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Frontiers in Endocrinology 2023Impaired testosterone secretion is a frequent following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical...
INTRODUCTION
Impaired testosterone secretion is a frequent following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical and biochemical findings are still scanty.
METHODS
Monocentric, retrospective analysis. Male patients transplanted <18 years between 1992 and 2021, surviving ≥2 years after HSCT and showing, upon enrollment, clinical and biochemical signs consistent with pubertal onset and progression were included. Clinical and biochemical data collected every 6-12 months were recorded.
RESULTS
Of 130 patients enrolled, 56% were prepubertal, while 44% were peri-/postpubertal upon HSCT. Overall, 44% showed spontaneous progression into puberty and normal gonadal profile, while the remaining experienced pubertal arrest (1%), isolated increase of FSH (19%), compensated (23%) or overt (13%) hypergonadotropic hypogonadism. Post-pubertal testicular volume (TV) was statistically smaller among patients still pre-pubertal upon HSCT ( 0.049), whereas no differences were recorded in adult testosterone levels. LH and testosterone levels showed a specular trend between 20 and 30 years, as a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. A variable degree of gonadal dysfunction was reported in 85%, 51%, 32% and 0% of patients following total body irradiation- (TBI), busulfan-, cyclophosphamide- and treosulfan-based regimens, respectively. TBI and busulfan cohorts were associated with the lowest probability of gonadal event-free course (<0.0001), while it achieved 100% following treosulfan. A statistically greater gonadotoxicity was detected after busulfan than treosulfan ( 0.024). Chemo-only regimens were associated with statistically larger TV (0.001), higher testosterone ( 0.008) and lower gonadotropin levels (0.001) than TBI. Accordingly, the latter was associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 2.34, CI 1.08-8.40), whereas being pre-pubertal upon HSCT was associated with a reduced risk (OR 0.15, CI 0.08-0.30).
CONCLUSIONS
a) patients pre-pubertal upon HSCT showed a reduced risk of testicular endocrine dysfunction, despite smaller adult TV; b) patients showed downwards trend in testosterone levels after full pubertal attainment, despite a compensatory increase in LH; c) treosulfan was associated to a statistically lower occurrence of hypogonadism than busulfan, with a trend towards larger TV, higher testosterone levels and lower gonadotropins.
Topics: Adult; Child; Humans; Male; Busulfan; Leydig Cells; Retrospective Studies; Hypogonadism; Hematopoietic Stem Cell Transplantation; Testosterone
PubMed: 38152128
DOI: 10.3389/fendo.2023.1292683 -
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 -
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 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 -
Biotechnic & Histochemistry : Official... Nov 2023Diabetes mellitus (DM) is a chronic disease at all ages including childhood and puberty. Failure to treat DM can cause retinopathy, nephropathy and neuropathy. Endocrine...
Diabetes mellitus (DM) is a chronic disease at all ages including childhood and puberty. Failure to treat DM can cause retinopathy, nephropathy and neuropathy. Endocrine and metabolic changes during the pubertal period complicate management of DM. Noopept is a cognitive enhancer that exhibits antidiabetic properties. We investigated the effect of noopept on the histopathology of the cornea, retina, kidney and pancreas in pubertal diabetic rats. We allocated 60 prepubertal male rats randomly into six groups of 10: untreated control (C), DM control (DC), noopept control (NC), DM + noopept (D + N), DM + insulin (D + I) and DM + insulin + noopept (D + I + N). DM was induced by streptozotocin in the DC, D + N, D + I and D + I + N groups. Noopept was administered to the NC, D + N and D + I + N groups; insulin was administered to the D + I and D + I + N groups for 14 days. On day 18 of the experiment, animals were sacrificed and eyes, kidneys and pancreata were excised for histological investigation. Renal tubule diameter and corneal and retinal thickness were increased significantly in DC groups compared to the control group. The D + I, D + N and D + I + N groups exhibited fewer DM induced pathological changes than the DC group. The D + I + N group exhibited no significant differences in renal tubule diameter and corneal and retinal thickness compared to the DC group. Our findings suggest that noopept is protective against DM end organ complications in streptozotocin induced diabetic pubertal rats.
Topics: Rats; Male; Animals; Diabetes Mellitus, Experimental; Streptozocin; Sexual Maturation; Kidney; Insulin; Pancreas
PubMed: 36946173
DOI: 10.1080/10520295.2023.2187460 -
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 -
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 -
International Urology and Nephrology Jul 2024Cryptorchidism is a well-defined risk factor for testicular germ cell tumors, whereas the underlying mechanisms have not been fully elucidated. Surgical procedures to...
PURPOSE
Cryptorchidism is a well-defined risk factor for testicular germ cell tumors, whereas the underlying mechanisms have not been fully elucidated. Surgical procedures to reposition undescended testicles into the scrotum (orchidopexy) in early childhood are recommended both to increase fertility potential and to reduce the risk of developing testicular tumors. However, treatment in the post-pubertal period is controversial. The aim of this study is to review the histopathology of orchiectomy specimens and determination of spermatogenesis in post-pubertal patients with non-treated cryptorchidism.
METHODS
Retrospective chart review was performed to assess the occurrence of TGCTs and determine spermatogenesis in post-pubertal individuals who underwent inguinal orchiectomy for undescended testis between January 2010 and December 2019. Age at the time of surgery, laterality, location of the undescended testis and pathology results were evaluated. All pathology specimens were reviewed by a blinded pathologist.
RESULTS
There were 23 patients in the cohort with a mean age of 21 years (range 13-46 years). All testes were in the inguinal canal. Our results indicated that 1 patient had seminoma. In the histological evaluation of the remaining 22 patients in whom no tumor was detected, normal spermatogenesis was not observed in any patient. Further, seminiferous tubules were not found in 19 patients. Maturation arrest was detected in the remaining 3 patients.
