Circulating MKRN3 Levels Decline Prior to Pubertal Onset and Through Puberty: A Longitudinal Study of Healthy Girls

Context: Puberty is initiated by a complex interaction of suppressing and stimulating factors. Genetic studies of familial central precocious puberty have suggested makorin ring finger protein 3(MKRN3) as a major inhibitor of GnRH secretion during childhood. Furthermore, genetic variation near MKRN3 (rs12148769) affects age at menarche in healthy girls. Objective: The purpose of this study was to evaluate whether serum levels of MKRN3 declined before pubertal onset in healthy girls. Design: This was a population-based longitudinal study of healthy Danish girls and a cohort study of early maturing girls. Setting: The study was performed in the general community and in a tertiary referral center for pediatric endocrinology. Patients or Other Participants: Healthy girls (n = 38) aged 9.3 years (range, 5.9-11.3 years) at baseline and followed for 6.0 years (2.7-7.6 years) (2006-2014) with blood sampling every 6 months and early maturing girls (n = 13) with breast development ay <8.3 years of age were included. Main Outcome Measures: Serum levels of MKRN3 were measured in 354 samples (median, 9 per girl; range, 2-14 per girl), and genotyping of variants near MKRN3 (rs12148769 and rs12439354) was performed. Results: MKRN3 concentrations declined preceding pubertal onset; the geometric mean (95% confidence interval) 3 years before pubertal onset vs the last visit before pubertal onset was 304 pg/mL (264-350 pg/mL) vs 257 pg/mL (243-273 pg/mL), corresponding to a reduction of 15% (1-27%) (P = .033). In prepubertal girls, circulating MKRN3 correlated negatively with gonadotropin levels: for FSH, r = -0.262 (P = .015) and for LH, r = -0.226 (P = .037). After adjustment, MKRN3 levels were lower in early maturing girls than in age-matched prepubertal girls: 171 pg/mL (<25-333 pg/mL) vs 262 pg/mL (94-624 pg/mL) (P = .051). Genetic variants near MKRN3 did not correlate with serum levels of MKRN3. Conclusions: Declining levels of circulating MKRN3 preceded pubertal onset. The negative correlation between MKRN3 and gonadotropins further supports MKRN3 as a major regulator of hypothalamic GnRH secretion during childhood. Undetectable or low MKRN3 levels were observed in a subgroup of patients with early onset of puberty.