Abstract
Purpose: Our purpose was to review the available literature concerning the pathogenesis of ovarian hyperstimulation syndrome and, in light of the most recent information, to attempt to provide further insight on this iatrogenic complication associated with the induction of ovulation.
Methods: Published studies related to this topic were identified through a computerized bibliographic search.
Conclusions: The exact mechanism for the development of ovarian hyperstimulation syndrome is still obscure. It is well established that the syndrome is associated with the process of ovulation induced by either luteinizing hormone or human chorionic gonadotropin. Following ovulation, one or more substances produced by the ovary are liberated in excess, increasing capillary permeability, resulting in the clinical features of the syndrome. It may well be that the syndrome is not triggered by a single mechanism but by the production and secretion of several substances acting in concert. These may include prostaglandins, cytokines, the ovarian rennin–angiotensin system, vascular endothelial growth factor, and nitric oxide.
Similar content being viewed by others
REFERENCES
Schenker JG, Weinstein D: Ovarian hyperstimulation syndrome: A current survey. Fertil Steril 1978;30:255–268
Schenker JG: Prevention and treatment of ovarian hyperstimulation. Hum Reprod 1993;8:653–659
Haning RV Jr, Austin CW, Carlson IH, Kuzma DL, Shapiro SS, Zweibel WJ: Plasma estradiol is superior to ultrasound and urinary estradiol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins. Fertil Steril 1983;40:31–36
Rabau E, David A, Serr DM, Mashiach S, Lunenfeld B: Human menopausal gonadotropins for anovulation and sterility: Results of 7 years of treatment. Am J Obstet Gynecol 1967;98:92–98
Tulandi T, McInnes RA, Arronet GH: Ovarian hyperstimulation syndrome following ovulation induction with human menopausal gonadotropin. Int J Fertil 1984;29:113–117
Golan A, Ron-El R, Herman A, Weinraub Z, Soffer Y, Caspi E: Ovarian hyperstimulation syndrome following D-Trp-6 luteinizing hormone-releasing hormone microcapsules and menotropin for in vitro fertilization. Fertil Steril 1988;50:912–916
Borenstein R, Elhalal U, Lunenfeld B, Schwartz ZS: Severe ovarian hyperstimulation syndrome: A re-evaluated therapeutic approach. Fertil Steril 1989;51:791–795
Herman A, Ron-El R, Golan A, Raziel A, Soffer Y, Caspi E: Pregnancy rate and ovarian hyperstimulation after luteal human chorionic gonadotropin in in vitro fertilization stimulated with gonadotropin-releasing hormone analog and menotropins. Fertil Steril 1990;53:92–96
Forman RG, Frydman R, Egan D, Ross C, Barlow DH: Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in vitro fertilization: A European series and a proposal for prevention. Fertil Steril 1990;53:502–509
Smitz J, Camus M, Devroey P, Erard P, Wisanto A, Van Steirteghem AC: Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/HMG superovulation for in-vitro fertilization. Hum Reprod 1990;5:933–937
Rizk B, Tan SL, Morcos S, Riddle A, Brinsden P, Mason BA, et al.: Heterotopic pregnancies after in vitro fertilization and embryo transfer. Am J Obstet Gynecol 1991;164:161–164.
MacDougall MJ, Tan SL, Jacobs HS: In-vitro fertilization and the ovarian hyperstimulation syndrome. Hum Reprod 1992;7:597–600
Southan AL, Janovsky NA: Massive ovarian hyperstimulation with clomiphene citrate. JAMA 1962;200:443
Scommegna A, Lash SR: Ovarian hyperstimulation, massive ascites, and singleton pregnancy after clomiphene. JAMA 1969;207:753–755
Pappas GD, Blanchette EJ: Transport of colloidal particles fron small blood vessels correlated with cyclic changes in permeability. Invest Ophthalmol 1965;4:1026–1036
Pride SM, James C, Ho Yuen B: The ovarian hyperstimulation syndrome. Semin Reprod Endocrinol 1990;8:247–260
Pellicer A, Miro F, Sampaio M, Gomez E, Bonilla-Musoles FM: In vitro fertilization as a diagnostic and therapeutic tool in a patient with partial 17,20-desmolase deficiency. Fertil Steril 1990;55:970–975
Meirow D, Schenker JG, Rosler A: Ovarian hyperstimulation syndrome with low estradiol in non classic 17alpha-hydroxylase, 17,20-lyase deficiency: What is the role of oestrogens? Hum Reprod 1996;11:2119–2121
Knox GE: Antihistamine blockage of the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1974;118:992–999
Gregely RZ, Paldi E, Erlik Y, Makler A: Treatment of ovarian hyperstimulation syndrome by antihistamine. Obstet Gynecol 1976;47:83–85
