Semin Reprod Med 2010; 28(6): 448-457
DOI: 10.1055/s-0030-1265670
© Thieme Medical Publishers

Physiology and Pathology of Ovarian Hyperstimulation Syndrome

Raúl Gómez1 , Sergio R. Soares2 , Cristiano Busso1 , Juan A. Garcia-Velasco3 , Carlos Simón1 , Antonio Pellicer1
  • 1Instituto Universitario IVI, Universidad de Valencia, Valencia, Spain
  • 2Instituto Valenciano de Infertilidad, IVI Lisboa, Portugal
  • 3Instituto Valenciano de Infertilidad, IVI Madrid, Spain
Further Information

Publication History

Publication Date:
16 November 2010 (online)

ABSTRACT

Ovarian hyperstimulation syndrome (OHSS) occurs when ovaries primed with follicle-stimulating hormone/leuteinizing hormone (LH) are subsequently exposed to human chorionic gonadotropin (hCG). The ultimate pathophysiological step underlying this clinical picture is increased vascular permeability (VP). With the administration of hCG, the expression vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) mRNA increases significantly rising to a maximum coinciding with peaked VP. Immunohistochemistry shows the presence of VEGF and VEGFR-2 proteins in the granulosa-lutein and endothelial cells of the entire corpus luteum. These findings suggest that the syndrome can be prevented by inducing ovulation with LH or gonadotropin-releasing hormone analogs, which prevent VEGF overexpression. Also, coadministration of a dopamine agonist inhibits phosphorylation of the receptor VEGFR-2. In a trial of 69 oocyte donors, the incidence of moderate OHSS was 20% with the dopamine agonist cabergoline and 44% with a placebo (p = 0.04). Another dopamine agonist, quinagolide, was also effective in nonpregnant patients, but those pregnant did not benefit from dopamine agonist administration. In conclusion, the pathophysiological mechanisms involved in OHSS show that targeting VEGF/VEGFR2 is an effective preventive approach to treat the syndrome. Pharmaco-prevention through dopamine agonists is effective only in nonpregnant high-risk OHSS women. Embryo cryopreservation plus dopamine agonist administration might be the most appropriate way to prevent OHSS in high-risk patients.

