Query: Precocious Puberty

title: Incidence and Prevalence of Central Precocious Puberty in Korea: An Epidemiologic Study Based on a National Database
abstract: To investigate the prevalence and incidence of central precocious puberty in Korea using claims data provided by the Health Insurance Review and Assessment Service in Korea as the population based epidemiologic study.  In this national registry based, longitudinal, epidemiologic study, patients who were registered with an International Classifications of Diseases, Tenth Revision diagnosis of central precocious puberty (E22.8 according to International Classifications of Diseases, Tenth Revision) and treated with gonadotropin releasing hormone agonist were included. We assessed the age and sex specific prevalence and incidence rates of central precocious puberty in Korea from 2008 to 2014.  A total of 37 890 girls and 1220 boys were newly registered with a diagnosis of central precocious puberty from 2008 to 2014. The overall incidence of central precocious puberty during the study period was 122.8 per 100 000 persons (girls, 262.8; boys, 7.0) The overall prevalence of central precocious puberty during the study period was 193.2 per 100 000 persons (girls, 410.6; boys, 10.9) The incidence and prevalence of central precocious puberty steeply increased during the study period in both girls and boys.  This epidemiologic study, based on a national registry that included Korean children, demonstrated that the incidence and prevalence rates of central precocious puberty were high and increased steeply during the study period. Further investigations to determine the underlying causes for this rapid increase in central precocious puberty are needed.

title: Central precocious puberty: From genetics to treatment.
abstract: Central precocious puberty (CPP) results from early activation of the hypothalamic pituitary gonadal (HPG) axis and follows the same sequence as normal puberty. While many factors involved in pubertal initiation remain poorly understood, the kisspeptin system is known to play a key role. Currently, mutations in the kisspeptin system, MKRN3, and DLK1 have been identified in sporadic and familial cases of CPP. The diagnosis is based on physical exam findings indicating advancing puberty and on laboratory tests confirming central HPG axis activation. GnRH analogs are the mainstay of treatment and are used with the goal of height preservation. Newer extended release formulations continue to be developed. Currently there is no evidence of long term complications associated with treatment. However, many areas remain to be explored such as targeted therapies and aspects of clinical management. Further investigation into psychological effects and additional data regarding long term outcomes, particularly in males, is needed.

title: Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty
abstract: Central precocious puberty (CPP) results from premature activation of the hypothalamic pituitary gonadal axis. Few genetic causes of CPP have been identified, with the most common being mutations in the paternally expressed imprinted gene MKRN3.  To identify the genetic etiology of CPP in a large multigenerational family.  Linkage analysis followed by whole genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long term follow up, and circulating levels of Delta like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mouse hypothalamus and in kisspeptin secreting neuronal cell lines in vitro.  Endocrine clinic of an academic medical center.  Patients with familial CPP were studied.  A complex defect of DLK1 ~14 kb deletion and 269 bp duplication) was identified in this family. This deletion included the 5' untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mouse hypothalamus and in kisspeptin neuron derived cell lines.  We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty.

