About Bioline  All Journals  Testimonials  Membership  News  Donations

Middle East Fertility Society Journal
Middle East Fertility Society
ISSN: 1110-5690
Vol. 9, Num. 2, 2004, pp. 107-111

Middle East Fertility Society Journal, Vol. 9, No. 2, 2004, pp. 107-111


Ovarian hyperstimulation syndrome: are preventive measures effective?

Comment by: Basil C. Tarlatzis, M.D, Leonidas Zepiridis M.D, Leonidas Zepiridis M.D,Thessaloniki, Greece

Code Number: mf04019


Infertility treatment has been changed dramatically over the last decades with the introduction of the new assisted reproduction techniques (ART). Ovarian stimulation, either to induce ovulation in the management of anovulatory infertility or for controlled ovarian hyperstimulation in the course of in vitro-fertilization, is a main part of the various ART. Nevertheless, ovarian stimulation entails the risk for the development of ovarian hyperstimulation syndrome (OHSS), the commonest complication as such. Hence, it is of great importance not only to know how to effectively induce ovulation but also how to prevent this severe potential risk.

Ovarian hyperstimulation syndrome is a well-known and important complication of ovulatory drugs. Its development has been described following ovulation induction with almost every drug used for ovarian stimulation, either in the management of anovulatory infertility or during controlled ovarian hyperstimulation for in-vitro fertilization, having an incidence of 0,5-2% (1). The employment of gonadotropin releasing hormone-agonists (GnRH-a) seems to be associated with an increased incidence of OHSS (2-4).


The effective preventive strategy of OHSS presumes updated knowledge of the relevant pathophysiology. OHSS is characterized by a wide spectrum of clinical and laboratory manifestations, including multicystic ovarian enlargement, massive extra-vascular fluid accumulation (peritoneal, pleural or pericardial cavity), combined with intravascular volume depletion, hemoconcentration and electrolytic disturbances (1). Rare but life-threatening complications following the severe forms of OHSS have been reported, such as thromboembolic phenomena, hypovolemic shock, liver dysfunction, renal failure and adult respiratory distress syndrome (5).

The factor(s) causing this phenomenon is until now, not fully elucidated. The main pathophysiological change responsible for OHSS development is thought to be an acute increase in vascular permeability (1), although arteriolar vasodilation (6) was also suggested. Several substances involved in ovarian physiology have been proposed as possible candidates. Initially, estrogens, histamine and prostaglandins were thought to cause OHSS (1). The ovarian renin-angiotensin system was then proposed as the most possible mediator of OHSS (7, 8, 9), but more recently, the vascular endothelial growth factor (VEGF) as well as cytokines, were proposed as protagonists in OHSS pathogenesis (7, 8, 10). Nevertheless, whatever the responsible factor is, it seems that human chorionic gonadotropin (HCG), exogenously administered or endogenously produced, play a key role in the development and clinical manifestation of OHSS (1).


While no authentic aetiologic therapeutic methods are currently available, only supportive treatment strategies have been suggested and therefore prevention of the syndrome is paramount.

a) Identification of the main risk factors

The identification of the possible risk factors has always been the key in the prevention of the syndrome. It seems that patients with severe forms of OHSS tend to be younger, while the effect of body weight and body mass index is controversial (11,12). The main predisposing factor for OHSS development appears to be the polycystic ovarian syndrome (PCOS) or solely the polycystic ovaries (13, 14). Hyperandrogenism, PCOS-related or not, constitutes an independent risk factor, whereas increased ovarian volume (>10cc) and the "necklace" sign, a common ultrasound finding in the ovaries of PCOS patients, is eventually linked with OHSS when present even in normoovulatory women (12). Moreover, patients with ovarian hypersensitivity to stimulation and high estradiol (E2) levels on the day of HCG administration tend to develop more frequently OHSS. In addition, the presence of large number of immature and intermediate follicles during ovulation induction and a large number of oocytes retrieved, are predictive of OHSS manifestation and severity (13). A specific combination of parameters (E2>6000pg/ml plus >30 oocytes retrieved) gave an 80% chance of developing severe OHSS (26).

b) Preventive measures

Since OHSS represents a potentially life-threatening condition, prevention still remains the main goal in the management of high risk patients (15). Various solutions to this potential problem have been proposed (Table 1).

The simple use of a reduced dose of hMG for IVF treatment is of limited benefit since a large proportion of the patients show inadequate response (27). The low-dose step-up protocols seem to be more appropriate in anovulatory PCOS patients who need ovulation induction, with satisfactory results (16). Recently, the step-down gonadotropin regimes were proposed as an effective alternative in the management of these patients either with ovulation induction or in-vitro fertilization (17).

