Materiały źródłowe

• #1 Precocious Puberty – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544313/

  Precocious puberty is classified into two major categories based on the etiology […] Central precocious puberty (GnRH dependent) […] Peripheral precocious puberty (GnRH independent) […] This type of precocious puberty represents true pubertal development due to the earlier maturation and activation of the HPG axis. Most of the time, the common cause in females is idiopathic, and in males, there is usually an underlying pathology. It is attributable to a multitude of conditions. […] The most common brain lesion causing CPP is hypothalamic hamartoma. The ectopic neural cells in the lesion serve as an accessory GnRH pulse generator. […] Precocious development of secondary sexual characteristics independent of the GnRH pulsatile secretion constitutes PPP; this is due to the production of sex steroids from endogenous or exogenous sources.

• #2 Precocious Puberty: Types, Pathogenesis and Updated Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10663169/

  Two types of precocious sexual maturation are recognized – namely central PP (CPP) and peripheral PP (PPP). […] PPP, the so-called GnRH-independent type, is the presence of early pubertal maturation not related to the central activation of the hypothalamic-pituitary-gonadal (HPG) axis. The etiology of PPP is classified into genetic or acquired disorders. The most common forms of congenital or genetic causes include familial male-limited PP (FMPP), McCune-Albright syndrome (MAS), and congenital adrenal hyperplasia (CAH). […] On the other hand, CPP is the most common and it is a gonadotropin-dependent form. It is due to premature maturation of the HPG axis. CPP may occur as genetic alterations, such as MKRN3, DLK1, or KISS1; as a part of mutations in the epigenetic factors that regulate the HPG axis, such as Lin28b and let-7; or as a part of syndromes, central lesions such as hypothalamic hamartoma, and others.

• #3 Precocious Pseudopuberty: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/923876-overview

  Puberty is the process of physical maturation manifested by an increase in growth rate and the appearance of secondary sexual characteristics. The Lawson Wilkins Pediatric Endocrine Society (LWPES) guidelines define precocious puberty as the appearance of any sign of secondary sexual maturation in boys younger than 9 years, in white girls younger than 7 years, and in black girls younger than 6 years. […] Precocious puberty can be divided into two distinct categories. The first category, referred to as central precocious puberty (CPP), is gonadotropin-dependent and involves the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. The second category, referred to as precocious pseudopuberty or peripheral precocious puberty (PPP), is gonadotropin-independent, and the presence of sex steroids is independent of pituitary gonadotropin release.

• #4 Precocious Puberty: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/924002-overview

  High-amplitude pulses of GnRH from the hypothalamus at the onset of puberty cause pulsatile increases in the pituitary gonadotropins LH and follicle-stimulating hormone (FSH). Increased LH levels stimulate production of sex steroids by testicular Leydig cells or ovarian granulosa cells. Pubertal levels of androgens or estrogens cause the physical changes of puberty, including penile enlargement and sexual hair in boys and breast development in girls. These levels also mediate the pubertal growth spurt. Increased FSH levels cause enlargement of the gonads in both sexes and eventually promote follicular maturation in girls and spermatogenesis in boys. Research has implicated a family of peptides called kisspeptins, produced in the central nervous system (CNS), in the regulation of GnRH secretion.

• #5 Precocious Puberty

  https://elsevier.health/en-US/preview/precocious-puberty-co

  Peripheral precocious puberty treatment depends on underlying cause. […] Puberty is triggered by an increase in pulsatile secretion of gonadotropin-releasing hormone (ie, gonadarche or activation of the hypothalamic-pituitary-gonadal axis). […] Gonadotropin-releasing hormone stimulates secretion of the gonadotropins luteinizing hormone and follicle-stimulating hormone. […] Luteinizing hormone stimulates ovaries to secrete estradiol and testes to secrete testosterone. […] Estradiol causes progressive breast enlargement, pubertal growth spurt in girls, and rapid bone age advancement. […] Testosterone causes penile enlargement and pubic hair growth in boys and, by conversion to estradiol, causes pubertal growth spurt in boys. […] Central precocious puberty is characterized by pulsatile release of gonadotropin-releasing hormone from hypothalamus resulting in activation of hypothalamic-pituitary-gonadal axis; subsequently, estrogen is produced in girls and testosterone is produced in boys. […] Secondary sex characteristics develop in a pattern of normal pubertal progression, leading to normal menses with ovulation and potential for pregnancy. […] Growth is accelerated and bone age is advanced.

• #6 Genetic factors in precocious puberty

  https://www.e-cep.org/journal/view.php?number=20125555474

  Pubertal onset is known to result from reactivation of the hypothalamic-pituitary-gonadal (HPG) axis, which is controlled by complex interactions of genetic and nongenetic factors. […] The cause of CPP in most girls is not identifiable and, thus, referred to as idiopathic CPP (ICPP), whereas boys are more likely to have an organic lesion in the brain. ICPP has a genetic background, as supported by studies showing that maternal age at menarche is associated with pubertal timing in their offspring. A gain of expression in the kisspeptin gene (KISS1), gain-of-function mutation in the kisspeptin receptor gene (KISS1R), loss-of-function mutation in makorin ring finger protein 3 (MKRN3), and loss-of-function mutations in the delta-like homolog 1 gene (DLK1) have been associated with ICPP. […] In the progression of CPP, epigenetic factors such as DNA methylation, histone posttranslational modifications, and noncoding ribonucleic acids may mediate the relationship between genetic and environmental factors.

