This is a prospective clinical randomized trial to investigate the efficacy of a cocktail style treatment by combining GnRH-ant, letrozole, and mifepristone on the prevention of OHSS in high-risk women compared with the monotherapy of mifepristone. Although the total incidence of OHSS is similar between the combination group and mifepristone group, the incidence of moderate and severe OHSS is remarkably decreased in the combination group (20.5% vs. 42.3%, P = 0.003), with significantly reductions in serum E2 level, ovarian diameter, and luteal phase. We suggest that this drug regimen can be used in clinical to minimize the severity of OHSS in high-risk women.
OHSS is a potentially life-threatening complication in COH treatments, which results from the release of vasoactive substances from the multiple corpora lutea, such as estrogens and VEGF, due to the ovarian hyperstimulation after oocyte maturation trigger. The incidence of OHSS shows a gradual decrease as the incessant sculpture of ovarian stimulation protocols, however, certain patients are at high risk of OHSS, such as PCOS and high responsive patients . The identification of patients susceptible to elicit a hyper-response to standard COH protocols would allow clinician to adjust their treatment, at a large extent, to minimize the severity of the symptoms. In clinical practice, all the symptoms, even with the severe OHSS symptoms, are vanished with the arrival of the menstruation. Therefore, medications that promote luteolysis are theoretically effective for the prevention or treatment of OHSS.
Recently, GnRH-ant administration during the luteal phase offers another therapeutic method for patients who developed to severe OHSS after oocyte retrieval. Treatment of 0.25 mg GnRH-ant for three days (from hCG + 5 to + 7) significantly accelerates patients’ recovery from severe OHSS symptoms and shows similar pregnant outcomes with the control group . Another study shows that 0.25 mg GnRH-ant administration from days 5 to 8 after oocyte retrieval for women who manifested early severe OHSS symptoms is associated with rapid regression of the syndrome and accelerated luteolysis . Although these two studies suggest a valid therapeutic effect of GnRH-ant on severe OHSS, the effect of GnRH-ant on OHSS prevention during the luteal phase remains undefined. Letrozole manifests promptly E2 reduction effect, two clinical trials show that letrozole treatment during the luteal phase effectively decrease the incidence of moderate and severe OHSS due to its luteolysis effect , and the incidence of OHSS is decreased as the increases in letrozole dose . Progesterone is secreted by corpora lutea and functions to maintain the corpora lutea, and progesterone withdraw is the trigger for luteal regression and menses initiation. Mifepristone is a well identified progesterone receptor antagonist, which is clinically used for emergency contraception by inhibiting embryo implantation and early pregnancy termination. Although the clinical application of mifepristone in OHSS treatment is limited, animal models show that progesterone is a key regulator for increased vascular permeability in mouse uterine vessels, and mifepristone blocks the effect of progesterone on vascular permeability . In hCG induced OHSS rat model, mifepristone could significantly reduce the ovarian enlargement and VEGF production [21, 22], suggesting the luteolysis effect of mifepristone is potentially effective for minimize the risk of OHSS.
We have previously used a rat model to determine the effect of GnRH-ant, letrozole, and mifepristone, alone or in combination, on the prevention of OHSS . The results have shown that GnRH-ant, letrozole, and mifepristone are all beneficial to prevent the progression of OHSS through different luteolytic mechanisms, and the combination group shows enhanced synergistic effect on preventing the progression of OHSS. Therefore, we proposed this prospective, randomized study to evaluate the effect of combination of GnRH-ant, letrozole, and mifepristone on preventing OHSS in high-risk women. The combination group shows decreases in the proportion of moderate and severe OHSS than that in mifepristone group, the clinical and laboratory index comparison demonstrates that the combination treatment accelerates luteolysis process and improves the participants’ hemoconcentration and liver function. These results suggest that the combination treatment by GnRH-ant, letrozole, and mifepristone is effectively to reduce the severity of OHSS in high-risk women.
