Journal of Molecular Neuroscience

, Volume 48, Issue 3, pp 617–622 | Cite as

Correlation Between Oocyte Number and Follicular Fluid Concentration of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Women After Superovulation Treatment

  • M. Koppan
  • A. Varnagy
  • D. Reglodi
  • R. Brubel
  • J. Nemeth
  • A. Tamas
  • L. Mark
  • J. Bodis


Follicular growth, ovulation, and luteinization are influenced by interactions of peptide and steroid hormone-signaling cascades in the ovary. Pituitary adenylate cyclase-activating polypeptide (PACAP) plays an important role in the regulation of several endocrine processes and is present in ovarian follicular fluid (FF). However, little is known about PACAP in FF with regard to maturation, ovulation, fertilization, and successful pregnancy. The aim of this pilot study was to investigate whether there is a correlation between PACAP concentration in FF and ovarian response to superovulation treatment in infertile women, performed in volunteers (n = 132; aged between 20 and 35). After treatment, the number of harvested oocytes was recorded and PACAP immunoreactivity in FF was measured by radioimmunoassay. All the corresponding PACAP concentrations were below 290 fmol/ml in cases when the number of harvested oocytes exceeded 14 per patient, while in all cases above 290 fmol/ml, the number of oocytes was below 14. Using these cutoff values, we determined three study groups: high-PACAP concentration, high-oocyte number, and low-PACAP concentration–low-oocyte number groups. Median values of PACAP concentration in these groups were 411.2, 106.5, and 101.0 fmol/ml, respectively, while the median values of harvested oocytes were 5.5, 19.0, and 5.0, respectively. Differences were significant, indicating a correlation between concentration of PACAP in FF and the number of recruited oocytes. Higher concentrations of PACAP in FF might be associated with lower number of developing oocytes, while low concentrations of PACAP might correlate with a markedly higher number of ova retrieved, thus predicting a higher chance for ovarian hyperstimulation. Our present study is among the first few human clinical studies with direct conclusions drawn for possible clinical impact of PACAP.


RIA Follicular fluid Superovulation treatment Human Neuropeptide 



This work was supported by Hungarian National Scientific Grants (OTKA, K72592, and CNK78480), Momentum Program of the Hungarian Academy of Sciences, SROP 4.1.2.B-10/2/KONV-20/0-0002, SROP-4.2.2/B-10/1-2010-0029, Bolyai Scholarship, and University of Pecs Medical School Research Grant 2010.


