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.
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.
Conover
C A
CA
Endocrine Unit, Mayo Clinic, Rochester, Minnesota 55905, USA.
Faessen
G F
GF
Ilg
K E
KE
Chandrasekher
Y A
YA
Christiansen
M
M
Overgaard
M T
MT
Oxvig
C
C
Giudice
L C
LC
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
D015415:Biomarkers; D008666:Metalloendopeptidases; D011266:Pregnancy-Associated Plasma Protein-A