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Transplantation and Cellular Therapy Aug 2022Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development,...
Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. We aimed to systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy before referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.
Topics: Adult; Child; Gonadal Disorders; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Semen Analysis; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 35644480
DOI: 10.1016/j.jtct.2022.05.036 -
Endocrine Connections Nov 2023Hypogonadism is a clinical syndrome resulting from failure to produce physiological concentrations of sex steroid hormones with accompanying symptoms, such as slowed... (Review)
Review
Hypogonadism is a clinical syndrome resulting from failure to produce physiological concentrations of sex steroid hormones with accompanying symptoms, such as slowed growth and delayed pubertal maturation. Hypogonadism may arise from gonadal disease (primary hypogonadism), dysfunction of the hypothalamic-pituitary axis (secondary hypogonadism) or functional hypogonadism. Disrupted puberty (delayed or absent) leading to hypogonadism can have a significant impact on both the physical and psychosocial well-being of adolescents with lasting effects. The diagnosis of hypogonadism in teenagers can be challenging as the most common cause of delayed puberty in both sexes is self-limited, also known as constitutional delay of growth and puberty (CDGP). Although an underlying congenital cause should always be considered in a teenager with hypogonadism, acquired conditions such as obesity, diabetes mellitus, other chronic diseases and medications have all been associated with low sex steroid hormone levels. In this review, we highlight some forms of functional hypogonadism in adolescents and the clinical challenges to differentiate normal variants from pathological states.
PubMed: 37615381
DOI: 10.1530/EC-23-0190 -
Indian Pediatrics Jul 2021To assess pubertal development and its determinants in adolescents with transfusion-dependent thalassemia (TDT).
OBJECTIVES
To assess pubertal development and its determinants in adolescents with transfusion-dependent thalassemia (TDT).
METHODS
In this cross-sectional study from a tertiary teaching hospital in Delhi, records of adolescents aged 17-19 years with TDT on regular transfusion at thalassemia day-care centre were reviewed. Pubertal development and its determinants were assessed.
RESULTS
Records of 58 (33 male) adolescents with TDT were reviewed. Among them, 42 (72.4%) had normal/delayed onset with spontaneous progression of puberty, while 16 (27.6%) had pubertal arrest/failure and received hormonal replacement therapy (HRT). Short stature was observed in all adolescents on HRT. Amongst other endocrinopathies, only hypoparathyroidism was found to be significantly higher in the HRT group. On multivariate analysis, serum ferritin (OR-1.005, 95% CI 1.002, 1.009) was observed to be the only significant determinant of pubertal arrest/failure.
CONCLUSIONS
A significant proportion of adolescents with TDT continue to have pubertal arrest/failure. High systemic iron load is the key determinant for this.
Topics: Adolescent; Blood Transfusion; Cross-Sectional Studies; Endocrine System Diseases; Humans; Male; Puberty; Thalassemia; beta-Thalassemia
PubMed: 33772533
DOI: No ID Found -
American Journal of Medical Genetics.... Dec 2017Mutations in the gene CHD7 cause CHARGE syndrome, a rare multi-organ syndromic disorder. Gonadal defects are common in individuals with CHARGE syndrome (seen in... (Review)
Review
Mutations in the gene CHD7 cause CHARGE syndrome, a rare multi-organ syndromic disorder. Gonadal defects are common in individuals with CHARGE syndrome (seen in ∼60-80% of cases) and represent the letter "G" in the CHARGE syndrome acronym. The gonadal defect in CHARGE syndrome results from congenital deficiency of the hypothalamic hormone Gonadotropin-releasing hormone (GnRH), which manifests clinically as pubertal failure and infertility, and biochemically as hypogonadotropic hypogonadism (low sex steroid hormone levels with inappropriately normal or low gonadotropin levels). In addition to the gonadal endocrine abnormalities, in a small minority of individuals with CHARGE, additional endocrine defects including growth hormone deficiency, multiple pituitary hormone deficits and primary hypothyroidism may also be seen. CHD7 mutations disrupt the targeting of olfactory axons and the migration of GnRH-synthesizing neurons during embryonic development, resulting in congenital idiopathic hypogonadotropic hypogonadism (IHH) and anosmia (or hyposmia), two features that define human Kallmann syndrome. Since Kallmann syndrome is one of the constituent phenotypes within CHARGE, recent studies have investigated the role of CHD7 mutations in individuals with IHH and established that deleterious missense mutations in CHD7 are associated with Kallmann syndrome as well as normosmic form of IHH. These missense mutations affect the ATPase and nucleosome remodeling activities of the CHD7 protein. These observations suggest that CHD7 protein function is critical for the ontogeny of GnRH neurons and neuroendocrine regulation of GnRH secretion.