title: The mystery of puberty initiation: genetics and epigenetics of idiopathic central precocious puberty (ICPP)
abstract: Puberty is a major developmental stage. Damaging mutations, considered as "mistakes of nature" have contributed to the unraveling of the networks implicated in the normal initiation of puberty. Genes involved in the abnormal hypothalamic pituitary gonadal (HPG) axis development, in the normosmic idiopathic hypogonadotropic hypogonadism (nIHH) in the X linked or autosomal forms of Kallmann syndrome and in precocious puberty have been identified (GNRH1, GNRHR, KISS1, GPR54, FGFR1, FGF8, PROK2, PROKR2, TAC3, TACR3, KAL1, PROK2, PROKR2, CHD7, LEP, LEPR, PC1, DAX1, SF 1, HESX 1, LHX3, PROP 1) Most of them were found to play critical roles in HPG axis development and regulation, the embryonic GnRH neuronal migration and secretion, the regulation and action of the hypothalamic GnRH. However, the specific neural and molecular mechanisms triggering GnRH secretion remain one of the scientific enigmas. Although GnRH neurons are probably capable of autonomously generating oscillations, many gonadal steroid dependent and independent mechanisms have also been proposed. It is now well proven that the secretion of GnRH is regulated by kisspeptin as well as by permissive or opposing signals mediated by neurokinin B and dynorphin. These three supra GnRH regulators compose the kisspeptin neurokinin B dynorphin neuronal (KNDy) system, a key player in pubertal onset and progression. Moreover, an ongoing increasing number of inhibitory, stimulatory and permissive networks acting upstream on GnRH neurons, such as GABA, NPY, LIN28B, MKRN3 and others integrate diverse hormonal and peripheral signals and have been proposed as the "gate keepers" of puberty, while epigenetic modifications play also an important role in puberty initiation.

title: Investigating the relationship between precocious puberty and obesity: a cross sectional study in Shanghai, China
abstract: Obesity is reported to be closely relevant to early sexual development but the relationship between sexual precocity and obesity or central obesity is still inconsistent, especially in boys. We aimed to investigate the relationship between precocious puberty and obesity as well as central obesity.  A large population based cross sectional study using multistage, stratified cluster random sampling.  Data from the Shanghai Children's Health, Education and Lifestyle Evaluation (SCHEDULE) study in June 2014.  Chinese children aged 6 12 years. Primary and secondary outcome measures Obesity was defined by WHO Child Growth Standards. Central obesity was defined by sex specific waist to height ratio (WHtR) cut offs (WHtR =0.48 for boys, WHtR =0.46 for girls) Precocious puberty was identified by Tanner stage of breast, pubic hair and testicle development. A kh2 test was performed to compare rates. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association between precocious puberty and general obesity and central obesity. Probit analysis was used for estimating the median age at entry into Tanner stage 2 or greater for breast, pubic hair and testicle development. Linear regression was utilised to compare the effects of WHtR and body mass index (BMI) on sex development indicators.  25.98% and 38.58% of boys with precocious puberty were respectively accompanied by obesity (OR=2.15, 95% CI=1.31 to 3.50) or central obesity (OR=2.10, 95% CI=1.46 to 3.03) meanwhile, 13.86% and 29.42% of girls with precocious puberty were respectively accompanied by obesity (OR=9.00, 95% CI=5.60 to 14.46) or central obesity (OR=5.40, 95% CI=4.10 to 7.12) The median ages of breast, pubic hair and testicle development decreased with BMI increase and median ages of thelarche and testicular development rather than pubarche were earlier in children with central obesity.  Earlier pubertal development was positively associated with obesity and central obesity in Chinese children.

title: A Critical Appraisal of the Effect of Gonadotropin Releasing Hormon Analog Treatment on Adult Height of Girls with Central Precocious Puberty
abstract: Central precocious puberty (CPP) is a diagnosis that pediatric endocrinologists worldwide increasingly make in girls of age 6 8 years and is mostly idiopathic. Part of the reason for increasing referral and diagnosis is the perception among the doctors as well as the patients that treatment of CPP with long acting gonadotropin releasing hormon analogues (GnRHa) promote height of the child. Although, the timing and the tempo of puberty does influence statural growth and achieved adult height, the extent of this effect is variable depending on several factors and is modest in most cases. Studies investigating GnRHa treatment in girls with idiopathic CPP demonstrate that treatment is able to restore adult height compromised by precocious puberty. However, reports on untreated girls with precocious puberty demonstrate that some of these girls achieve their target height without treatment as well, thus, blurring the net effect of GnRHa treatment on height in girls with CPP. Clinical studies on treatment of girls with idiopathic CPP on adult stature suffers from the solid evidence base due mainly to the lack of well designed randomized controlled studies and our insufficiencies of predicting adult height of a child with narrow precision. This is particularly true for girls in whom age of pubertal onset is close to physiological age of puberty, which are the majority of cases treated with GnRHa nowadays. Heterogeneous nature of pubertal tempo (progressive vs. nonprogressive) leading to different height outcomes also complicates the interpretation of the results in both treated and untreated cases. This review will attemp to summarize and critically appraise available data in the field.

