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.

Trial registration: ClinicalTrials.gov NCT01438034.

Keywords: Delayed puberty; constitutional delay; hypogonadotropic hypogonadism; kisspeptin.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Summary of recruitment and participation.

Figure 2.

Neuroendocrine characteristics of children presenting with delayed or stalled puberty. A, A schematic of the protocol. Details of the protocol are given in Chan et al (20). At the first visit, participants had serum luteinizing hormone (LH) measured to assess spontaneous pulsatility overnight and to chart responses to kisspeptin and gonadotropin-releasing hormone (GnRH). Participants then received exogenous pulsatile GnRH to enhance pituitary responsiveness to GnRH. They then returned for a second visit to measure LH secretion in response to kisspeptin and GnRH after this pituitary “priming.” B, Results for participant A, a “kisspeptin nonresponder.” C, Results for participant B, a “kisspeptin responder.”

Figure 3.

Distinct responses to kisspeptin in children who progressed through puberty and those who did not. Girls (open circles) and boys (filled circles) presenting with delayed or stalled puberty underwent kisspeptin-stimulation testing to assess the change in luteinizing hormone in response to exogenous kisspeptin (∆LHkisspeptin). Participants were then followed until age 18 years to determine whether they progressed through puberty spontaneously.

Figure 4.

Additional hormonal evaluation of children who progressed or did not progress through puberty. Girls (open circles) and boys (filled circles) presenting with delayed and stalled puberty were evaluated for A, serum luteinizing hormone (LH) and B, follicle-stimulating hormone (FSH) at the time of presentation and C, the change in LH in response to exogenous gonadotropin-releasing hormone (GnRH). D, Boys were additionally evaluated for serum inhibin B.