Pubertal development and regulation
Open accessAbstract
Puberty marks the end of childhood and is a period when individuals undergo physiological and psychological changes to achieve sexual maturation and fertility. The hypothalamic-pituitary-gonadal axis controls puberty and reproduction and is tightly regulated by a complex network of excitatory and inhibitory factors. This axis is active in the embryonic and early postnatal stages of life and is subsequently restrained during childhood, and its reactivation culminates in puberty initiation. The mechanisms underlying this reactivation are not completely known. The age of puberty onset varies between individuals and the timing of puberty initiation is associated with several health outcomes in adult life. In this Series paper, we discuss pubertal markers, epidemiological trends of puberty initiation over time, and the mechanisms whereby genetic, metabolic, and other factors control secretion of gonadotropin-releasing hormone to determine initiation of puberty.
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Written from the paper’s full text.
TL;DR
Puberty is initiated by reactivation of pulsatile GnRH secretion after childhood quiescence, controlled by a complex network of excitatory and inhibitory factors. This review summarizes pubertal markers, secular trends, and genetic/metabolic regulators including kisspeptin, neurokinin B, MKRN3, leptin, insulin, and ghrelin.
Key findings
- The hypothalamic-pituitary-gonadal axis is active in mid-gestation and early postnatal minipuberty, then restrained until puberty; normal puberty is defined as onset at 8–12 years in girls and 9–14 years in boys, usually lasting 3–4 years.
- Genetic modulation is substantial: around 50–80% of variation in pubertal onset may be genetically determined; a genetic defect is identified in approximately 40% of isolated hypogonadotropic hypogonadism cases, and MKRN3 is the most common known genetic defect associated with central precocious puberty.
- Kisspeptin (KISS1/KISS1R) and neurokinin B (TAC3/TACR3) are key excitatory inputs to GnRH; MKRN3 is an imprinted inhibitory factor, with paternally inherited mutations causing central precocious puberty.
- Metabolic signals gate reproduction: leptin is permissive for hypothalamic-pituitary-gonadal maturation, insulin may modulate GnRH/gonadotrope function, and ghrelin inhibits gonadotropin pulsatility; a recent study reported earlier or later puberty timing was associated with increased risks for 48 adverse outcomes.
Methods
- Narrative Series review; no primary data collection. Literature search of MEDLINE and PubMed for English articles up to June 1, 2015, using terms such as “puberty,” “puberty onset,” or “GnRH regulation,” combined with “regulation,” “markers,” “Tanner stages,” “trends,” “metabolism,” “kisspeptin,” “tachykinin,” “MKRN3,” “leptin,” “insulin,” and “GWAS.”
- Relevant papers were read in full, reference lists were searched, and the most relevant were selected on the basis of design, findings, and time of publication.
Limitations
- Stated: the precise mechanisms that trigger puberty initiation remain elusive; endocrine disruptor effects on GnRH secretion are controversial and difficult to assess in humans, with a paucity of definitive data; population studies of puberty timing have limited comparability and use different methods.
- Stated: many associations between puberty timing and health outcomes are epidemiological and need validation; the mechanism by which MKRN3 regulates the axis is not completely understood, and further studies with larger samples are needed.
- Evident from the text: as a narrative review, it lacks a systematic search, formal quality assessment, or meta-analysis, and many mechanistic conclusions rely on animal models and genetic studies.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 152 cited sources checked · 0 supported · 0 flagged
- Premisecitation
In both sexes, pubarche is dependent on an increase in adrenal androgen production, a physiological event termed adrenarche.
“In both sexes, pubarche is dependent on an increase in adrenal androgen production, a physiological event termed adrenarche.8”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Kempná, 2015, Regulation of androgen biosynthesis—a short review and preliminary results from the hyperandrogenic starvation NCI-H295R cell model, Mol Cell Endocrinol source
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- Premisecitation
The age of puberty onset is associated with subsequent health outcomes.
“The age of puberty onset is associated with subsequent health outcomes.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [15] Velie, 2005, Lifetime reproductive and anthropometric risk factors for breast cancer in postmenopausal women, Breast Dis source
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- cites [16] Elks, 2013, Age at menarche and type 2 diabetes risk: the EPIC-InterAct study, Diabetes Care source
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- cites [17] Lakshman, 2009, Early age at menarche associated with cardiovascular disease and mortality, J Clin Endocrinol Metab source
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- Premisecitation
In girls with late initiation of puberty, there can be a decrease in the interval between thelarche and menarche.
“In girls with late initiation of puberty, there can be a decrease in the interval between thelarche and menarche.6”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Parent, 2003, The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration, Endocr Rev source
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- Study design and conductreasoning
Because of differences in study designs and methods used to assess puberty initiation, it can be difficult to determine the exact age of puberty onset in population studies.
“For these reasons and because of differences in study designs and methods used to assess puberty initiation, it can be difficult to determine the exact age of puberty onset in population studies.”
Quote in the paperNot a substantial claim - Premisecitation
In boys, testicular enlargement is followed by an increase in growth velocity and subsequent spermarche.
“In boys, testicular enlargement is followed by an increase in growth velocity and subsequent spermarche.7”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Biro, 1995, Pubertal staging in boys, J Pediatr source
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- Interpretationnone given
The augmentation of activators of GnRH secretion together with the suppression of inhibitors of GnRH secretion culminates in puberty initiation.
“Evidence suggests that the augmentation of activators of GnRH secretion together with the suppression of inhibitors of GnRH secretion culminates in puberty initiation.”
Quote in the paperNot a substantial claim - Premisecitation
Puberty is initiated with a sustained increase in pulsatile release of GnRH from the hypothalamus after a quiescent period during childhood.
“Puberty is initiated with a sustained increase in pulsatile release of GnRH from the hypothalamus after this quiescent period.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Terasawa, 2001, Neurobiological mechanisms of the onset of puberty in primates, Endocr Rev
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- Study design and conductcitation
The effects of endocrine disruptors on GnRH secretion and therefore on the initiation of puberty and reproduction are still controversial and difficult to assess in human beings.
“The effects of endocrine disruptors on GnRH secretion and therefore on the initiation of puberty and reproduction are still controversial and difficult to assess in human beings.22”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Parent, 2015, Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: revision of human observations and mechanistic insight from rodents, Front Neuroendocrinol source
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- Premisecitation
Two European studies in which careful physical examination was used to ascertain breast development showed no substantial advance in age of puberty onset.
“By contrast, two European studies in which careful physical examination was used to ascertain breast development showed no substantial advance in age of puberty onset.24,25”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Environmental factors might have effects on the neuroendocrine system, particularly during fetal and early postnatal life.
“Environmental factors might have effects on the neuroendocrine system, particularly during fetal and early postnatal life;22”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Parent, 2015, Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: revision of human observations and mechanistic insight from rodents, Front Neuroendocrinol source
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- Premisecitation
The decrease in average age of menarche between the mid-19th and mid-20th centuries has been attributed to improvements in general health, nutrition, and other living conditions during this period.
“This change has been attributed to improvements in general health, nutrition, and other living conditions during this period.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Wyshak, 1982, Evidence for a secular trend in age of menarche, N Engl J Med source
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- Premisecitation
A large cross-sectional study of about 17 000 girls in the USA (the Pediatric Research in Office Settings [PROS] study) used information obtained from mothers and photography, and the results suggested an advancement of pubertal development in the second half of the 20th century.
“A large cross-sectional study of about 17 000 girls done in an office setting in the USA (the Pediatric Research in Office Settings [PROS] study) used information obtained from mothers and photography, and the results suggested an advancement of pubertal development in the second half of the 20th century.23”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] Herman-Giddens, 1997, Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network, Pediatrics source
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- Premisecitation
Studies have shown a decrease in the average age of menarche between the mid-19th and the mid-20th centuries in the USA and in some countries in Europe.
