The DOI matches its Crossref record; 118 of the 120 references it cites were found in a registry or an index; 1 of the 152 sources its claims cite were checked for support.
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.
Overview
AI snapshot
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.
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Claims the paper makes
100 Not checked yet · 10 Own interpretation · 7 No basis given · 4 Own method · 1 Partly supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The KISS1 positive regulation is believed to be important for the LH surge in females of many mammalian species.61”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
The Discussion reports that blocking kisspeptin in the preoptic area prevented an estrogen-induced LH surge in female rats and links AVPV KiSS-1 neurons to estrogen positive feedback. The cited paper supports the proposed importance of this regulation in rats, but the passages do not establish it for females of many mammalian species. (LLM, conf=0.86)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
In the paper
“In both sexes, pubarche is dependent on an increase in adrenal androgen production, a physiological event termed adrenarche.8”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“The age of puberty onset is associated with subsequent health outcomes.”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [15] Velie, 2005, Lifetime reproductive and anthropometric risk factors for breast cancer in postmenopausal women, Breast Dis source
- Not checked yetcites [16] Elks, 2013, Age at menarche and type 2 diabetes risk: the EPIC-InterAct study, Diabetes Care source
- Not checked yetcites [17] Lakshman, 2009, Early age at menarche associated with cardiovascular disease and mortality, J Clin Endocrinol Metab source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In girls with late initiation of puberty, there can be a decrease in the interval between thelarche and menarche.6”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Normal puberty and pubertal markers
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“In boys, testicular enlargement is followed by an increase in growth velocity and subsequent spermarche.7”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [7] Biro, 1995, Pubertal staging in boys, J Pediatr source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Evidence suggests that the augmentation of activators of GnRH secretion together with the suppression of inhibitors of GnRH secretion culminates in puberty initiation.”
§ Pubertal development and regulation > Introduction
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
In the paper
“Puberty is initiated with a sustained increase in pulsatile release of GnRH from the hypothalamus after this quiescent period.”
§ Pubertal development and regulation > Introduction
What the sources say
- Not checked yetcites [1] Terasawa, 2001, Neurobiological mechanisms of the onset of puberty in primates, Endocr Rev
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Environmental factors might have effects on the neuroendocrine system, particularly during fetal and early postnatal life;22”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“This change has been attributed to improvements in general health, nutrition, and other living conditions during this period.”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [20] Wyshak, 1982, Evidence for a secular trend in age of menarche, N Engl J Med source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [20] Wyshak, 1982, Evidence for a secular trend in age of menarche, N Engl J Med source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“By contrast, isolated hypogonadotropic hypogonadism is more typically associated with normal olfactory and GnRH neuronal development, but impaired regulation of GnRH secretion.33,35”
§ Pubertal development and regulation > Disorders of puberty > Delayed puberty
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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
- Not checked yetcites [41] Zacharias, 1969, Age at menarche. Genetic and environmental influences, N Engl J Med source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“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.”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Role of GnRH
What the sources say
- Not checked yetcites [36] Belchetz, 1978, Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
In the paper
“These and other data suggest that around 50–80% of the variation in pubertal onset might be genetically determined.40”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [40] Palmert, 2003, Genetic approaches to stature, pubertal timing, and other complex traits, Mol Genet Metab source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Role of GnRH
What the sources say
- Not checked yetcites [40] Palmert, 2003, Genetic approaches to stature, pubertal timing, and other complex traits, Mol Genet Metab source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Impairment of the migration of these neurons is often associated with genetic defects.33–35”
§ Pubertal development and regulation > Disorders of puberty > Delayed puberty
What the sources say
- Not checked yetcites [33] Bianco, 2009, The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism, Nat Rev Endocrinol source
- Not checked yetcites [34] Cadman, 2007, Molecular pathogenesis of Kallmann's syndrome, Horm Res
- Not checked yetcites [35] Semple, 2010, The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions, Clin Endocrinol (Oxf) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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 yetcites [43] Seminara, 2003, The GPR54 gene as a regulator of puberty, N Engl J Med source
