ESPE Abstracts (2016) 86 RFC12.8

Circulating MKRN3 Levels Decline During Puberty in Healthy Boys

Alexander S. Busch, Casper P. Hagen, Kristian Almstrup & Anders Juul

Department of Growth and Reproduction & EDMaRC, Rigshospitalet, Copenhagen, Denmark

Background: Initiation and progression of puberty requires concerted action of activating and inhibiting factors. Recently, cases of central precocious puberty have been linked to loss-of-function mutations of makorin RING-finger protein 3 (MKRN3) indicating a pivotal inhibitory role of MKRN3 on GnRH secretion.

Objective and hypotheses: To investigate peripubertal circulating MKRN3 levels in healthy boys.

Method: Healthy boys (n=60) aged [median (range)] 9.3 (5.8–11.8) years at baseline were followed for 6.0 (0.5–7.6) years (2006–2014) with blood sampling and clinical examinations every 6 months. Age at pubertal onset was approximated using the date between two visits when a boy’s uni- or bilateral testicular volume increased from <4 to ≥4 ml. Serum levels of MKRN3 were measured: 623 samples, median (range) 12 (2–14) per boy.

Results: Circulating MKRN3 levels exhibited a broad variation during puberty (all samples, median: 122 pg/ml, range <25–1285 pg/ml). MKRN3 levels declined prior to onset of puberty; the geometric mean (95% CI) 5 years prior to onset of puberty vs. last visit before onset of puberty was 216 (169–272) pg/ml vs 128 (118–139) pg/ml (P<0.001), respectively. MKRN3 levels continued to decrease as puberty progressed. Each boy seemed to maintain his individual MKRN3 set point during puberty. Prepubertal MKRN3 levels were not associated with age at onset of puberty (r=−0.163, P=0.213). Further, no significant correlations were observed between MKRN3 and gonadotropin levels nor total testosterone levels within each pubertal stage.

Conclusion: Continuously declining MKRN3 levels in boys prior to pubertal onset support MKRN3 as an inhibitor of GnRH secretion during childhood. Marked inter-individual variation of MKRN3 at time of pubertal onset suggests an individual set-point for reactivation of GnRH secretion.

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