Pride SM, Ho Yuen B, Moon YS: Clinical, endocrinologic, and intraovarian prostaglandin F responses tp H-1 receptor blockade in the ovarian hyperstimulation syndrome: studies in the rabbit model. Am J Obstet Gynecol 1984;148:670–674
Erlik Y, Naot Y, Friedman M, Ben-David E, Paldi E: Histamine levels in ovarian hyperstimulation syndrome. Obstet Gynecol 1979;53:580–582
Katz Z, Lancet M, Borenstein R, Chemke J: Absence of teratogenicity of indomethacin in ovarian hyperstimulation syndrome. Int J Fertil 1984;29:186–188
Yuen BH, McComb P, Sy L, Lewis J, Cannon W: Plasma prolactin, human chorionic gonadotropin, estradiol, testosterone, and progesterone in ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1979;133:316–320
Raabe MA, McCoshen JA: Epithelial regulation of prolactin effect on amniotic permeability. Am J Obstet Gynecol 1986;154:130–134
Niederer W, Richardson BP, Donatsch P: Hormonal control of aqueous humour production. Exp Eye Res 1975;20:329–340
Leung P, Ho Yuen B, Moon YS: Effect of prolactin in an experimental model of the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1983;145:847–849
Navot D, Margalioth EJ, Laufer N, Birkenfeld A, Relou A, Rosler A, et al.: Direct correlation between plasma renin activity and severity of the ovarian hyperstimulation syndrome. Fertil Steril 1987;48:57–61
Itskovitz J, Sealey JE: Ovarian prorenin renin-angiotensin system. Obstet Gynecol Surv 1987;42:545–551
Ezra Y, Simon A, Yaron A, Laufer N, Navot D: Angiotensin-I-converting enzyme and its correlation with human follicular fluid steroids. Eur J Obstet Gynecol Reprod Biol 1992;44:71–75
Morris RS, Paulson RJ: The ovarian renin angiotensin system: Recent advances and their relationship to assisted reproductive technologies. Assist Reprod Rev 1993;3:2–6
Delbaere A, Bergmann PJM, Gervy-Decoster C, Staroukine M, Englert Y: Angiotensin II immunoreactivity is elevated in ascites during severe ovarian hyperstimulation syndrome: Implication for pathophysiology and clinical management. Fertil Steril 1994;62:731–737
Fernadez LA, Twickler J, Mead A: Neovascularization produced by angiotensin II. J Lab Clin Med 1985;105:141–145
Paulson RJ, Do YS, Hsueh WA, Eggena P, Lobo RA: Ovarian renin production in vitro and in vivo: Characterization and clinical correlation. Fertil Steril 1989;51:634–638
Alexander RW, Gimborne MA Jr: Stimulation of prostaglandin E synthesis in cultured human umbilical vein smooth muscle cells. Proc Natl Acad Sci USA 1976;73:1617–1620
Robertson AL, Khairallah PA: Effects of angiotensin II and some analogues on vascular permeability in the rabbit. Circ Res 1972;31:923–931
Morris RS, Wong IL, Paulson RJ: Angiotensin-converting enzyme-inhibition of the gonadotropin-stimulated rabbit—Effect on estradiol production. J Assist Reprod Genet 1995;12:326–329
Morris RS, Wong IL, Kirkman E, et al.: Inhibition of ovarian-derived prorenin to angiotensin cascade in the treatment of ovarian hyperstimulation syndrome. Hum Reprod 1995;10:1355–1358
Sifton DW (ed): Physician Desk Reference. Montvale, NJ, Medical Economics, 1994, pp 1556–1557
Briggs GG, Freeman RK, Yaffe SJ (eds): Drugs in Pregnancy and Lactation, 3rd ed. Baltimore, Williams and Wilkins, 1990, pp 83–87, 232–235
Pellicer A, Palumbo A, DeCherney AH, Naftolin F: Blockade of ovulation by an angiotensin antagonist. Science 1988;240:1660–1661
Adashi EY: The potential relevance of cytokines to ovarian physiology: The emerging role of resident ovarian cells of the white blood cell series. Endocr Rev 1990;11:454–464
Dinarello CA: Interleukin-1 and its related cytokines. Adv Immunol 1989; 44:153–205
Loukides JA, Loy RA, Edwards R, Honig J, VisintinI, Polan ML: Human follicular fluids contain tissue macrophages. J Clin Endocrinol Metab 1990; 71:1363–1367
Arici A, Oral E, Bukulmez O, Buradagunta S, Engin O, Olive DL: Interleukin-8 expression and modulation in human preovulatory follicles and ovarian cells. Endocrinology 1996;137:3762–3769
Sirotkin AV, Luck MR: Potential leukocyte attractants in the bovine periovulatory ovary. Reprod Nutr Dev 1995;35:675–683
Cavender JL, Murdoch WJ: Morphological studies of the microcirculatory system of periovulatory ovine follicles. Biol Reprod 1988;39:989–997
Dinarello CA: Interleukin-1 and interleukin-1 antagonism. Blood 1991;77:1627–1652
Friedlander MA, Loret de Mola JR, Goldfarb JM: Elevated levels of interleukin-6 in ascites and serum from women with ovarian hyperstimulation syndrome. Fertil Steril 1993;60:826–833