- Not checked yetcites [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 yetcites [45] Topaloglu, 2011, Neurokinin B signalling in the human reproductive axis, Mol Cell Endocrinol source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Kisspeptin stimulates gonadotropin release less potently but in a more physiologically effective way than do current treatments with GnRH analogues.57”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“Neurons co-expressing kisspeptin and NKB in the human mediobasal hypothalamus often co-express substance P.65”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [65] Hrabovszky, 2013, Substance P immunoreactivity exhibits frequent colocalization with kisspeptin and neurokinin B in the human infundibular region, PLoS One source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“The first gene with an inhibitory effect on GnRH secretion with mutations identified in human beings was MKRN3 (table, figure 2).”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [49] Teles, 2008, A GPR54-activating mutation in a patient with central precocious puberty, N Engl J Med source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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).”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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
boosteddirectn = 10- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“In animal models, the KISS1 neurons appear to mediate sex steroid feedback effects in the hypothalamus.58,59”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [58] Li, 2007, Estrogen regulates KiSS1 gene expression through estrogen receptor alpha and SP protein complexes, Endocrinology source
- Not checked yetcites [59] Smith, 2007, KiSS-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season, Endocrinology source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
In the paper
“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.”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“The regulation of gonadotropin release by the tachykinins and their receptors occurs at least partly through actions on KISS1 neurons in mice.67”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [67] Navarro, 2015, The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction, Endocrinology source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
In the paper
“Its protein structure has a ubiquitin ligase domain”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [79] Abreu, 2015, A new pathway in the control of the initiation of puberty: the MKRN3 gene, J Mol Endocrinol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“MKRN3 expression in the arcuate nucleus of mice is high prepubertally and decreases before puberty initiation, reaching very low levels in adult life.52”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [81] Perry, 2009, Meta-analysis of genome-wide association data identifies two loci influencing age at menarche, Nat Genet source
- Not checked yetcites [82] Sulem, 2009, Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche, Nat Genet source
- Not checked yetcites [83] He, 2009, Genome-wide association studies identify loci associated with age at menarche and age at natural menopause, Nat Genet source
- Not checked yetcites [84] Ong, 2009, Genetic variation in LIN28B is associated with the timing of puberty, Nat Genet source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The identification of this novel factor in the GnRH network arose from whole-exome sequencing analysis of families with central precocious puberty.52”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Following this inheritance pattern, all MKRN3 mutations identified in patients with central precocious puberty were inherited from their fathers.52”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Many other genes have been identified in association with developmental defects in GnRH neurons.”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [35] Semple, 2010, The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions, Clin Endocrinol (Oxf) source
- Not checked yetcites [46] Silveira, 2013, Approach to the patient with hypogonadotropic hypogonadism, J Clin Endocrinol Metab source
- Not checked yetcites [47] Topaloglu, 2012, Inactivating KISS1 mutation and hypogonadotropic hypogonadism, N Engl J Med source
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [90] Hanchate, 2012, SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome, PLoS Genet source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Mutations in LIN28B have not been identified in patients with central precocious puberty or constitutional delay of growth and puberty.86,87”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [86] Tommiska, 2010, LIN28B in constitutional delay of growth and puberty, J Clin Endocrinol Metab source
- Not checked yetcites [87] Silveira-Neto, 2012, Absence of functional LIN28B mutations in a large cohort of patients with idiopathic central precocious puberty, Horm Res Paediatr source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [85] Gajdos, 2010, Genetic determinants of pubertal timing in the general population, Mol Cell Endocrinol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: LIN28B encodes a regulator of the let-7 class of microRNAs.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This finding implicates common variation near MKRN3 as an important source of variation in pubertal timing in the general population.”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [80] Perry, 2014, Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche, Nature source
plaincorrelationaln = 182,416- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [96] Farooqi, 2014, 20 years of leptin: human disorders of leptin action, J Endocrinol source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [98] Farooqi, 2007, Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor, N Engl J Med source
- Not checked yetcites [99] Montague, 1997, Congenital leptin deficiency is associated with severe early-onset obesity in humans, Nature source
