Polycystic ovary syndrome (PCOS) is the most common fertility disorder, affecting up to 20% of women attending fertility clinics [1]. One of the main characteristics of PCOS is chronic anovulation, with a significant proportion of affected women resistant to the induction of ovulation by clomiphene citrate [2]. Although gonadotropins can successfully induce ovulation in 75% of women who do not respond to clomiphene citrate, ovarian stimulation with exogenous gonadotropins significantly increases the risk of ovarian hyperstimulation syndrome (OHSS) in PCOS patients [3,4]. Several strategies have been developed to prevent OHSS, but none have proven completely successful [5,6].

Since immature oocytes can be successfully matured and fertilized in vitro, resulting in the delivery of healthy babies, in vitro maturation (IVM) has emerged as an alternative to conventional in vitro fertilization (IVF) [7]. IVM involves the aspiration of immature oocytes from unstimulated or mildly stimulated ovaries, with subsequent maturation and fertilization in vitro. This is an attractive treatment modality since it reduces the cost of assisted reproductive technology (ART) and avoids the risk of OHSS [8]. These advantages may be more pronounced in women with PCOS due to their elevated risk of OHSS [9]. Furthermore, it is easy to identify multiple ovarian follicles by ultrasonography in PCOS patients, which makes it possible to retrieve a higher number of immature oocytes. This is consistent with previous reports indicating that the pregnancy rates of women with PCOS are higher than those of women with normal ovaries in IVM treatment, possibly due to the advantage of having a greater number of retrieved oocytes [10,11]. However, the pregnancy outcomes of IVM are still lower than those of conventional IVF, even in PCOS patients, which makes clinicians hesitant to choose IVM to treat PCOS patients when ART is needed [12]. Although a few studies have tried to identify independent factors predicting the pregnancy outcomes of IVM in PCOS patients, no clinical guidelines or protocols are available for identifying patients with PCOS who might be suitable for IVM without compromised pregnancy outcomes. Thus, we performed a retrospective cohort study to identify clinical factors that would be helpful in selecting a subgroup of patients with PCOS for possible IVM treatment, and found that serum anti-Müllerian hormone (AMH) levels are a useful factor in predicting the pregnancy outcomes of PCOS patients before beginning IVM treatment. Furthermore, a subsequent retrospective case-control study of patients with PCOS who had serum AMH levels ≥8.5 ng/mL reinforced this result. Our findings provide a clinical basis for establishing guidelines for selecting PCOS patients who would most likely benefit from IVM, with pregnancy outcomes comparable to those observed using IVF.

This study included 186 consecutive patients with PCOS who underwent hCG-primed IVM treatment without gonadotropin stimulation. The mean age of the patients was 32.33±3.22 years, the mean BMI was 22.06±3.35 kg/m², the duration of infertility was 3.88±2.55 years, the mean number of immature oocytes retrieved was 16.15±8.43, and the overall live birth rate was 30.1% (56/186).

Comparisons of patients' characteristics (age, BMI, and AFCs) and basal hormone concentrations (AMH, FSH, LH, total testosterone, and DHEA-S) between the live birth and non-pregnant groups showed that serum levels of AMH and LH were significantly higher in the patients who experienced live birth (AMH, 12.29±5.94 ng/mL vs. 9.44±4.13 ng/mL, p=0.002; LH, 10.67±6.21 IU/L vs. 8.62±5.15 IU/L, p=0.025) (Table 1).

Among the laboratory outcomes (Table 2), the numbers of immature oocytes retrieved, matured oocytes in IVM, fertilized oocytes, and frozen embryos were significantly higher in the patients who experienced live birth (18.93±10.04 vs. 14.95±7.35, p=0.009; 11.21±6.40 vs. 8.03±4.31, p=0.001; 9.59±5.86 vs. 6.56±3.63, p=0.001; 0.80±1.28 vs. 0.29±0.83, p=0.007, respectively).

