Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay

Abstract

Context The management of youth with delayed puberty is hampered by difficulty in predicting who will eventually progress through puberty and who will fail to attain adult reproductive endocrine function. The neuropeptide kisspeptin, which stimulates gonadotropin-releasing hormone (GnRH) release, can be used to probe the integrity of the reproductive endocrine axis. Objective We sought to determine whether responses to kisspeptin can predict outcomes for individuals with pubertal delay. Design, Setting, and Participants We conducted a longitudinal cohort study in an academic medical center of 16 children (3 girls and 13 boys) with delayed or stalled puberty. Intervention and Outcome Measures Children who had undergone kisspeptin- and GnRH-stimulation tests were followed every 6 months for clinical evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results All participants who had responded to kisspeptin with a rise in luteinizing hormone (LH) of 0.8 mIU/mL or greater subsequently progressed through puberty (n = 8). In contrast, all participants who had exhibited LH responses to kisspeptin ≤ 0.4 mIU/mL reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (P = .0002). Moreover, the kisspeptin-stimulation test outperformed GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion The kisspeptin-stimulation can assess future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty.

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

“… 98 In a parallel study in adolescents with pubertal delay (3 females and 13 males), peak LH post kisspeptin stimulation was demonstrated to be superior to GnRH stimulation testing for predicting capacity to progress through puberty. 99 All eight study participants with a maximum LH response to kisspeptin of ≤0.4 IU/L reached age 18 years without developing physical signs of puberty, thus confirming the diagnosis of hypogonadotropic hypogonadism. While further research is required to delineate the parameters of using kisspeptin in clinical paediatric practice, this is a promising area for the biochemical diagnosis of GnRH deficiency in adolescence.…”

Review of human genetic and clinical studies directly relevant to GnRH signalling

“…Some children show a robust response and others show little to none. However, in these children, the response to kisspeptin administration appears to predict future pubertal entry 59 . Specifically, in a longitudinal cohort study, all children with pubertal delay who had responded to kisspeptin with a rise in LH of ≥0.8 mIU/ml progressed through puberty ( n = 8) but all participants whose LH response was ≤0.4 mIU/ml did not ( n = 8).…”

Recent advances in understanding and managing Kallmann syndrome

“…• Failure to properly contextualise pubertal delay associated with “red flag” clinical features as indicating CHH, rather than the more common scenario of constitutional delay 46 . Of note, kisspeptin stimulation recently proved to be a promising diagnostic tool in differentiating CHH and CDGP in a small cohort of adolescents, overcoming the limited discriminatory power of other tests including GnRH-stimulated LH, inhibin B, and genetic tests 47 , albeit larger-scale study would be necessary to validate the results.…”