“Studies have shown a decrease in the average age of menarche between the mid-19th and the mid-20th centuries in the USA and in some countries in Europe.20”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Wyshak, 1982, Evidence for a secular trend in age of menarche, N Engl J Med source
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- Premisecitation
Isolated hypogonadotropic hypogonadism is more typically associated with normal olfactory and GnRH neuronal development, but impaired regulation of GnRH secretion.
“By contrast, isolated hypogonadotropic hypogonadism is more typically associated with normal olfactory and GnRH neuronal development, but impaired regulation of GnRH secretion.33,35”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [33] Bianco, 2009, The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism, Nat Rev Endocrinol source
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- cites [35] Semple, 2010, The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions, Clin Endocrinol (Oxf) source
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- Premisecitation
Data showing an association between the ages at which a mother and her children attain pubertal milestones and between the timing of puberty within ethnic groups are suggestive of genetic modulation of the reproductive endocrine axis.
“Data showing an association between the ages at which a mother and her children attain pubertal milestones and between the timing of puberty within ethnic groups are suggestive of genetic modulation of the reproductive endocrine axis.23,41”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [23] Herman-Giddens, 1997, Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network, Pediatrics source
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- cites [41] Zacharias, 1969, Age at menarche. Genetic and environmental influences, N Engl J Med source
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- Premisecitation
In the 1970s, Belchetz and colleagues showed in animal models that intermittent release of GnRH is required for the activation of the pituitary-gonadal axis.
“In the 1970s, Belchetz and colleagues36 showed in animal models that intermittent release of GnRH is required for the activation of the pituitary-gonadal axis.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Belchetz, 1978, Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone, Science source
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- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
- Premisecitation
These and other data suggest that around 50-80% of the variation in pubertal onset might be genetically determined.
“These and other data suggest that around 50–80% of the variation in pubertal onset might be genetically determined.40”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Palmert, 2003, Genetic approaches to stature, pubertal timing, and other complex traits, Mol Genet Metab source
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- Premisereasoning
The most compelling evidence for specific GnRH neural inputs comes from genetic studies in patients with pubertal disorders.
“Many studies have been done to investigate candidate mechanisms governing GnRH release; however, the most compelling evidence for specific GnRH neural inputs comes from genetic studies in patients with pubertal disorders.”
Quote in the paperSubstantial claim - Premisecitation
Evidence suggests that a complex interaction between nutritional, environmental, and genetic factors is involved in the regulation of puberty initiation.
“The exact mechanism that leads to the reinstatement of pulsatile GnRH secretion is not known, but evidence suggests that a complex interaction between nutritional, environmental, and genetic factors is involved in the regulation of puberty initiation.40”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Palmert, 2003, Genetic approaches to stature, pubertal timing, and other complex traits, Mol Genet Metab source
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- Premisecitation
Impairment of the migration of GnRH and olfactory neurons is often associated with genetic defects.
“Impairment of the migration of these neurons is often associated with genetic defects.33–35”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [33] Bianco, 2009, The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism, Nat Rev Endocrinol source
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- cites [34] Cadman, 2007, Molecular pathogenesis of Kallmann's syndrome, Horm Res
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- cites [35] Semple, 2010, The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions, Clin Endocrinol (Oxf) source
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- Premisecitation
Two of the most important excitatory components of the GnRH network were identified with the demonstration that the genetic loss of such inputs results in failure to initiate the GnRH pulse generator at the expected time of puberty, resulting in isolated hypogonadotropic hypogonadism.
“Two of the most important excitatory components of the GnRH network were identified with the demonstration that the genetic loss of such inputs results in failure to initiate the GnRH pulse generator at the expected time of puberty, resulting in isolated hypogonadotropic hypogonadism.42–45”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [42] de Roux, 2003, Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54, Proc Natl Acad Sci USA source
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- cites [43] Seminara, 2003, The GPR54 gene as a regulator of puberty, N Engl J Med source
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- cites [44] Topaloglu, 2009, TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction, Nat Genet source
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- cites [45] Topaloglu, 2011, Neurokinin B signalling in the human reproductive axis, Mol Cell Endocrinol source
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- Premisecitation
Kisspeptin stimulates gonadotropin release less potently but in a more physiologically effective way than do current treatments with GnRH analogues.
“Kisspeptin stimulates gonadotropin release less potently but in a more physiologically effective way than do current treatments with GnRH analogues.57”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [57] Jayasena, 2015, Direct comparison of the effects of intravenous kisspeptin-10, kisspeptin-54 and GnRH on gonadotrophin secretion in healthy men, Hum Reprod source
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- Premisecitation
Mutations in KISS1 were also identified in patients with isolated hypogonadotropic hypogonadism and central precocious puberty, strengthening the evidence base for the association of this system with pubertal onset.
“Mutations in KISS1 were also identified in patients with isolated hypogonadotropic hypogonadism and central precocious puberty, strengthening the evidence base for the association of this system with pubertal onset.47,48”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Neurons co-expressing kisspeptin and NKB in the human mediobasal hypothalamus often co-express substance P.
“Neurons co-expressing kisspeptin and NKB in the human mediobasal hypothalamus often co-express substance P.65”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Hrabovszky, 2013, Substance P immunoreactivity exhibits frequent colocalization with kisspeptin and neurokinin B in the human infundibular region, PLoS One source
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- Premisecitation
The first gene with an inhibitory effect on GnRH secretion with mutations identified in human beings was MKRN3.
“The first gene with an inhibitory effect on GnRH secretion with mutations identified in human beings was MKRN3 (table, figure 2).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
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- Premisecitation
A non-constitutively activating mutation in KISS1R was the first identified genetic cause of central precocious puberty, reported in an adopted girl with breast development with slow progression that had first been noted at birth and that progressed at age 7 years.
“A non-constitutively activating mutation in KISS1R was the first identified genetic cause of central precocious puberty, reported in an adopted girl with breast development with slow progression that had first been noted at birth and that progressed at age 7 years.49”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Teles, 2008, A GPR54-activating mutation in a patient with central precocious puberty, N Engl J Med source
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- Premisenone given
In many mammalian species, KISS1 expression is negatively regulated in the arcuate nucleus and positively regulated in the anteroventral periventricular nucleus and preoptic area by sex steroids.
“In many mammalian species, KISS1 expression is negatively regulated in the arcuate nucleus and positively regulated in the anteroventral periventricular nucleus and preoptic area by sex steroids.”
Quote in the paperNot a substantial claim - Premisecitation
The KISS1 positive regulation is believed to be important for the LH surge in females of many mammalian species.
“The KISS1 positive regulation is believed to be important for the LH surge in females of many mammalian species.61”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [61] Adachi, 2007, Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats, J Reprod Dev source
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- Premisecitation
Homozygous loss-of-function mutations in the genes encoding the NKB receptor (TACR3) and neurokinin B (TAC3) were identified, providing compelling evidence that the NKB system is necessary for the activation of the hypothalamic-pituitary-gonadal axis in puberty.
“Homozygous loss-of-function mutations in the genes encoding the NKB receptor (TACR3) and neurokinin B (TAC3) were identified, providing compelling evidence that the NKB system is necessary for the activation of the hypothalamic-pituitary-gonadal axis in puberty (table, figure 2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Topaloglu, 2009, TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction, Nat Genet source
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- Premisecitation
In animal models, the KISS1 neurons appear to mediate sex steroid feedback effects in the hypothalamus.