• #7 Frontiers | Childhood obesity and central precocious puberty

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1056871/full

  The hormonal profile in peri-pubertal girls with obesity is characterized by hyperinsulinemia and higher HOMA-IR index, especially evident in early puberty. […] The identification of Kiss1, and its receptor Gpr54 is considered to be a breakthrough in puberty. […] The Kiss1 system is sensitive to metabolic conditions, and an important transmitter for impacting puberty. […] AMPK is widely expressed in metabolic organs and also co-expressed in Kiss 1 neurons, therefore the brain AMPK is likely to integrate metabolic/nutritional status and the onset of puberty in obesity. […] The interaction of mTOR and kisspeptin might further drive the initiation of CPP. […] Central ceramide signaling mediates obesity-induced precocious puberty.

• #8 Precocious Puberty: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/924002-overview

  The hypothesized mechanisms that suppress the onset of puberty in early childhood include (1) the HPG axis, which is highly sensitive to feedback inhibition by small amounts of sex steroids, and (2) central neural pathways that suppress the release of GnRH pulses. […] Most patients, particularly girls suspected of having CPP, are otherwise healthy children whose pubertal maturation begins at the early end of the normal distribution curve. CNS imaging studies of these girls aged 6-8 years usually reveal no structural abnormalities. While older studies reported a significant proportion of abnormal findings such as tumors, subsequent reports have found an incidence of clinically significant brain imaging findings of less than 1%, even in girls below age 6 years. […] Abnormal computed tomography (CT) or MRI scans are more frequent among boys with CPP than among girls. However, a nationwide, retrospective Italian study by Cassio et al of 193 boys with CPP who were otherwise normal and healthy reported that CNS abnormalities were responsible for the condition in 5.7% of cases, while a Korean study of 138 boys with CPP and a mean age of 9.5 years found no pathologic findings; this suggests that the incidence of CNS lesions causing CPP in boys is much lower than past studies had found.

• #9 Central precocious puberty: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/central-precocious-puberty/

  Central precocious puberty is a condition that causes early sexual development in girls and boys. […] The cause of central precocious puberty is often unknown. The most common known genetic cause of central precocious puberty is mutations in the MKRN3 gene. Changes in other genes are rare causes of the condition, and researchers suspect that changes in genes that have not yet been identified may also be involved in central precocious puberty. […] The protein produced from the MKRN3 gene plays a role in directing the onset of puberty. Puberty begins when a gland in the brain called the hypothalamus is stimulated to release bursts of a hormone called gonadotropin releasing hormone (GnRH). This hormone triggers the release of other hormones that direct sexual development. Research suggests that the MKRN3 protein blocks (inhibits) the release of GnRH from the hypothalamus, thus holding off the onset of puberty.

• #10 Central precocious puberty: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/central-precocious-puberty/

  The MKRN3 gene mutations involved in central precocious puberty are thought to lead to production of a nonfunctional MKRN3 protein. Although the mechanism is unclear, researchers speculate that without the MKRN3 protein to inhibit GnRH release, the hypothalamus releases bursts of the hormone, which stimulates the onset of puberty earlier than normal. […] Central precocious puberty follows an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. When passed from parent to child, the condition is known as familial central precocious puberty. In familial cases associated with the MKRN3 gene, the mutation is inherited from the father.

• #11 Revista Española Endocrinología Pediátrica – Deciphering the genetic basis of central precocious puberty

  https://www.endocrinologiapediatrica.org/modules.php?name=articulos&d_op=&idarticulo=805&idlangart=ES&preproduccion=

  The role of MKRN3 in the pathogenesis of CPP was first demonstrated in 2013, when whole exome sequence analysis was performed in several families with CPP. […] MKRN3 loss-of-function mutations were the most prevalent cause of familial CPP, followed by DLK1 loss-of-function mutations, affecting, respectively, 22% and 4% of the studied families; both affecting exclusively families with paternal transmission. […] Genetic and epigenetic abnormal findings associated with human CPP phenotype revealed that this endocrine pediatric condition has a strongly influence of epigenetic mechanisms (especially, methylation modifications) as demonstrated by identification of loss-of-mutations in two imprinted genes (MKRN3, DLK1) and its potential association with epigenetic syndromes (Temple syndrome, Prader-Willi syndrome and Rett syndromes).

• #12 Genetic etiologies of central precocious puberty

  https://www.pfmjournal.org/journal/view.php?doi=10.23838/pfm.2021.00107

  Pubertal onset is a complex process, which is influenced by genetic and environmental factors, such as obesity and endocrine-disrupting chemicals. […] Genetic factors are suggested to account for 50% to 80% of the variation in puberty initiation, as indicated by the greater concordance of pubertal timing observed in monozygotic twins than in dizygotic twins. […] Although genetic factors play a crucial role in CPP development, only few associated genes have been identified. […] To date, four monogenic genes have been identified: KISS1, KISS1R, MKRN3, and DLK1. […] Genetic factors are considered play a crucial role in pubertal onset. […] Greater concordance of pubertal timing has been found in monozygotic twins than in dizygotic twins. […] Despite the strong heritability of pubertal timing, our understanding of the underlying genetics remains limited.

