Genetic Variations in FSH Action Affect Sex Hormone Levels and Breast Tissue Size in Infant Girls: A Pilot Study.
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.



To investigate whether genetic polymorphisms altering FSH action affect serum levels of female reproductive hormones and breast development as early as during minipuberty.



Longitudinal study.



Population-based cohort study.



A total of 402 healthy girls at 3 months of age.



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.



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.



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.
Department of Growth and Reproduction (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark.
Louise Scheutz
LS
Henriksen
Department of Growth and Reproduction (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark.
Casper P
CP
Hagen
Department of Growth and Reproduction (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark.
Maria
M
Assens
Department of Growth and Reproduction (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark.
Alexander S
AS
Busch
Department of Growth and Reproduction (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark.
Niels E
NE
Skakkebæk
Department of Growth and Reproduction (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark.
Kristian
K
Almstrup
Department of Growth and Reproduction (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (L.S.H., C.P.H., M.A., A.S.B., N.E.S., K.A., K.M.M.), Rigshospitalet, DK-2100 Copenhagen, Denmark.
Katharina M
KM
Main
D001940:Breast / Q000254:growth & development*; D015331:Cohort Studies; D005260:Female; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D012739:Gonadal Steroid Hormones / Q000097:blood*; D006801:Humans; D007223:Infant; D009929:Organ Size; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D011962:Receptors, FSH / Q000235:genetics*
D037201:Follicle Stimulating Hormone, beta Subunit; D012739:Gonadal Steroid Hormones; D011962:Receptors, FSH