“In animal models, the KISS1 neurons appear to mediate sex steroid feedback effects in the hypothalamus.58,59”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [58] Li, 2007, Estrogen regulates KiSS1 gene expression through estrogen receptor alpha and SP protein complexes, Endocrinology source
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- cites [59] Smith, 2007, KiSS-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season, Endocrinology source
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- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
- Premisecitation
The report by Gianetti and colleagues of reversibility of isolated hypogonadotropic hypogonadism in a high proportion of patients with TACR3 mutations suggested that the NKB system is not absolutely required for GnRH regulation after the maturation of the hypothalamic-pituitary-gonadal axis.
“The report by Gianetti and colleagues63 of reversibility of isolated hypogonadotropic hypogonadism in a high proportion of patients with TACR3 mutations suggested that the NKB system is not absolutely required for GnRH regulation after the maturation of the hypothalamic-pituitary-gonadal axis.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [63] Gianetti, 2010, TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood, J Clin Endocrinol Metab source
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- Premisecitation
The regulation of gonadotropin release by the tachykinins and their receptors occurs at least partly through actions on KISS1 neurons in mice.
“The regulation of gonadotropin release by the tachykinins and their receptors occurs at least partly through actions on KISS1 neurons in mice.67”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [67] Navarro, 2015, The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction, Endocrinology source
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- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
- Premisecitation
The MKRN3 protein has a ubiquitin ligase domain.
“Its protein structure has a ubiquitin ligase domain”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [79] Abreu, 2015, A new pathway in the control of the initiation of puberty: the MKRN3 gene, J Mol Endocrinol source
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- Premisecitation
MKRN3 expression in the arcuate nucleus of mice is high prepubertally and decreases before puberty initiation, reaching very low levels in adult life.
“MKRN3 expression in the arcuate nucleus of mice is high prepubertally and decreases before puberty initiation, reaching very low levels in adult life.52”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
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- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
- Premisecitation
In 2009, genome-wide association studies identified an association between the locus 6q21 (in or near the LIN28B gene) and age at menarche and height.
“In 2009, genome-wide association studies identified an association between the locus 6q21 (in or near the LIN28B gene) with age at menarche and height.81–84”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [81] Perry, 2009, Meta-analysis of genome-wide association data identifies two loci influencing age at menarche, Nat Genet source
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- cites [82] Sulem, 2009, Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche, Nat Genet source
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- cites [83] He, 2009, Genome-wide association studies identify loci associated with age at menarche and age at natural menopause, Nat Genet source
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- cites [84] Ong, 2009, Genetic variation in LIN28B is associated with the timing of puberty, Nat Genet source
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- Premisecitation
The identification of MKRN3 arose from whole-exome sequencing analysis of families with central precocious puberty.
“The identification of this novel factor in the GnRH network arose from whole-exome sequencing analysis of families with central precocious puberty.52”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
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- Premisereasoning
All MKRN3 mutations identified in patients with central precocious puberty were inherited from their fathers.
“Following this inheritance pattern, all MKRN3 mutations identified in patients with central precocious puberty were inherited from their fathers.52”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
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- Premisecitation
Many other genes have been identified in association with developmental defects in GnRH neurons.
“Many other genes have been identified in association with developmental defects in GnRH neurons.”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [35] Semple, 2010, The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions, Clin Endocrinol (Oxf) source
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- cites [46] Silveira, 2013, Approach to the patient with hypogonadotropic hypogonadism, J Clin Endocrinol Metab source
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- cites [53] Miraoui, 2013, Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism, Am J Hum Genet source
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- cites [88] Tornberg, 2011, Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism, Proc Natl Acad Sci USA source
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- cites [89] Kim, 2010, WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome, Am J Hum Genet source
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- cites [90] Hanchate, 2012, SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome, PLoS Genet source
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- Premisecitation
Mutations in LIN28B have not been identified in patients with central precocious puberty or constitutional delay of growth and puberty.
“Mutations in LIN28B have not been identified in patients with central precocious puberty or constitutional delay of growth and puberty.86,87”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [86] Tommiska, 2010, LIN28B in constitutional delay of growth and puberty, J Clin Endocrinol Metab source
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- cites [87] Silveira-Neto, 2012, Absence of functional LIN28B mutations in a large cohort of patients with idiopathic central precocious puberty, Horm Res Paediatr source
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- Premisecitation
The mechanism by which LIN28B is associated with the control of GnRH secretion is unknown.
“Although several other human studies replicated the findings from the genome-wide association studies, the mechanism by which this gene is associated with the control of GnRH secretion is unknown.85”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [85] Gajdos, 2010, Genetic determinants of pubertal timing in the general population, Mol Cell Endocrinol source
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- Rests on an assumption: LIN28B encodes a regulator of the let-7 class of microRNAs.
- Interpretationcitation
Common variation near MKRN3 is an important source of variation in pubertal timing in the general population.
“This finding implicates common variation near MKRN3 as an important source of variation in pubertal timing in the general population.”
Quote in the paperSubstantial claim - Premisecitation
In a recent meta-analysis of genome-wide association and custom-genotyping array studies of age at menarche in up to 182,416 women of European descent, a variant downstream of MKRN3 had the largest effect size for association with menarche when the variant was paternally inherited.
“In a recent meta-analysis of genome-wide association and custom-genotyping array studies of age at menarche in up to 182 416 women of European descent, a variant downstream of MKRN3 had the largest effect size for association with menarche when the variant was paternally inherited.80”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [80] Perry, 2014, Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche, Nature source
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- Premisecitation
The attainment of appropriate leptin concentrations is indispensable for the maturation of the hypothalamic-pituitary-gonadal axis, normal pubertal progression, and maintenance of fertility.
“As has been shown for bodyweight, the attainment of appropriate leptin concentrations is indispensable for the maturation of the hypothalamic-pituitary-gonadal axis, normal pubertal progression, and maintenance of fertility.96”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [96] Farooqi, 2014, 20 years of leptin: human disorders of leptin action, J Endocrinol source
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- Premisecitation
Homozygous mutations in genes encoding leptin (LEP) or leptin receptor (LEPR) cause hypogonadotropic hypogonadism in human beings.
“The finding that homozygous mutations in genes encoding leptin (LEP) or leptin receptor (LEPR) cause hypogonadotropic hypogonadism in human beings emphasises the role of leptin in reproduction.98–100”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [98] Farooqi, 2007, Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor, N Engl J Med source
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- cites [99] Montague, 1997, Congenital leptin deficiency is associated with severe early-onset obesity in humans, Nature source
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- Premisecitation
Serum leptin concentrations and leptin mRNA concentrations in adipose tissue are associated positively and very closely with fat mass.
“Serum leptin concentrations and leptin mRNA concentrations in adipose tissue are associated positively and very closely with fat mass.94”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [94] Considine, 1996, Serum immunoreactive-leptin concentrations in normal-weight and obese humans, N Engl J Med source
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- Premisecitation
A threshold bodyweight is necessary for pubertal development and reproduction.
“A threshold bodyweight is necessary for pubertal development and reproduction.91”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [91] Frisch, 1970, Height and weight at menarche and a hypothesis of critical body weights and adolescent events, Science source
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- Premisecitation
Animal and human studies in the 1960s and 1970s showed that the proper function of the hypothalamic-pituitary-gonadal axis is gated by metabolic and nutritional factors.
“Animal and human studies in the 1960s and 1970s showed that the proper function of the hypothalamic-pituitary-gonadal axis is gated by metabolic and nutritional factors.91,92”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [91] Frisch, 1970, Height and weight at menarche and a hypothesis of critical body weights and adolescent events, Science source
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- Premisecitation
Individuals with homozygous mutations in LEPR presented with early-onset morbid obesity and reduced growth hormone and thyrotropin secretion.