Logistic regression analysis indicated that among all the parameters listed in Tables 1 and 2, serum AMH level and the number of fertilized oocytes in IVM were independent predictive factors for live birth with unstandardized coefficients (95% confidence interval [CI]) of 0.078 (95% CI, 1.005–1.164; p=0.037) and 0.113 (95% CI, 1.038–1.208, p=0.003), respectively. Furthermore, ROC curve analysis showed that these two parameters were capable of distinguishing patients who experienced live birth from non-pregnant patients in IVM treatment (AMH: area under the curve [AUC]=0.640, 95% CI, 0.551–0.730, p=0.002; number of fertilized oocytes: AUC=0.667, 95% CI, 0.581–0.752, p<0.001). The cut-off levels for the serum AMH level and the number of fertilized oocytes were determined to be 8.5 ng/mL and five oocytes, respectively. Patients with values greater than these cut-off levels had significantly higher live birth rates (36.4% [39/107] vs. 21.5% [17/79], odds ratio=2.092, p=0.028; 35.0% [49/140] vs. 15.2% [7/46], odds ratio=3.000, p=0.011, respectively) (Table 3).

We then performed correlation analyses and multivariate linear regression to examine whether any factors pre dicted the number of fertilized oocytes before the initiation of IVM cycles. Serum AMH levels and AFCs exhibited a linear correlation with the number of fertilized oocytes in IVM. Subsequently, multivariate linear regression analysis using the stepwise regression method showed that the unstandardized coefficients were 0.227 (p<0.001) and 0.187 (p=0.007) for AFCs and serum AMH levels, respectively. Collectively, these results suggest that a patient's AFC and serum AMH level can be used to estimate the number of fertilized oocytes, one of the predictive factors for pregnancy outcomes in the IVM treatment of PCOS patients (number of estimated fertilized oocytes=1.243+[0.227×AFC] +[0.187×AMH]).

In order to validate the clinical significance of serum AMH levels in identifying the patients with PCOS most likely to benefit from IVM without compromised pregnancy outcomes, we subsequently compared the pregnancy outcomes of the patients in the IVM cohort (n=107) with those of patients with PCOS who underwent conventional IVF cycles (n=177) as a retrospective case-control study. No differences were found in terms of age, BMI, infertility duration and serum levels of FSH and LH (data not shown). IVM cycles showed comparable pregnancy, ongoing pregnancy, and live birth outcomes per ET (pregnancy rate, 46.7% [50/107] vs. 57.7% [71/123], p=0.096; ongoing pregnancy rate, 37.4% [40/107] vs. 43.9% [54/123], p=0.316; live birth rate, 36.4% [39/107] vs. 42.3% [52/123], p=0.367); and no cases of OHSS were observed in the patients who received IVM treatment (0% [0/107] vs. 21.5% [38/177], p<0.001) (Table 4).

IVM is an attractive ART option for patients with PCOS or those with polycystic-like ovaries because it eliminates the risk of OHSS that is present during conventional IVF. However, it is difficult for clinicians to choose IVM as an alternative for PCOS because the pregnancy outcomes of IVM are poorer than those of conventional IVF. Thus, it is clinically critical to identify predictive factors capable of distinguishing patients with PCOS who could benefit from IVM without compromised pregnancy outcomes. Previous studies have suggested that the number of immature oocytes retrieved may be positively correlated with the pregnancy outcomes of patients undergoing IVM [10,11,14,15,16,17,18,19]. However, it is not known whether any aspects of the hormonal and clinical profiles of patients could predict pregnancy outcomes before the initiation of IVM treatment. Herein, we have identified serum AMH levels as a valuable predictive factor that can be used to identify patients who are suitable for IVM. Furthermore, the subsequent retrospective case-control analysis of patients with PCOS whose serum AMH levels were higher than 8.5 ng/mL reinforced the finding that IVM led to pregnancy outcomes that are comparable to conventional IVF in these patients (Table 4). Our results suggest that IVM is a viable alternative ART treatment for PCOS patients if the patients are properly selected.