  1. Apa R, Lanzone A, Mastrandrea M, Miceli F, Caruso A et al (1997) Control of human luteal steroidogenesis: role of growth hormone-releasing hormone, vasoactive intestinal peptide, and pituitary adenylate cyclase-activating peptide. Fertil Steril 68:1097–1102PubMedCrossRefGoogle Scholar
  2. Apa R, Lanzone A, Miceli F, Vaccari S, Macchione E, Stefanini M et al (2002) Pituitary adenylate cyclase-activating polypeptide modulates plasminogen activator expression in rat granulosa cell. Biol Reprod 66:830–835PubMedCrossRefGoogle Scholar
  3. Apostolakis EM, Lanz R, O'Malley BW (2004) Pituitary adenylate cyclase-activating peptide: a pivotal modulator of steroid-induced reproductive behavior in female rodents. Mol Endocrinol 18:173–183PubMedCrossRefGoogle Scholar
  4. Apostolakis EM, Riherd DN, O'Malley BW (2005) PAC1 receptors mediate pituitary adenylate cyclase-activating polypeptide- and progesterone-facilitated receptivity in female rats. Mol Endocrinol 19:2798–2811PubMedCrossRefGoogle Scholar
  5. Arimura A (2007) PACAP: the road to discovery. Peptides 28:1617–1619PubMedCrossRefGoogle Scholar
  6. Barberi M, Muciaccia B, Morelli MB, Stefanini M, Cecconi S, Canipari R (2007) Expression localisation and functional activity of pituitary adenylate cyclase-activating polypeptide, vasoactive intestinal polypeptide and their receptors in mouse ovary. Reproduction 134:281–292PubMedCrossRefGoogle Scholar
  7. Bodis J, Koppan M, Kornya L, Tinneberg HR, Torok A (2001) Influence of melatonin on basal and gonadotropin-stimulated progesterone and estradiol secretion of cultured human granulosa cells and in the superfused granulosa cell system. Gynecol Obstet Invest 52:198–202PubMedCrossRefGoogle Scholar
  8. Bodis J, Koppan M, Kornya L, Tinneberg HR, Torok A (2002) The effect of catecholamines, acetylcholine and histamine on progesterone release by human granulosa cells in a granulosa cell superfusion system. Gynecol Endocrinol 16:259–264PubMedGoogle Scholar
  9. Borzsei R, Mark L, Tamas A, Bagoly T, Bay C, Csanaky K et al (2009) Presence of pituitary adenylate cyclase activating polypeptide-38 in human plasma and milk. Eur J Endocrinol 160:561–565PubMedCrossRefGoogle Scholar
  10. Brubel R, Boronkai A, Reglodi D, Racz B, Nemeth J, Kiss P et al (2010) Changes in the expression of pituitary adenylate cyclase-activating polypeptide in the human placenta during pregnancy and its effects on the survival of JAR choriocarcinoma cells. J Mol Neurosci 42:450–458PubMedCrossRefGoogle Scholar
  11. Brubel R, Reglodi D, Jambor E, Koppan M, Varnagy A, Biro Z et al (2011) Investigation of pituitary adenylate cyclase activating polypeptide in human gynecological and other biological fluids by using MALDI TOF mass spectrometry. J Mass Spectrom 46:189–194PubMedCrossRefGoogle Scholar
  12. D'Angelo A, Brown J, Amso NN (2011) Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2:CD002811Google Scholar
  13. Gras S, Hannibal J, Georg B, Fahrenkrug J (1996) Transient periovulatory expression of pituitary adenylate cyclase activating peptide in rat ovarian cells. Endocrinology 137:4779–4785PubMedCrossRefGoogle Scholar
  14. Gras S, Host E, Fahrenkrug J (2005) Role of pituitary adenylate cyclase-activating peptide (PACAP) in the cyclic recruitment of immature follicles in the rat ovary. Regul Pept 128:69–74PubMedCrossRefGoogle Scholar
  15. Jayaprakasan K, Herbert M, Moody E, Stewart JA, Murdoch AP (2007) Estimating the risks of ovarian hyperstimulation syndrome (OHSS): implications for egg donation for research. Hum Fertil (Camb) 10:183–187CrossRefGoogle Scholar
  16. Koppan M, Bodis J, Verzar Z, Tinneberg HR, Torok A (2004) Serotonin may alter the pattern of gonadotropin-induced progesterone release of human granulosa cells in superfusion system. Endocrine 24:155–159PubMedCrossRefGoogle Scholar
  17. Kornya L, Bodis J, Koppan M, Tinneberg HR, Torok A (2001) Modulatory effect of acetylcholine on gonadotropin-stimulated human granulosa cell steroid secretion. Gynecol Obstet Invest 52:104–107PubMedCrossRefGoogle Scholar
  18. Kotani E, Usuki S, Kubo T (1997) Rat corpus luteum expresses both PACAP and PACAP type IA receptor mRNAs. Peptides 18:1453–1455PubMedCrossRefGoogle Scholar
  19. Koves K, Kantor O, Molnar J, Heinzlmann A, Szabo E, Szabo F et al (2003) The role of PACAP in gonadotropic hormone secretion at hypothalamic and pituitary levels. J Mol Neurosci 20:141–152PubMedCrossRefGoogle Scholar