“In addition to the reproductive phenotype, individuals with homozygous mutations in LEPR presented with early-onset morbid obesity and reduced growth hormone and thyrotropin secretion.100”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [100] Clément, 1998, A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction, Nature source
Not checked in the free run.
- Premisecitation
The decrease in the average age of puberty initiation between the mid-19th and mid-20th centuries suggested an association of nutrition and environmental factors with reproduction.
“The decrease in the average age of puberty initiation between the mid-19th and mid-20th centuries suggested an association of nutrition and environmental factors with reproduction,20,41”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Kisspeptin has been used in clinical studies to induce ovulation in infertile women.
“For example, kisspeptin has been used in clinical studies to induce ovulation in infertile women.112”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [112] Prague, 2015, Potential clinical use of kisspeptin, Neuroendocrinology source
Not checked in the free run.
- Interpretationreasoning
Some of the positive effects of insulin on the reproductive system might derive from its ability to stimulate leptin secretion.
“therefore, some of the positive effects of insulin on the reproductive system might derive from its ability to stimulate leptin secretion.106”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [106] Barr, 1997, Insulin stimulates both leptin secretion and production by rat white adipose tissue, Endocrinology source
Not checked in the free run.
- Interpretationcitation
Leptin has a central role for normal reproductive and neuroendocrine function.
“reinforcing the central role of leptin for normal reproductive and neuroendocrine function.103”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Welt, 2004, Recombinant human leptin in women with hypothalamic amenorrhea, N Engl J Med source
Not checked in the free run.
- Interpretationreasoning
The association of nutrition and environmental factors with reproduction was substantiated by the identification of leptin as an important link between both systems, together with the characterisation of the effects of the metabolic hormones, insulin and ghrelin, on the reproductive axis.
“which was substantiated by the identification of leptin as an important link between both systems, together with the characterisation of the effects of the metabolic hormones, insulin and ghrelin, on the reproductive axis.”
Quote in the paperSubstantial claim - Premisecitation
Studies show an increase in IGF-1 expression during puberty in human beings.
“Moreover, studies show an increase in IGF-1 expression during puberty in human beings.109”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [109] Luna, 1983, Somatomedins in adolescence: a cross-sectional study of the effect of puberty on plasma insulin-like growth factor I and II levels, J Clin Endocrinol Metab source
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- Premisecitation
Another systemic hormone with a major role in the regulation of reproduction is the pancreatic hormone insulin.
“Another systemic hormone with a major role in the regulation of reproduction is the pancreatic hormone insulin (figure 3).104”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [104] Pralong, 2010, Insulin and NPY pathways and the control of GnRH function and puberty onset, Mol Cell Endocrinol source
Not checked in the free run.
- Interpretationnone given
In this system, a major hierarchical role is held by GnRH neurons.
“In this system, a major hierarchical role is held by GnRH neurons.”
Quote in the paperSubstantial claim- Rests on an assumption: GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids.
- Interpretationreasoning
The identification of mutations in MKRN3 in patients with different ethnic origins and its expression pattern in the hypothalamus of mice support the association of MKRN3 with GnRH regulation.
“Although the mechanism by which MKRN3 regulates the hypothalamic-pituitary-gonadal axis is still to be elucidated, the identification of mutations in this gene in patients with different ethnic origins and its expression pattern in the hypothalamus of mice support the association of MKRN3 with GnRH regulation.”
Quote in the paperSubstantial claim- Rests on an assumption: GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids.
- Interpretationnone given
MKRN3 is the first imprinted gene to be implicated in GnRH regulation.
“It is the first imprinted gene to be implicated in GnRH regulation.”
Quote in the paperSubstantial claim- Rests on an assumption: GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids.
- Interpretationnone given
Different from the other genetic factors regulating the hypothalamic-pituitary-gonadal axis, MKRN3 operates in an inhibitory mode.
“Different from the other genetic factors regulating the hypothalamic-pituitary-gonadal axis, MKRN3 operates in an inhibitory mode.”
Quote in the paperNot a substantial claim- Rests on an assumption: GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids.
- Premisecitation
Genetic studies have led to the identification of the most common known genetic cause of central precocious puberty, MKRN3.
“More recently, genetic studies have led to the identification of the most common known genetic cause of central precocious puberty, MKRN3.52”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
Not checked in the free run.
- Premisecitation
Insulin is a major regulator of leptin production.
“Insulin is a major regulator of leptin production; therefore, some of the positive effects of insulin on the reproductive system might derive from its ability to stimulate leptin secretion.106”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [106] Barr, 1997, Insulin stimulates both leptin secretion and production by rat white adipose tissue, Endocrinology source
Not checked in the free run.
- Premisecitation
Increasing evidence implicates epigenetic mechanisms in timing of puberty.
“Increasing evidence implicates epigenetic mechanisms in timing of puberty.114”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [114] Lomniczi, 2015, Epigenetic regulation of female puberty, Front Neuroendocrinol source
Not checked in the free run.
- Interpretationcitation
The availability of powerful new technologies has contributed to expanding knowledge of the regulation of puberty and recognising the role of genetic imprinting in the control of the activation of GnRH secretion at the time of puberty initiation.
“The availability of powerful new technologies has contributed to expanding our knowledge of the regulation of puberty and recognising the role of genetic imprinting in the control of the activation of GnRH secretion at the time of puberty initiation.114”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [114] Lomniczi, 2015, Epigenetic regulation of female puberty, Front Neuroendocrinol source
Not checked in the free run.
- Rests on an assumption: GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids.
- May combine two claims. 48
- Classified as probably not a substantial claim. 19
May combine two claims.
PremisecitationIn humans, the hypothalamic-pituitary-gonadal axis is active in the mid-gestational fetus but silenced towards the end of gestation.
“In human beings, the hypothalamic-pituitary-gonadal axis is active in the mid-gestational fetus, but silenced towards the end of gestation.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Kuiri-Hänninen, 2014, Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty, Horm Res Paediatr source
Not checked in the free run.
May combine two claims.
PremisecitationThe age at puberty onset varies greatly between individuals, different ethnic populations, and between the sexes; girls on average experience the onset of puberty at younger ages than boys and are more likely to have idiopathic central precocious puberty, whereas boys are more predisposed to idiopathic delayed puberty.
“The age at puberty onset varies greatly between individuals, different ethnic populations, and between the sexes; girls on average experience the onset of puberty at younger ages than boys and are more likely to have idiopathic central precocious puberty, whereas boys are more predisposed to idiopathic delayed puberty.12,13”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [12] Biro, 2006, Pubertal correlates in black and white girls, J Pediatr source
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- cites [13] Wu, 2002, Ethnic differences in the presence of secondary sex characteristics and menarche among US girls: the Third National Health and Nutrition Examination Survey, 1988–1994, Pediatrics source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn boys, testosterone concentration rises to a peak at age 1-3 months, then falls in conjunction with the falling LH concentration.
“In boys, testosterone concentration rises to a peak at age 1–3 months, but then falls in conjunction with the falling LH concentration.2”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Kuiri-Hänninen, 2014, Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty, Horm Res Paediatr source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPuberty is deemed physiological when it begins between the ages of 8 and 12 years in girls and between 9 and 14 years in boys.
“Puberty is deemed physiological when it begins between the ages of 8 and 12 years in girls and between 9 and 14 years in boys.14”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Rosenfield, 2009, Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index, Pediatrics source
Not checked in the free run.
- Rests on an assumption: The age limits used to define normal pubertal timing (8–12 years in girls and 9–14 years in boys) are appropriate despite the limitations of population studies.