- Not checked yetcites [100] Clément, 1998, A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Serum leptin concentrations and leptin mRNA concentrations in adipose tissue are associated positively and very closely with fat mass.94”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [94] Considine, 1996, Serum immunoreactive-leptin concentrations in normal-weight and obese humans, N Engl J Med source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A threshold bodyweight is necessary for pubertal development and reproduction.91”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [91] Frisch, 1970, Height and weight at menarche and a hypothesis of critical body weights and adolescent events, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [91] Frisch, 1970, Height and weight at menarche and a hypothesis of critical body weights and adolescent events, Science source
- Not checked yetcites [92] Frisch, 1974, Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset, Science source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [100] Clément, 1998, A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Conclusions
What the sources say
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“For example, kisspeptin has been used in clinical studies to induce ovulation in infertile women.112”
§ Pubertal development and regulation > Conclusions
What the sources say
- Not checked yetcites [112] Prague, 2015, Potential clinical use of kisspeptin, Neuroendocrinology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“therefore, some of the positive effects of insulin on the reproductive system might derive from its ability to stimulate leptin secretion.106”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [106] Barr, 1997, Insulin stimulates both leptin secretion and production by rat white adipose tissue, Endocrinology source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“reinforcing the central role of leptin for normal reproductive and neuroendocrine function.103”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [103] Welt, 2004, Recombinant human leptin in women with hypothalamic amenorrhea, N Engl J Med source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Conclusions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Moreover, studies show an increase in IGF-1 expression during puberty in human beings.109”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Another systemic hormone with a major role in the regulation of reproduction is the pancreatic hormone insulin (figure 3).104”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [104] Pralong, 2010, Insulin and NPY pathways and the control of GnRH function and puberty onset, Mol Cell Endocrinol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this system, a major hierarchical role is held by GnRH neurons.”
§ Pubertal development and regulation > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Conclusions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is the first imprinted gene to be implicated in GnRH regulation.”
§ Pubertal development and regulation > Conclusions
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Different from the other genetic factors regulating the hypothalamic-pituitary-gonadal axis, MKRN3 operates in an inhibitory mode.”
§ Pubertal development and regulation > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
- 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.
In the paper
“More recently, genetic studies have led to the identification of the most common known genetic cause of central precocious puberty, MKRN3.52”
§ Pubertal development and regulation > Conclusions
What the sources say
- Not checked yetcites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [106] Barr, 1997, Insulin stimulates both leptin secretion and production by rat white adipose tissue, Endocrinology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Increasing evidence implicates epigenetic mechanisms in timing of puberty.114”
§ Pubertal development and regulation > Conclusions
What the sources say
- Not checked yetcites [114] Lomniczi, 2015, Epigenetic regulation of female puberty, Front Neuroendocrinol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“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”
§ Pubertal development and regulation > Conclusions
What the sources say
- Not checked yetcites [114] Lomniczi, 2015, Epigenetic regulation of female puberty, Front Neuroendocrinol source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
- It may state two separate claims as one. 48
- Probably not a substantial claim. 19
In the paper
“In human beings, the hypothalamic-pituitary-gonadal axis is active in the mid-gestational fetus, but silenced towards the end of gestation.”
§ Pubertal development and regulation > Introduction
What the sources say
- Not checked yetcites [2] Kuiri-Hänninen, 2014, Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty, Horm Res Paediatr source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [12] Biro, 2006, Pubertal correlates in black and white girls, J Pediatr source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In boys, testosterone concentration rises to a peak at age 1–3 months, but then falls in conjunction with the falling LH concentration.2”
§ Pubertal development and regulation > Introduction
What the sources say
- Not checked yetcites [2] Kuiri-Hänninen, 2014, Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty, Horm Res Paediatr source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [14] Rosenfield, 2009, Thelarche, pubarche, and menarche attainment in children with normal and elevated body mass index, Pediatrics source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Puberty and reproduction are controlled by the hypothalamic-pituitary-gonadal axis.1”
§ Pubertal development and regulation > Introduction
What the sources say
- Not checked yetcites [1] Terasawa, 2001, Neurobiological mechanisms of the onset of puberty in primates, Endocr Rev
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [10] Grumbach, 2002, The neuroendocrinology of human puberty revisited, Horm Res
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The first sign of puberty initiation is typically thelarche (breast development) in girls and testicular enlargement in boys.”
