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.

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OR11-01 Using Kisspeptin to Predict Pubertal Outcomes for Youth With Pubertal Delay

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.2090 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Yee-Ming Chan ◽

Margaret Flynn Lippincott ◽

Priscila Sales Barroso ◽

Cielo Alleyn ◽

Jill Brodsky ◽

...

Keyword(s):

Inhibin B ◽

Stimulation Test ◽

Delayed Puberty ◽

Laboratory Studies ◽

Pubertal Delay ◽

Gnrh Release ◽

Reproductive Endocrine ◽

Physical Examinations ◽

Outcomes For Children ◽

Endocrine Axis

Abstract Background: The management of youth presenting with delayed puberty is challenging because it can be difficult to predict which children will eventually progress through puberty and which children will not. We have previously shown that exogenous administration of the neuropeptide kisspeptin, which stimulates GnRH release, can be used to probe the integrity of the reproductive endocrine axis. We hypothesized that responses to kisspeptin could predict outcomes for individuals with pubertal delay. Methods: We conducted a longitudinal study of 16 children (3 girls and 13 boys) with delayed or stalled puberty who had undergone stimulation testing with kisspeptin and GnRH. Participants were followed with serial physical examinations and laboratory studies every six months for evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing. Results: “Kisspeptin responders” who had responded to kisspeptin with a rise in LH of 0.8 mIU/mL or greater all subsequently progressed through puberty (n = 8). In contrast, “kisspeptin nonresponders” who had exhibited LH responses to kisspeptin ≤0.4 mIU/mL all reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (p = 0.0002), with sensitivity and specificity of 100% (95% CI 74-100%). Moreover, the kisspeptin-stimulation test outperformed overnight LH measurements, GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes. Conclusion: The kisspeptin-stimulation test can be used to reveal 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

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Timing of Pubertal Onset in Girls and Boys with Constitutional Delay

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab270 ◽

2021 ◽

Author(s):

Elfa Jonsdottir-Lewis ◽

Amalia Feld ◽

Ryan Ciarlo ◽

Erica Denhoff ◽

Henry A Feldman ◽

...

Keyword(s):

Sex Steroids ◽

Medical Records ◽

Medical Center ◽

Academic Medical Center ◽

Delayed Puberty ◽

Normal Variation ◽

Time To Event ◽

Academic Medical ◽

Constitutional Delay ◽

Age Range

Abstract Context The decision whether to treat a child with delayed puberty with sex steroids is primarily based on patient, family, and provider preference. Knowing when children with constitutional delay eventually enter puberty would inform this decision. Objective, Design, Setting, Participants, and Outcome Measures To estimate and compare rates of pubertal entry, we conducted a retrospective cohort study by reviewing medical records of children evaluated for delayed puberty at a large academic medical center between 2000 and 2015, extracting data on pubertal status for all clinical visits, then conducting time-to-event analyses. Results Of 392 girls and 683 boys with delayed puberty, constitutional delay was the most common cause, found in 32% of girls and 70% of boys. In a subcohort of 97 girls and 243 boys who were prepubertal at one or more visits, we observed a broad age range for pubertal entry, up to >16 years for girls and >17 years for boys. The probability of entering puberty within the next year for 12- to 15.5-year-old girls and 13.5- to 16.5-year-old boys with delayed puberty ranged between 38% and 74%. No differences in the rates of pubertal entry were seen between girls and boys after data harmonization. Conclusion The broad range of ages at pubertal entry for children with constitutional delay challenges the concept that constitutional delay is merely an extreme of normal variation. Discussions with patients and families about management should consider the possibility that some children may need to wait years after presentation until puberty starts.

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Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00146 ◽

2019 ◽

Vol 104 (10) ◽

pp. 4304-4318 ◽

Cited By ~ 4

Author(s):

Margaret F Lippincott ◽

Silvia León ◽

Yee-Ming Chan ◽

Chrysanthi Fergani ◽

Rajae Talbi ◽

...

Keyword(s):

Pulse Generator ◽

Medical Center ◽

Academic Medical Center ◽

Pulse Frequency ◽

Pulse Generation ◽

Loss Of Function ◽

Neurokinin B ◽

Gene Encoding ◽

Reproductive Endocrine ◽

Pulse Characteristics

Abstract Context Kisspeptin–neurokinin B (NKB)–dynorphin neurons are critical regulators of the hypothalamic–pituitary–gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear. Objective To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB. Design Case/control. Setting Academic medical center. Participants Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice. Interventions Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin. Main Outcome Measures LH pulse characteristics. Results Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin. Conclusion The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.

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