GnRH-ant protocol has been recommended for PCOS women to reduce the incidence of OHSS. A meta analysis reported that GnRH-ant group does not reduce the incidence of severe OHSS, but significantly reduce the incidence of moderate and severe OHSS when compared with GnRH-a group . Another study showed that GnRH-ant protocol significantly lower OHSS rates in general IVF patients and PCOS women. However, the ongoing pregnancy rate was significantly lower in GnRH-ant group than GnRH-a group in general IVF patients . In China, luteal long GnRH-a and follicular phase long GnRH-a protocols are the preferred options for first IVF cycle patients in most IVF centers. In this study, tubal factor is the primary etiology in included participants, and the proportions of luteal GnRH-a, GnRH-ant, and follicular phase GnRH-a protocols are not differed between combination and mifepristone groups. GnRH-ant protocol does not lower the incidence of moderate and severe OHSS in combination group or mifepristone group. These results suggest that COH protocols may not be associated with the severity of the symptoms.
In the present study, oocyte retrieval number, serum E2 level on hCG + 0, VEGF level and ovarian diameter on hCG + 5 are associated with the severity of the symptoms. E2 level has been served as a reliable predictor for identifying high-risk women of OHSS during the COH, and estrogens are shown to increase vascular permeability in uterine and ovarian circulation. However, some cases of OHSS are reported in women with low E2 level and natural conceived pregnancy , and large doses of E2 treatment could not reproduce OHSS in animal model, indicating that E2 alone is not able to initiate OHSS. VEGF is strongly implicated as a vasoactive factor and plays important role in regulating angiogenesis and vascular permeability. VEGF is also involved in hCG-dependent ovarian angiogenesis, and increased VEGF mRNA and protein levels are detected in serum and peritoneal fluids in women with high risk of OHSS . Cabergoline, a dopamine agonist with anti-VEGF activity, has been demonstrated to be an effective and safe drug for the prevention of OHSS . E2 itself does not exhibit direct vasoactive effects, but E2 induces endometrial VEGF expression and stimulates microvessel endothelial cell proliferation and vascular expansion , suggesting that E2 and VEGF are both essential for the initiation of OHSS.
Previous study shows letrozole treatment, although decrease the incidence of moderate and severe OHSS, could increase VEGF level on hCG + 7 , indicating that letrozole-induced E2 reduction is not able to suppress VEGF expression. Follicular E2 and VEGF levels are decreased in PCOS women received GnRH-ant protocol , and serum VEGF level is down-regulated by both of GnRHa and GnRH-ant, which may partially explain the decreases in OHSS in GnRHa trigger and GnRH-ant protocol . Ordinal multinomial logistic regression analysis also shows serum E2 level on hCG + 0 and VEGF level on hCG + 5 are associated with the severity of OHSS, therefore, targeting in reduction of serum E2 and VEGF levels is theoretically for OHSS prevention. In the present study, serum E2 level on hCG + 0 is comparable between the two groups. However, serum E2 levels on hCG + 3 and + 5 are dramatically decreased in the combination group. Serum VEGF levels on hCG + 3 and + 5 are similar between the two groups, but the VEGF level on hCG + 5 is significantly higher in OHSS cases than that in non-OHSS women and positively related to the severity of OHSS.
OHSS is characterized as enlarged ovaries and the categories of OHSS is diagnosed partially based on the ovarian diameter. In this study, the ovarian diameter on hCG + 5 is significantly reduced in the combination group than that in mifepristone group, and logistic regression analysis shows that the ovarian diameter is associated with the severity of OHSS. The luteal phase in combination group is shorter than mifepristone group, and the proportion of women with < 5 days of luteal phase is higher in combination group. During the clinical observational frame after oocyte retrieval, the proportion of patients without any OHSS related symptoms is significantly increased in the combination group, and most of patients in combination group are recovered and back to normal life more quickly than mifepristone group. These results suggest that the synergistic effect of GnRH-ant, letrozole and mifepristone could accelerate luteolysis effect and prevent the occurrence of moderate and severe OHSS.
Strengths and limitations
This is a prospective and randomized clinical trial, and the evaluation on participants’ symptoms is blinded to the grouping. This study has a major limitation in control group design regarding the monotherapy of GnRH-ant or letrozole as a prospective randomized study. Our previous animal OHSS model showed that that the combination group has an synergistic effect than monotherapy; Mifepristone has been used as the primary preventive therapy to accelerate luteolysis for high risk women in our center. However, the effect of mifepristone on OHSS prevention remains unknown. Therefore, the combination treatment was set as experiment group, and mifepristone was set as control group in this clinical trial.