§ Pubertal development and regulation > Normal puberty and pubertal markers
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“This maturational process generally begins at about age 6 years, several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche).9”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [9] Xing, 2015, Development of adrenal cortex zonation, Endocrinol Metab Clin North Am source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Pubertal development and regulation > Introduction
What the sources say
- Not checked yetcites [2] Kuiri-Hänninen, 2014, Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty, Horm Res Paediatr source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [15] Velie, 2005, Lifetime reproductive and anthropometric risk factors for breast cancer in postmenopausal women, Breast Dis source
- Not checked yetcites [16] Elks, 2013, Age at menarche and type 2 diabetes risk: the EPIC-InterAct study, Diabetes Care source
- Not checked yetcites [17] Lakshman, 2009, Early age at menarche associated with cardiovascular disease and mortality, J Clin Endocrinol Metab source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Menarche is regarded as the final marker of puberty in girls.5”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [5] Kaprio, 1995, Common genetic influences on BMI and age at menarche, Hum Biol
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This restraint is removed at birth, leading to reactivation of the axis and an increase in gonadotropin concentrations.2”
§ Pubertal development and regulation > Introduction
What the sources say
- Not checked yetcites [2] Kuiri-Hänninen, 2014, Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty, Horm Res Paediatr source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Epidemiology and trends
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Disorders of puberty > Delayed puberty
What the sources say
- Not checked yetcites [32] Schwanzel-Fukuda, 1999, Origin and migration of luteinizing hormone-releasing hormone neurons in mammals, Microsc Res Tech source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Production of sex steroids independent of the activation of the hypothalamic-pituitary-gonadal axis results in gonadotropin-independent or peripheral precocious puberty.”
§ Pubertal development and regulation > Disorders of puberty > Precocious puberty
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [26] Aksglaede, 2009, Recent decline in age at breast development: the Copenhagen Puberty Study, Pediatrics source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Disorders of puberty > Precocious puberty
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal puberty and pubertal markers
What the sources say
- Not checked yetcites [18] Golub, 2008, Public health implications of altered puberty timing, Pediatrics source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Most of these associations have been based on epidemiological studies and need to be validated and studied further.”
§ Pubertal development and regulation > Normal puberty and pubertal markers
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [21] Euling, 2008, Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings, Pediatrics source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Disorders of puberty > Precocious puberty
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“A genetic defect has been identified in approximately 40% of known cases.”
§ Pubertal development and regulation > Disorders of puberty > Delayed puberty
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [28] Chumlea, 2003, Age at menarche and racial comparisons in US girls, Pediatrics source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Epidemiology and trends
What the sources say
- Not checked yetcites [21] Euling, 2008, Examination of US puberty-timing data from 1940 to 1994 for secular trends: panel findings, Pediatrics source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Role of GnRH
What the sources say
- Not checked yetcites [1] Terasawa, 2001, Neurobiological mechanisms of the onset of puberty in primates, Endocr Rev
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Role of GnRH
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Role of GnRH
What the sources say
- Not checked yetcites [38] Plant, 1978, The arcuate nucleus and the control of gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatta), Endocrinology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [54] Dhillo, 2005, Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males, J Clin Endocrinol Metab source
- Not checked yetcites [55] George, 2011, Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men, J Clin Endocrinol Metab source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Role of GnRH
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [45] Topaloglu, 2011, Neurokinin B signalling in the human reproductive axis, Mol Cell Endocrinol source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [60] Smith, 2005, Regulation of Kiss1 gene expression in the brain of the female mouse, Endocrinology source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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
plaindirectn = 10- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
In the paper
“Substance P and neurokinin A have been reported to stimulate the gonadotropic axis in men.66”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [66] Coiro, 1992, Luteinizing hormone response to an intravenous infusion of substance P in normal men, Metabolism source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [52] Abreu, 2013, Central precocious puberty caused by mutations in the imprinted gene MKRN3, N Engl J Med source
- Not checked yetcites [71] de Vries, 2004, Familial central precocious puberty suggests autosomal dominant inheritance, J Clin Endocrinol Metab source
- Not checked yetcites [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
- Not checked yetcites [73] Lee, 2015, Low frequency of MKRN3 mutations in central precocious puberty among Korean girls, Horm Metab Res
- Not checked yetcites [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
- Not checked yetcites [75] Schreiner, 2014, MKRN3 mutations in familial central precocious puberty, Horm Res Paediatr source
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [77] Hughes, 2013, Releasing the brake on puberty, N Engl J Med source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Findings from animal models about the regulation of GnRH secretion and the reproductive axis are relevant to human puberty initiation.
