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Hormone Research in Paediatrics 2019This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses... (Review)
Review
This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.
Topics: Adolescent; Child; Female; Gonadotropin-Releasing Hormone; Humans; Male; Puberty, Precocious
PubMed: 31319416
DOI: 10.1159/000501336 -
Best Practice & Research. Clinical... Sep 2021Sexual maturation in humans is characterized by a unique individual variability. Pubertal onset is a highly heritable polygenic trait but it is also affected by... (Review)
Review
Sexual maturation in humans is characterized by a unique individual variability. Pubertal onset is a highly heritable polygenic trait but it is also affected by environmental factors such as obesity or endocrine disrupting chemicals. The last 30 years have been marked by a constant secular trend toward earlier age at onset of puberty in girls and boys around the world. More recent data, although more disputed, suggest an increased incidence in idiopathic central precocious puberty. Such trends point to a role for environmental factors in pubertal changes. Animal data suggest that the GnRH-neuronal network is highly sensitive to endocrine disruption during development. This review focuses on the most recent data regarding secular trend in pubertal timing as well as potential new epigenetic mechanisms explaining the developmental and transgenerational effects of endocrine disrupting chemicals on pubertal timing.
Topics: Animals; Endocrine Disruptors; Female; Humans; Male; Obesity; Puberty; Puberty, Precocious; Sexual Maturation
PubMed: 34563408
DOI: 10.1016/j.beem.2021.101579 -
Best Practice & Research. Clinical... Aug 2018Central precocious puberty (CPP) results from early activation of the hypothalamic - pituitary -gonadal (HPG) axis and follows the same sequence as normal puberty. While... (Review)
Review
Central precocious puberty (CPP) results from early activation of the hypothalamic - pituitary -gonadal (HPG) axis and follows the same sequence as normal puberty. While many factors involved in pubertal initiation remain poorly understood, the kisspeptin system is known to play a key role. Currently, mutations in the kisspeptin system, MKRN3, and DLK1 have been identified in sporadic and familial cases of CPP. The diagnosis is based on physical exam findings indicating advancing puberty and on laboratory tests confirming central HPG axis activation. GnRH analogs are the mainstay of treatment and are used with the goal of height preservation. Newer extended release formulations continue to be developed. Currently there is no evidence of long-term complications associated with treatment. However, many areas remain to be explored such as targeted therapies and aspects of clinical management. Further investigation into psychological effects and additional data regarding long-term outcomes, particularly in males, is needed.
Topics: Calcium-Binding Proteins; Child; Female; Gonadotropin-Releasing Hormone; Humans; Intercellular Signaling Peptides and Proteins; Kisspeptins; Male; Membrane Proteins; Mutation; Puberty, Precocious; Ribonucleoproteins; Ubiquitin-Protein Ligases
PubMed: 30086862
DOI: 10.1016/j.beem.2018.05.008 -
Frontiers in Endocrinology 2022Gonadotrophin dependent sexual precocity, commonly referred to as central precocious puberty (CPP), results from a premature reactivation of the... (Review)
Review
Gonadotrophin dependent sexual precocity, commonly referred to as central precocious puberty (CPP), results from a premature reactivation of the hypothalamic-pituitary-gonadal (HPG) axis before the normal age of pubertal onset. CPP is historically described as girls who enter puberty before the age of eight, and boys before the age of nine. Females are more likely to be diagnosed with idiopathic CPP; males diagnosed with CPP have a greater likelihood of a defined etiology. These etiologies may include underlying CNS congenital defects, tumors, trauma, or infections as well as environmental, genetic, and epigenetic factors. Recently, genetic variants and mutations which may cause CPP have been identified at both the level of the hypothalamus and the pituitary. Single nucleotide polymorphisms (SNPs), monogenetic mutations, and modifications of the epigenome have been evaluated in relationship to the onset of puberty; these variants are thought to affect the development, structure and function of GnRH neurons which may lead to either precocious, delayed, or absent pubertal reactivation. This review will describe recent advances in the field of the genetic basis of puberty and provide a clinically relevant approach to better understand these varying etiologies of CPP.