Topics: Abnormalities, Multiple; Animals; CHARGE Syndrome; DNA Helicases; DNA-Binding Proteins; Disease Models, Animal; Endocrine System Diseases; Genetic Association Studies; Genitalia; Humans; Mice; Mutation; Phenotype
PubMed: 29152903
DOI: 10.1002/ajmg.c.31585 -
Minerva Endocrinologica Jun 2016The phenomenon known as "mini-puberty" refers to activation of the neonatal hypothalamo-pituitary axis causing serum concentrations of gonadotrophins and testosterone... (Review)
Review
The phenomenon known as "mini-puberty" refers to activation of the neonatal hypothalamo-pituitary axis causing serum concentrations of gonadotrophins and testosterone (T) to approach adult male levels. This early neonatal period is a key proliferative window for testicular germ cells and immature Sertoli cells. Although failure to spontaneously initiate (adolescent) puberty is the most evident consequence of a defective gonadotropin-releasing hormone (GnRH) neurosecretory network, absent mini-puberty is also likely to have a major impact on the reproductive phenotype of men with congenital hypogonadotrophic hypogonadism (CHH). Furthermore, the phase of male mini-puberty represents a key window-of-opportunity to identify congenital GnRH deficiency (either isolated CHH, or as part of combined pituitary hormone deficiency) in childhood. Among male neonates exhibiting "red flag" indicators for CHH (i.e. maldescended testes with or without cryptorchidism) a single serum sample (between 4-8 weeks of life) can pinpoint congenital GnRH deficiency far more rapidly and with much greater accuracy than dynamic tests performed in later childhood or adolescence. Potential consequences for missing absent mini-puberty in a male neonate include the lack of monitoring of pubertal progression/lack of progression, and the missed opportunity for early therapeutic intervention. This article will review our current understanding of the mechanisms and clinical consequences of mini-puberty. Furthermore, evidence for the optimal clinical management of patients with absent mini-puberty will be discussed.
Topics: Gonadotropins; Humans; Hypogonadism; Infant, Newborn; Male; Puberty; Puberty, Delayed; Testosterone
PubMed: 27213784
DOI: No ID Found -
Digestive Diseases and Sciences Apr 2021Growth delay with height and weight impairment is a common feature of pediatric inflammatory bowel diseases (PIBD). Up to 2/3 of Crohn Disease patients have impaired... (Review)
Review
Growth delay with height and weight impairment is a common feature of pediatric inflammatory bowel diseases (PIBD). Up to 2/3 of Crohn Disease patients have impaired weight at diagnosis, and up to 1/3 have impaired height. Ulcerative colitis usually manifests earlier with less impaired growth, though patients can be affected. Ultimately, growth delay, if not corrected, can reduce final adult height. Weight loss, reduced bone mass, and pubertal delay are also concerns associated with growth delay in newly diagnosed PIBD patients. The mechanisms for growth delay in IBD are multifactorial and include reduced nutrient intake, poor absorption, increased fecal losses, as well as direct effects from inflammation and treatment modalities. Management of growth delay requires optimal disease control. Exclusive enteral nutrition (EEN), biologic therapy, and corticosteroids are the primary induction strategies used in PIBD, and both EEN and biologics positively impact growth and bone development. Beyond adequate disease control, growth delay and pubertal delay require a multidisciplinary approach, dependent on diligent monitoring and identification, nutritional rehabilitation, and involvement of endocrinology and psychiatry services as needed. Pitfalls that clinicians may encounter when managing growth delay include refeeding syndrome, obesity (even in the setting of malnutrition), and restrictive diets. Although treatment of PIBD has improved substantially in the last several decades with the era of biologic therapies and EEN, there is still much to be learned about growth delay in PIBD in order to improve outcomes.
Topics: Causality; Colitis, Ulcerative; Crohn Disease; Failure to Thrive; Humans; Patient Care Management
PubMed: 33433805
DOI: 10.1007/s10620-020-06759-5 -
Journal of Pediatric Surgery Jun 2022Pediatric intestinal failure (PIF) affects nutrition, metabolism, and endocrine development, but its downstream impact on puberty is unknown.
BACKGROUND
Pediatric intestinal failure (PIF) affects nutrition, metabolism, and endocrine development, but its downstream impact on puberty is unknown.