  20. Lee J, Park HJ, Choi HS, Kwon HB, Arimura A, Lee BJ et al (1999) Gonadotropin stimulation of pituitary adenylate cyclase-activating polypeptide (PACAP) messenger ribonucleic acid in the rat ovary and the role of PACAP as a follicle survival factor. Endocrinology 140:818–826PubMedCrossRefGoogle Scholar
  21. Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L et al (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164:567–574PubMedCrossRefGoogle Scholar
  22. Navot D, Bergh PA, Laufer N (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 58:249–261PubMedGoogle Scholar
  23. Papanikolaou EG, Pozzobon C, Kolibianakis EM, Camus M, Tournaye H, Fatemi HM et al (2006) Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertil Steril 85:112–120PubMedCrossRefGoogle Scholar
  24. Park JY, Park JH, Park HJ, Lee JY, Lee YI, Lee K et al (2001) Stage-dependent regulation of ovarian pituitary adenylate cyclase-activating polypeptide mRNA levels by GnRH in cultured rat granulosa cells. Endocrinology 142:3828–3835PubMedCrossRefGoogle Scholar
  25. Pesce M, Canipari R, Ferri GL, Siracusa G, De FM (1996) Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates adenylate cyclase and promotes proliferation of mouse primordial germ cells. Development 122:215–221PubMedGoogle Scholar
  26. Reglodi D, Borzsei R, Bagoly T, Boronkai A, Racz B, Tamas A et al (2008) Agonistic behavior of PACAP6-38 on sensory nerve terminals and cytotrophoblast cells. J Mol Neurosci 36:270–278PubMedCrossRefGoogle Scholar
  27. Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K et al (2011) Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470:492–497PubMedCrossRefGoogle Scholar
  28. Richards JS, Russell DL, Ochsner S, Hsieh M, Doyle KH, Falender AE et al (2002) Novel signaling pathways that control ovarian follicular development, ovulation, and luteinization. Recent Prog Horm Res 57:195–220PubMedCrossRefGoogle Scholar
  29. Sayasith K, Brown KA, Sirois J (2007) Gonadotropin-dependent regulation of bovine pituitary adenylate cyclase-activating polypeptide in ovarian follicles prior to ovulation. Reproduction 133:441–453PubMedCrossRefGoogle Scholar
  30. Sherwood NM, Krueckl SL, McRory JE (2000) The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 21:619–670PubMedCrossRefGoogle Scholar
  31. Sherwood NM, Adams BA, Isaac ER, Wu S, Fradinger EA (2007) Knocked down and out: PACAP in development, reproduction and feeding. Peptides 28:1680–1687PubMedCrossRefGoogle Scholar
  32. Szabo F, Horvath J, Heinzlmann A, Arimura A, Koves K (2002) Neonatal PACAP administration in rats delays puberty through the influence of the LHRH neuronal system. Regul Pept 109:49–55PubMedCrossRefGoogle Scholar
  33. Szabo E, Nemeskeri A, Arimura A, Koves K (2004) Effect of PACAP on LH release studied by cell immunoblot assay depends on the gender, on the time of day and in female rats on the day of the estrous cycle. Regul Pept 123:139–145PubMedCrossRefGoogle Scholar
  34. Vaccari S, Latini S, Barberi M, Teti A, Stefanini M, Canipari R (2006) Characterization and expression of different pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal polypeptide receptors in rat ovarian follicles. J Endocrinol 191:287–299PubMedCrossRefGoogle Scholar
  35. Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O et al (2009) Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61:283–357PubMedCrossRefGoogle Scholar
  36. Zhong Y, Kasson BG (1994) Pituitary adenylate cyclase-activating polypeptide stimulates steroidogenesis and adenosine 3',5'-monophosphate accumulation in cultured rat granulosa cells. Endocrinology 135:207–213PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • M. Koppan
    • 1
    • 2
  • A. Varnagy
    • 1
  • D. Reglodi
    • 2
  • R. Brubel
    • 2
  • J. Nemeth
    • 3
  • A. Tamas
    • 2
  • L. Mark
    • 4
  • J. Bodis
    • 1
  1. 1.Department of Obstetrics and GynecologyUniversity of Pecs, Clinical CenterPecsHungary
  2. 2.Department of Anatomy, MTA-PTE Lendulet PACAP Research GroupUniversity of PecsPecsHungary
  3. 3.Department of Pharmacology and PharmacotherapyUniversity of DebrecenDebrecenHungary
  4. 4.Department of Biochemistry and Medical ChemistryUniversity of PecsPecsHungary

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