• #13 Genetic etiologies of central precocious puberty

  https://www.pfmjournal.org/journal/view.php?number=110

  Pubertal onset is a complex process, which is influenced by genetic and environmental factors, such as obesity and endocrine-disrupting chemicals. […] Genetic factors are suggested to account for 50% to 80% of the variation in puberty initiation, as indicated by the greater concordance of pubertal timing observed in monozygotic twins than in dizygotic twins. […] Although genetic factors play a crucial role in CPP development, only few associated genes have been identified. […] To date, four monogenic genes have been identified: KISS1, KISS1R, MKRN3, and DLK1. […] Genetic factors are considered play a crucial role in pubertal onset. […] Greater concordance of pubertal timing has been found in monozygotic twins than in dizygotic twins. […] Genetic factors are suggested to account for 50% to 80% of the variation in the initiation of puberty.

• #14 Genetic etiologies of central precocious puberty

  https://www.pfmjournal.org/journal/view.php?doi=10.23838/pfm.2021.00107

  These findings provide a new perspective on the development of puberty. […] The regulation of puberty is multifactorial and is known to be associated with various genetic and environmental factors. However, the pathophysiology of pubertal onset is not entirely understood yet. […] Many research groups have sought to identify the genetic causes of CPP; but, to date, only four monogenic genes have been identified: KISS1, KISS1R, MKRN3, and DLK1.

• #15 Genetic etiologies of central precocious puberty

  https://www.pfmjournal.org/journal/view.php?number=110

  The exact mechanisms by which MKRN3 mutations affect HPG axis activation remain unclear. […] The regulation of puberty is multifactorial and is known to be associated with various genetic and environmental factors. […] However, the pathophysiology of pubertal onset is not entirely understood yet. […] Many research groups have sought to identify the genetic causes of CPP; but, to date, only four monogenic genes have been identified: KISS1, KISS1R, MKRN3, and DLK1. […] These findings suggest the existence of genetic heterogeneity across ethnic groups and highlight the requirement for further genetic studies.

• #16 Genetic factors in precocious puberty

  https://www.e-cep.org/journal/view.php?number=20125555474

  Genetic factors may be involved in the diagnosis of ICPP in both girls and boys. […] The genetic background of pubertal onset is supported by studies showing that maternal age at menarche is associated with pubertal timing in her offspring. […] Of these genes, only 4 (KISS, KISS1R, MKRN3, and DLK1) have been confirmed to play a role in patients diagnosed with CPP to date. […] The kisspeptin gene (KISS1) is a key factor related to pubertal onset. […] A study showed that KISS1 mutations lead to CPP, which then leads to elevated kisspeptin levels. […] The kisspeptin receptor (KISS1R) gene has a structure similar to that of the galanin receptor. […] A study suggested that an autosomal-dominant missense mutation in KISS1R (a gain-of-function mutation) results in activation of the intracellular signaling pathway and can be related to CPP.

• #17 Genetic etiologies of central precocious puberty

  https://www.pfmjournal.org/journal/view.php?doi=10.23838/pfm.2021.00107

  The important function of the KISS1/KISS1R system in the pubertal process makes it necessary to investigate the mutations and polymorphisms in the KISS1 gene and their association with CPP as well as the KISS1R gene. […] MKRN3 mutations are now the most commonly known genetic factors in CPP. […] The prevalence of MKRN3 mutations was 33% to 46% in familial and 0.4% to 3.8% in sporadic CPP. […] The MKRN3 mutation was identified in only one out of 260 with CPP in Korea, which is significantly lower compared to Western countries that reported CPP to be associated with MKRN3 gene mutations. […] The MKRN3 gene was detected on chromosome 15q11.2, which is a critical region and has been shown to play a role in Prader-Willi syndrome. […] The mechanism by which imprinting genes influences pubertal expression remains unknown.

• #18 Genetic factors in precocious puberty

  https://www.e-cep.org/journal/view.php?number=20125555474

  The MKRN3 gene is believed to suppress pubertal onset in humans as well. […] A few studies have suggested that decreased serum MKRN3 levels are observed in girls and boys before pubertal onset. […] The DLK1 gene has 5 exons and encodes a transmembrane protein belonging to the epidermal growth factor-like family of proteins. […] The DLK1 protein plays a role in the differentiation of neuroendocrine cells as well as osteogenesis, adipogenesis, hematopoiesis, and hepatocyte production. […] The GABRA1 gene, located on chromosome 5q34, encodes the gamma-aminobutyric acid (GABA)-A receptor 1 subunit. […] Loss-of-function mutations or polymorphisms in GABRA1 can be established to explain premature GnRH release. […] The LIN28B gene is a human homolog of the lineage-28 (lin-28) gene of Caenorhabditis elegans that is essential for the timing of developmental events.

• #19 Genetic factors in precocious puberty

  https://www.e-cep.org/journal/view.php?number=20125555474

  The NPY gene and its protein expression in monkeys were negatively related to GnRH pulse generator activity. […] Loss-of-function mutations in the TAC3 or TACR3 genes were identified in subjects with familial hypogonadotropic hypogonadism, suggesting that the NKB and NK3R pathways are indispensable components of pubertal onset. […] The epigenetic mechanism of ICPP in humans remains unclear.