May combine two claims.
PremisecitationThe landmark studies of Marshall and Tanner (1969) classified puberty into five stages in girls and boys on the basis of somatic changes in breast, pubic hair, and genital development, and have been widely used to assess puberty development.
“The landmark studies of Marshall and Tanner (1969), which classified puberty into five stages in girls and boys on the basis of somatic changes in breast, pubic hair, and genital development, have been widely used to assess puberty development.3,4”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationThe hypothalamic-pituitary-gonadal axis controls puberty and reproduction and is tightly regulated by a complex network of excitatory and inhibitory factors.
“Puberty and reproduction are controlled by the hypothalamic-pituitary-gonadal axis.1”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Terasawa, 2001, Neurobiological mechanisms of the onset of puberty in primates, Endocr Rev
Not checked in the free run.
May combine two claims.
PremisecitationAdrenarche seems to be specific to human and some non-human primates, and the absence of adrenarche in human beings does not seem to prevent fertility nor to substantially affect the timing of gonadarche.
“Notably, adrenarche seems to be specific to human and some non-human primates, and the absence of adrenarche in human beings does not seem to prevent fertility nor to substantially affect the timing of gonadarche.10”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Grumbach, 2002, The neuroendocrinology of human puberty revisited, Horm Res
Not checked in the free run.
May combine two claims.
Premisenone givenThe first sign of puberty initiation is typically thelarche (breast development) in girls and testicular enlargement in boys.
“The first sign of puberty initiation is typically thelarche (breast development) in girls and testicular enlargement in boys.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAdrenarche generally begins at about age 6 years, several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche).
“This maturational process generally begins at about age 6 years, several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche).9”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Xing, 2015, Development of adrenal cortex zonation, Endocrinol Metab Clin North Am source
Not checked in the free run.
May combine two claims.
PremisecitationGonadotropin concentrations gradually decrease towards age 6 months, except FSH concentration in girls, which remains raised until age 3-4 years.
“These concentrations then gradually decrease towards age 6 months, with the exception of FSH concentration in girls, which remains raised until age 3–4 years.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Kuiri-Hänninen, 2014, Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty, Horm Res Paediatr source
Not checked in the free run.
May combine two claims.
PremisecitationEarly age at menarche is a risk factor for breast cancer, cardiovascular disease, depression, behavioural disorders, diabetes, and increased all-cause mortality.
“Early age at menarche is a risk factor for breast cancer,15 cardiovascular disease, depression, behavioural disorders, diabetes, and increased all-cause mortality.16,17”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [15] Velie, 2005, Lifetime reproductive and anthropometric risk factors for breast cancer in postmenopausal women, Breast Dis source
Not checked in the free run.
- cites [16] Elks, 2013, Age at menarche and type 2 diabetes risk: the EPIC-InterAct study, Diabetes Care source
Not checked in the free run.
- cites [17] Lakshman, 2009, Early age at menarche associated with cardiovascular disease and mortality, J Clin Endocrinol Metab source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMenarche is regarded as the final marker of puberty in girls.
“Menarche is regarded as the final marker of puberty in girls.5”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Kaprio, 1995, Common genetic influences on BMI and age at menarche, Hum Biol
Not checked in the free run.
May combine two claims.
PremisecitationThe restraint of the hypothalamic-pituitary-gonadal axis is removed at birth, leading to reactivation of the axis and an increase in gonadotropin concentrations.
“This restraint is removed at birth, leading to reactivation of the axis and an increase in gonadotropin concentrations.2”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Kuiri-Hänninen, 2014, Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty, Horm Res Paediatr source
Not checked in the free run.
May combine two claims.
Study design and conductnone givenThe assessment of secular trends in male pubertal development is even more challenging because there are so few studies analysing puberty development in boys, and pubertal markers are even less reliable in boys than in girls.
“The assessment of secular trends in male pubertal development is even more challenging because there are so few studies analysing puberty development in boys, and pubertal markers are even less reliable in boys than in girls.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThere are substantial racial differences in sexual maturation; non-Hispanic black and Mexican-American ethnic origins are independently associated with earlier pubertal development in girls.
“There are substantial racial differences in sexual maturation; it is thought that non-Hispanic black and Mexican-American ethnic origins are independently associated with earlier pubertal development in girls.13”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Wu, 2002, Ethnic differences in the presence of secondary sex characteristics and menarche among US girls: the Third National Health and Nutrition Examination Survey, 1988–1994, Pediatrics source
Not checked in the free run.
May combine two claims.
PremisecitationKallmann's syndrome typically results from abnormal fetal development of GnRH neurons; both GnRH and olfactory neurons originate from the olfactory placode and migrate together into the CNS during embryogenesis.
“Kallmann’s syndrome typically results from abnormal fetal development of GnRH neurons; both GnRH and olfactory neurons originate from the olfactory placode and migrate together into the CNS during embryogenesis.32”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Schwanzel-Fukuda, 1999, Origin and migration of luteinizing hormone-releasing hormone neurons in mammals, Microsc Res Tech source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenProduction of sex steroids independent of the activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-independent or peripheral precocious puberty.
“Production of sex steroids independent of the activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-independent or peripheral precocious puberty.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn a more recent Danish study, 954 girls assessed in 2006-08 were compared with those studied in 1991-93, and substantially earlier breast development was noted in the girls born more recently.
“However, in a more recent Danish study, 954 girls assessed in 2006–08 were compared with those studied in 1991–93, and substantially earlier breast development was noted in the girls born more recently.26”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Aksglaede, 2009, Recent decline in age at breast development: the Copenhagen Puberty Study, Pediatrics source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenMost cases of central precocious puberty in girls and up to 60% of cases in boys do not have a detectable CNS lesion and are described as idiopathic central precocious puberty.
“Most cases of central precocious puberty in girls and up to 60% of cases in boys do not have a detectable CNS lesion and are described as idiopathic central precocious puberty.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationEarly puberty in boys is a risk factor for testicular cancer and delayed puberty can be a cause of being bullied, poor self-esteem, and psychosocial distress.
“Early puberty in boys is a risk factor for testicular cancer and delayed puberty can be a cause of being bullied, poor self-esteem, and psychosocial distress.18”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Golub, 2008, Public health implications of altered puberty timing, Pediatrics source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenMost of the associations between puberty timing and health outcomes have been based on epidemiological studies and need to be validated and studied further.
“Most of these associations have been based on epidemiological studies and need to be validated and studied further.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationResults from some studies have suggested that age of puberty onset in boys might be occurring earlier than in the past, but additional studies are required to confirm this tendency.
“Similar to what has been reported in girls, results from some studies have suggested that age of puberty onset in boys might be occurring earlier than in the past, but additional studies are required to confirm this tendency.27”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Herman-Giddens, 2001, Secondary sexual characteristics in boys: estimates from the national health and nutrition examination survey III, 1988–1994, Arch Pediatr Adolesc Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIt has been proposed that there was a trend towards an earlier onset of breast development and menarche in girls from 1940 to 1994.
“Although still controversial because of the limited comparability of the data from studies in different populations and the use of different methods, it has also been proposed that there was a trend towards an earlier onset of breast development and menarche in girls from 1940 to 1994.21”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Euling, 2008, Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings, Pediatrics source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenGnRH-dependent or central precocious puberty is caused by early maturation of the hypothalamic-pituitary-gonadal axis, resulting in pulsatile secretion of GnRH and subsequent activation of the gonads.
“GnRH-dependent or central precocious puberty is caused by early maturation of the hypothalamic-pituitary-gonadal axis, resulting in pulsatile secretion of GnRH and subsequent activation of the gonads.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenA genetic defect has been identified in approximately 40% of known cases of isolated hypogonadotropic hypogonadism.
