TY - JOUR

T1 - Genetic variations in FSH action affect sex hormone levels and breast tissue size in infant girls

T2 - A pilot study

AU - Henriksen, Louise Scheutz

AU - Hagen, Casper P

AU - Assens, Maria

AU - Busch, Alexander S.

AU - Skakkebæk, Niels E.

AU - Almstrup, Kristian

AU - Main, Katharina M.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - Context: Single nucleotide polymorphisms altering FSH action (FSHB -211G>T, FSHR -29G>A, and FSHR 2039A>G) are associated with peripubertal and adult levels of reproductive hormones and age at pubertal onset in girls. Objective: To investigate whether genetic polymorphisms altering FSH action affect serum levels of female reproductive hormones and breast development as early as during minipuberty. Design: Longitudinal study. Setting: Population-based cohort study. Participants: A total of 402 healthy girls at 3 months of age. Main Outcome Measures: Analyses of single nucleotide polymorphisms by PCR using Kompetitive Allele Specific PCR genotyping assays; identification of glandular breast tissue by palpation and measurement of the diameter. Serum levels of anti-Müllerian hormone, FSH, LH, estradiol, inhibin B, and sex hormone-binding globulin were assessed by immunoassays. Results: FSHR -29G>A was associated with both FSH and anti-Müllerian hormone levels with an A allele effect size of -0.8 IU/L (P = .005) and 1.4 nmol/L (P = .003), respectively. FSHR 2039A>G correlated with breast tissue size with a negative additive effect of minor alleles (P=.021), whereas the effect on estradiol levels was only present in homozygotes. FSHB -211T carriers had smaller breast tissue size than girls who without a minor allele; GT+TT 10.5 (confidence interval 9.4 -11.5) mm vs GG 12.1 (confidence interval 11.4-12.8) mm, P = .014. Conclusions: Our study indicates that 3 genetic polymorphisms altering FSH action, especially FSHR -29G>A and FSHR 2039A>G, affect female hormone profile and glandular breast tissue development already during minipuberty. Thus, genetic variations of FSH signaling appear to determine the individual set point of the hypothalamic-pituitary-gonadal axis already early in life.

AB - Context: Single nucleotide polymorphisms altering FSH action (FSHB -211G>T, FSHR -29G>A, and FSHR 2039A>G) are associated with peripubertal and adult levels of reproductive hormones and age at pubertal onset in girls. Objective: To investigate whether genetic polymorphisms altering FSH action affect serum levels of female reproductive hormones and breast development as early as during minipuberty. Design: Longitudinal study. Setting: Population-based cohort study. Participants: A total of 402 healthy girls at 3 months of age. Main Outcome Measures: Analyses of single nucleotide polymorphisms by PCR using Kompetitive Allele Specific PCR genotyping assays; identification of glandular breast tissue by palpation and measurement of the diameter. Serum levels of anti-Müllerian hormone, FSH, LH, estradiol, inhibin B, and sex hormone-binding globulin were assessed by immunoassays. Results: FSHR -29G>A was associated with both FSH and anti-Müllerian hormone levels with an A allele effect size of -0.8 IU/L (P = .005) and 1.4 nmol/L (P = .003), respectively. FSHR 2039A>G correlated with breast tissue size with a negative additive effect of minor alleles (P=.021), whereas the effect on estradiol levels was only present in homozygotes. FSHB -211T carriers had smaller breast tissue size than girls who without a minor allele; GT+TT 10.5 (confidence interval 9.4 -11.5) mm vs GG 12.1 (confidence interval 11.4-12.8) mm, P = .014. Conclusions: Our study indicates that 3 genetic polymorphisms altering FSH action, especially FSHR -29G>A and FSHR 2039A>G, affect female hormone profile and glandular breast tissue development already during minipuberty. Thus, genetic variations of FSH signaling appear to determine the individual set point of the hypothalamic-pituitary-gonadal axis already early in life.

U2 - 10.1210/jc.2016-1672

DO - 10.1210/jc.2016-1672

M3 - Journal article

C2 - 27270476

AN - SCOPUS:84984675561

VL - 101

SP - 3191

EP - 3198

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 8

ER -