ESPE Abstracts (2014) 82 HA2

Pubertal Onset in Girls is Strongly Influenced by Genetic Variation in Promoters Affecting FSH Action

Casper P Hagen, Kaspar Sørensen, Lise Aksglaede, Annette Mouritsen, Mikkel G Mieritz, Jeanette Tinggaard, Christine Wohlfart-Veje, Jørgen H Petersen, Katharina M Main, Ewa Rajpert-De Meyts, Kristian Almstrup & Anders Juul


Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark


Background: FSH stimulates ovarian follicle maturation and estradiol synthesis which is responsible for breast development. Age at pubertal onset varies substantially among healthy girls. Although more than half of the variation is heritable, only a small part has been attributed to specific genetic polymorphisms identified so far.

Objective and Hypotheses: We assessed the effect on pubertal onset of three genetic polymorphisms affecting FSH action.

Method: Combined cross-sectional and longitudinal cohort study of 964 healthy girls, age 8–13 years. Puberty was defined as Tanner breast stage ≥2 by palpation. DNA was isolated from blood and FSHB −211 G>T, FSHR −29 G>A, and FSHR 2039 A>G were genotyped by competitive allele-specific PCR.

Results: Girls homozygous for FSHR −29 AA (reduced FSH receptor expression) entered puberty 7.4 (2.5–12.4) months later than carriers of the common variants FSHR −29 GG+GA, P=0.003. In a combined model, puberty occurred on average 8.0 months later in carriers of either FSHR −29 AA or FSHB −211 TT (reduced FSH production) compared with girls with at least one WT allele (10.63 vs 9.96 years, P=0.001). The number of minor alleles (FSHR −29 A and FSHB −211 T) was positively associated with age at pubertal onset (β 1.9 months, P=0.025).

Conclusion: For the first time we demonstrate that age at breast development is highly influenced by genetic variation in promoters affecting FSH action. To our knowledge, this is the strongest genetic effect on age at pubertal onset in girls published to date.