“A genetic defect has been identified in approximately 40% of known cases.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe age at menarche of non-Hispanic black girls is substantially earlier than that of non-Hispanic white and Mexican-American girls, and the mean age for onset of breast development in African-American girls is also earlier than that in white girls.
“The age at menarche of non-Hispanic black girls is substantially earlier than that of non-Hispanic white and Mexican-American girls, and the mean age for onset of breast development in African-American girls is also earlier than that in white girls.28”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] Chumlea, 2003, Age at menarche and racial comparisons in US girls, Pediatrics source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe amount of body fat and exposure to endocrine disruptors, particularly oestrogenic compounds and antiandrogens, have been suggested as important factors associated with the trend in pubertal timing.
“The amount of body fat and exposure to endocrine disruptors, particularly oestrogenic compounds and antiandrogens, have been suggested as important factors associated with this trend in pubertal timing.21”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Euling, 2008, Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings, Pediatrics source
Not checked in the free run.
May combine two claims.
PremisecitationResults from animal studies suggest that catecholamines and glutamate are components of the excitatory input to GnRH secretion, whereas γ-aminobutyric acid (GABA) might be a component of the inhibitory network.
“Results for these studies suggest that catecholamines and glutamate are components of the excitatory input, whereas -aminobutyric acid (GABA) might be a component of the inhibitory network.1”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Terasawa, 2001, Neurobiological mechanisms of the onset of puberty in primates, Endocr Rev
Not checked in the free run.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
May combine two claims.
PremisecitationThe discovery of the kisspeptin system as a crucial component for pubertal activation of the hypothalamic-pituitary-gonadal axis occurred in 2003, when loss-of-function mutations of the KISS1R gene were identified in individuals with isolated hypogonadotropic hypogonadism, establishing KISS1R inactivation as a cause of this disorder.
“The discovery of the kisspeptin system as a crucial component for pubertal activation of the hypothalamic-pituitary-gonadal axis occurred in 2003, when loss-of-function mutations of the KISS1R (previously known as GPR54) gene were identified in individuals with isolated hypogonadotropic hypogonadism, establishing KISS1R inactivation as a cause of this disorder (table, figure 2).42,43”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationStudies of agonadal human beings have shown that the prepubertal suppression of hypothalamic-pituitary-gonadal function occurs even in the absence of feedback by sex steroids, suggesting that the juvenile pause represents a state of neurally determined functional stasis rather than immaturity of the GnRH neurons.
“Studies of agonadal human beings have shown that the prepubertal suppression of hypothalamic-pituitary-gonadal function occurs even in the absence of feedback by sex steroids, suggesting that the juvenile pause represents a state of neurally determined functional stasis rather than immaturity of the GnRH neurons.39”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Conte, 1980, Correlation of luteinizing hormone-releasing factor-induced luteinizing hormone and follicle-stimulating hormone release from infancy to 19 years with the changing pattern of gonadotropin secretion in agonadal patients: relation to the restraint of puberty, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
PremisecitationLesions of the arcuate nucleus have been shown to abolish LH pulsatility, consistent with the idea that there is a higher order input into the network of GnRH neurons regulating GnRH secretion.
“Although the mechanism that causes the pulsatility of the GnRH neuronal network can be intrinsic to the GnRH neurons themselves,37 lesions of the arcuate nucleus have been shown to abolish LH pulsatility, consistent with the idea that there is a higher order input into the network of GnRH neurons regulating GnRH secretion.38”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Plant, 1978, The arcuate nucleus and the control of gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatta), Endocrinology source
Not checked in the free run.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
May combine two claims.
PremisecitationAdministration of kisspeptin results in increases in plasma LH concentrations in healthy men, and in women kisspeptin also induces LH release, although the response varies across the menstrual cycle.
“Administration of kisspeptin results in increases in plasma LH concentrations in healthy men,54,55 and in women kisspeptin also induces LH release, although the response varies across the menstrual cycle.56”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [54] Dhillo, 2005, Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males, J Clin Endocrinol Metab source
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- cites [55] George, 2011, Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [56] Chan, 2012, Kisspeptin administration to women: a window into endogenous kisspeptin secretion and GnRH responsiveness across the menstrual cycle, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
Study design and conductreasoningStudies in patients with pubertal disorders have not identified genetic defects in the genes encoding catecholamines, glutamate, or GABA, which undermines the evidence for their potential roles, but does not rule them out entirely as important for puberty initiation.
“Studies in patients with pubertal disorders have not identified genetic defects in the genes encoding these factors, which undermines the evidence for their potential roles, but does not rule them out entirely as important for puberty initiation.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationOther studies did not show a similar frequency of reversibility, and it is still not definitively known whether the NKB system is essential for the excitatory GnRH regulatory network after pubertal development.
“However, other studies did not show a similar frequency of reversibility,45 and it is still not definitively known whether the NKB system is essential for the excitatory GnRH regulatory network after pubertal development.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Topaloglu, 2011, Neurokinin B signalling in the human reproductive axis, Mol Cell Endocrinol source
Not checked in the free run.
May combine two claims.
PremisecitationKISS1 neurons express oestrogen receptor α and receive sex steroid signals from the gonads, which regulate KISS1 expression and control the release of GnRH.
“These neurons express oestrogen receptor a and receive sex steroid signals from the gonads, which regulate KISS1 expression and control the release of GnRH.60”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [60] Smith, 2005, Regulation of Kiss1 gene expression in the brain of the female mouse, Endocrinology source
Not checked in the free run.
May combine two claims.
PremisecitationIn 2009, Topaloglu and colleagues identified NKB as an important factor for human puberty initiation, studying ten consanguineous families with multiple affected members who had isolated hypogonadotropic hypogonadism.
“It was not until 2009 that Topaloglu and colleagues44 identified NKB as an important factor for human puberty initiation, studying ten consanguineous families with multiple affected members who had isolated hypogonadotropic hypogonadism.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Topaloglu, 2009, TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction, Nat Genet source
Not checked in the free run.
May combine two claims.
PremisecitationAlthough the effect of NKB on GnRH secretion depends on the hormonal context, administration of NKB has been shown to elicit strong stimulation of LH production mediated by GnRH in animal models.
“Although the effect of NKB on GnRH secretion depends on the hormonal context, administration of NKB has been shown to elicit strong stimulation of LH production mediated by GnRH in animal models.64”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [64] Ramaswamy, 2010, Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus, Endocrinology source
Not checked in the free run.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSubstance P and neurokinin A have been reported to stimulate the gonadotropic axis in men.
“Substance P and neurokinin A have been reported to stimulate the gonadotropic axis in men.66”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [66] Coiro, 1992, Luteinizing hormone response to an intravenous infusion of substance P in normal men, Metabolism source
Not checked in the free run.
May combine two claims.
PremisecitationMKRN3 is the most common genetic defect associated with central precocious puberty so far; families with central precocious puberty from several different ethnic groups harbour mutations in this gene.
“MKRN3 is the most common genetic defect associated with central precocious puberty so far; families with central precocious puberty from several different ethnic groups harbour mutations in this gene.52,71–76”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
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- cites [71] de Vries, 2004, Familial central precocious puberty suggests autosomal dominant inheritance, J Clin Endocrinol Metab source
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- cites [72] Hagen, 2015, Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls, J Clin Endocrinol Metab source
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- cites [73] Lee, 2015, Low frequency of MKRN3 mutations in central precocious puberty among Korean girls, Horm Metab Res
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- cites [74] Macedo, 2014, Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3, J Clin Endocrinol Metab source
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- cites [75] Schreiner, 2014, MKRN3 mutations in familial central precocious puberty, Horm Res Paediatr source
Not checked in the free run.