None of the sources cited for this claim have been checked yet.
In the paper
“The maternal MKRN3 allele is imprinted and only the paternal allele is expressed.68–70”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [70] Hershko, 1999, Imprinted methylation and its effect on expression of the mouse Zfp127 gene, Gene source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“MKRN3 belongs to the Makorin family, a family of E3 ubiquitin ligases.78”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [93] Ahima, 2000, Leptin regulation of neuroendocrine systems, Front Neuroendocrinol source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine receptor family.97”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [97] Tartaglia, 1995, Identification and expression cloning of a leptin receptor, OB-R, Cell source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
What the sources say
- Not checked yetcites [35] Semple, 2010, The recent genetics of hypogonadotrophic hypogonadism—novel insights and new questions, Clin Endocrinol (Oxf) source
- Not checked yetcites [46] Silveira, 2013, Approach to the patient with hypogonadotropic hypogonadism, J Clin Endocrinol Metab source
- Not checked yetcites [47] Topaloglu, 2012, Inactivating KISS1 mutation and hypogonadotropic hypogonadism, N Engl J Med source
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [90] Hanchate, 2012, SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome, PLoS Genet source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [95] Tena-Sempere, 2007, Roles of ghrelin and leptin in the control of reproductive function, Neuroendocrinology source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Pubertal development and regulation > Conclusions
What the sources say
- Not checked yetcites [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 yetcites [43] Seminara, 2003, The GPR54 gene as a regulator of puberty, N Engl J Med source
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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.
In the paper
“However, the precise site of action of insulin at the hypothalamic level in vivo remains in question.107”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [107] Roa, 2014, Connecting metabolism and reproduction: roles of central energy sensors and key molecular mediators, Mol Cell Endocrinol source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Genomic imprinting hypothetically evolved to control the dosage of developmentally important genes and occurs in about 100 mammalian genes.113”
§ Pubertal development and regulation > Conclusions
What the sources say
- Not checked yetcites [113] Bartolomei, 2011, Mammalian genomic imprinting, Cold Spring Harb Perspect Biol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- 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.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [103] Welt, 2004, Recombinant human leptin in women with hypothalamic amenorrhea, N Engl J Med source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pubertal development and regulation > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because of its paramount evolutionary importance, the reproductive system is controlled by a complex regulatory network.”
§ Pubertal development and regulation > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- Rests on an assumption: Pubertal development culminates with reproductive competence.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [105] Moret, 2009, Insulin modulation of luteinizing hormone secretion in normal female volunteers and lean polycystic ovary syndrome patients, Neuroendocrinology source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“IGF-1 is structurally homologous to insulin and findings suggest that it is also involved in GnRH regulation.108”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [108] Wolfe, 2014, The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1), Front Neuroendocrinol source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
What the sources say
- Not checked yetcites [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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Pubertal development and regulation > Conclusions
What the sources say
- Not checked yetcites [80] Perry, 2014, Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche, Nature source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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 the citing paper
“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 Platynereis (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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Pubertal development and regulation > Normal puberty and pubertal markers
“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”
§ Pubertal development and regulation > Disorders of puberty > Delayed puberty
“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.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Metabolic factors that affect GnRH secretion
“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”
§ Pubertal development and regulation > References
“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”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
“#### LIN33B”
§ Pubertal development and regulation > Normal physiological controls of the timing of onset and progression of puberty > Genes involved in GnRH regulation
“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.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Pubertal development and regulation > Normal puberty and pubertal markers
“The landmark studies of Marshall and Tanner (1969), which classified puberty into five stages in girls and boys”
§ Pubertal development and regulation > References
“3. Marshall WA Tanner JM Variations in the pattern of pubertal changes in boys Arch Dis Child 1970 45 13 23 5440182 PMC2020414”
Citations
Cites
Serum Immunoreactive-Leptin Concentrations in Normal-Weight and Obese Humans
Considine, R. V., Sinha, M. K., Heiman, M. L., Kriauciunas, A., Stephens, T. W., Nyce, M. R., Ohannesian, J. P., Marco, C. C., McKee, L. J., Bauer, T. L., et al. (1996) · New England Journal of Medicine · doi:10.1056/nejm199602013340503 · Cited by 6,326
Variations in pattern of pubertal changes in girls
Marshall, W. A., & Tanner, J. M. (1969) · Archives of Disease in Childhood · doi:10.1136/adc.44.235.291 · Cited by 5,963
Variations in the pattern of pubertal changes in boys
Marshall, W. A., & Tanner, J. M. (1970) · Archives of Disease in Childhood · doi:10.1136/adc.45.239.13 · Cited by 5,147
Identification and expression cloning of a leptin receptor, OB-R.