CONCLUSION
Testicular germ cell carcinoma was found in 4% of the patients who underwent post-pubertal orchiectomy. In addition, none of the undescended testes had normal spermatogenetic activity. Thus, orchiectomy should be considered in post-pubertal males with unilateral undescended testis that do not need the endocrinological activity of the testis.
Topics: Humans; Male; Cryptorchidism; Testicular Neoplasms; Neoplasms, Germ Cell and Embryonal; Retrospective Studies; Adolescent; Spermatogenesis; Adult; Young Adult; Middle Aged; Risk Factors; Orchiectomy; Risk Assessment
PubMed: 38349599
DOI: 10.1007/s11255-024-03963-4 -
Reviews in Endocrine & Metabolic... Jun 2024The results of many studies in recent years indicate a significant impact of pituitary function on bone health. The proper function of the pituitary gland has a... (Review)
Review
The results of many studies in recent years indicate a significant impact of pituitary function on bone health. The proper function of the pituitary gland has a significant impact on the growth of the skeleton and the appearance of sexual dimorphism. It is also responsible for achieving peak bone mass, which protects against the development of osteoporosis and fractures later in life. It is also liable for the proper remodeling of the skeleton, which is a physiological mechanism managing the proper mechanical resistance of bones and the possibility of its regeneration after injuries. Pituitary diseases causing hypofunction and deficiency of tropic hormones, and thus deficiency of key hormones of effector organs, have a negative impact on the skeleton, resulting in reduced bone mass and susceptibility to pathological fractures. The early appearance of pituitary dysfunction, i.e. in the pre-pubertal period, is responsible for failure to achieve peak bone mass, and thus the risk of developing osteoporosis in later years. This argues for the need for a thorough assessment of patients with hypopituitarism, not only in terms of metabolic disorders, but also in terms of bone disorders. Early and properly performed treatment may prevent patients from developing the bone complications that are so common in this pathology. The aim of this review is to discuss the physiological, pathophysiological, and clinical insights of bone involvement in pituitary disease.
Topics: Humans; Hypopituitarism; Osteoporosis; Bone and Bones; Bone Density
PubMed: 38565758
DOI: 10.1007/s11154-024-09878-w -
Journal of Pediatric Urology Aug 2023Anatomical studies of hypospadias show failure of zipping-up of histologically normal urethral plate and corpus spongiosum. With the commonly utilized substitution...
Post-pubertal functional outcomes of one-stage anatomical reconstruction of the corpus spongiosum, bulbo-spongiosus muscle and dartos in 46 children with proximalhypospadias.
INTRODUCTION
Anatomical studies of hypospadias show failure of zipping-up of histologically normal urethral plate and corpus spongiosum. With the commonly utilized substitution urethroplasties for proximal hypospadias, a reconstructed urethra of just an "epithelial-lined tube" with no spongiosal support, is apt to long-term urinary and ejaculatory dysfunctions. We completed a one-stage anatomical reconstruction in children with proximal hypospadias whenever the ventral curvature could be reduced to <30° and evaluated the post-pubertal outcomes.
METHOD
This is a retrospective analysis of prospectively maintained data on one-stage anatomical repair of proximal hypospadias between 2003 and 2021. In children with proximal hypospadias, the corpus spongiosum, bulbo-spongiosus muscle (BSM), Bucks', and Dartos' layers of the shaft were anatomically re-aligned prior to assessing the ventral curvature visually. When the curvature was >30°, the urethral plate was divided at the glans for a 2-stage procedure, and those patients were excluded from the study. Otherwise, the anatomical repair was continued (this series). The Hypospadias Objective Scoring Evaluation (HOSE) and the Paediatric Penile Perception Score (PPPS) were used for post-pubertal assessment.
RESULTS
Prospective records provided details of 105 patients with proximal hypospadias who had complete primary anatomical repair. The median age at surgery was 1.6 years, and 15.9 years at the post-pubertal assessment. Forty-one (39%) had complications that necessitated re-operations. Thirty-five (33.3%) patients had complications involving the urethra. For fistula and diverticula, eighteen cases required only one corrective procedure, while one required two. Other 16 patients required an average of 1.78 corrective operations for severe chordee and/or breakdown, with 7 requiring Bracka's 2-stage procedure.
RESULTS OF PUBERTAL REVIEW
Fifty patients (47.6%) were over 14 years old; 46 (92.0%) had pubertal reviews and scoring, while four were lost to follow-up. The mean HOSE score was 14.8/16, and the mean PPPS score was 17.8/18. Five patients had residual curvature of >10°. 17 and 10 patients, respectively, were unable to comment on glans firmness and ejaculation quality. During erections, 26/29 (89.7%) patients reported a firm glans, and 36/36 (100%) reported normal ejaculations.
CONCLUSION
This study proves the need for reconstruction of normal anatomy for normal post-pubertal function. In all proximal hypospadias, we strongly recommend anatomical reconstruction (zipping up) of the corpus spongiosum and BSM. When the curvature can be reduced to <30°, a complete one-stage reconstruction is possible; otherwise, anatomical reconstruction of the bulbar and proximal penile urethra is recommended, reducing the length of the epithelial-lined substitution tube for the distal shaft and glans.
Topics: Male; Child; Humans; Infant; Adolescent; Hypospadias; Retrospective Studies; Prospective Studies; Urologic Surgical Procedures, Male; Urethra; Muscles; Treatment Outcome
PubMed: 37012103
DOI: 10.1016/j.jpurol.2023.03.024