• #20 Revista Española Endocrinología Pediátrica – Molecular Advances in Central Precocious Puberty

  https://www.endocrinologiapediatrica.org/modules.php?name=articulos&idarticulo=514&idlangart=ES

  The role of this gene in the pathogenesis of CPP was first demonstrated in 2013, when we performed whole exome sequence analysis in 40 members of fifteen families with CPP. […] Rigorous criteria were used to filter the variants and identify the mutations likely to be causative of the phenotype for CPP. […] These recent studies indicate that DLK1 is a novel link between reproduction and metabolism. […] Pharmacological and non-pharmacological perturbations of DNA methylation and histone modifications in animal models were able to modulate gene expression, resulting in delayed or advanced puberty, indicating that the initiation of puberty requires repression of target repressor genes. […] We identified 120 differentially methylated regions (DMR) and the majority of them (99%) was hypermethylated in girls at pubertal development. The genomic region with the biggest methylation difference was related to the promoter of a zing finger gene (ZNF57).

• #21 Aberrant Notch Signaling Pathway as a Potential Mechanism of Central Precocious Puberty

  https://www.mdpi.com/1422-0067/23/6/3332

  Aberrant Notch Signaling Pathway as a Potential Mechanism of Central Precocious Puberty […] The Notch signaling pathway is highly conserved during evolution. It has been well documented that Notch signaling regulates cell proliferation, migration, and death in the nervous, cardiac, and endocrine systems. […] Recently, several studies have reported that mutations in genes related to the Notch signaling pathway were found in patients with central precocious puberty (CPP). […] The Notch signaling pathway is a genetically highly conserved signaling cascade that plays an important role in maintaining homeostasis and regulates embryonic development, cell proliferation, and cell death. […] Recent studies have reported that the Notch signaling pathway may be associated with the onset and progression of puberty.

• #22 Aberrant Notch Signaling Pathway as a Potential Mechanism of Central Precocious Puberty

  https://www.mdpi.com/1422-0067/23/6/3332

  The exact mechanism of how the Notch signaling pathway affects the onset of puberty remains unknown. […] The genes involved in the Notch signaling pathway, including Notch receptors, Dll1, Hes1, and Hey1 are expressed in progenitor cells of the anterior pituitary during postnatal development and in the adult pituitary. […] The DLK1 intracellular domain has been shown to negatively regulate Notch signaling by disrupting the RBPJ-κ/Notch signaling pathway. […] Therefore, these studies support that DLK1, which is a noncanonical ligand of the Notch signaling pathway, may play a role in regulating pubertal onset or progression, although the exact mechanism of its involvement is unknown.

• #23

  https://www.archivesofmedicalscience.com/Central-precocious-puberty-etiology-with-particular-consideration-of-neurological,121051,0,2.html

  Damage to the central nervous system (CNS) due to the increased intracranial pressure or tumor may eliminate this inhibitory effect and lead to precocious puberty. […] The etiology of CPP is very diverse. In girls, idiopathic CPP accounts for the vast majority of cases. However, recently the incidence of idiopathic cases has decreased due to the detection of gene mutations that lead to premature activation of the GnRH pulse generator. In boys, however, organic changes in the CNS are much more prevalent (40-75% of cases), which prompts imaging assessment of the CNS in each case of CPP among boys. […] The pathomechanism of CPP in HH patients is not well understood. Currently, several hypotheses are considered: a) HH acts as an ectopic GnRH pulse generator; b) HH is composed of transforming growth factor (TGF-) producing astroglial cells that could cause premature activation of pulsatile GnRH release; c) due to increased CNS pressure associated with the presence of tumor mass, reduced influence of inhibitory neurotransmitters on GnRH neurons in the hypothalamus is observed.

• #24 Precocious Puberty: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/924002-overview

  CNS abnormalities associated with precocious puberty include the following: Tumors (eg, astrocytomas, gliomas, germ cell tumors secreting human chorionic gonadotropin [HCG]), Hypothalamic hamartomas, Acquired CNS injury caused by inflammation, surgery, trauma, radiation therapy, or abscess, Congenital anomalies (eg, hydrocephalus, arachnoid cysts, suprasellar cysts).

• #25 Precocious Puberty | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/27608

  Precocious puberty is classified into two major categories based on the etiology […] Central Precocious puberty (CPP) represents true pubertal development due to the earlier maturation and activation of the HPG axis. […] The most common brain lesion causing CPP is hypothalamic hamartoma. […] The ectopic neural cells in the lesion serve as an accessory GnRH pulse generator. […] The exact mechanism is not known, but suggestions are that better nutrition and exposure to endocrine disrupting chemicals can play a role. […] Recent years have seen some interesting associations with mutations of kisspeptin (KISS1) and makorin ring finger (MRF3) genes and their receptors. […] These genes are responsible for the stimulatory and inhibitory signals to the GnRH release. […] Loss or gain of function mutations in these genes results in CPP.

