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Claus Oxvig

Effect of pregnancy-associated plasma protein-A (PAPP-A) single-nucleotide polymorphisms on the level and activity of PAPP-A and the hormone profile in fluid from normal human small antral follicles

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  • Jane Alrø Bøtkjær, Laboratory of Reproductive Biology, Juliane Marie Center for Women, Children, and Reproduction, Copenhagen University Hospital, Copenhagen University, Copenhagen, Denmark
  • Tanni Borgbo, University of Copenhagen, Denmark
  • Søren Kløverpris
  • ,
  • Pernille Rimmer Noer
  • Claus Oxvig
  • Claus Yding Andersen, Institut for Gynækologi, Obstetrik og Pædiatri, Denmark
Objective: To reveal a possible relationship between two single nucleotide polymorphisms (SNPs) in PAPP-A—1224 (rs7020782) and
327 (rs12375498)—and the level and activity of PAPP-A in follicular fluid (FF) of human small antral follicles, and to analyze the
intrafollicular hormone levels.
Design: Laboratory investigation.
Setting: University hospital.
Patient(s): Fifty volunteer women who contributed a total of 210 samples of FF from normal small antral follicles.
Intervention(s): Genotyping and measurement of antigen levels of steroids, PAPP-A, stanniocalcin-2 (STC2), and antim€ullerian
hormone (AMH) plus activity of PAPP-A toward insulin-like growth factor binding protein 4 (IGFBP-4).
Main Outcome Measure(s): Measurement of PAPP-A levels and hormones with enzyme-linked immunosorbent assay (ELISA) and
PAPP-A activity toward radiolabeled IGFBP-4.
Result(s): Women homozygous for the minor C allele of the 1224 SNP showed a statistically significantly lower level of PAPP-A
protein and activity in FF compared with women carrying the major A allele. These women also displayed nonsignificant reduced
levels of estradiol and increased levels of AMH and androgen. A statistically significant correlation between FF levels of PAPP-A
activity and the molar ratio of PAPP-A/STC2 was obtained. The 327 SNP did not show statistically significant associations.
Conclusion(s): This study presents a statistically significant effect of the 1224 SNP on the level and activity of PAPP-A in human
follicles, suggesting that the FF level of bioactive insulin-like growth factor depends on the genotype. We observed STC2 to be an
important regulator of PAPP-A in human FF. The 1224 SNP has previously been associated with recurrent pregnancy loss, so
further evaluation of an underlying mechanism including aberrant control of insulin-like growth factor activity is warranted. (Fertil
Steril 2016;-:-–-. 2016 by American Society for Reproductive Medicine.)
Key Words: Human follicles, human ovarian steroidogenesis, IGF signaling, PAPP-A, single-nucleotide polymorphisms
Original languageEnglish
JournalFertility and Sterility
Pages (from-to)1778-1786.e8
Publication statusPublished - 25 Oct 2016

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