REFERENCES

  • 1 Navot D, Bergh P A, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment.  Fertil Steril. 1992;  58(2) 249-261
  • 2 Navot D, Bergh P A, Laufer N. The ovarian hyperstimulation syndrome. In: Adashi EY, Rock JA, Rosenwaks Z Reproductive Endocrinology, Surgery and Technology. Philadelphia, PA; Lippincott-Raven 1996: 2225-2232
  • 3 Golan A, Ron-el R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review.  Obstet Gynecol Surv. 1989;  44(6) 430-440
  • 4 Delvigne A, Rozenberg S. Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS).  Hum Reprod Update. 2003;  9(1) 77-96
  • 5 Rizk B. Ovarian Hyperstimulation Syndrome: Epidemiology, Pathophysiology, Prevention and Management. 1st ed. New York, NY; Cambridge University Press 2006: 10-33
  • 6 Amarin Z O. Bilateral partial oophorectomy in the management of severe ovarian hyperstimulation syndrome. An aggressive, but perhaps life-saving procedure.  Hum Reprod. 2003;  18(4) 659-664
  • 7 McClure N, Leya J, Radwanska E, Rawlins R, Haning Jr R V. Luteal phase support and severe ovarian hyperstimulation syndrome.  Hum Reprod. 1992;  7(6) 758-764
  • 8 Balasch J, Fábregues F, Arroyo V. Peripheral arterial vasodilation hypothesis: a new insight into the pathogenesis of ovarian hyperstimulation syndrome.  Hum Reprod. 1998;  13(1O, 1O) 2718-2730
  • 9 Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohí J, Simón C. The pathogenesis of ovarian hyperstimulation syndrome: in vivo studies investigating the role of interleukin-1beta, interleukin-6, and vascular endothelial growth factor.  Fertil Steril. 1999;  71(3) 482-489
  • 10 Delvigne A, Rozenberg S. Systematic review of data concerning etiopathology of ovarian hyperstimulation syndrome.  Int J Fertil Womens Med. 2002;  47(5) 211-226
  • 11 Senger D R, Galli S J, Dvorak A M, Perruzzi C A, Harvey V S, Dvorak H F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.  Science. 1983;  219(4587) 983-985
  • 12 Senger D R, Connolly D T, Van de Water L, Feder J, Dvorak H F. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor.  Cancer Res. 1990;  50(6) 1774-1778
  • 13 Roberts W G, Palade G E. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor.  J Cell Sci. 1995;  108(Pt 6) 2369-2379
  • 14 Wei M H, Popescu N C, Lerman M I, Merrill M J, Zimonjic D B. Localization of the human vascular endothelial growth factor gene, VEGF, at chromosome 6p12.  Hum Genet. 1996;  97(6) 794-797
  • 15 Burchardt M, Burchardt T, Chen M W et al. Expression of messenger ribonucleic acid splice variants for vascular endothelial growth factor in the penis of adult rats and humans.  Biol Reprod. 1999;  60(2) 398-404
  • 16 Yamamoto S, Konishi I, Tsuruta Y et al. Expression of vascular endothelial growth factor (VEGF) during folliculogenesis and corpus luteum formation in the human ovary.  Gynecol Endocrinol. 1997;  11(6) 371-381
  • 17 Phillips H S, Hains J, Leung D W, Ferrara N. Vascular endothelial growth factor is expressed in rat corpus luteum.  Endocrinology. 1990;  127(2) 965-967
  • 18 de Vries C, Escobedo J A, Ueno H, Houck K, Ferrara N, Williams L T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor.  Science. 1992;  255(5047) 989-991
  • 19 Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin C H. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor.  J Biol Chem. 1994;  269(43) 26988-26995
  • 20 Shalaby F, Rossant J, Yamaguchi T P et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.  Nature. 1995;  376(6535) 62-66
  • 21 Kendall R L, Wang G, Thomas K A. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR.  Biochem Biophys Res Commun. 1996;  226(2) 324-328
  • 22 Roeckl W, Hecht D, Sztajer H, Waltenberger J, Yayon A, Weich H A. Differential binding characteristics and cellular inhibition by soluble VEGF receptors 1 and 2.  Exp Cell Res. 1998;  241(1) 161-170
  • 23 Gómez R, Simón C, Remohí J, Pellicer A. Vascular endothelial growth factor receptor-2 activation induces vascular permeability in hyperstimulated rats, and this effect is prevented by receptor blockade.  Endocrinology. 2002;  143(11) 4339-4348
