title: Pregnancy-associated plasma protein-a is the insulin-like growth factor binding protein-4 protease secreted by human ovarian granulosa cells and is a marker of dominant follicle selection and the corpus luteum.
abstract: Insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and IGFBP proteases are important in ovarian function. IGFs stimulate granulosa steroidogenesis, an effect that is inhibited by IGFBP-4 and augmented by IGFBP-4 proteolysis. We have recently identified the IGFBP-4 protease in human ovarian follicular fluid (FF) as pregnancy-associated plasma protein-A (PAPP-A). In the current study, we identify the IGFBP-4 protease secreted by cultured human ovarian granulosa cells as PAPP-A, based on specific immunoinhibition and immunodepletion of the IGFBP-4 protease activity with PAPP-A polyclonal antibodies and immunorecognition by PAPP-A monoclonal antibodies in ELISA. PAPP-A was barely detectable in conditioned media (CM) from granulosa derived from </=9 mm androgen-dominant follicles, but was secreted by cultured granulosa from estrogen-dominant follicles >/=9 mm, coincident with dominant follicle selection, and by luteinizing granulosa. PAPP-A levels in CM from the latter did not change in response to IGF-II or hCG (100 ng/mL). A naturally occurring inhibitor of PAPP-A, proform of eosinophil major basic protein (proMBP), was detected by ELISA in estrogen-dominant follicular fluid FF, but not in CM from granulosa or luteinizing granulosa cells treated with IGF-II (0-200 ng/mL), FSH (0-100 ng/mL) or hCG (0-100 ng/mL), suggesting an alternative source (other than granulosa) for proMBP, compared to PAPP-A. The data demonstrate granulosa cells as a source of PAPP-A in human ovary and suggest that PAPP-A is a marker of ovarian follicle selection and corpus luteum formation. In addition the data suggest complex regulation of this system in human ovary.
authors.affiliation: Endocrine Unit, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Conover
authors.forename: G F
authors.initials: GF
authors.lastname: Faessen
authors.forename: K E
authors.initials: KE
authors.lastname: Ilg
authors.forename: Y A
authors.initials: YA
authors.lastname: Chandrasekher
authors.forename: M
authors.initials: M
authors.lastname: Christiansen
authors.forename: M T
authors.initials: MT
authors.lastname: Overgaard
authors.forename: C
authors.initials: C
authors.lastname: Oxvig
authors.forename: L C
authors.initials: LC
authors.lastname: Giudice
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers; D003338:Corpus Luteum / Q000502:physiology*; D005260:Female; D015571:Follicular Fluid / Q000737:chemistry; D006107:Granulosa Cells / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000378:metabolism*; D006080:Ovarian Follicle / Q000254:growth & development*; D011266:Pregnancy-Associated Plasma Protein-A / Q000032:analysis / Q000378:metabolism*; D011817:Rabbits
chemical_list: D015415:Biomarkers; D008666:Metalloendopeptidases; D011266:Pregnancy-Associated Plasma Protein-A