Fostering Fertility: despite ovarian hyperstimulation
Ob/Gyns are increasingly likely to find themselves managing ovarian hyperstimulation syndrome, a troubling and potentially life-threatening complication of ovulation induction. Here, an expert discusses predicting, preventing, and treating this challenging condition.
Predicting OHSS
All patients undergoing superovulation should be monitored via serum E2levels and transvaginal ultrasonography (TVUS) of the ovaries. Risk factors for severe OHSS include young age (less than 35 years), lean habitus, high E2levels, pregnancy, and a greater follicle number.2 In fact, the number of small (less than 9 mm) and intermediate-size (9 to 15 mm) follicles is positively correlated with worsening OHSS, as these follicles continue to grow and produce E2following hCG administration.8
Patients with polycystic ovary syndrome (PCOS) and/or a “necklace sign” on ovarian ultrasound also face increased risk.2 Hyperinsulinemic PCOS patients have higher E2 levels, more immature follicles, and an increased rate of OHSS with superovulation using follicle-stimulating hormone (FSH) than do normoinsulinemic PCOS patients. Women with PCOS also are more sensitive to gonadotropin stimulation due to a greater quantity of small antral follicles responsive to FSH.9 Because of this greater sensitivity, a “gentler” protocol with lower doses of these agents should be used. “Pure” FSH for superovulation was developed with these patients in mind, as they frequently have higher LH:FSH ratios. (The additional LH in the older formulations was felt to be detrimental.) Unfortunately, no difference between these regimens has been seen in clinical use.10 Laparoscopic ovarian drilling may decrease the risk of OHSS in subsequent cycles in women with PCOS.11
Because hypogonadotropic patients have a lower risk of OHSS than PCOS patients, some physicians have attempted to render PCOS patients hypogonadotropic using pituitary suppression with GnRH agonists prior to gonadotropin administration—with little success.1,12,13 In fact, the risk of OHSS is greater with protocols utilizing GnRH agonists for pituitary suppression in patients with or without PCOS.2,14
Prevention
Since OHSS entails significant morbidity and the potential for mortality and lacks a specific treatment, clinicians should focus on prevention. Unfortunately, because we are unable to consistently identify patients at risk, preventive efforts will meet with only partial success.
As mentioned earlier, OHSS is dependent on hCG stimulation. Thus, it may be limited by reducing or eliminating exogenous hCG. One option is reducing the ovulatory dose of hCG from 10,000 IU to 5,000 IU, although we lack data supporting the efficacy of this approach.2,15 However, when exogenous progesterone (P4) is given instead of hCG for luteal support, the risk of OHSS is decreased without compromising pregnancy or implantation rates.2
Withholding hCG. Although withholding the ovulatory dose of hCG should avert OHSS, there is no consensus on the criteria for cycle cancellation. For example, if hCG were withheld based on the lowest E2level at which OHSS occurred, approximately 50% of pregnancy cycles would be cancelled.6
Coasting. One way to avoid the frustration and financial loss that accompany the cancellation of cycles with high E2levels is to discontinue gonadotropins and “coast” the cycles until E2 decreases to an acceptable range. The ovulatory dose of hCG then can be administered.15 Although this reduces the incidence of severe OHSS, longer coasting intervals also result in lower pregnancy rates.15
Substituting GnRH agonists. As mentioned earlier, ovulation rarely occurs in gonadotropin stimulated cycles in the absence of hCG as a surrogate LH surge. Although hCG and LH are structurally and functionally similar, hCG has a much longer plasma half-life. Thus, the stimulatory effect on the ovary persists much longer with hCG than with an endogenous LH surge, increasing the risk of developing OHSS.
GnRH and its agonists have been given at midcycle to induce an endogenous LH surge in patients at risk for OHSS.16 A single 0.5-mg subcutaneous dose of leuprolide acetate (Lupron; TAP Pharmaceuticals, Lake Forest, Ill) increases serum LH for 34 hours, whereas hCG levels remain elevated for 6 days following a single intramuscular injection of 5,000 IU.17 Although pregnancy rates with GnRH and hCG appear to be similar, data are insufficient to document a lower incidence of OHSS with GnRH.
Further, GnRH as the ovulation trigger can be used only in gonadotropin-stimulation protocols that do not include GnRH agonists for pituitary suppression, as the pituitary is refractive to the additional GnRH. Recently, GnRH antagonists that leave the pituitary responsive to GnRH, or one of its agonists, have become clinically available for pituitary suppression at midcycle. In the near future, recombinant LH may be used to induce the preovulatory surge, which should lower the likelihood of OHSS.16
Aspirating follicles. Since many of the suspected etiologic factors in OHSS have been found in high concentrations in follicular fluid, follicle aspiration may be beneficial. Stimulation cycles at risk for OHSS (i.e., those with high E2levels) can be salvaged by conversion to in vitro fertilization (IVF), if available. Although severe OHSS may still occur despite follicle aspiration, the serum E2levels are generally several-fold higher than permissible without aspiration.