title: Higher phthalate concentrations are associated with precocious puberty in normal weight Thai girls
abstract: The cause of precocious puberty may be associated with genetics and other conditions such as central nervous system (CNS) insults, or the exposure to endocrine disrupting chemicals (EDCs) Phthalates is known to be one of the EDCs and have estrogenic and antiandrogenic activities, and may be associated with advanced puberty. The objective of the study was to determine the association between urinary phthalate metabolites and advanced puberty.  A cross sectional study was conducted in patients with precocious puberty (breast onset <8 years, n=42) and early puberty (breast onset 8 9 years, n=17) compared to age matched controls (n=77) Anthropometric measurements, estradiol, basal and gonadotropin releasing hormone (GnRH) stimulated follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, uterine sizes, ovarian diameters and bone ages (BA) were obtained. Urine samples were collected and mono methyl phthalate (MMP) and mono ethyl phthalate (MEP) were analyzed by high performance liquid chromatography (HPLC) and adjusted with urine creatinine.  The median adjusted MEP concentration in girls with precocious puberty, was greater than in normal girls (6105.09 vs. 4633.98 mg/g Cr: p<0.05) and had the same trend among early puberty and normal puberty (5141.41 vs. 4633.98 mg/g Cr: p=0.4) but was not statistically significant.  Precocious puberty girls had an association with increased MEP concentration. This is the first report of the association between urinary phthalate levels and precocious puberty in Thai girls.

title: Causes, diagnosis, and treatment of central precocious puberty.
abstract: Central precocious puberty results from the premature activation of the hypothalamic pituitary gonadal axis. It mimics physiological pubertal development, although at an inappropriate chronological age (before 8 years in girls and 9 years in boys) It can be attributable to cerebral congenital malformations or acquired insults, but the cause in most cases in girls remains unknown. MKRN3 gene defects have been identified in familial disease, with important basic and clinical results. Indeed, genetic analysis of this gene should be included in the routine clinical investigation of familial and idiopathic cases of central precocious puberty. Gonadotropin releasing hormone agonists are the gold standard treatment. The assessment and management of this disease remain challenging for paediatric endocrinologists. In this Series paper, we describe current challenges involving the precise diagnosis and adequate treatment of this disorder.

title: Postnatal feeding with high fat diet induces obesity and precocious puberty in C57BL/6J mouse pups: a novel model of obesity and puberty
abstract: Childhood obesity and obesity related metabolic complications are induced by a high fat postnatal diet. The lack of a suitable animal model, however, remains a considerable challenge in obesity studies. In the current study, we provided high fat diet (HFD) to dams during lactation and to pups after weaning. We also developed a novel model of C57BL/6J mouse pups with HFD induced postnatal obesity. Results showed that feeding with HFD induces fat deposition and obesity in pups. Furthermore, HFD more potently increased the body weight (BW) of male than female pups. HFD fed female pups were obese, underwent precocious puberty, and showed increased kisspeptin expression in the hypothalamus. However, parental obesity and precocious puberty exerted no synergistic effects on the HFD induced postnatal weight gain and puberty onset of the pups. Interestingly, some HFD fed litters with normal BW also exhibited precocious puberty. This finding suggested that diet composition but not BW triggers puberty onset. Our model suggests good construction validity of obesity and precocious puberty. Furthermore, our model can also be used to explore the mutual interactions between diet induced postnatal childhood obesity and puberty.

title: Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.
abstract: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic pituitary gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations.  An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non mutated patients.  MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4 6.0) vs 7.0 years (6.0 7.0) P=0.01)  MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.