Abstract
Purpose
To compare clinical pregnancy outcomes between patients with and without cysts observed on baseline ultrasound at the beginning of an in-vitro fertilization (IVF) cycle and to provide guidance on how to manage IVF cycles in patients presenting with simple follicular cysts.
Methods
Patients who were admitted to the hospital aged 18–45 years and diagnosed as having follicle cysts measuring > 10 mm at the beginning of an IVF cycle, were included in the study as the cyst group. The control group was selected in a way that would be compatible with the age of the cyst group and the causes of infertility. Cyst diameters were also divided into three groups as 10–15 mm, 16–20 mm, and > 21 mm. The patients’ anti-mullerian hormone levels, the presence of cysts, serum estradiol, luteinizing hormone and progesterone levels, the number of oocytes retrieved, the number of embryos, the fertilization rate, the clinical pregnancy outcome, and the live birth rate were evaluated.
Results
There was no statistically significant difference between the cyst and control groups in terms of clinical pregnancy, live birth rates, and miscarriage rates. Total antral follicle count was significantly higher in the clinical pregnancy group than in the non-pregnancy group. In the cyst group, the mean serum E2 value on the day of ovulation trigger day was significantly higher in the non-cycle cancellation group than in the cycle cancellation group. The cyst diameter values were analyzed in relation to cycle cancellation using ROC analysis and the cut-off value was determined as 14 mm, calculated based on the Youden Index.
Conclusion
In follicles < 14 mm, cycles can be started without hesitation. Although pregnancy rates tend to decline in patients with cysts ≥ 21 mm, the difference remains statistically insignificant. Prospective randomized controlled studies with a high number of patients are needed on this subject.
Keywords: Assisted reproductive techniques, Clinical pregnancy outcome, Follicular cyst, In vitro fertilization
What does this study add to the literature?
| Based on the findings, in-vitro fertilization (IVF) cycles can be initiated without hesitation in the presence of follicles <14 mm, and serum E2 level measured on the day of ovulation trigger,which plays a crucial role in determining pregnancy outcomes, is also of significant importance.IVF treatment can be initiated by considering both the presence of cysts and the number of antral follicles surrounding the cyst. |
Introduction
Infertility is a prevalent condition with significant psychological, economic, demographic, and medical implications. The World Health Organization (WHO) recognizes infertility as a public health issue, estimating that there are approximately 72.4 million individuals with infertility globally [1]. Infertility is defined as the inability to achieve a successful pregnancy after at least 1 year of regular, unprotected intercourse. For women aged over 35 years, this period is reduced to 6 months [2]. Infertility affects approximately 10–15% of couples worldwide [3]. Approximately 85–90% of healthy couples conceive within the first year of trying; however, 10–15% of couples in the reproductive age group are considered infertile. As women age, particularly beyond their mid-thirties, the likelihood of infertility increases, reaching about 25% by their late thirties, with fertility declining more rapidly after the age of 40 years [4]. Assisted reproductive technology (ART) cycles, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), have revolutionized infertility treatment, offering hope to many couples facing reproductive challenges.
Despite the advancements in ART, a range of factors continue to influence pregnancy outcomes, and ovarian factors remain of particular interest in predicting and improving clinical success. Among these factors, the presence of simple ovarian follicular cysts is frequently encountered during ART cycles. However, the clinical significance of these cysts remains a subject of debate. Simple follicular cysts are commonly defined as fluid-filled sacs that originate from follicles. They are often detected during transvaginal ultrasound performed prior to or during the initiation of ovarian stimulation protocols in ART cycles. Although most simple cysts are benign and asymptomatic, their potential impact on ovarian function, response to stimulation, and subsequent pregnancy outcomes has been the focus of many studies. Previous studies have produced mixed results regarding the implications of simple follicular cysts on ART outcomes. Some researchers have suggested that cysts may be associated with reduced ovarian reserve or an impaired response to gonadotropins, potentially leading to suboptimal oocyte retrieval [5, 6]. Conversely, other studies have reported no significant impact on clinical pregnancy rates [7–9]. The contradictory findings highlight the need for further investigation to clarify whether simple follicular cysts pose a significant risk to reproductive success in ART cycles or whether they can be managed conservatively without intervention. Functional ovarian cysts rarely occur during IVF/ICSI stimulation cycles. The most likely cause is prior ovarian stimulation or the flare-up effect of gonadotropin-releasing hormone (GnRH) analogs. Some physicians recommend aspirating these cysts before starting ovarian stimulation, whereas others prefer conservative treatment with GnRH analogs until ovarian suppression is achieved. The impact of cyst aspiration on IVF outcomes is still under investigation [10–12]. The aim of our study was to compare clinical pregnancy outcomes between patients with and without cysts observed on baseline ultrasound at the beginning of an IVF cycle and to provide guidance on how to manage IVF cycles in patients presenting with simple follicular cysts.