Tartaglia, L. A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G. J., Campfield, L. A., Clark, F. T., Deeds, J., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90151-5 · Cited by 3,496
The Diagnosis of Polycystic Ovary Syndrome during Adolescence
Witchel, S. F., Oberfield, S., Rosenfield, R. L., Codner, E., Bonny, A., Ibáñez, L., Pena, A., Horikawa, R., Gomez-Lobo, V., Joel, D., et al. (2015) · Hormone Research in Paediatrics · doi:10.1159/000375530 · Cited by 3,113
Congenital leptin deficiency is associated with severe early-onset obesity in humans
Montague, C. T., Farooqi, I. S., Whitehead, J. P., Soos, M. A., Rau, H., Wareham, N. J., Sewter, C. P., Digby, J. E., Mohammed, S. N., Hurst, J. A., et al. (1997) · Nature · doi:10.1038/43185 · Cited by 2,936
The GPR54 Gene as a Regulator of Puberty
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S., Shagoury, J. K., Bo-Abbas, Y., Kuohung, W., Schwinof, K. M., Hendrick, A. G., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa035322 · Cited by 2,557
Self-citationHypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
de Roux, N., Genin, E., Carel, J.-C., Matsuda, F., Chaussain, J.-L., & Milgrom, E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1834399100 · Cited by 2,431
A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction
Clément, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V., Cassuto, D., Gourmelen, M., Dina, C., Chambaz, J., Lacorte, J.-M., et al. (1998) · Nature · doi:10.1038/32911 · Cited by 2,346
Parent, A.-S., Teilmann, G., Juul, A., Skakkebaek, N. E., Toppari, J., & Bourguignon, J.-P. (2003) · Endocrine Reviews · doi:10.1210/er.2002-0019 · Cited by 1,762
Cited by
Sorted by citations
Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance
Handelsman, D. J., Hirschberg, A. L., & Bermon, S. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00020 · Cited by 594
Worldwide Secular Trends in Age at Pubertal Onset Assessed by Breast Development Among Girls
Eckert‐Lind, C., Busch, A. S., Petersen, J. H., Biro, F. M., Butler, G. E., Bräuner, E. V., & Juul, A. (2020) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/jamapediatrics.2019.5881 · Cited by 517
The Role of Kisspeptin in the Control of the Hypothalamic-Pituitary-Gonadal Axis and Reproduction
Xie, Q., Kang, Y., Zhang, C., Ye, X., Wang, C., Liu, J., Yu, C., Zhao, H., & Huang, D. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.925206 · Cited by 257
Metabolic regulation of kisspeptin — the link between energy balance and reproduction
Navarro, V. M. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0363-7 · Cited by 240
Clinical Advances in Sex- and Gender-Informed Medicine to Improve the Health of All
Bartz, D., Chitnis, T., Kaiser, U. B., Rich-Edwards, J. W., Rexrode, K. M., Pennell, P. B., Goldstein, J. M., O’Neal, M. A., LeBoff, M. S., Behn, M., et al. (2020) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2019.7194 · Cited by 241
Self-citation
Metadata
- 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
- 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 › Reproductive Medicine › Reproductive Biology and Fertility
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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.
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