  • 24 Gómez R, Simón C, Remohí J, Pellicer A. Administration of moderate and high doses of gonadotropins to female rats increases ovarian vascular endothelial growth factor (VEGF) and VEGF receptor-2 expression that is associated to vascular hyperpermeability.  Biol Reprod. 2003;  68(6) 2164-2171
  • 25 Bates D O, Hillman N J, Williams B, Neal C R, Pocock T M. Regulation of microvascular permeability by vascular endothelial growth factors.  J Anat. 2002;  200(6) 581-597
  • 26 Neulen J, Yan Z, Raczek S et al. Human chorionic gonadotrophin-dependent expression of vascular endothelial growth factor/VP factor in human granulosa cells: importance in ovarian hyperstimulation syndrome.  J Clin Endocrinol Metab. 1995;  80 1967-1971
  • 27 McClure N, Healy D L, Rogers P A et al. Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome.  Lancet. 1994;  344(8917) 235-236
  • 28 Albert C, Garrido N, Mercader A et al. The role of endothelial cells in the pathogenesis of ovarian hyperstimulation syndrome.  Mol Hum Reprod. 2002;  8(5) 409-418
  • 29 Wang T H, Horng S G, Chang C L et al. Human chorionic gonadotropin-induced ovarian hyperstimulation syndrome is associated with up-regulation of vascular endothelial growth factor.  J Clin Endocrinol Metab. 2002;  87(7) 3300-3308
  • 30 Abramov Y, Barak V, Nisman B, Schenker J G. Vascular endothelial growth factor plasma levels correlate to the clinical picture in severe ovarian hyperstimulation syndrome.  Fertil Steril. 1997;  67(2) 261-265
  • 31 Chen C D, Wu M Y, Chen H F, Chen S U, Ho H N, Yang Y S. Prognostic importance of serial cytokine changes in ascites and pleural effusion in women with severe ovarian hyperstimulation syndrome.  Fertil Steril. 1999;  72(2) 286-292
  • 32 Pau E, Alonso-Muriel I, Gómez R et al. Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome.  Hum Reprod. 2006;  21(6) 1453-1460
  • 33 Yen S SC, Llerena O, Little B, Pearson O H. Disappearance rates of endogenous luteinizing hormone and chorionic gonadotropin in man.  J Clin Endocrinol Metab. 1968;  28(12) 1763-1767
  • 34 Gómez R, Lima I, Simón C, Pellicer A. Administration of low-dose LH induces ovulation and prevents vascular hyperpermeability and vascular endothelial growth factor expression in superovulated rats.  Reproduction. 2004;  127(4) 483-489
  • 35 European Recombinant LH Study Group . Human recombinant luteinizing hormone is as effective as, but safer than, urinary human chorionic gonadotropin in inducing final follicular maturation and ovulation in in vitro fertilization procedures: results of a multicenter double-blind study.  J Clin Endocrinol Metab. 2001;  86(6) 2607-2618
  • 36 Diedrich K, Ludwig M, Felberbaum R E. The role of gonadotropin-releasing hormone antagonists in in vitro fertilization.  Semin Reprod Med. 2001;  19(3) 213-220
  • 37 Manau D, Fábregues F, Arroyo V, Jiménez W, Vanrell J A, Balasch J. Hemodynamic changes induced by urinary human chorionic gonadotropin and recombinant luteinizing hormone used for inducing final follicular maturation and luteinization.  Fertil Steril. 2002;  78(6) 1261-1267
  • 38 García-Velasco J A, Zúñiga A, Pacheco A et al. Coasting acts through downregulation of VEGF gene expression and protein secretion.  Hum Reprod. 2004;  19(7) 1530-1538
  • 39 Cerrillo M, Rodríguez S, Mayoral M, Pacheco A, Martínez-Salazar J, Garcia-Velasco J A. Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction.  Fertil Steril. 2009;  91(4, Suppl) 1526-1528
  • 40 Xu L, Yoneda J, Herrera C, Wood J, Killion J J, Fidler I J. Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growth factor receptor tyrosine kinases.  Int J Oncol. 2000;  16(3) 445-454
  • 41 Ujioka T, Matsuura K, Tanaka N, Okamura H. Involvement of ovarian kinin-kallikrein system in the pathophysiology of ovarian hyperstimulation syndrome: studies in a rat model.  Hum Reprod. 1998;  13(11) 3009-3015
  • 42 Fong T A, Shawver L K, Sun L et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.  Cancer Res. 1999;  59(1) 99-106
