boys, associations with BPA were also inverse, whereas associations with phthalate metabolites were close to the null or positive.
CONCLUSIONS
Several high-molecular-weight phthalates and BPA were associated with later puberty in girls and earlier puberty in boys included in the CHAMACOS cohort study. Childhood overweight/obesity may modify these associations. https://doi.org/10.1289/EHP3424.
Topics: Adolescent; Benzhydryl Compounds; California; Child; Endocrine Disruptors; Environmental Pollutants; Female; Humans; Longitudinal Studies; Male; Maternal Exposure; Phenols; Phthalic Acids; Pregnancy; Prenatal Exposure Delayed Effects; Sexual Maturation
PubMed: 30203993
DOI: 10.1289/EHP3424 -
Epidemiology (Cambridge, Mass.) Sep 2017Tobacco smoke contains known hormonally active chemicals and reproductive toxicants. Several studies have examined prenatal maternal smoking and offspring age at...
BACKGROUND
Tobacco smoke contains known hormonally active chemicals and reproductive toxicants. Several studies have examined prenatal maternal smoking and offspring age at menarche, but few examined earlier pubertal markers, nor accounted for exposure during childhood. Our objective was to examine pre- and postnatal smoke exposure in relation to timing of early pubertal events.
METHODS
An ethnically diverse cohort of 1239 girls was enrolled at age 6-8 years old for a longitudinal study of puberty at three US sites. Girls participated in annual or semi-annual exams to measure anthropometry and Tanner breast and pubic hair stages. Prenatal and current tobacco smoke exposures, as well as covariates, were obtained from parent questionnaire. Cotinine was measured in urine collected at enrollment. Using accelerated failure time models, we calculated adjusted time ratios for age at pubertal onset (maturation stages 2 or higher) and smoke exposure.
RESULTS
Girls with higher prenatal (≥5 cigarettes per day) or secondhand smoke exposure had earlier pubic hair development than unexposed (adjusted time ratio: 0.92 [95% CI = 0.87, 0.97] and 0.94 [95% CI = 0.90, 0.97], respectively). Including both exposures in the same model yielded similar associations. Higher urinary cotinine quartiles were associated with younger age at breast and pubic hair onset in unadjusted models, but not after adjustment.
CONCLUSIONS
Greater prenatal and childhood secondhand smoke exposure were associated with earlier onset of pubic hair, but not breast, development. These exposures represent modifiable risk factors for early pubertal development that should be considered for addition to the extensive list of adverse effects from tobacco smoke.
Topics: Age Factors; Child; Cotinine; Female; Humans; Longitudinal Studies; Menarche; Pregnancy; Prenatal Exposure Delayed Effects; Tobacco Smoke Pollution
PubMed: 28661938
DOI: 10.1097/EDE.0000000000000704