• #26 Precocious Puberty: Types, Pathogenesis and Updated Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC10663169/

  The pathogenesis of hypothalamic hamartomas in activating GnRH neurons is questioned. It may activate surrounding glial cells (and secondarily GnRH) through TGF or provide indirect evidence through the presence of GnRH immunoreactivity within the tumor that indicates excess GnRH production. […] Gliomatous cells have been reported to express the GnRH receptor. Other lesions, including pineal cysts, hydrocephalus, infiltrative lesions, meningomyelocele, infectious diseases, and encephalopathies, were reported to be associated with CPP.

• #27

  https://www.archivesofmedicalscience.com/Central-precocious-puberty-etiology-with-particular-consideration-of-neurological,121051,0,2.html

  The prevalence of CPP increases following cranial exposure to radiation due to tumors or leukemia. Low doses of radiation (18-24 Gy) used in the prophylactic treatment of the CNS in acute lymphoblastic leukemia and moderate doses (25.0-47.5 Gy) used in the treatment of brain tumors in children increase the risk of CPP. […] The cause of CPP remains undetected among girls in more than 90% of cases (idiopathic precocious puberty). Idiopathic precocious puberty is significantly less prevalent among boys and CPP is mostly the result of lesions in the CNS. […] However, genetic testing for these mutations is still rarely performed.

• #28 Precocious Puberty | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/27608

  Peripheral Precocious Puberty (PPP) constitutes the precocious development of secondary sexual characteristics independent of the GnRH pulsatile secretion; this is due to the production of sex steroids from endogenous or exogenous sources. […] Testitoxicosis is a rare autosomal dominant disorder with the clinical phenotype limited to males. […] It is caused by a germline activating mutation of the LH receptor gene, resulting in the activation of the Leydig cells and high testosterone levels. […] McCune-Albright syndrome is a sporadic condition caused by activating mutation of the GNAS 1 gene, which encodes the alpha subunit of the G protein. […] This gene activation increases the cAMP formation, and all its dependent receptors become hyper-functional.

• #29 Precocious Pseudopuberty: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/923876-overview

  The etiology of PPP can be categorized into either genetic or acquired disorders, and some vary by gender. Congenital or genetic causes include McCune-Albright syndrome (MAS), familial male-limited precocious puberty (FMPP), and congenital adrenal hyperplasia (CAH). Acquired causes include tumors that secrete human chorionic gonadotropin (HCG); sex steroidexcreting tumors of the adrenal gland, ovary, or testis; or exposure to exogenous sex hormones. […] In gonadotropin-independent precocious puberty, the presence of testosterone in boys or estrogen in girls is not secondary to activation of the HPG axis. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations are low, and response to exogenous gonadotropin-releasing hormone (GnRH) is suppressed (prepubertal). […] Circulating sex steroids (testosterone or estrogen) cause secondary sexual development. The sex steroids (estrogen or testosterone) come from either the adrenal gland or the gonad, independent of the hypothalamic-pituitary portion of the pubertal axis.

• #30 Precocious Pseudopuberty: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/923876-overview

  Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. […] McCune-Albright syndrome (MAS) involves the overactivity of the cyclic adenosine monophosphate (cAMP) signaling pathway. […] Familial male precocious puberty (FMPP), also called testotoxicosis, is a dominant mutation in the LH receptor gene that results in the production of a receptor that is capable of spontaneous activation in the absence of either LH or HCG. […] Van Wyk-Grumbach syndrome is a rare syndrome characterized by hypothyroidism, precocious puberty with multicystic ovaries, and features of polycystic ovarian disease (PCOD). The exact mechanism for the development of sexual precocity secondary to hypothyroidism is unknown.

• #31 Precocious Puberty – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544313/

  Tumors are rare causes of PPP. There is an increased androgen production in CAH, adrenal tumors, and Leydig cell tumors. […] Testitoxicosis is a rare autosomal dominant disorder with the clinical phenotype limited to males. It is caused by a germline activating mutation of the LH receptor gene, resulting in the activation of the Leydig cells and high testosterone levels. […] The decision to treat depends on the age of the child and the progression of puberty. If the child has rapidly progressing symptoms or if bone age is significantly advanced, consider treatment. […] GnRH agonists are the standard of care. […] GnRH agonist therapy is generally considered safe, with no reported significant adverse events. […] Treatment is directed towards eliminating the source of sex steroids. […] The primary care providers and the pediatric endocrinologists should have a detailed conversation explaining the early pubertal changes even if it’s a benign variant. […] Precocious puberty is becoming increasingly common owing to a multitude of factors such as genetics, lifestyle changes, and exposure to endocrine disrupting chemicals.

• #32 Precocious Pseudopuberty: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/923876-overview

  In aromatase excess syndromes, an apparent increase in the extraglandular aromatization of androgens leads to an increase in the circulating estrogen levels. This is associated with isosexual precocious puberty in girls and prepubertal gynecomastia in boys. […] The exact pathophysiology varies with the underlying cause of precocious puberty. […] The etiologies of precocious pseudopuberty (PPP) can vary between boys and girls and include production of sex steroids by the gonad in an unregulated fashion, such as in McCune-Albright syndrome (MAS) or familial male-limited precocious puberty (FMPP); sex steroid secretion by the adrenal gland as occurs in congenital adrenal hyperplasia (CAH); tumors that secrete human chorionic gonadotropin (HCG); sex steroidexcreting tumors of the adrenal gland, ovary, or testis; or exposure to exogenous sex hormones.