Methods
The study was designed as a retrospective observational analysis and conducted in accordance with the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all participants. Ethical approval for the study was granted by the Dokuz Eylül University Non-Interventional Research Ethics Committee (Decision number: 2020/24-18, Date: 05/10/2020). The study population comprised patients who were admitted to the hospital between January 2010 and 2020, aged 18 to 45 years, and diagnosed as having follicular cysts larger than 10 mm at the beginning of the IVF cycle. These patients constituted the cyst group. A control group was selected to match the cyst group in terms of age and underlying causes of infertility. Data for both groups were retrospectively retrieved from the hospital’s electronic database.
The inclusion criteria for the study were as follows: patients aged 18 to 45 years who had follicular cysts > 10 mm identified on baseline ultrasonography (USG) at the start of the IVF cycle, and who subsequently underwent fresh embryo transfer. The exclusion criteria included the presence of endometriosis or dermoid cysts, patients undergoing cycles for oocyte freezing, those who underwent frozen-thawed embryo transfer cycles, individuals with suspicious adnexal masses observed during examination, history of pelvic radiotherapy/systemic chemotherapy, endocrinologic conditions such as congenital adrenal hyperplasia, Cushing’s syndrome, hyperprolactinemia, or lactation, as well as patients with unknown post-embryo transfer outcomes, and those who could not be reached from the database.
Retrospective evaluations included patient age, gravidity and parity, infertility etiology, comorbidities, prior surgical history, medication use, smoking status, and the presence of galactorrhea. Additionally, baseline assessments were performed for AMH levels, IVF stimulation protocols, right and left ovarian antral follicle count, presence and laterality of cysts on baseline USG, and serum estradiol (E2), luteinizing hormone (LH), and progesterone levels. Data were also collected on the duration of stimulation, initial gonadotropin doses, total dosage of gonadotropins, the day of human chorionic gonadotropin (hCG) trigger, serum E2 and progesterone levels on the ovulation trigger day, mid-luteal phase E2 and progesterone levels, cycle cancellation rates, number of oocytes retrieved, number of metaphase II (MII) oocytes, fertilization rates, number of embryos, and endometrial thickness on the day of embryo transfer. The cyst and control groups were compared with respect to serum E2, LH, and progesterone values on the day of ovulation triggering. A total of 137 patients with cysts were included in the cyst group, and 136 patients without cysts were included in the control group. The cyst diameters were further subdivided into three categories: 10–15 mm, 16–20 mm, and > 21 mm. Key outcome variables, including the number of oocytes retrieved, number of MII oocytes, fertilization rate, and number of embryos, were analyzed. Additionally, the day of embryo transfer, the number and grade of embryos transferred, and endometrial thickness on the day of the embryo transfer were evaluated. Serum beta-hCG levels were measured 2 weeks after embryo transfer to determine pregnancy outcomes, with levels > 5 mIU/mL classified as positive pregnancy test. Clinical pregnancy was confirmed by the detection of fetal heart activity on transvaginal USG 3 weeks after a positive beta-hCG result. Live birth rate was defined as the delivery of at least one living infant after 24 completed weeks of gestation. Miscarriage was defined as any clinical pregnancy lost before pregnancy week 12.
Statistical analysis
Statistical analysis of the research data was performed using the SPSS 22.0 statistical package. In the descriptive findings section, categorical variables are presented as frequencies and percentages, and continuous variables are expressed as mean ± standard deviation and median (min, max). The Chi-square test was used to compare the distribution of categorical variables between the groups. The normality of the continuous variables was assessed using both visual methods (histograms and probability plots) and analytical tests (Kolmogorov–Smirnov/Shapiro–Wilk tests). For continuous variables with normal distribution, comparisons between groups were made using Student’s t-test. For continuous variables that did not follow normal distribution, the Kruskal–Wallis test was used to compare cyst diameter groups. When significant differences were observed between groups, pairwise comparisons were conducted using the Bonferroni-corrected Chi-square test for categorical variables and the Bonferroni-corrected Mann–Whitney U test for non-normally distributed continuous variables. Pearson’s correlation test was used to assess relationships between normally distributed continuous variables, and Spearman’s correlation test was used for variables that did not meet the normality assumption. Multivariable logistic regression analysis (forward conditional selection method) was performed to determine significant factors independently associated with clinical pregnancy. Statistically significant variables according to univariate analysis results were included to multivariable logistic regression analysis. Additionally, the effects of certain variables on predicting cycle cancellation were evaluated using receiver operating characteristics (ROC) curve analysis. A p-value of < 0.05 was considered statistically significant in this study. Post-hoc power analysis was performed using the G*Power 3.1 program. The minimum number of samples determined for 80% test power was determined as 97 for each group.