The use of GnRH-a in order to alter the ovarian response to stimulation, requires an extremely long period of administration (> 8 weeks), which makes it inconvenient for the patients (12). More recently, the use of GnRH antagonists for ovarian stimulation has been reported to be associated with a lower incidence of OHSS, although in a recent Cochrane review a clear benefit from their use as compared to the long GnRH-a protocols was not shown (18).

HCG is thought to be the main triggering factor for OHSS. Cycle cancellation encloses certain emotional implications for the patients and therefore, valid alternatives were tried. Thus, several manipulations of exogenous ovulatory HCG administration have been proposed for the prevention of an imminent OHSS (15). However, since withholding of ovulatory HCG is accompanied by cycle cancellation, some authors advice to delay HCG with discontinuation of gonadotropins but not of GnRH-agonists, in order to achieve lower E2 levels on the day of HCG administration (20, 12). Large healthy follicles can tolerate with this gonadotrophin deprivation (due to their granulossa cells), but small ones cannot. The result is to reduce the number of the developing follicles, E2 levels and therefore the severity of OHSS, while keeping comparable pregnancy rates. This preventive strategy is now referred to as 'coasting' and is very widely used.

Reduction of the ovulatory HCG dose from 10,000 to 5,000 IU has also been proposed as a preventive measure, but the efficacy of this practice needs to be proved (12).

Several authors have described the use of a short-term GnRH-a administration in order to induce an endogenous LH surge in non-GnRH-a stimulated cycles. This is thought to provide a more physiological hormone milieu, thus avoiding OHSS development (12).

In GnRH-a stimulated cycles, the administration of GnRH-a may be continued after the ovulatory HCG cancellation, in an attempt to minimize the gonadotropic stimulus on the ovary (2). The value of GnRH-a prolongation in the luteal phase as an additional preventive measure has not been confirmed and is still controversial (19).

Elective embryo-cryopreservation has been proposed as an alternative to cycle cancellation, since the avoidance of pregnancy lessens the incidence and the severity of OHSS in high risk patients (19).

Embryo transfer may be differed in a subsequent unstimulated cycle and the effectiveness of this policy obviously depends on the availability and the efficacy of the cryopreservation program (12). The elective cryopreservation of all embryos from women with high E2 levels reduces the severity but not the incidence of OHSS (28). However, in a recent Cochrane review, it seems that there is insufficient evidence to support the routine use of embryo cryopreservation instead of prophylactic albumin administration or elective fresh embryo-transfer (21).

Alternatively, in cases of mild OHSS it is possible to culture until the blastocyst stage and electively transfer one or two embryos. This practice offers the advantage to follow-up the patients for a more prolonged period, which allows a safer estimation of the severity of OHSS. Moreover, elective transfer of one or two embryos limits the possibility of multiple gestation, which worsens the clinical course of OHSS.

Conversion of ovarian stimulation/intrauterine insemination (IUI) cycles with excessive ovarian response to IVF has been proposed as another option to prevent the occurence or to reduce the severity of an imminent OHSS (13), by making use of the protective effect of follicular aspiration (12). The repeat aspiration of early corpus luteum cysts at the day of embryo transfer or later in IVF cycles has also been described as an effective preventive measure (22).

The prophylactic administration of albumin is thought to exert a protective effect on OHSS presentation due to its osmotic and binding properties: it draws extracellular fluid into the circulation and may bind and inactivate the vasoactive intermediates responsible for the pathogenesis of OHSS (23). In a recent Cochrane review, it is shown that there is a clear benefit from the administration of intravenous albumin at the time of oocyte retrieval for the prevention of OHSS development in high risk patients (relative risk=0,35) (24).

The suppression of ovarian steroids via the administration of high doses of estrogens plus progesterone during the luteal phase was recently assessed in a prospective randomized study revealing a significant reduce in the incidence and severity of OHSS without compromising the pregnancy rates (25). Nevertheless there is insufficient evidence to support the routine use of these steroids due to lack of adequate data.

Laparoscopic ovarian electrocautery or laser to ovaries, is an option held for women with a history of repeated OHSS. Its rather empirical use makes it a secondary option with no much data available for its effectivity (29).

Lowering the ovarian oestrodiol synthesis, ketokonazole, may lower the cancellation rates in high risk patients for OHSS (30). However due to the limited available data, this new approach needs further evaluation.

The technique of aspirating follicles after an HCG injection and their further maturing in vitro (= In Vitro Maturation of oocytes), has been assessed in PCOS patients giving lowest hyperstimulation incidence. However, continued improvements in laboratory techniques should result in higher implantation and clinical pregnancy rates and therefore reduce the need for numerous oocytes to be retrieved. IVM is a promising reproductive technology. Obviously, more clinical data are needed to support its benefits (31- 34).