• #33 Precocious Puberty: An Unusual Presentation of Hypothyroidism

  https://jpp.mums.ac.ir/article_2165.html

  Hypothyroidism is usually associated with delayed pubertal development but in rare occasions precocious puberty may ensue which is seen in cases of prolonged and untreated hypothyroidism. This is also called the Van Wyk Grumbach syndrome. […] Delayed puberty is a common manifest- tation in hypothyroid patients but rarely can it present as precocious puberty. The onset is usually with breast enlargement and vaginal bleeding in girls and testicular enlargement without virilization in boys. This presentation is also called as Van Wyk Grumbach syndrome. […] Hypothyroidism associated precocious puberty is also called Van Wyk Grumbach syndrome. It was first described in 1960 by Van Wyk and Grumbach. In girls the onset of symptoms is with thelarche followed by menarche and charactaristicly there is no development of pubic or axillary hair and opposite the patients with true precocious puberty these patients have a decreased linear growth.

• #34 The Role of Pediatric Nutrition as a Modifiable Risk Factor for Precocious Puberty

  https://www.mdpi.com/2075-1729/11/12/1353

  The interactions between genetic, endocrine, and environmental factors are crucial in pubertal timing. Nutritional status is considered one of the most important factors involved in pubertal development and it was estimated to explain as much as 25% of the variation in the timing of puberty. […] This narrative review presents an overview on the role of nutritional factors as determinants of the timing of sexual maturation, focusing on early-life and childhood nutrition. […] A diet characterized by a high energy, fat, and protein intake and a high glycemic index associated with unbalanced micronutrient supplies seems to be involved in hormonal stimulation, leading to the precocious activation of puberty. […] More than 20% of the variation in pubertal timing may be explained by the nutritional status during early life and childhood. This correlation can be related to rapid weight gain during infancy and childhood, but some effects are also independent of weight gain. […] Breast milk, the recommended form of nutrition from birth to six months, seems to have an important protective role against early puberty onset, mainly due to its positive influence on infant growth rate and childhood overweight prevention.

• #35 Frontiers | Childhood obesity and central precocious puberty

  https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1056871/full

  Childhood obesity is a major public health problem worldwide, and the relationship between obesity and central precocious puberty has long been confirmed, however, the mechanisms underlying this association remain elusive. […] The development of CPP is both determined by genetic and environmental factors. The past decade has confirmed a series of core genes of CPP, such as the kisspeptin gene (KISS1), the kisspeptin receptor gene (KISS1R), the makorin ring finger protein 3 (MKRN3), and the Delta-like non-canonical Notch ligand 1 (DLK1). […] The epidemic of childhood obesity serves as the major companion for CPP, suggesting the impact of nutritional and metabolic cues on the HPG axis. […] There is clear evidence to support the effects of higher childhood body mass index (BMI) on the onset and development of puberty in both boys and girls.

• #36 Metabolic characteristics and pathogenesis of precocious puberty in girls: the role of perfluorinated compounds | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-023-03032-0

  The correlation analysis between PFCs and the clinical phenotype in girls with PP as well as the endogenous metabolites driven by PFCs will help to reveal the impact of PFCs on the occurrence and development of precocious puberty in girls and the preliminary mechanisms. […] The disturbed metabolic pathway and network induced by CPP and PT. […] The link of clinical phenotype-PFCs-metabolic characteristics in the CPP girls indicated that PFCs may cause disturbance of metabolic network of CPP girls by disturbing endocrine homeostasis and/or directly affecting metabolite characteristics. […] The significantly reduced level of VD in the CPP girls further indicated the affected bone growth of the CPP girls. […] The occurrence of CPP may be closely related to high BMI of girls. […] The disordered trend of pyruvate metabolism and butyrate metabolism kept almost consistent between CPP and PT, indicating that pyruvate metabolism and butyrate metabolism disorder are possibly a common phenomenon of PP.

• #37 Unbalanced dietary patterns contribute to the pathogenesis of precocious puberty by affecting gut microbiota and host metabolites | bioRxiv

  https://www.biorxiv.org/content/10.1101/2021.04.07.438759v1

  Unbalanced dietary patterns contribute to the pathogenesis of precocious puberty by affecting gut microbiota and host metabolites. […] Precocious puberty (PP) mostly stems from endocrine disorders. However, its triggering factors, especially for the early onset of partial PP, and the associated pathogenic mechanisms remain ambiguous. […] The analysis revealed substantial alterations in gut microbiota, serum metabolites, as well as lifestyle patterns in the PP group, which were characterized by an elevated abundance of β-glucuronidase-producing and butyrate-producing bacteria, and excessive lipid concentration with decreased levels of organic nitrogen compounds in the serum of the participants. […] Furthermore, structural equation modeling revealed that unhealthy dietary habits were the primary contributors for the alteration of gut microbiota and serum metabolites, triggering the imbalance in the host hormones that leads to premature physical development. […] Our study determines a causal relationship among the gut microbiota, host metabolites, diet, and clinical characteristics of preadolescent girls who experienced early onset of PP, and formulates non-invasive diagnostic tools demonstrating excellent performance for the early detection of PP.