METHODS
A retrospective review was performed of patients age >8 years with PIF managed at an intestinal rehabilitation program. Outcomes of interest were peak height velocity (PHV), age at PHV, and age at pubertal onset (Tanner stage 2). Outcomes were stratified by sex and compared to established norms.
RESULTS
Of 110 patients with PIF, 54.5% were male. Compared to the CDC 50th percentile, PHV in PIF patients was similar for females (8.09±2.36 vs. 7.37 cm/yr;p = 0.23) but significantly higher for males (9.27±2.56 vs. 7.91 cm/yr;p = 0.038). Age at PHV in PIF patients was significantly younger for both males (12.31±2.14 vs. 13.38 years;p = 0.049) and females (10.70±1.06 vs. 11.71 years;p = 0.001). PIF patients reached pubertal onset earlier than published norms; this was significant for males (12.41±1.80 vs. 13.44 years;p = 0.014), but not for females (10.45±1.81 vs. -11.15 years;p = 0.13). The mean height-for-age Z-score was -1.2, with 20% of patients having a Z-score less than -2.
CONCLUSIONS
Pubertal onset and growth are neither delayed nor diminished in patients with PIF. The high incidence of short stature, however, highlights the importance of optimizing prepubertal linear growth to attain full height potential.
TYPE OF STUDY
Prognosis study (Retrospective cohort study).
Topics: Body Height; Child; Female; Humans; Intestinal Failure; Male; Puberty; Retrospective Studies
PubMed: 35287963
DOI: 10.1016/j.jpedsurg.2022.01.057 -
Handbook of Experimental Pharmacology 2020During puberty, with activation of the hypothalamic pituitary axis that has been quiescent since the neonatal period, linear growth accelerates, secondary sexual...
During puberty, with activation of the hypothalamic pituitary axis that has been quiescent since the neonatal period, linear growth accelerates, secondary sexual characteristics develop, and adult fertility potential and bone mass are achieved, together with psychosocial and emotional maturation.Disordered pubertal onset and progress, either early or late, presents frequently for endocrine care. Where a disorder is found, due either to a central hypothalamic pituitary cause or to primary gonadal failure, pharmacotherapeutic interventions are required to alter the trajectory of disturbed pubertal onset or progress and for maintenance of adolescent and adult sex hormone status. This paper describes pharmacologic interventions used for pubertal disorders but is not intended to address the diagnostic cascade in detail.
Topics: Adolescent; Adult; Gonadal Steroid Hormones; Humans; Hypothalamus; Sexual Maturation
PubMed: 31144045
DOI: 10.1007/164_2019_208 -
Journal of Developmental and Behavioral... Sep 2023Klinefelter syndrome (KS; 47, XXY), the most common sex chromosome aneuploidy in males, is characterized by testicular failure and testosterone deficiency as well as a...
OBJECTIVE
Klinefelter syndrome (KS; 47, XXY), the most common sex chromosome aneuploidy in males, is characterized by testicular failure and testosterone deficiency as well as a variety of cognitive, social, and emotional challenges. In the current study, we aimed to clarify the cognitive-behavioral profile of peripubertal boys with KS using measures of cognition, academic achievement, adaptive behavior, and quality of life.
METHOD
We compared 47 boys with KS (7-16 years of age) with 55 performance IQ-matched boys without KS on measures of cognition (WISC-V), executive function (BRIEF-2), academic achievement (KTEA-3), adaptive behavior (Vineland-3), and quality of life (PROMIS). In exploratory analyses, we examined associations among these measures and potential associations with pubertal metrics.
RESULTS
Boys with KS demonstrated a significantly different profile of cognition, behavioral ratings of executive function, academic achievement, adaptive behavior, and quality of life compared with their typically developing peers, with, on average, lower functioning. The groups showed significantly different correlations between cognition and aspects of quality of life. No associations were observed between behavior and pubertal development.
CONCLUSION
Taken together, these findings indicated that boys with KS are at increased risk for cognitive difficulties, which may affect academic achievement, adaptive behavior, and quality of life. Although initial exploratory analyses indicated that the magnitude of these alterations was not correlated with severity of testicular failure, longitudinal analyses currently being conducted by our group may help clarify the trajectory of these difficulties through the pubertal transition and testosterone replacement.
Topics: Male; Adolescent; Child; Humans; Academic Success; Klinefelter Syndrome; Quality of Life; Cognition; Adaptation, Psychological; Testosterone
PubMed: 37696031
DOI: 10.1097/DBP.0000000000001201