Alexander S Busch1, Casper P Hagen1, Kristian Almstrup1, Anders Juul1. 1. Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC).
Abstract
CONTEXT: Initiation and progression of puberty requires concerted action of hypothalamic activating and inhibiting factors. Recently, cases of familial central precocious puberty have been linked to loss-of-function mutations of makorin RING-finger protein 3 (MKRN3) indicating a pivotal inhibitory role of the protein on GnRH secretion. OBJECTIVE: To investigate peripubertal circulating MKRN3 levels in healthy boys. DESIGN: Population-based longitudinal study in healthy Danish boys. SETTING: General community. PATIENTS OR OTHER PARTICIPANTS: Healthy boys (n = 60) aged (median [range]) 9.3 (5.8-11.8) years at baseline followed for 6.0 (0.5-7.6) years (2006-2014) with blood sampling every 6 months. INTERVENTION: None. MAIN OUTCOME MEASURES: Serum levels of MKRN3: 623 samples, median (range) 12 (2-14) per boy. RESULTS: MKRN3 levels declined before onset of puberty; the geometric mean (95% confidence interval) 5 years before onset of puberty vs last visit before onset of puberty was 216 (169-272) pg/mL vs 128 (118-139) pg/mL (P < .001), respectively. MKRN3 levels continued to decrease as puberty progressed. MKRN3 levels were not associated with age at onset of puberty. CONCLUSION: Declining MKRN3 before pubertal onset support MKRN3 as an inhibitor of GnRH secretion during midchildhood.
CONTEXT: Initiation and progression of puberty requires concerted action of hypothalamic activating and inhibiting factors. Recently, cases of familial central precocious puberty have been linked to loss-of-function mutations of makorin RING-finger protein 3 (MKRN3) indicating a pivotal inhibitory role of the protein on GnRH secretion. OBJECTIVE: To investigate peripubertal circulating MKRN3 levels in healthy boys. DESIGN: Population-based longitudinal study in healthy Danish boys. SETTING: General community. PATIENTS OR OTHER PARTICIPANTS: Healthy boys (n = 60) aged (median [range]) 9.3 (5.8-11.8) years at baseline followed for 6.0 (0.5-7.6) years (2006-2014) with blood sampling every 6 months. INTERVENTION: None. MAIN OUTCOME MEASURES: Serum levels of MKRN3: 623 samples, median (range) 12 (2-14) per boy. RESULTS:MKRN3 levels declined before onset of puberty; the geometric mean (95% confidence interval) 5 years before onset of puberty vs last visit before onset of puberty was 216 (169-272) pg/mL vs 128 (118-139) pg/mL (P < .001), respectively. MKRN3 levels continued to decrease as puberty progressed. MKRN3 levels were not associated with age at onset of puberty. CONCLUSION: Declining MKRN3 before pubertal onset support MKRN3 as an inhibitor of GnRH secretion during midchildhood.
Authors: Violeta Heras; Susana Sangiao-Alvarellos; Maria Manfredi-Lozano; María J Sanchez-Tapia; Francisco Ruiz-Pino; Juan Roa; Maribel Lara-Chica; Rosario Morrugares-Carmona; Nathalie Jouy; Ana P Abreu; Vincent Prevot; Denise Belsham; Maria J Vazquez; Marco A Calzado; Leonor Pinilla; Francisco Gaytan; Ana C Latronico; Ursula B Kaiser; Juan M Castellano; Manuel Tena-Sempere Journal: PLoS Biol Date: 2019-11-07 Impact factor: 9.593