  • 43 Kuenen B C, Tabernero J, Baselga J et al. Efficacy and toxicity of the angiogenesis inhibitor SU5416 as a single agent in patients with advanced renal cell carcinoma, melanoma, and soft tissue sarcoma.  Clin Cancer Res. 2003;  9(5) 1648-1655
  • 44 Pauli S A, Tang H, Wang J et al. The vascular endothelial growth factor (VEGF)/VEGF receptor 2 pathway is critical for blood vessel survival in corpora lutea of pregnancy in the rodent.  Endocrinology. 2005;  146(3) 1301-1311
  • 45 Zimmermann R C, Hartman T, Bohlen P, Sauer M V, Kitajewski J. Preovulatory treatment of mice with anti-VEGF receptor 2 antibody inhibits angiogenesis in corpora lutea.  Microvasc Res. 2001;  62(1) 15-25
  • 46 Zimmermann R C, Hartman T, Kavic S et al. Vascular endothelial growth factor receptor 2-mediated angiogenesis is essential for gonadotropin-dependent follicle development.  J Clin Invest. 2003;  112(5) 659-669
  • 47 Heryanto B, Lipson K E, Rogers P A. Effect of angiogenesis inhibitors on oestrogen-mediated endometrial endothelial cell proliferation in the ovariectomized mouse.  Reproduction. 2003;  125(3) 337-346
  • 48 Basu S, Nagy J A, Pal S et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor.  Nat Med. 2001;  7(5) 569-574
  • 49 Shelesnyak M C. Disturbance of hormone balance in the female rat by a single injection of ergotoxine ethanesulphonate.  Am J Physiol. 1955;  180(1) 47-49
  • 50 Ciccarelli E, Grottoli S, Razzore P et al. Long-term treatment with cabergoline, a new long-lasting ergoline derivate, in idiopathic or tumorous hyperprolactinaemia and outcome of drug-induced pregnancy.  J Endocrinol Invest. 1997;  20(9) 547-551
  • 51 Gómez R, González-Izquierdo M, Zimmermann R C et al. Low-dose dopamine agonist administration blocks vascular endothelial growth factor (VEGF)-mediated vascular hyperpermeability without altering VEGF receptor 2-dependent luteal angiogenesis in a rat ovarian hyperstimulation model.  Endocrinology. 2006;  147(11) 5400-5411
  • 52 Parast C V, Mroczkowski B, Pinko C, Misialek S, Khambatta G, Appelt K. Characterization and kinetic mechanism of catalytic domain of human vascular endothelial growth factor receptor-2 tyrosine kinase (VEGFR2 TK), a key enzyme in angiogenesis.  Biochemistry. 1998;  37(47) 16788-16801
  • 53 Álvarez C, Martí-Bonmatí L, Novella-Maestre E et al. Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction.  J Clin Endocrinol Metab. 2007;  92(8) 2931-2937
  • 54 Vanrell J A, Balasch J. Prolactin in the evaluation of luteal phase in infertility.  Fertil Steril. 1983;  39(1) 30-33
  • 55 Bohnet H G, Mühlenstedt D, Hanker J P, Schneider H P. Prolactin oversuppression.  Arch Gynakol. 1977;  223(3) 173-178
  • 56 Carizza C, Abdelmassih V, Abdelmassih S et al. Cabergoline reduces the early onset of ovarian hyperstimulation syndrome: a prospective randomized study.  Reprod Biomed Online. 2008;  17(6) 751-755
  • 57 Álvarez C, Alonso-Muriel I, García G et al. Implantation is apparently unaffected by the dopamine agonist Cabergoline when administered to prevent ovarian hyperstimulation syndrome in women undergoing assisted reproduction treatment. A pilot study.  Hum Reprod. 2007;  22 3210-3214
  • 58 Ricci E, Parazzini F, Motta T et al. Pregnancy outcome after cabergoline treatment in early weeks of gestation.  Reprod Toxicol. 2002;  16(6) 791-793
  • 59 Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E. Dopamine agonists and the risk of cardiac-valve regurgitation.  N Engl J Med. 2007;  356(1) 29-38
  • 60 Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G. Valvular heart disease and the use of dopamine agonists for Parkinson's disease.  N Engl J Med. 2007;  356(1) 39-46
  • 61 Busso C, Fernández-Sánchez M, Garćia-Velasco J A et al. The non-ergot derived dopamine agonist quinagolide in prevention of early hyperstimulation syndrome in IVF patients a randomized, double-blind, placebo-controlled trial.  Hum Reprod. 2010;  25(4) 995-1004

Antonio PellicerM.D. 

Plaza de la Policía Local

3, 46015, Valencia, Spain

Email: apellicer@ivi.es

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