Genetic regulation in pubertal delay

Abstract

Delayed puberty represents the clinical presentation of a final common pathway for many different pathological mechanisms. In the majority of patients presenting with significantly delayed puberty, there is a clear family history of delayed or disturbed puberty, and pubertal timing is known to be a trait with strong heritability. Thus, genetic factors clearly play a key role in determining the timing of puberty, and mutations in certain genes are recognised as responsible for delayed or absent puberty in a minority of patients. Through the identification of causal genetic defects such as these we have been able to learn a great deal about the pathogenesis of disrupted puberty and its genetic regulation. Firstly, deficiency in key genes that govern the development of the gonadotropin-releasing hormone system during fetal development may result in a spectrum of conditions ranging from isolated delayed puberty to absent puberty with anosmia. Secondly, a balance of inhibitory and excitatory signals, acting upstream of GnRH secretion, are vital for the correct timing of puberty. These act to repress the hypothalamic–pituitary–gonadal axis during mid-childhood and allow it to reactivate at puberty, and alterations in this equilibrium can cause delayed (or precocious) puberty. Thirdly, disturbances of energy metabolism inputs to the kisspeptin–GnRH system may also lead to late onset of puberty associated with changes in body mass.

Interpretation of reproductive hormones before, during and after the pubertal transition—Identifying health and disordered puberty

“…Diagnosis may require more extended or resource‐intensive investigations, such as measurement of gonadotropin response to stimulation with GnRH or, more recently, kisspeptin, as well as genetic analysis with whole‐exome or panel testing. 100 The expertize of the clinical team to put together these pieces of the jigsaw puzzle is key, to allow appropriately directed management in a limited‐time window, to minimize negative outcomes and optimize therapeutic care for our patients.…”

A classification of genes involved in normal and delayed male puberty

“… 69 The involvement of multiple innervations from suprahypothalamic areas may provide flexibility and precise coordination in the regulation of the GnRH neuronal activity manifested in the episodic release of GnRH. 71 Table 3 shows the list of 51 genes that have been identified to modulate GnRH neuronal activity 4 , 10 , 23 , 37 , 38 , 49 , 64 , 72 and mutations in 9 genes have been identified to cause delayed puberty 4 , 25 , 26 , 72 ( Table 1 ).…”

Psychosocial and energetic factors on human female pubertal timing: a systematized review

“…Evolutionary theorists suggest that pubertal timing is facultative at the species level (MacDonald, 1999 ; Stearns, 1992 ; Surbey, 1990 ; Wasser & Barash, 1983 ). There is robust evidence that pubertal onset (from relatively early to more delayed on a continuum) is highly heritable, with heritability commonly estimated greater than 0.40 (Eaves et al, 2004 ; Howard, 2019 ; Morris et al, 2011 ; Zhu et al, 2018 ). However, because a single genotype can exhibit myriad phenotypic expressions (‘norm of reaction’), the probabilistic impact of genetics on pubertal timing may well depend on local socioecological conditions (Ellis, 2004 ; Mcintyre & Kacerosky, 2011 ; Stearns & Koella, 1986 ; Worthman et al, 2019 ).…”