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.