Hurwitz A, Loukides J, Ricciarelli E, Botero L, Katz E, McAllister JM, Garcia JE, Rohan R, Adashi EY, Hernandez ER: Human intraovarian interleukin-1 (IL-1) system: highly compartmentalized and hormonally dependent regulation of the genes encoding IL-1, its receptor, and its receptor antagonist. J Clin Invest 1992;89:1746–1754
Revel A, Barak V, Lavy Y, Anteby E, Amit A, Finci-Yeheskel Z, et al.: Characterization of intraperitoneal cytokines and nitrites in women with severe ovarian hyperstimulation syndrome. Fertil Steril 1996;66:66–71
Abramov Y, Schenker JG, Lewin A, Friedler S, Nisman B, Barak V: Plasma inflammatory cytokines correlate to the ovarian hyperstimulation syndrome. Hum Reprod 1996;11:1381–1386
Orvieto R, Ben-Rafael Z: The immune system in severe ovarian hyperstimulation syndrome. Isr J Med Sci 1996;32:1180–1182
Motro B, Itin A, Sachs I, Keshet E: Pattern of IL-6 gene expression in vivo suggests a role for this cytokine in angiogenesis. J Cell Biol 1990;87:3092–3096
Veale D, Yanni G, Bresnihan B, FitzGerald O: Production of angiotensin converting enzyme by rheumatoid synovial membrane. Ann Rheum Dis 1992;51:476–480
Watson JM, Sensintaffar JL, Berek JS, Martinez-Maza O: Constitutive production of interleukin 6 by ovarian cancer cell lines and by primary ovarian tumor cultures. Cancer Res 1990;50:6959–6965
Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ: Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 1996;271:736–741
Loret de Mola JR, Flores JP, Baumgardner GP, Goldfarb JM, Gindlesperger V, Friedlander MA: Elevated interleukin-6 levels in the ovarian hyperstimulation syndrome: Ovarian immunohistochemical localization of interleukin-6 signal. Obstet Gynecol 1996;87:581–587
Kishimoto T: The biology of IL-6. Blood 1989;74:1–10
Terranova PF, Sancho-Tello M, Hunter VG: TNF and ovarian function. In The Ovary, EY Adashi, CK Leung, (eds). New York, Raven Press, 1993, pp. 395–411
Loret de Mola JR, Baumgardner GP, Goldfarb JM, Friedlander MA: Ovarian hyperstimulation syndrome: Pre-ovulatory serum concentrations of interleukin-6, interleukin-1 receptor antagonist and tumour necrosis factor-alpha cannot predict its occurrence. Hum Reprod 1996;11:1377–1380
Robertson D, Selleck K, Suikkari AM, Hurley V, Moohan J, Healy D: Urinary vascular endothelial growth factor concentrations in women undergoing gonadotrophin treatment. Hum Reprod 1995;10:2478–2482
Neulen J, Yan Z, Raczek S, Weindel K, Keck C, Weich HA, et al.: Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: Importance in ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 1995;80:1967–1971
McClure N, Healy DI, Rogers PA, Sullivan J, Beaton L, Haning Jr RV, et al.: Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet 1994;344:235–236
Krasnow JS, Berga SL, Guzick DS, Zeleznik AJ, Yeo KT: Vascular permeability factor and vascular endothelial growth factor in ovarian hyperstimulation syndrome: A preliminary report. Fertil Steril 1996;65:552–555
Abramov Y, Brak V, Nisman B, Schenker JG: Vascular endothelial growth factor plasma levels correlate to the clinical picture in severe ovarian hyperstimulation syndrome. Fertil Steril 1997;67:261–265
Van Voorhis BJ, Dunn MS, Snyder GD, Weiner CP: Nitric oxide: An autocrine regulator of human granulosa-luteal cell steroidogenesis. Endocrinology 1994;135:1799–1806
Shukovski L, Tsafriri A: The involvement of nitric oxide in the ovulatory process in the rat. Endocrinology 1994;135:2287–2290
Ben Shlomo I, Kokia E, Jackson MJ, Adashi EY, Payne DW: Interleukin-1 beta stimulates nitrite production in the rat ovary: Evidence for heterologous cell-cell interaction and for insulinmediated regulation of the inducible isoform of nitric oxide synthase. Biol Reprod 1994;51:310–318
Fillep JG, Foldes-Filep E, Sirois P: Nitric oxide modulates vascular permeability in the rat coronary circulation. Br J Pharmacol 1993;108:323–326
Kubes P, Granger DN: Nitric oxide modulates microvascular permeability. Am J Physiol 1992;262:611–615
McCall TB, Boughton-Smith NK, Palmer RM, Whittle BJ, Moncada S: Synthesis of nitric oxide from L-arginine by neutrophils. Biochem J 1989;261:293–296
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Simon, A., Revel, A., Hurwitz, A. et al. The Pathogenesis of Ovarian Hyperstimulation Syndrome: A Continuing Enigma. J Assist Reprod Genet 15, 202–209 (1998). https://doi.org/10.1023/A:1023052419627
Issue Date:
DOI: https://doi.org/10.1023/A:1023052419627