- cites [76] Settas, 2014, Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
InterpretationreasoningTaken together, the findings suggest that the loss of function of MKRN3 results in early puberty, implying an inhibitory role of MKRN3 on GnRH secretion.
“Taken together, these findings suggest that the loss of function of MKRN3 results in early puberty, implying an inhibitory role of MKRN3 on GnRH secretion.77”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [77] Hughes, 2013, Releasing the brake on puberty, N Engl J Med source
Not checked in the free run.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
May combine two claims.
PremisecitationThe maternal MKRN3 allele is imprinted and only the paternal allele is expressed.
“The maternal MKRN3 allele is imprinted and only the paternal allele is expressed.68–70”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [68] Jong, 1999, Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader–Willi syndrome genetic region, Hum Mol Genet source
Not checked in the free run.
- cites [69] Jong, 1999, A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader–Willi syndrome critical region, Hum Mol Genet source
Not checked in the free run.
- cites [70] Hershko, 1999, Imprinted methylation and its effect on expression of the mouse Zfp127 gene, Gene source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMKRN3 belongs to the Makorin family, a family of E3 ubiquitin ligases.
“MKRN3 belongs to the Makorin family, a family of E3 ubiquitin ligases.78”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [78] Gray, 2000, The ancient source of a distinct gene family encoding proteins featuring RING and C(3)H zinc-finger motifs with abundant expression in developing brain and nervous system, Genomics source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMKRN3 is located in the Prader-Willi syndrome critical region on chromosome 15 and before the identification of its role in puberty, the few reports about this gene came from research into Prader-Willi syndrome.
“MKRN3 is located in the Prader-Willi syndrome critical region on chromosome 15 and before the identification of its role in puberty, the few reports about this gene came from research into Prader-Willi syndrome.68,69”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [68] Jong, 1999, Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader–Willi syndrome genetic region, Hum Mol Genet source
Not checked in the free run.
- cites [69] Jong, 1999, A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader–Willi syndrome critical region, Hum Mol Genet source
Not checked in the free run.
May combine two claims.
PremisecitationLeptin is an adipocyte-derived hormone, a satiety factor secreted in proportion to the amount of body energy stores, and was one of the first factors linking metabolism with the reproductive axis.
“Leptin, an adipocyte-derived hormone, is a satiety factor secreted in proportion to the amount of body energy stores, and was one of the first factors linking metabolism with the reproductive axis.93”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [93] Ahima, 2000, Leptin regulation of neuroendocrine systems, Front Neuroendocrinol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLeptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine receptor family.
“Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine receptor family.97”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [97] Tartaglia, 1995, Identification and expression cloning of a leptin receptor, OB-R, Cell source
Not checked in the free run.
May combine two claims.
PremisecitationThese genes affect GnRH neuronal migration and are associated with hypogonadotropic hypogonadism with anosmia, or Kallmann's syndrome.
“These genes affect GnRH neuronal migration and are associated with hypogonadotropic hypogonadism with anosmia, or Kallmann’s syndrome (table).35,46,47,53,88–90”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [35] Semple, 2010, The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions, Clin Endocrinol (Oxf) source
Not checked in the free run.
- cites [46] Silveira, 2013, Approach to the patient with hypogonadotropic hypogonadism, J Clin Endocrinol Metab source
Not checked in the free run.
- cites [47] Topaloglu, 2012, Inactivating KISS1 mutation and hypogonadotropic hypogonadism, N Engl J Med source
Not checked in the free run.
- cites [53] Miraoui, 2013, Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism, Am J Hum Genet source
Not checked in the free run.
- cites [88] Tornberg, 2011, Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism, Proc Natl Acad Sci USA source
Not checked in the free run.
- cites [89] Kim, 2010, WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome, Am J Hum Genet source
Not checked in the free run.
- cites [90] Hanchate, 2012, SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome, PLoS Genet source
Not checked in the free run.
May combine two claims.
PremisecitationLeptin is a permissive metabolic signal to the reproductive system; its circulating concentrations inform the actual size of energy reserves not only to the reproductive axis, but to several body systems.
“Leptin is a permissive metabolic signal to the reproductive system; its circulating concentrations inform of the actual size of energy reserves not only to the reproductive axis, but to several body systems.95”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [95] Tena-Sempere, 2007, Roles of ghrelin and leptin in the control of reproductive function, Neuroendocrinology source
Not checked in the free run.
May combine two claims.
PremisecitationLeptin treatment of patients with hypogonadotropic hypogonadism and a homozygous mutation in LEP resulted in the induction of menstrual cycles, development of secondary sexual characteristics, and pulsatile gonadotropin secretion.
“Leptin treatment of patients with hypogonadotropic hypogonadism and a homozygous mutation in LEP resulted in the induction of menstrual cycles, development of secondary sexual characteristics, and pulsatile gonadotropin secretion.101,102”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [101] Licinio, 2004, Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults, Proc Natl Acad Sci USA source
Not checked in the free run.
- cites [102] von Schnurbein, 2012, Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism, Horm Res Paediatr source
Not checked in the free run.
May combine two claims.
PremisecitationAlthough studies in animals have led to identification of regulators of GnRH such as catecholamines, GABA, and glutamate, genetic studies of patients with pubertal disorders have resulted in the identification of a major regulatory hub for the GnRH neurons-ie, the hypothalamic neurons expressing kisspeptin and neurokinin B.
“Although studies in animals have led to identification of regulators of GnRH such as catecholamines, GABA, and glutamate, genetic studies of patients with pubertal disorders have resulted in the identification of a major regulatory hub for the GnRH neurons—ie, the hypothalamic neurons expressing kisspeptin and neurokinin B.42–44”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [42] de Roux, 2003, Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54, Proc Natl Acad Sci USA source
Not checked in the free run.
- cites [43] Seminara, 2003, The GPR54 gene as a regulator of puberty, N Engl J Med source
Not checked in the free run.
- cites [44] Topaloglu, 2009, TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction, Nat Genet source
Not checked in the free run.
- Rests on an assumption: GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe precise site of action of insulin at the hypothalamic level in vivo remains in question.
“However, the precise site of action of insulin at the hypothalamic level in vivo remains in question.107”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [107] Roa, 2014, Connecting metabolism and reproduction: roles of central energy sensors and key molecular mediators, Mol Cell Endocrinol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationGenomic imprinting hypothetically evolved to control the dosage of developmentally important genes and occurs in about 100 mammalian genes.
“Genomic imprinting hypothetically evolved to control the dosage of developmentally important genes and occurs in about 100 mammalian genes.113”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [113] Bartolomei, 2011, Mammalian genomic imprinting, Cold Spring Harb Perspect Biol source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe regulation of GnRH secretion is still not completely understood, but there has been a substantial expansion of understanding of the signals involved in this regulation in the past two decades.
“The regulation of GnRH secretion is still not completely understood, but we have witnessed a substantial expansion of our understanding of the signals involved in this regulation in the past two decades.”
Quote in the paperSubstantial claim- Rests on an assumption: GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids.
May combine two claims.
PremisecitationLeptin administration in women with hypothalamic amenorrhoea (a state of relative leptin deficiency) restored reproductive function, induced ovulation, and increased circulating concentrations of thyroxine, insulin-like growth factor 1 (IGF-1), and bone markers.