Prevention of OHSS starts at the history taking point, clinical and baseline scan examination. Young patients or patients with PCO ovaries need less aggressive regimens avoiding the use of LH preparations. Coasting techniques of HCG and reducing of its ovulatory dose may help. The novel GnRH-antagonist protocols are also promising.    Meticulous  aspiration  of all  follicles  is necessary with or without repetitions before embryo transfer. Cryopreservation of the embryos and deferred embryo transfer reduces the severity but not the incidence of OHSS. However, the only preventive measure that has evidence based efficacy is the prophylactic albumin administration.

In Vitro maturation of oocytes could be a viable alternative in high risk patients in order to avoid 'classical' controlled ovarian hyperstimulation and thus to have practically no OHSS risk. However, further development of the technique is necessary. Furthermore, the administration of anti-VEGF monoclonic antibodies or PI-3K (phosphatidylinositol-3 kinase) pathway inhibitors, might be a new treatment strategy, assuming that VEGF holds a key role in the development of OHSS.


  1. Editorial. Ovarian hyperstimulation syndrome. Lancet 1991;338:1111-1112.
  2. Mordel N, Schenker JG. Gonadotrophin-releasing hormone agonist and ovarian hyper-stimulation syndrome in assisted reproduction (Review). Hum Reprod 1993; 8:2009-2014.
  3. Smitz J, Ron-El R, TarlatzisBC. The use of gonadotrophin releasing hormone agonists for in vitro fertilization and other assisted procreation techniques: Experience from three centers. Hum Reprod 1992; 7:49-66.
  4. TarlatzisBC and Grimbizis G. Gonadotropin releasing hormone agonists in controlled ovarian hyperstimulation. References en Gynecologie Obstetrique 1997a; 5:181-190.
  5. Delvigne A. and Rozenberg S. Epidemiology and prevention of ovarian hype-rstimulation syndrome (OHSS): a review. Hum Reprod Update 2002; 8: 559-577.
  6. Balasch J, Arroyo V, Fabregues F, Salo J, Jiménez W, Paré JC, Vanrell JA. Neuro-hormonal and Hemodynamic Changes in Severe Cases of the Ovarian Hyper-stimulation Syndrome. Ann Intern Med 1994; 121: 27-33.
  7. Bergh PA, Navot D. Ovarian hyperstimulation syndrome: A review of pathophysio-logy. J Ass Reprod Genet 1992; 9:429-438.
  8. Morris RS, and Paulson RJ. Ovarian derived prorenin-angiotensin cascade in human reproduction. Fertil Steril 1994; 62:1105-1114.
  9. Morris RS, Paulson RJ, Lindheim SR, Legro RS, Lobo RA and Sauer MV. Angio-tensin-converting enzyme inhibition reverses luteal phase steroid production in oocyte donors. Fertil Steril 1995; 63:854-858.
  10. Neulen J, Yan Z, Raczek S, Weinder K, Keck Ch, Weich HA, Marme D, and Breckwoldt M. Human Chorionic Gonadotropin dependent expression of Vascular endothelial growth factor / Vascular Permeability Factor in human granulose cells: importance in ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 1995; 80:1967- 71.
  11. Golan A, Ron-El A, Herman A, Soffer Y, Weinraub, Z, Caspi, E. Ovarian hyper-stimulation syndrome: an update review. Obstet Gynecol Surv 1989; 44: 430-440.
  12. Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel repro-ductive technologies: prevention and treatment. Fertil Steril 1992; 58: 249-261.
  13. Rizk B, Aboulghar M. Modern management of ovarian hyperstimulation syndrome (Review). Hum Reprod 1991; 6: 1082-1087.
  14. Tarlatzis BC and Grimbizis G. Assisted Reproduction Techniques in Polycystic Ovarian Syndrome. Ann NY Acad Sci 1993; 687:280-287.
  15. Tarlatzis BC and Grimbizis G. Prevention of the ovarian hyperstimulation syndrome. In Hedon B, Bringer J, Mares P (eds), Fertility and Sterility: A Current Overview. Proceedings of the 15th World Congress on Fertility and Sterility, Montpellier, France, 17-22 September 1995. The Parthenon Publishing Group, p. 205-209.
  16. Homburg R, Levy T, Ben-Rafael Z. A comparative prospective study of conventional regimen with chronic low-dose administration of follicle-stimulating hormone for an-ovulation associated with polycystic ovary syndrome. Fertil Steril 1995; 63:729-733.
  17. Fauser BCJM, Donderwinkel P, Schoot DC. The step-down principle in gonadotrophin treatment and the role of GnRH analogues. Bailliere's Clinical Obstetrics and Gynecology 1993; 7:309-330.
