Evidence That the Insulin-Like Growth Factor Binding Protein-4 Protease in Human Ovarian Follicular Fluid Is Pregnancy Associated Plasma Protein-A

Conover, Cheryl A.; Oxvig, Claus; Overgaard, Michael T.; Christiansen, Michael; Giudice, Linda C.

doi:10.1210/jcem.84.12.6342

Cited by 120Growth Hormone and Insulin-like Growth FactorsReproductive Biology and FertilityOvarian function and disorders

The DOI matches its Crossref record.

Evidence That the Insulin-Like Growth Factor Binding Protein-4 Protease in Human Ovarian Follicular Fluid Is Pregnancy Associated Plasma Protein-A

Conover, Cheryl A., Oxvig, Claus, Overgaard, Michael T., Christiansen, Michael, Giudice, Linda C.·1999·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jcem.84.12.6342

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Abstract

Ovarian insulin-like growth factor binding protein-4 (IGFBP-4) proteolysis is involved in the regulation of follicular development, but until now the identity of the responsible enzyme was unknown. In this study, we identify the IGFBP4 protease in human follicular fluid as pregnancy associated plasma protein-A (PAPP-A) based on distinctive IGFBP-4 cleavage pattern, the same protease inhibitor profile, specific inhibition and immunodepletion of IGFBP-4 protease activity with PAPP-A polyclonal antibodies, and immunorecognition by PAPP-A monoclonal antibodies in ELISA. Furthermore, PAPP-A levels in estrogen-dominant and androgen-dominant follicular fluids reflect their IGFBP-4 proteolytic activity. PAPP-A was also secreted by human granulosa cells, the reputed source of IGFBP-4 protease activity in follicular fluid. We have the molecular and biochemical tools to begin to delineate the regulation and biological function of PAPP-A in normal and dysregulated follicular development and atresia.

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A high concentration of PAPPA is found in the serum of pregnant women.
“A high concentration of this protein is found in the serum of pregnant women (Silahtaroglu et al. 1993; Conover et al. 1999; Lawrence et al. 1999).”
From Limb-Girdle Muscular Dystrophy Type 2H Associated with Mutation in TRIM32, a Putative E3-Ubiquitin–Ligase Gene (2002) · cites this paper as Conover et al. 1999