• #38 Enrichment analyses of diseases and pathways associated with precocious puberty using PrecocityDB | Scientific Reports

  https://www.nature.com/articles/s41598-021-83446-z

  Precocious puberty (PP) is an important endocrine disorder affecting children globally. Several genes, SNPs and comorbidities are reported to be associated with PP; however, this data is scattered across scientific literature and has not been systematically collated and analysed. […] Pathway enrichment analysis of PP-associated genes revealed that endocrine and cancer-related pathways are highly enriched. Disease enrichment analysis indicated that individuals with PP seem to be highly likely to suffer from reproductive and metabolic disorders such as PCOS, hypogonadism, and insulin resistance. […] The cause of PP can be ascribed to genetic, metabolic, or environmental factors. 70-80% of the variance in pubertal timing can be attributed to genetic factors. Genetic studies suggest that PP has an autosomal dominant mode of inheritance. Mutations in genes that are involved in sexual development such as MKRN3, KISS1, GPR54, CYP19A1, and LHCGR contribute to PP.

• #39 Enrichment analyses of diseases and pathways associated with precocious puberty using PrecocityDB | Scientific Reports

  https://www.nature.com/articles/s41598-021-83446-z

  The highest number of SNPs associated with PP was reported for MKRN3 (Makorin ring finger protein 3) followed by LHCGR (luteinizing hormone (LH)/choriogonadotropin receptor gene), KISS1 (Kisspeptin), KISS1R (Kisspeptin receptor), and LIN28B (Lin-28 Homolog B). MKRN3 gene is the most widely studied gene for its association with precocious puberty. […] Mutations in MKRN3, KISS1 and KISS1R contribute to precocious puberty by activating gonadotropic axis. Inactivating LHCGR mutations in females lead to amenorrhea and infertility, whereas activating LHCGR mutations in males have been associated with familial male-limited precocious puberty (FMPP). […] To evaluate the comorbidity risk, disease and pathway enrichment analyses of gene-set in PP were performed. Some of the top pathways identified were ovarian steroidogenesis, GnRH signalling, estrogen signalling, and thyroid hormone signalling pathways; these pathways are known to be critical for PP, PCOS and cancers.

• #40

  https://journals.lww.com/md-journal/fulltext/2023/12010/efficacy_and_mechanism_of_nourishing_yin_and.73.aspx

  Central precocious puberty (CPP) is due to the early activation of the hypothalamus-pituitary-gonadal axis, and its incidence is on the rise. […] The pathogenesis of CPP is caused by the early activation of the hypothalamus-pituitary-gonadal axis, the increase of pulsatile secretion of gonadotropin releasing hormone (GnRH), and the early secretion of sex hormones, which leads to premature closure of the epiphysis. […] The mechanism of the core herb pair of NYPF therapy for CPP through muti-components, muti-targets and muti-pathways. […] The pathogenesis of CPP is still unclear. According to the majority of researchers, it is associated with the early activation of the hypothalamus-pituitary-gonadal axis and the release of sex hormones. […] PPI network analysis found that TP53, JUN, AKT1, ESR1, TNF, IL6, CCND1, MAPK1, BCL2, EGFR, IL1B, and PTGS2 are the core targets of Zhimu- Huangbai to interfere with CPP. […] KEGG enrichment analysis suggested that Endocrine resistance, MAPK signaling pathway, and PI3K-Akt signaling pathway were the main pathways for the core herb pair against CPP.

• #41 The first central precocious puberty proteomic profiles revealed multiple metabolic networks and novel key disease-associated proteins | Aging

  https://www.aging-us.com/article/203676

  Though central precocious puberty (CPP) as a disease that seriously affects the development of a child is increasing year by year, treatment options remain limited and is the same as the 1980s method. […] These are mainly due to the complex pathogenesis of central precocious puberty. […] Our data established the first proteome profile of CPP revealed 163 down-regulated and 129 were up-regulated differentially expressed proteins. […] These altered proteins were primarily enriched in three metabolic process including energy metabolism, amino acid metabolism and nitrogenous base metabolism. […] The identified altered members of the metabolic signaling are valuable and potential novel therapeutic targets of central precocious puberty.

• #42 Precocious puberty – Wikipedia

  https://en.wikipedia.org/wiki/Precocious_puberty

  If no cause can be identified, it is considered idiopathic or constitutional. […] Secondary sexual development induced by sex steroids from other abnormal sources is referred to as peripheral precocious puberty or precocious pseudopuberty. […] Although the causes of early puberty are still somewhat unclear, girls who have a high-fat diet and are not physically active or are obese are more likely to physically mature earlier. […] High levels of beta-hCG in serum and cerebrospinal fluid observed in a 9-year-old boy suggest a pineal gland tumor. […] The gene MKRN3, which is a maternally imprinted gene, was first cloned by Jong et al. in 1999. […] MKRN3 appears to act as a „brake” on the central hypothalamic-pituitary access. Thus, loss of function mutations of the protein allow early activation of the GnRH pathway and cause phenotypic CPP. […] Overall, puberty blockers have demonstrated an excellent safety and efficacy profile in the treatment of precocious puberty.

• #43 Mechanism of precocious puberty in McCune-Albright syndrome (MAS) | Pediatric Research

  https://www.nature.com/articles/pr19812276

  The hypotheses to explain precocious puberty in the MAS include premature pubertal gonadotropin secretion, and autonomous ovarian estradiol (E2) secretion without gonadotropin (LH and FSH) activation. […] We conclude that in MAS changes in ovarian estradiol secretion appear to be independent of changes in plasma gonadotropin concentration.