  18. Al-Inamy H. and Aboulghar M. GnRH antagonists in assisted reproduction: a Cochrane review. Hum Reprod 2002; 17; 874-885.
  19. Wada I, Macnamee M, Brinsden P. Letters to the Editor. Prevention and treatment of ovarian hyperstimulation. Hum Reprod 1993; 8:2245-2247.
  20. Schenker JG. Prevention and treatment of ovarian hyperstimulation (Review). Hum Reprod 1993; 8:653-659.
  21. D' Angelo A. and Amso N.N. Embryo freezing for preventing ovarian hyper-stimulation syndrome: a Cochrane review. Hum Reprod 2002; 17; 2787-2794.
  22. Amit A, Yaron Y, Yovel I, Peyser MR, David MP, Botchan A, Lessing JB. Repeated aspiration of ovarian follicles and early corpus luteum cysts in an in-vitro fertilization program reduces the risk of ovarian hyperstimulation syndrome in high responders. Hum Reprod 1993; 8:1184-1186.
  23. Asch RH, Ivery G, Goldsman M, Frederick JL. Stone SC, Balmaceda JP. The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome (Clinical Report). Hum Reprod 1993; 8:1015-1020.
  24. Aboulghar M., Evers J.H., Al-Inamy H. Intravenous albumin for preventing severe ovarian hyperstimulation syndrome: a Cochrane review. Hum Reprod 2002; 17: 3027-3032.
  25. 25.     Scwarzler P. Abendstein BJ, Klingler A, Kreuzer E, Rjosk HK. Prevention of severe OHSS in IVF patients by steroidal ovarian suppression - a prospective randomized study. Hum Fertil (Camb), 2003; Aug; 6(3): 125-129.
  26. Asch RH, Li HP, Balmaceda JP, Weckstein LN, Stone SC. Severe OHSS in assisted reproductive technology: definition of high risk groups. Hum Reprod 1991; Nov; 6(10): 1395-9.
  27. Wada I, Matson PL, Troup SA, Lieberman BA. Use of buserelin and low dose hMG for IVF in women at risk for OHSS. J Assist Reprod Genet 1995; Apr; 12(4): 252-7.
  28. Wada I, Matson PL, Troup SA, Morroll DR, Hunt L, Lieberman BA. Does elective cryopreservation of all embryos from women at risk of OHSS reduce the incidence of the condition? Br J Obs Gynaecol 1993; Mar; 10(3): 265-9.
  29. Rimington MR, Walker SM, Shaw RW. The use of laparoscopic ovarian electrocautery in preventing cancellation of IVF treatment cycles due to risk for OHSS in women with PCOS. Hum Reprod 1997; 12: 1443-7.
  30. Gal M, Eldar-Geva T, Margalioth EJ, Barr I, Orly J, Diamant YZ. Attenuation of ovarian response by low dose ketokonazole during superovulation in patients with PCOS. Fertil Steril 1999; 72: 26-31.
  31. Chian RC, Gulekli B, Buckett WM, Tan SL: Priming with human chorionic gonadotropin before retrieval of immature oocytes in women with infertility due to the polycystic ovary syndrome. N EnglJ Med 341 (21): 1624-1626, 1999.
  32. Chian RC, Buckett WM, Tulandi T, Tan SL: Prospective randomized study of human chorionic gonadotrophin priming before immature oocyte retrieval from unstimulated women with polycystic ovarian syndrome. Hum Reprod 15(1): 165-170, 2000.
  33. Cha KY, Han SY, Chung HM, Choi DH, LimJM, Lee WS et al.: Pregnancies and deliveries after in vitro maturation culture followed by in vitro fertilization and embryo transfer without stimulation in women with polycystic ovary syndrome. Fertil Steril 73(5): 978-983, 2000.
  34. Child TJ, Abdul Jalil AI, Gulekli B, Tan SL: In-vitro maturation of immature oocytes from infertile women with normal ovaries, polycystic ovaries, or polycystic ovarian syndrome. Fertil Steril 76: 936-942, 2001.
  35. Jaffe RB, Gordon JD, Byrne A, Hu L, Geva E. Angiogenesis in the normal and noeplastic ovary. Advances in Infertility Treatment. 2002; Jan; 15-37

Basil C. Tarlatzis, M.D,
Leonidas Zepiridis M.D,
Grigoris Grimbizis, M.D.
Unit for Human Reproduction
1st Department of Obstetrics and Gynaecology
Aristotle University of Thessaloniki, Greece

© Copyright 2004 - Middle East Fertility Society

The following images related to this document are available:

Photo images

Home Faq Resources Email Bioline
© Bioline International, 1989 - 2020, Site last up-dated on 19-Mar-2020.
Site created and maintained by the Reference Center on Environmental Information, CRIA, Brazil
System hosted by the Internet Data Center of Rede Nacional de Ensino e Pesquisa, RNP, Brazil