“Moreover, leptin administration in women with hypothalamic amenorrhoea (a state of relative leptin deficiency) restored reproductive function, induced ovulation, and increased circulating concentrations of thyroxine, insulin-like growth factor 1 (IGF-1), and bone markers, reinforcing the central role of leptin for normal reproductive and neuroendocrine function.103”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [103] Welt, 2004, Recombinant human leptin in women with hypothalamic amenorrhea, N Engl J Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationreasoningThese findings have important clinical implications, not only to aid in diagnosis and improve genetic counselling, but also to contribute to the development of new therapies for reproductive disorders.
“These findings have important clinical implications, not only to aid in diagnosis and improve genetic counselling, but also to contribute to the development of new therapies for reproductive disorders.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).
Interpretationnone givenBecause of its paramount evolutionary importance, the reproductive system is controlled by a complex regulatory network.
“Because of its paramount evolutionary importance, the reproductive system is controlled by a complex regulatory network.”
Quote in the paperNot a substantial claim- Rests on an assumption: Pubertal development culminates with reproductive competence.
May combine two claims.
PremisecitationStudies have suggested that insulin acts on the hypothalamic-pituitary-gonadal axis at the level of the hypothalamus to directly or indirectly modulate GnRH secretion (possibly via kisspeptin), as well as at the level of the pituitary gonadotrope.
“Studies have suggested that insulin acts on the hypothalamic-pituitary-gonadal axis at the level of the hypothalamus to directly or indirectly modulate GnRH secretion (possibly via kisspeptin), as well as at the level of the pituitary gonadotrope.105”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [105] Moret, 2009, Insulin modulation of luteinizing hormone secretion in normal female volunteers and lean polycystic ovary syndrome patients, Neuroendocrinology source
Not checked in the free run.
May combine two claims.
PremisecitationIGF-1 is structurally homologous to insulin and findings suggest that it is also involved in GnRH regulation.
“IGF-1 is structurally homologous to insulin and findings suggest that it is also involved in GnRH regulation.108”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [108] Wolfe, 2014, The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1), Front Neuroendocrinol source
Not checked in the free run.
May combine two claims.
PremisecitationGhrelin has direct actions on the brain and the pituitary, where it has an inhibitory effect on gonadotropin pulsatility and decreases LH responsiveness to GnRH, as well as a stimulatory effect on prolactin secretion, probably involving direct action on somatomammotroph cells.
“Ghrelin has direct actions on the brain and the pituitary, where it has an inhibitory effect on gonadotropin pulsatility and decreases LH responsiveness to GnRH, as well as a stimulatory effect on prolactin secretion, probably involving direct action on somatomammotroph cells.111”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [111] Lanfranco, 2008, Acylated ghrelin inhibits spontaneous luteinizing hormone pulsatility and responsiveness to naloxone but not that to gonadotropin-releasing hormone in young men: evidence for a central inhibitory action of ghrelin on the gonadal axis, J Clin Endocrinol Metab source
Not checked in the free run.
May combine two claims.
PremisecitationAfter identification of the association of MKRN3 with puberty regulation, single nucleotide polymorphisms in imprinted gene regions were linked to the age of menarche, supporting puberty timing as a selective trait.
“After identification of the association of MKRN3 with puberty regulation, single nucleotide polymorphisms in imprinted gene regions were linked to the age of menarche, supporting puberty timing as a selective trait.80”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [80] Perry, 2014, Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche, Nature source
Not checked in the free run.
The paper relies on this without support.
Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
“In the 1970s, Belchetz and colleagues36 showed in animal models that intermittent release of GnRH is required for the activation of the pituitary-gonadal axis.”
The paper relies on this without support.
The age limits used to define normal pubertal timing (8–12 years in girls and 9–14 years in boys) are appropriate despite the limitations of population studies.
“Puberty is deemed physiological when it begins between the ages of 8 and 12 years in girls and between 9 and 14 years in boys.14”
The paper relies on this without support.
LIN28B encodes a regulator of the let-7 class of microRNAs.
“LIN28B encodes a regulator of the let-7 class of microRNAs.”
The paper relies on this without support.
GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids.
“GnRH is secreted in a unique pulsatile manner by neurons located in the hypothalamus to stimulate the pituitary gonadotropins and gonadal sex steroids.”
The paper relies on this without support.
Pubertal development culminates with reproductive competence.
“Pubertal development culminates with reproductive competence.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In vertebrates, an increase in the activity of GnRH neurons in the hypothalamus is the key event for the precise timing of sexual maturation.
“In vertebrates, an increase in the activity of GnRH neurons in the hypothalamus is the key event for the precise timing of sexual maturation (14).”
From Corazonin signaling integrates energy homeostasis and lunar phase to regulate aspects of growth and sexual maturation in <i>Platynereis</i> (2020) · cites this paper as [14]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Two different thresholds are given for delayed puberty in girls
MinorOne passage classifies onset after age 12 years in girls as delayed, whereas the clinical definition uses absence or incomplete development by age 13 years.
“Puberty is deemed physiological when it begins between the ages of 8 and 12 years in girls and between 9 and 14 years in boys.14”
“Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics by age 13 years in girls or age 14 years in boys.”
Ghrelin's stated effect on GnRH responsiveness contradicts the cited study
MinorThe text says ghrelin decreases LH responsiveness to GnRH, while the title of the cited study says responsiveness to GnRH was not inhibited.
“Ghrelin has direct actions on the brain and the pituitary, where it has an inhibitory effect on gonadotropin pulsatility and decreases LH responsiveness to GnRH”
“111. Lanfranco F Bonelli L Baldi M Acylated ghrelin inhibits spontaneous luteinizing hormone pulsatility and responsiveness to naloxone but not that to gonadotropin-releasing hormone in young men: evidence for a central inhibitory action of ghrelin on the gonadal axis”
Section heading names LIN33B instead of LIN28B
MinorThe section heading names LIN33B, but the section discusses LIN28B throughout.
“#### LIN33B”
“In 2009, genome-wide association studies identified an association between the locus 6q21 (in or near the LIN28B gene) with age at menarche and height.”
Boys' Marshall-Tanner study is dated 1969 in the text but 1970 in the references
MinorThe text dates the landmark studies of puberty in both girls and boys to 1969, but its cited study of boys is dated 1970.
“The landmark studies of Marshall and Tanner (1969), which classified puberty into five stages in girls and boys”
“3. Marshall WA Tanner JM Variations in the pattern of pubertal changes in boys Arch Dis Child 1970 45 13 23 5440182 PMC2020414”
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- Authors
- Abreu, A. P., & Kaiser, U. B.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Kaiser, Ursula B
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 4
- Issue
- 3
- Pages
- 254-264
- ISSN
- 2213-8587 (ISSN-L)
- PMC
- PMC5192018
- OpenAlex
- W2265634200
- Semantic Scholar
- 655fc7f3d2a7fedc6e0eb93b002542b9ee2d5e75
- Cited by
- 611
- References
- 120
- Citations by year
- 2026: 55 · 2025: 64 · 2024: 73 · 2023: 74 · 2022: 59 · 2021: 58 · 2020: 130 · 2019: 45 · 2018: 33 · 2017: 16 · 2016: 3 · 2015: 1
- FWCI
- 4.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- US National Institutes of Health [NIH]) through cooperative agreement (U54 HD028138)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- puberty, hypothalamic-pituitary-gonadal axis, puberty onset, gonadotropin-releasing hormone, timing of puberty, genetic factors, metabolic factors, sexual maturation, fertility
- MeSH terms
- Adolescent, Child, Female, Gonadal Disorders, Humans, Hypothalamo-Hypophyseal System, Gonadotropin-Releasing Hormone, Male, Pituitary-Adrenal System, Puberty, Ribonucleoproteins, Sexual Maturation, Tachykinins, RNA-Binding Proteins, Ubiquitin-Protein Ligases, Kisspeptins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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