Results
The mean age of the cyst group was 34.93 ± 5.17 years. The control group had a significantly higher mean age of 36.31 ± 4.75 years (p = 0.022*). The mean duration of stimulation was 9.72 ± 2.00 days for the cyst group and 10.24 ± 1.87 days for the control group, significantly longer in the control group (p = 0.027). Additionally, the mean total dosage of gonadotropins was 3193.6 ± 1240.5 IU in the cyst group and 3593.2 ± 1204.6 IU in the control group, with the control group requiring a significantly higher dose (p = 0.007) (Table 1).
Table 1.
Comparison of treatment response variables between the cyst and control groups
| Cyst Group n = 137 |
Control Group n = 136 |
p | |
|---|---|---|---|
| Number of stimulations | 1.55 ± 0.83 | 1.47 ± 0.83 | 0.404 |
| Total antral follicle count | 7.53 ± 4.80 | 7.80 ± 4.70 | 0.641 |
| Duration of stimulation (days) | 9.72 ± 2.00 | 10.24 ± 1.87 | 0.027* |
| Total gonadotropin dose (IU) | 3193.6 ± 1240.5 | 3593.2 ± 1204.6 | 0.007* |
| Trigger day | 11.85 ± 1.88 | 12.20 ± 2.00 | 0.136 |
| Total number of oocytes | 6.81 ± 4.73 | 6.41 ± 4.10 | 0.450 |
| Number of M2 oocytes retrieved | 5.73 ± 3.73 | 5.33 ± 3.56 | 0.382 |
| Number of PN | 4.13 ± 2.96 | 3.84 ± 3.05 | 0.465 |
| Number of embryos | 4.06 ± 2.94 | 3.76 ± 2.80 | 0.420 |
All values are expressed as mean ± standard deviation, number or %.
PN Pronucleus
* indicates statistically significant difference at p 0.05
There was no statistically significant difference between the cyst and control groups regarding maximum E2, LH, and progesterone levels, as well as mid-luteal serum E2 and progesterone levels, the number of embryos transferred, endometrial thickness, gestational age at birth, and neonatal birth weight. Similarly, clinical pregnancy rates, live birth rates, and miscarriage rates did not differ significantly between the groups. Additionally, no significant differences were observed between the cyst and control groups in terms of IVF protocol, gonadotropin type (urinary or recombinant), or ovulation-triggering agent. However, the distribution of progesterone levels exhibited a statistically significant difference between the groups (p < 0.001). The incidence of multiple pregnancies was 6.57% in the cyst group and 1.47% in the control group, with a significantly lower rate in the control group (p = 0.032). The mean age was 36.15 ± 4.99 years in the non-clinical pregnancy group and 33.86 ± 4.65 years in the clinical pregnancy group, indicating a significantly younger age in the clinical pregnancy group (p = 0.001). The total antral follicle count was 7.01 ± 4.18 in the non-clinical pregnancy group and 9.81 ± 5.77 in the clinical pregnancy group, with a significantly higher count in the clinical pregnancy group (p = 0.001). The total dosage of gonadotropins was 3481.8 ± 1282.1 IU in the non-clinical pregnancy group and 3101.7 ± 1032.4 IU in the clinical pregnancy group, with a significantly lower dose in the clinical pregnancy group (p = 0.017). The serum LH level on the day of ovulation triggering was 2.95 ± 3.16 mIU/mL in the non-clinical pregnancy group and 1.76 ± 1.04 mIU/mL in the clinical pregnancy group, with a significantly lower LH level in the clinical pregnancy group (p < 0.001). Additionally, the mid-luteal serum E2 level was 499.4 ± 403.1 pg/mL in the non-clinical pregnancy group and 767.4 ± 616.1 pg/mL in the clinical pregnancy group, with a significantly higher E2 level in the clinical pregnancy group (p = 0.048) (Table 2).
Table 2.