Topics: Humans; Male; Female; Puberty, Precocious; Gonadotropin-Releasing Hormone; Epigenesis, Genetic; Puberty; Epigenomics
PubMed: 36531492
DOI: 10.3389/fendo.2022.1029137 -
American Family Physician Nov 2017Disorders of puberty can profoundly impact physical and psychosocial well-being. Precocious puberty is pubertal onset before eight years of age in girls and before nine... (Review)
Review
Disorders of puberty can profoundly impact physical and psychosocial well-being. Precocious puberty is pubertal onset before eight years of age in girls and before nine years of age in boys. Patients with early isolated pubertal changes, prepubertal linear growth, and no worrisome neurologic symptoms typically have a benign pattern of development and should be monitored in the appropriate clinical context. Among patients with true precocious puberty, or full activation of the hypothalamic-pituitary-gonadal axis, most girls have an idiopathic etiology, whereas it is commonly due to identifiable pathology on imaging in boys. History and physical examination should be followed by measurements of serum follicle-stimulating hormone, luteinizing hormone, and testosterone (boys) or estradiol (girls); thyroid function testing; and bone age radiography. Brain magnetic resonance imaging should be performed in girls younger than six years, all boys with precocious puberty, and children with neurologic symptoms. Delayed puberty is the absence of breast development in girls by 13 years of age and absence of testicular growth to at least 4 mL in volume or 2.5 cm in length in boys by 14 years of age. Constitutional delay of growth and puberty is a common cause of delayed puberty; however, functional or persistent hypogonadism should be excluded. History and physical examination should be followed by measurements of serum follicle-stimulating hormone, luteinizing hormone, and testosterone (boys) or estradiol (girls); and bone age radiography. Abnormal growth velocity necessitates assessment of serum thyroid function, prolactin, and insulinlike growth factor I. Boys 14 years and older and girls 13 years and older may benefit from sex steroid treatment to jump-start puberty. Referral to a pediatric endocrinologist may be warranted after the initial evaluation.
Topics: Adolescent; Age of Onset; Body Height; Child; Estradiol; Female; Follicle Stimulating Hormone; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Gonadotropins, Pituitary; Humans; Hypothalamo-Hypophyseal System; Luteinizing Hormone; Male; Menarche; Puberty, Precocious; Sexual Maturation
PubMed: 29094880
DOI: No ID Found -
Endocrine Reviews Mar 2023The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or...
The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.
Topics: Humans; Puberty, Precocious; Gonadotropin-Releasing Hormone; Hypothalamic Diseases; Hypothalamus; Puberty; Ubiquitin-Protein Ligases
PubMed: 35930274
DOI: 10.1210/endrev/bnac020 -
Clinical Endocrinology Oct 2021Central precocious puberty (CPP) results from early activation of the hypothalamic-pituitary-gonadal (HPG) axis. The current state of knowledge of the complex neural... (Review)
Review
Central precocious puberty (CPP) results from early activation of the hypothalamic-pituitary-gonadal (HPG) axis. The current state of knowledge of the complex neural network acting at the level of the hypothalamus and the GnRH neuron to control puberty onset has expanded, particularly in the context of molecular interactions. Along with these advances, the knowledge of pubertal physiology and pathophysiology has also increased. This review focuses on regulatory abnormalities occurring at the hypothalamic level of the HPG axis to cause CPP. The clinical approach to diagnosis of puberty and pubertal disorders is also reviewed, with a particular focus on aetiologies of CPP. The recent identification of mutations in MKRN3 and DLK1 in familial as well sporadic forms of CPP has changed the state of the art of the approach to patients with CPP. Genetic advances have also had important repercussions beyond consideration of puberty alone. Syndromic disorders and central nervous system lesions associated with CPP are also discussed. If untreated, these conditions may lead to adverse physical, psychosocial and medical outcomes.
Topics: Gonadotropin-Releasing Hormone; Humans; Mutation; Puberty; Puberty, Precocious; Ubiquitin-Protein Ligases
PubMed: 33797780
DOI: 10.1111/cen.14475 -
Endocrinology and Metabolism Clinics of... Jun 2024
Topics: Humans; Puberty, Delayed; Puberty, Precocious; Female; Child
PubMed: 38677873
DOI: 10.1016/j.ecl.2024.03.001 -
European Journal of Endocrinology Oct 2020Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and... (Review)
Review
Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader-Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.
Topics: Adolescent; Child; Female; Genome-Wide Association Study; Genomic Imprinting; Humans; Kisspeptins; Male; Mutation; Puberty; Puberty, Precocious; Receptors, Kisspeptin-1
PubMed: 32698138
DOI: 10.1530/EJE-20-0103 -
Minerva Pediatrica Dec 2020
Topics: Adolescent; Child; Child Nutritional Physiological Phenomena; Child, Preschool; Female; Growth; Growth Disorders; Humans; Infant; Infant, Newborn; Male; Puberty; Puberty, Delayed; Puberty, Precocious; Sex Factors
PubMed: 32731737
DOI: 10.23736/S0026-4946.20.06018-1