Ovarian Hyperstimulation Syndrome: A Preventable Syndrome?

Zev Rosenwaks, M.D., Claudio Benadiva, M.D.

Ovarian hyperstimulation syndrome (OHSS) is a dangerous and potentially life-threatening complication of controlled ovarian stimulation (COS). Although death has been rarely reported in extreme (or critical) cases, the syndrome is more often associated with debilitating and incapacitating symptoms. Considering that ovarian stimulation is performed on healthy uncompromised infertility patients and in healthy oocyte donors, every effort should be made to prevent or eliminate this complication. Although it has been generally accepted that OHSS is an inevitable and possibly unavoidable complication of COS, this issue of Seminars in Reproductive Medicine presents contemporary approaches for avoiding or virtually preventing this iatrogenic syndrome. Although the primary approach for avoiding OHSS should be the identification of the patient at risk and individualizing stimulation protocols, other post-stimulation strategies appear promising.

In this issue of Seminars in Reproductive Medicine, we have invited a panel of world experts to share their experience and understanding of the pathophysiology of OHSS.

Drs. Zivi, Simon and Laufer present a comprehensive description of the risk factors associated with OHSS along with a thorough review of various classification systems. Based on their extensive experience, they provide practical guidelines and approaches for treating patients at risk for developing OHSS.

Dr. Gomez et al elegantly describe their experimental paradigms that have shed light on the pathophysiology of OHSS. Using a rat model, they demonstrated conclusively that the hyperpermeability found in OHSS is related to human chorionic gonadotropin (hCG)-mediated increased expression of vascular endothelial growth factor (VEGF) followed by activation of the VEGF2 receptor (VEGFR-2). Moreover, they describe a novel approach for alleviating moderate OHSS by using dopamine agonists to inhibit vascular endothelial growth factor receptor (VEGFR)-2 phosphorylation and activation. It is of interest that this mechanistic approach only obviates early OHSS but not pregnancy-associated late OHSS.

Managing the patient with OHSS after the symptoms have already presented remains a challenge. Therefore, most efforts continue to be focused on avoiding or minimizing the risk of developing the syndrome. Dr. Papanikolaou and colleagues review the most recent evidence evaluating the accuracy of different OHSS predictive parameters. They also provide practical guidelines to assist the practitioner in identifying the patient at risk at different stages of their treatment cycle. Basal anti-Müllerian hormone, antral follicle count, and the number of follicles on the day of hCG administration appear to be the most promising tools for identifying patients at risk.

The choice of the gonadotropin starting dose is an important factor for the primary prevention of OHSS. Dr. Olivennes discusses the use of the CONSORT dosing algorithm, which individualizes the dose of recombinant follicle-stimulating hormone (FSH) for assisted reproduction technologies, assigning 37.5 IU increments according to each individual patient's characteristics. The use of this algorithm achieved an adequate oocyte yield and good pregnancy rates in a preliminary study.

In addition to individualization of gonadotropin dosage, several stimulation protocol strategies have been proposed for treating the high-risk polycystic ovary syndrome (PCOS) or PCO-like patient. One widely used approach has been the oral contraceptive (OCP) dual suppression protocol developed by Dr. Rosenwaks, one of the editors of this issue. Dr. Damario describes the Weill-Cornell program's experience with this protocol whereby OCP treatment is combined with gonadotropin-releasing hormone agonist (GnRHa) downregulation followed by a low dose gonadotropin step-down regimen. This approach has resulted in a lower cancellation rate and favorable clinical and ongoing pregnancy rates per initiated cycle while mitigating the risk of OHSS.

When a high response is noted during ovarian stimulation, steps should be taken to minimize the risk of OHSS. Several preventive tactics have been attempted, including reducing the hCG trigger dose or by withholding gonadotropin administration (“coasting”). Dr. Kashyap reviews the experience with hCG dosage adjustments in combination with “gentle” gonadotropin stimulation. She describes a sliding scale hCG dosage regimen based on estradiol (E₂) levels on the day of the ovulatory trigger. Coasting, or withholding gonadotropins, has been used to reduce the risk of OHSS. This strategy endeavors to “starve” the gonadotropin-sensitive smaller follicles in high-response patients while allowing the larger follicles to thrive in a gonadotropin-inhospitable milieu. The observed drop of E₂ from exceedingly high levels to lower levels appears to be a result of apoptosis of the smaller follicles. Drs. Abdallah et al review the efficacy of this approach, reflecting their extensive experience at Cornell and that of the literature.

Current data also show that coasting is less likely to be required in GnRH antagonist based protocols, and when applied, less days of coasting are needed before the hCG trigger as compared with GnRHa-based protocols. Indeed, Dr. Griesinger argues that there is sound evidence that routine use of GnRH antagonists instead of GnRHa during ovarian stimulation drastically reduces the relative risk of OHSS. GnRH antagonists are therefore useful for primary OHSS prevention. Moreover, in patients with early-onset OHSS, reinitiation of GnRH antagonist in the luteal phase as a measure of tertiary prevention might lead to rapid regression of the syndrome; however only limited data on this new concept are available in the literature.

Drs. Kol and Itskovitz-Eldor make an even stronger argument for using antagonist protocols for patients at high risk of developing OHSS. Indeed, in this scenario, they pioneered GnRHa use for triggering endogenous luteinizing hormone release to promote final oocyte maturation and ovulation.

Although many investigators have demonstrated that GnRHa use to trigger final oocyte maturation is virtually always effective in preventing OHSS, most studies have reported lower ongoing pregnancy rates and higher miscarriage rates when this approach is used compared with hCG-triggered ovulation. Poor pregnancy outcomes with a GnRHa trigger have been attributed to early luteolysis and abnormal luteal phase steroid production. Thus skepticism and reluctance have impeded the implementation of these protocols. Drs. Engmann and Benadiva have been able to achieve excellent pregnancy rates when aggressive luteal and early pregnancy supplementation with E₂ and progesterone (P) are provided. Indeed, the key factor in achieving favorable ongoing pregnancy rates with the use of GnRHa trigger appears to be adequate luteal phase support with both E₂ and P.

A popular approach for preventing OHSS has been avoiding embryo transfer and eliminating the potential corpora luteal exposure to hCG of an early pregnancy. Dr D'Angelo summarizes and extends her previously published observations regarding embryo freezing efficacy in preventing OHSS. Although the data are inconclusive and retrospective in nature, it is clear that freezing alone does not prevent OHSS.

The final approach presented for preventing OHSS involves avoiding gonadotropin stimulation. Dr. Huang and colleagues argue that in vitro maturation (IVM) of immature oocytes represents an effective strategy to prevent OHSS. IVM has been an established assisted reproductive technique (ART) treatment option in many centers worldwide. Although IVM may not replace standard IVF, it may play an increasingly important role in ART, especially for high responders and those patients at risk of OHSS.

Recognizing that OHSS may never be fully eliminated, it is critical for the practicing physician not only to recognize the syndrome but also to be thoroughly familiar with how it should be treated. Based on his extensive experience, Professor Aboulghar summarizes the currently described treatment approaches for OHSS. In a practical, straightforward manner he lays out a treatment paradigm that is simple and cost effective.

This issue of Seminars in Reproductive Medicine endeavors to provide the reader with a comprehensive review of our contemporary understanding of the pathophysiology, prevention strategies, and management of OHSS. It is eminently clear that if not totally preventable, severe OHSS can be successfully minimized.