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Konev, A. A., Smolyanova, T. I., Kharitonov, A. V., Serebryanaya, D. V., Kozlovsky, S. V., Kara, A. N., Feygina, E. E., Katrukha, A. G., & Postnikov, A. B. (2015) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2015.05.010 · Cited by 25
Differential regulation of pregnancy associated plasma protein (PAPP)-A during pregnancy in human and mouse
Qin, X., Sexton, C., Byun, D. W., et al. (2002) · Growth Hormone & IGF Research · doi:10.1016/s1096-6374(02)00046-1 · Cited by 25
Identification of genes with higher expression in human uterine leiomyomas than in the corresponding myometrium
Wu, X. (2002) · Molecular Human Reproduction · doi:10.1093/molehr/8.3.246 · Cited by 24
“Intact IGFBP-4 is a potent inhibitor of IGF action in vitro, and PAPPA cleavage of IGFBP-4 may lead to increased bioavailability of IGF in leiomyomas (Conover et al., 1999; Lawrence et al., 1999; Mazerbourg et al., 2000).”
Background
Effects of Mutated Pregnancy-Associated Plasma Protein-A on Atherosclerotic Lesion Development in Mice
Boldt, H. B., Bale, L. K., Resch, Z. T., Oxvig, C., Overgaard, M. T., & Conover, C. A. (2012) · Endocrinology · doi:10.1210/en.2012-1552 · Cited by 23
Self-citation
Role of Components of the Insulin-like Growth Factor System in the Early Stages of Ovarian Follicular Persistence in Cattle
Rodríguez, F. M., Gareis, N. C., Hein, G. J., et al. (2017) · Journal of Comparative Pathology · doi:10.1016/j.jcpa.2017.07.010 · Cited by 22
Insulin-like growth factor binding proteins in granulosa and thecal cells from bovine ovarian follicles at different stages of development1,2
Roberts, A. J., & Echternkamp, S. E. (2003) · Journal of Animal Science · doi:10.2527/2003.81112826x · Cited by 22
“Mounting evidence indicates that proteolysis of specific IGFBP contribute to diminished binding activity in follicular fluid from humans (Chandrasekher et al., 1995; Conover et al., 1999; 2001) and domestic species (Mazerbourg et al., 2000; Rivera et al., 2001; Spicer et al., 2001).”
Background
Insulin-like growth factor, insulin-like growth factor–binding protein-4, and pregnancy-associated plasma protein-A gene expression in human granulosa cell tumors
Alexiadis, M., Mamers, P. M., Chu, S., et al. (2006) · International Journal of Gynecological Cancer · doi:10.1111/j.1525-1438.2006.00724.x · Cited by 20
Pregnancy-associated plasma protein A up-regulated by progesterone promotes adhesion and proliferation of trophoblastic cells.
Wang, J., Liu, S., Qin, H., et al. (2014) · PubMed · Cited by 18
Implications of the PAPP-A-IGFBP-IGF-1 pathway in the pathogenesis and treatment of polycystic kidney disease
Kashyap, S., Zeidler, J. D., Chini, C. C. S., & Chini, E. N. (2020) · Cellular Signalling · doi:10.1016/j.cellsig.2020.109698 · Cited by 15
First Trimester PAPP-A Levels Associated with Early Prediction of Pregnancy Induced Hypertension
Meloni, P., D’Angeli, I., Piazze, J., et al. (2009) · Hypertension in Pregnancy · doi:10.3109/10641950802601211 · Cited by 15
IGF-Binding Protein-4 Expression and IGF-Binding Protein-4 Protease Activity Are Regulated Coordinately in Smooth Muscle During Postnatal Development and After Vascular Injury
Smith, E. P., Kamyar, A., Niu, W., et al. (2001) · Endocrinology · doi:10.1210/endo.142.10.8452 · Cited by 14
“a distinct IGFBP-4 protease and the subsequent availability of mouse PAPP-A cDNA probes (27, 39, 49), we were unable to demonstrate definitively that the activity detected in our”
Actions of GnRH antagonists on IGF-II, IGF-binding protein-2 and pregnancy-associated plasma protein-A in human granulosa-lutein cells
Weiss, J., Krautmacher, B., Polack, S., et al. (2003) · European Journal of Endocrinology · doi:10.1530/eje.0.1490031 · Cited by 13
“This is in agreement with recent studies showing high levels of PAPP-A and consequently no detected IGFBP-4 in dominant follicles or granulosa-lutein cells (30, 32 ).”
BackgroundMethodResultInfluential
A common variant of the pregnancy-associated plasma protein-A (PAPPA) gene encodes a protein with reduced proteolytic activity towards IGF-binding proteins
Bøtkjær, J. A., Noer, P. R., Oxvig, C., & Andersen, C. Y. (2019) · Scientific Reports · doi:10.1038/s41598-019-49626-8 · Cited by 13
Self-citation
IGFBP-4 Proteolysis by PAPP-A in a Primary Culture of Rat Neonatal Cardiomyocytes under Normal and Hypertrophic Conditions
Serebryanaya, D. V., Adasheva, D. A., Konev, A. A., et al. (2021) · Biochemistry (Moscow) · doi:10.1134/s0006297921110043 · Cited by 12
May all your femurs be long!
Nyberg, D. A. (2008) · Ultrasound in Obstetrics and Gynecology · doi:10.1002/uog.5358 · Cited by 12
Follicular fluid and serum levels of Inhibin A and pregnancy-associated plasma protein A in patients undergoing IVF
Moos, J., Filova, V., Pavelkova, J., et al. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.01.102 · Cited by 12
Decreased Expression of Placental Proteins in Recurrent Pregnancy Loss: Functional Relevance and Diagnostic Value
Tóth, E., Györffy, D., Posta, M., Hupuczi, P., Balogh, A., Szalai, G., Orosz, G., Orosz, L., Szilágyi, A., Oravecz, O., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031865 · Cited by 13
PAPP-A-Specific IGFBP-4 Proteolysis in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Adasheva, D. A., Lebedeva, O. S., Goliusova, D. V., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098420 · Cited by 9
“Previous studies have shown that PAPP-A cleaves IGFBP-4 in the conditioned medium of fibroblasts and follicular fluid of human, bovine, porcine, and horse ovaries [9,10].”
Result
Insulin‐like growth factors and their binding proteins: Potential relevance to reproductive physiology
Yoshimura, Y. (2003) · Reproductive Medicine and Biology · doi:10.1046/j.1445-5781.2003.00016.x · Cited by 9
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
Bøtkjær, J. A., Borgbo, T., Kløverpris, S., Noer, P. R., Oxvig, C., & Andersen, C. Y. (2016) · Fertility and Sterility · doi:10.1016/j.fertnstert.2016.09.008 · Cited by 8
Self-citation
The expression of pregnancy-associated plasma protein-A (PAPP-A) in human blastocoel fluid–conditioned media: a proof of concept study
Kavoussi, S. K., Chen, S., Wininger, J. D., et al. (2022) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-022-02393-4 · Cited by 8
“For example, the presence of immunoreactive PAPP-A has been demonstrated in culture medium conditioned by human ovarian granulosa cells [29].”
Background
Localization and cellular distribution of pregnancy-associated plasma protein–a and major basic protein in human ovary and corpora lutea throughout the menstrual cycle
Rhoton-Vlasak, A. S., Gleich, G. J., Bischof, P., et al. (2003) · Fertility and Sterility · doi:10.1016/s0015-0282(03)00077-3 · Cited by 8
Studies on regulation of IGF (insulin-like growth factor)-binding protein (IGFBP) 4 proteolysis by pregnancy-associated plasma protein-A (PAPP-A) in cells treated with phorbol ester
Sivanandam, A., Mohan, S., Kita, H., et al. (2004) · Biochemical Journal · doi:10.1042/bj20030937 · Cited by 8
Growth Hormone, Insulin-Like Growth Factors, and the Ovary
Bondy, C., ZHOU, J., & Arraztoa, J. (2006) · Elsevier eBooks · doi:10.1016/b978-012515400-0/50018-x · Cited by 8
PAPPA’s role in female reproduction
Schaab, A. M., Stroud, K. L., Nguyen, D. T., Moses, J. C., Hart, J., Aplin, Z. J., Chosed, R. J., Fox, C. W., Green, L. J., LaVoie, H. A., et al. (2025) · Reproduction · doi:10.1530/rep-25-0012 · Cited by 7
PAPP-A in Indian Water Buffalo (Bubalus bubalis) Ovary: Phylogeny, Expression, Hormonal Regulation, and Sequence Characterization
Nayan, V., Bhardwaj, A., & Singh, D. (2013) · Agricultural Research · doi:10.1007/s40003-013-0062-x · Cited by 7
“Subsequently, PAPP-A was also shown to be expressed by osteoblasts, vascular smooth muscle cells, and ovarian granulosa cells, as well as by placental trophoblasts in culture [5, 11, 14, 20].”
PAPP-A2 nowy regulator procesu wzrastania
Banaszak-Ziemska, M., & Niedziela, M. (2017) · Endokrynologia Polska · doi:10.5603/ep.a2017.0060 · Cited by 7
“It is also present in pregnancy serum [21] and ovarian follicular fluid [22].”
Background
Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition
Sridar, J., Mafi, A., Judge, R. A., et al. (2023) · Communications Chemistry · doi:10.1038/s42004-023-01032-y · Cited by 6
Specific cleavage of IGFBP-4 by papp-a in nervous tissue
Dya, G. A., Lebedeva, O. S., Gushchevarov, D. A., et al. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150655 · Cited by 6
First-Trimester Combined Screening Is Effective for the Detection of Unbalanced Chromosomal Translocations at 11 to 12 Weeks of Gestation
Huang, S., Chang, C.-L., Cheng, P., et al. (2013) · Reproductive Sciences · doi:10.1177/1933719113508818 · Cited by 6
“The PAPP-A, produced by the placental trophoblast, can increase the bioavailability of insulin-like growth factors, which in turn stimulates trophoblast invasion and modulates glucose and amino acid transport in the placenta.(8,9) Fetal chromosomal aberrations, including common trisomies (21, 18, and Table 4.”
Background
Growth Hormone, Insulin-like Growth Factors and the Female Reproductive System
Bondy, C. A., & Zhou, J. (2005) · Advances in experimental medicine and biology · doi:10.1007/0-387-26274-1_4 · Cited by 6
Regulation of Granulosa Cell-Derived Insulin-Like Growth Factor Binding Proteins (IGFBPs): Role for Protein Kinase-C in the Pre- and Posttranslational Modulation of IGFBP-4 and IGFBP-51
Chamoun, D., Choi, D., Tavares, A. B., Udoff, L. C., Levitas, E., Resnick, C. E., Rosenfeld, R. G., & Adashi, E. Y. (2002) · Biology of Reproduction · doi:10.1095/biolreprod.101.001214 · Cited by 6
Histological study on the effect of vitamin C on ischemia–reperfusion injury in the adult rat ovary
Nasr, S., Elgendy, M. S., Sayed, S., & Aly, A. M. (2014) · The Egyptian Journal of Histology · doi:10.1097/01.ehx.0000452614.96818.85 · Cited by 5
PAPP-A enhances the antioxidative effects of IGF-1 during bovine in vitro embryo production
Franchi, F. F., dos Santos, P. H., Fontes, P. K., Quaglio, A. E. V., Nunes, S. G., Mingoti, G. Z., & Castilho, A. C. S. (2024) · Theriogenology · doi:10.1016/j.theriogenology.2024.07.016 · Cited by 5

