1. Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls.
- Author
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Hagen CP, Sørensen K, Mieritz MG, Johannsen TH, Almstrup K, and Juul A
- Subjects
- Adolescent, Child, Child, Preschool, Female, Follicle Stimulating Hormone blood, Genotype, Healthy Volunteers, Humans, Longitudinal Studies, Luteinizing Hormone blood, Prospective Studies, Ubiquitin-Protein Ligases, Puberty blood, Puberty, Precocious blood, Ribonucleoproteins blood
- Abstract
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.
- Published
- 2015
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