Adult Consequences of Self-Limited Delayed Puberty

Zhu, Jia; Chan, Yee-Ming

doi:10.1542/peds.2016-3177

Cited by 109 publications

(78 citation statements)

References 122 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, cases of self-limited DP may also encompass older children with delayed pubertal progression, a diagnosis that is aided by the use of puberty nomograms [8]. Self-limited DP is associated with adverse health outcomes including short stature, reduced bone mineral density, and compromised psychosocial health [9].…”

Section: Investigating the Inheritance Of Delayed Pubertymentioning

confidence: 99%

The Genetic Basis of Delayed Puberty

Howard

2017

Neuroendocrinology

View full text Add to dashboard Cite

The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes including short stature, reduced bone mineral density, and compromised psychosocial health. Self-limited delayed puberty (DP) is a highly heritable trait, which often segregates in an autosomal dominant pattern; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Some insights into the genetic mutations that lead to familial DP have come from sequencing genes known to cause gonadotropin-releasing hormone (GnRH) deficiency, most recently via next-generation sequencing, and others from large-scale genome-wide association studies in the general population. Investigation of the genetic control of DP is complicated by the fact that this trait is not rare and that the phenotype is likely to represent a final common pathway, with a variety of different pathogenic mechanisms affecting the release of the puberty “brake.” These include abnormalities of GnRH neuronal development and function, GnRH receptor and luteinizing hormone/follicle-stimulating hormone abnormalities, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis. Thus, genetic control of pubertal timing can range from early fetal life via development of the GnRH network to those factors directly influencing the puberty brake during mid-childhood.

show abstract

Section: Investigating the Inheritance Of Delayed Pubertymentioning

confidence: 99%

The Genetic Basis of Delayed Puberty

Howard

2017

Neuroendocrinology

View full text Add to dashboard Cite

show abstract

“…Specifically, DP patients are at risk of decreased bone mineral density, osteoporosis (26,27) and psychological distress (28,29). In addition, recently associated increased risk has been shown for outcomes such as cervical cancer, myocardial infarction and poor overall health (12,30). Thus, the genetic control of human puberty is not only a fascinating scientific puzzle but also has potential for and transiently transfected with EAP1 plasmids (WT and mutated; 200 ng/well).…”

Section: Discussionmentioning

confidence: 99%

“…DP is defined as the absence of testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 standard deviations (SDs) later than the population mean (11). In absence of any identifiable cause, DP usually resolves by the age of 18 years, and in this case is referred to as self-limited, or constitutional, DP (12). Self-limited DP is commonly familial and segregates with an autosomal dominant inheritance patterns in >70% of families, indicating a strong genetic basis of the trait.…”

Section: Introductionmentioning

confidence: 99%

EAP1 regulation of GnRH promoter activity is important for human pubertal timing

Mancini¹,

Howard²,

CP³

et al. 2019

ESPE

View full text Add to dashboard Cite

The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunof luorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.

show abstract

“…In addition, selflimited DP may also encompass older children with delayed pubertal progression, a diagnosis that is aided by the use of puberty normograms ( Figure 1) (23). Self-limited DP is associated with adverse health outcomes including short stature, reduced bone mineral density and compromised psychosocial health (24).…”

Section: Etiologymentioning

confidence: 99%

Management of hypogonadism from birth to adolescence

Howard

Dunkel

2018

Best Practice & Research Clinical Endocrinology & Metab

View full text Add to dashboard Cite

Management of patients with hypogonadism is dependent on the underlying cause. Whilst functional hypogonadism presenting as delayed puberty in adolescence is relatively common, permanent hypogonadism presenting in infancy or adolescence is unusual. The main differential diagnoses of delayed puberty include self-limited delayed puberty (DP), idiopathic hypogonadotropic hypogonadism (IHH) and hypergonadotropic hypogonadism. Treatment of self-limited DP involves expectant observation or short courses of low dose sex steroid supplementation. More complex and involved management is required in permanent hypogonadism to achieve both development of secondary sexual characteristics and to maximize the potential for fertility. This review will cover the options for management involving sex steroid or gonadotropin therapy, with discussion of benefits, limitations and specific considerations of the different treatment options.

show abstract

Adult Consequences of Self-Limited Delayed Puberty

Cited by 109 publications

References 122 publications

The Genetic Basis of Delayed Puberty

The Genetic Basis of Delayed Puberty

EAP1 regulation of GnRH promoter activity is important for human pubertal timing

Management of hypogonadism from birth to adolescence

Contact Info

Product

Resources

About