Pregnancy Associated Plasma Protein-A in Human Ovarian Follicular Fluid
Sinosich, M. J., Saunders, D. M., WESTERGAARD, L. W., et al. (1985) · Protides of the biological fluids · doi:10.1016/b978-0-08-031739-7.50068-9 · Cited by 3
Study on the concentration of insulin-like growth factor-I in follicular fluid with the reproduction
Yang, W. (2009) · Chinese Journal of Birth Health & Heredity
Follicular fluid and serum levels of Inhibin A and pregnancy-associated plasma protein A in patients undergoing IVF
Moos, J., Filova, V., Pavelkova, J., et al. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.01.102 · Cited by 12
Insulin-like growth factor I (IGF-I) levels in follicular fluid from human preovulatory follicles: correlation with serum IGF-I levels
Rabinovici, J., Dandekar, P., Angle, M. J., Rosenthal, S. M., & Martin, M. C. (1990) · Fertility and Sterility · doi:10.1016/s0015-0282(16)53756-x · Cited by 54
Quantitative Analysis of Insulin-like Growth Factor-Modulated Proteolysis of Insulin-like Growth Factor Binding Protein-4 and -5 by Pregnancy-Associated Plasma Protein-A
Gyrup, C., & Oxvig, C. (2007) · Biochemistry · doi:10.1021/bi062229i · Cited by 54
Self-citation