• #44 Precocious Puberty: An Unusual Presentation of Hypothyroidism

  https://jpp.mums.ac.ir/article_2165.html

  The exact hormonal mechanism of hypothyroidism associated precocious puberty is not understood. Wyk and Grumbach explained that in response to thyroid hormone deficiency overproduction of gonadotropins as well as thyrotropin (which both share common subunit) occurs. But these elevated gonadotropins have been shown to be bioinactive in earlier studies and also absence of characteristics of gonadotropin excess such as advanced bone age in these cases makes the gonadotropin excess as the underlying mechanism unlikely. […] Another theory is that interaction of TSH with human FSH receptor is the possible mechanism of this syndrome. Elevated levels of TSH produce FSH like effects on the gonads in the absence of LH effects. This seems to be the most likely mechanism of this syndrome.

• #45

  https://dah-journal.com/index.php/dah/article/view/15

  Precocious puberty can be distinguished in central, or peripheral, based on the presence or absence of the Hypothalamic- Pituitary- Gonadal axis activation. […] The pathogenesis of peripheral precocious puberty (PPP) is based mainly on excessive estrogenic exposure, either endogenous or exogenous. […] The congenital causes of PPP include McCune- Albright syndrome (MAS) and Congenital Adrenal Hyperplasia (CAH). […] The main causes of acquired PPP are oestrogen producing tumours, which are mainly of ovarian or adrenal origin, hypothyroidism and environmental oestrogens or substances with estrogenic function.

• #46 Metabolic characteristics and pathogenesis of precocious puberty in girls: the role of perfluorinated compounds | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-023-03032-0

  Precocious puberty (PP) in girls is traditionally defined as the onset of breast development before the age of 8 years. […] This study aimed to screen specific biomarkers of PT and CPP and elucidate their underlying pathogenesis. […] Clinical phenotypes and PFCs drive the metabolic characteristics and cause metabolic disturbances in CPP and PT. […] PFC exposure is associated with endocrine homeostasis imbalance. PFC exposure and/or endocrine disturbance directly or indirectly drive metabolic changes and form overall metabolic network perturbations in CPP and PT. […] The elevation of formate, ethanol, and 3-hydroxybutyrate may serve as the early diagnostic indicator for PP in girls. […] The main clinical manifestation of the PT girls is simple breast development due to exposure to the peripheral estrogen environment.

• #47 Analysis of risk factors of precocious puberty in children | BMC Pediatrics | Full Text

  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-023-04265-x

  The multifactor logistic regression analysis shows that the risk factors of childrens precocious puberty included gender (female), bone age (10 years old), and daily exercise time (0.9 h), E2 (66.00pmol/L), FSH (6.00U/L), LH (3.50U/L), leptin (8.00 G/L), mothers menarche time (12 years old), living environment (chemical industry zone), consumption of nutritional supplements (often), consumption of high-protein food (often), and sleep time (10 h). […] In conclusion, childrens gender, bone age, exercise habits, E2, FSH, LH, leptin, mothers menarche time, living environment, eating habits, sleep time and other factors are closely related to precocious puberty in children. […] Therefore, clinicians should pay attention to childrens gender, bone age, exercise habits, E2, FSH, LH, leptin, mothers menarche time, living environment, eating habits, sleep time and other factors to alert the occurrence of precocious puberty.

• #48 Precocious Puberty Animal Models – WuXi Biology

  https://wuxibiology.com/resource/precocious-puberty-animal-models/

  The causes of peripheral precocious puberty include gonadal tumors, adrenal diseases, other diseases, or exposure to exogenous hormones. […] The pubertal development of rodents and non-human primates is similar to that of humans, with clear characteristics of gonadal development, making them commonly used animal models in the study of the pathogenesis of precocious puberty and preclinical research. […] The Danazol-induced female rat model of precocious puberty is a preclinical model used to explore the causes of precocious puberty and to validate pharmacodynamics. […] However, for neonates whose nervous system is not yet fully developed, especially animals within 7 days after birth, Danazol can prematurely activate the HPG axis, leading to a precocious puberty phenotype in rats. […] The rising rate of precocious puberty in children has drawn increasing attention to this disorder. With deepening understanding of its mechanisms and the development of new drugs, the application of preclinical models is becoming more and more important.

• #49 The Role of Pediatric Nutrition as a Modifiable Risk Factor for Precocious Puberty

  https://www.mdpi.com/2075-1729/11/12/1353

  Puberty is a critical phase of growth and development characterized by a complex process regulated by the neuroendocrine system. Precocious puberty (PP) is defined as the appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal. The timing of puberty has important public health, clinical, and social implications. In fact, it is crucial in psychological and physical development and can impact future health. Nutritional status is considered as one of the most important factors modulating pubertal development. […] Several studies have proposed mechanisms by which energy imbalance, macro/micronutrient food content and dietary patterns may modulate the premature activation of the HPG axis, inducing PP. An increase in knowledge on the mechanism whereby nutrients may influence puberty will be useful in developing nutritional recommendations to maintain the regular timing of puberty.

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