Pubertal development and regulation

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.”

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

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”

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

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”

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

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”

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

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”

What the sources say

• Not checked yetcites [3] Marshall, 1970, Variations in the pattern of pubertal changes in boys, Arch Dis Child source
• Not checked yetcites [4] Marshall, 1969, Variations in pattern of pubertal changes in girls, Arch Dis Child source

In the paper

“Puberty and reproduction are controlled by the hypothalamic-pituitary-gonadal axis.1”

What the sources say

• Not checked yetcites [1] Terasawa, 2001, Neurobiological mechanisms of the onset of puberty in primates, Endocr Rev

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”

What the sources say

• Not checked yetcites [10] Grumbach, 2002, The neuroendocrinology of human puberty revisited, Horm Res

In the paper

“The first sign of puberty initiation is typically thelarche (breast development) in girls and testicular enlargement in boys.”

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”

What the sources say

• Not checked yetcites [9] Xing, 2015, Development of adrenal cortex zonation, Endocrinol Metab Clin North Am source

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.”

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

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”

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

In the paper

“Menarche is regarded as the final marker of puberty in girls.5”

What the sources say

• Not checked yetcites [5] Kaprio, 1995, Common genetic influences on BMI and age at menarche, Hum Biol

In the paper

“This restraint is removed at birth, leading to reactivation of the axis and an increase in gonadotropin concentrations.2”

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

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.”

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”

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

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”

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

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.”

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”

What the sources say

• Not checked yetcites [26] Aksglaede, 2009, Recent decline in age at breast development: the Copenhagen Puberty Study, Pediatrics source

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.”

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”

What the sources say

• Not checked yetcites [18] Golub, 2008, Public health implications of altered puberty timing, Pediatrics source

In the paper

“Most of these associations have been based on epidemiological studies and need to be validated and studied further.”

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”

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

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”

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

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.”

In the paper

“A genetic defect has been identified in approximately 40% of known cases.”

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”

What the sources say

• Not checked yetcites [28] Chumlea, 2003, Age at menarche and racial comparisons in US girls, Pediatrics source

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”

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

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”

What the sources say

• Not checked yetcites [1] Terasawa, 2001, Neurobiological mechanisms of the onset of puberty in primates, Endocr Rev

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”

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

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”

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

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”

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

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”

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

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.”

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.”

What the sources say

• Not checked yetcites [45] Topaloglu, 2011, Neurokinin B signalling in the human reproductive axis, Mol Cell Endocrinol source

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”

What the sources say

• Not checked yetcites [60] Smith, 2005, Regulation of Kiss1 gene expression in the brain of the female mouse, Endocrinology source

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.”

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

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”

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

In the paper

“Substance P and neurokinin A have been reported to stimulate the gonadotropic axis in men.66”

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

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”

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

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”

What the sources say

• Not checked yetcites [77] Hughes, 2013, Releasing the brake on puberty, N Engl J Med source

In the paper

“The maternal MKRN3 allele is imprinted and only the paternal allele is expressed.68–70”

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

In the paper

“MKRN3 belongs to the Makorin family, a family of E3 ubiquitin ligases.78”

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

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”

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

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”

What the sources say

• Not checked yetcites [93] Ahima, 2000, Leptin regulation of neuroendocrine systems, Front Neuroendocrinol source

In the paper

“Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine receptor family.97”

What the sources say

• Not checked yetcites [97] Tartaglia, 1995, Identification and expression cloning of a leptin receptor, OB-R, Cell source

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”

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

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”

What the sources say

• Not checked yetcites [95] Tena-Sempere, 2007, Roles of ghrelin and leptin in the control of reproductive function, Neuroendocrinology source

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”

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

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”

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

In the paper

“However, the precise site of action of insulin at the hypothalamic level in vivo remains in question.107”

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

In the paper

“Genomic imprinting hypothetically evolved to control the dosage of developmentally important genes and occurs in about 100 mammalian genes.113”

What the sources say

• Not checked yetcites [113] Bartolomei, 2011, Mammalian genomic imprinting, Cold Spring Harb Perspect Biol source

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.”

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”

What the sources say

• Not checked yetcites [103] Welt, 2004, Recombinant human leptin in women with hypothalamic amenorrhea, N Engl J Med source

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.”

In the paper

“Because of its paramount evolutionary importance, the reproductive system is controlled by a complex regulatory network.”

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”

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

In the paper

“IGF-1 is structurally homologous to insulin and findings suggest that it is also involved in GnRH regulation.108”

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

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”

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

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”

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