Authors: Conover, C. A., Oxvig, C., Overgaard, M. T., Christiansen, M., & Giudice, L. C.
Affiliations: Mayo Clinic (US)
Aarhus University (DK)
Statens Serum Institut (DK)
Stanford Medicine (US)
ORCID: Conover, Cheryl A.
Oxvig, Claus
Overgaard, Michael T.
Christiansen, Michael
Giudice, Linda C.
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 1999-12
Volume: 84
Issue: 12
Pages: 4742-4745
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jcem.84.12.6342
OpenAlex: W2051842303
Cited by: 120
References: 0
Citations by year: 2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 5 · 2015: 4 · 2014: 2 · 2013: 2 · 2012: 3
FWCI: 8.07
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
Funders: Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD031579, HD 31579-05)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Keywords: IGFBP-4, PAPP-A, follicular fluid, granulosa cells, folliculogenesis, follicular atresia
MeSH terms: Edetic Acid, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Female, Fertilization in Vitro, Fibroblasts, Humans, Metalloendopeptidases, Phenanthrolines, Pregnancy-Associated Plasma Protein-A, Follicular Fluid, Culture Media, Conditioned, Insulin-Like Growth Factor Binding Protein 4

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Evidence That the Insulin-Like Growth Factor Binding Protein-4 Protease in Human Ovarian Follicular Fluid Is Pregnancy Associated Plasma Protein-A

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