It is well known that serum AMH level is the best currently available measure of the ovarian reserve. Not only is AMH used in a variety of clinical situations, such as infertility treatment including ART, it also is used for the prediction of reproductive lifespan, ovarian dysfunction (especially PCOS), and gonadotoxic cancer therapy or ovarian surgery [20]. However, only a handful of studies have evaluated the clinical significance of serum AMH levels in IVM treatment [15,18,19]. These studies have suggested that serum AMH levels are associated with the number of immature oocytes retrieved or the number of matured oocytes in IVM. Although the oocyte yield may be associated with pregnancy outcomes, it is impossible to determine the exact number of oocytes that will be produced before the cycle starts. Thus, these previous studies were not able to show any direct relevance of serum AMH levels to pregnancy outcomes. They were practically limited because the enrolled patients were heterogeneous and/or the pregnancy outcomes were too poor to evaluate the significance of serum AMH levels in patients undergoing IVM. Furthermore, they did not include the live birth rate as a pregnancy outcome. Our results, for the first time, demonstrated that serum AMH levels ≥8.5 ng/mL were an independent factor capable of directly predicting pregnancy outcomes in patients with PCOS before the initiation of IVM treatment.

OHSS is a serious iatrogenic complication observed in some patients who undergo gonadotropic ovarian stimulation. In severe forms of OHSS, life-threatening complications may occur, including pleural or pericardial effusion, adult respiratory distress syndrome, thromboembolic events, myocardial or cerebral infarctions, and even death [21]. Various techniques exist for preventing OHSS, but none are completely effective. PCOS is a well-known pre-existing risk factor for OHSS, and serum AMH levels have been associated with the incidence of OHSS in IVF cycles [22,23,24]. The present study showed that no patients experienced OHSS during IVM, as was expected since exogenous ovarian stimulation drugs were not used (Table 4). Collectively, these results indicate that patients with PCOS who are at a high risk for OHSS in conventional IVF cycles would be good candidates for IVM without any concerns regarding OHSS.

The group of patients with PCOS whose AMH levels were greater than 8.5 ng/mL had significantly higher pregnancy and live birth rates (Table 3). This could be explained by the observation that patients in this group were more likely to produce a larger number of good quality embryos. In fact, the number of immature oocytes retrieved, in vitro-matured oocytes, fertilized oocytes, and frozen embryos were significantly higher in the patients who experienced live birth (Table 2). Patients with serum AMH levels higher than 8.5 ng/mL had a greater number of immature oocytes retrieved and subsequently matured oocytes (data not shown), leading to more good-quality embryos and remaining frozen blastocysts, respectively (1.64±1.15 vs. 2.20±1.56, p=0.01; 0.24±0.63 vs. 0.59±1.20, p=0.01).

IVM has been shown to be less successful than conventional IVF [10,12,25,26] or comparable pregnancy outcomes [27]. Furthermore, two recent studies have reported that the live birth rates of patients undergoing IVM were significantly lower than those of patients undergoing conventional IVF [8,28]. However, we present evidence that IVM may have comparable live birth rates and ongoing pregnancy rates if patients with PCOS are carefully selected (Table 4). Since the best way to treat PCOS in ART is to maximize pregnancy outcomes while minimizing the risk of OHSS, IVM is a safe and efficient alternative ART treatment if the patients are properly selected based on robust predictive factors, such as serum AMH levels. Although this was a retrospective study, we attempted to compensate for the practical limitations inherent to retrospective studies. Only the first cycles of IVM and conventional IVF in PCOS patients were included, and the largest cohort of patients with PCOS yet analyzed was included in this study. Nonetheless, this study underscores the relevance of well-designed randomized prospective studies in demonstrating the clinical significance of serum AMH levels as a guideline for choosing ART options for PCOS patients.

In conclusion, serum AMH levels are a useful factor in predicting pregnancy outcomes for patients with PCOS before beginning IVM treatment. This study suggests that IVM may be an attractive ART option for PCOS patients if the patients are properly selected using robust predictive factors, such as serum AMH levels.