Comparison of biochemical parameters according to the presence of clinical pregnancy
| Clinical pregnancy | p | ||
|---|---|---|---|
| ( – ) | ( +) | ||
| Age (year) | 36.15 ± 4.99 | 33.86 ± 4.65 | 0.001* |
| AMH (ng/mL) | 0.92 ± 0.86 | 1.30 ± 0.97 | 0.053 |
| Total antral follicle count | 7.01 ± 4.18 | 9.81 ± 5.77 | 0.001* |
| E2 level (pg/mL) | 64.57 ± 51.42 | 63.06 ± 36.60 | 0.908 |
| LH level (mIU/mL) | 4.24 ± 2.60 | 4.17 ± 2.52 | 0.920 |
| P4 level (ng/mL) | 0.42 ± 0.28 | 0.77 ± 1.25 | 0.263 |
| Total gonadotropin dose (IU) | 3481.8 ± 1282.1 | 3101.7 ± 1032.4 | 0.017* |
| Ovulation trigger day | 12.11 ± 2.04 | 11.75 ± 1.57 | 0.145 |
| Maximum E2 level (pg/mL) | 1490.2 ± 990.7 | 1523.8 ± 776.3 | 0.829 |
| Trigger day LH level (mIU/mL) | 2.95 ± 3.16 | 1.76 ± 1.04 | < 0.001* |
| Trigger day P4 level (ng/mL) | 0.97 ± 1.01 | 0.97 ± 1.18 | 0.989 |
| Midluteal E2 level (pg/ mL) | 499.4 ± 403.1 | 767.4 ± 616.1 | 0.048* |
| Midluteal P4 level (ng/mL) | 21.50 ± 24.31 | 31.07 ± 21.44 | 0.077 |
All values are expressed as mean ± standard deviation, number or %
* indicates statistically significant difference at p 0.05
The total number of oocytes was 6.34 ± 4.25 in the non-clinical pregnancy group and 8.52 ± 4.13 in the clinical pregnancy group, with a significantly higher count observed in the clinical pregnancy group (p < 0.001). The number of metaphase-II(M2) oocytes retrieved was 5.08 ± 3.64 in the non-clinical pregnancy group and 6.91 ± 3.34 in the clinical pregnancy group, showing a significantly higher number in the clinical pregnancy group (p < 0.001). The number of pronucleus (PN) was 3.68 ± 3.11 in the non-clinical pregnancy group and 4.81 ± 2.54 in the clinical pregnancy group, with a significantly higher number of fertilized oocytes in the clinical pregnancy group (p = 0.010). The number of embryos was 3.60 ± 2.93 in the non-clinical pregnancy group and 4.73 ± 2.53 in the clinical pregnancy group, which was significantly higher in the clinical pregnancy group (p = 0.007) (Table 3).
Table 3.
Comparison of reproductive outcomes according to the presence of clinical pregnancy
| Clinical pregnancy | p | ||
|---|---|---|---|
| ( – ) | ( +) | ||
| Number of oocytes | 6.34 ± 4.25 | 8.52 ± 4.13 | < 0.001* |
| Number of M2 oocytes retrieved | 5.08 ± 3.64 | 6.91 ± 3.34 | < 0.001* |
| Number of PN | 3.68 ± 3.11 | 4.81 ± 2.54 | 0.010* |
| Number of embryos | 3.60 ± 2.93 | 4.73 ± 2.53 | 0.007* |
| Number of embryos transferred | 1.58 ± 0.50 | 1.66 ± 0.48 | 0.271 |
| Endometrial thickness (mm) | 10.56 ± 2.29 | 10.79 ± 2.61 | 0.511 |
All values are expressed as mean ± standard deviation, number or %
* indicates statistically significant difference at p 0.05
The embryo transfer day showed a statistically significant difference between the clinical pregnancy group and the non-clinical pregnancy group, and the groups that created the difference were determined as D2 and D5 transfers (p = 0.021). In the non-clinical pregnancy group, luteal estrogen use was determined as 72.22%, and in the clinical pregnancy group, it was found as 27.78%, significantly lower in the pregnancy group (p = 0.001). The percentage distribution of progesterone showed a statistically significant difference between the clinical pregnancy group and the non-clinical pregnancy group, and the group that created the difference was determined as the group using transvaginal + intramuscular progesterone combination (p = 0.039) (Table 4).
Table 4.
Comparison of drug history according to the presence of clinical pregnancy
| Clinical pregnancy | p | |||
|---|---|---|---|---|
| ( – ) | ( +) | |||
| n (%) | ||||
| Gonadotropin type | Highly purified urinary FSH | 2 (50.00%) | 2 (50.00%) | 0.567 |
| Highly purified hMG | 3 (60.00%) | 2 (40.00%) | ||
| Recombinant combination | 39 (72.22%) | 15 (27.78%) | ||
| Recombinant + urinary combination | 91 (75.83%) | 29 (24.17%) | ||
| Highly purified HMG + recombinant combination | 18 (78.26%) | 5 (21.74%) | ||
| Urinary | 25 (83.33%) | 5 (16.67%) | ||
| Highly purified urinary FSH + urinary combination | 31 (83.78%) | 6 (16.22%) | ||
| Ovulation trigger | Dual trigger | 43 (65.15% | 23 (34.85%) | 0.070 |
| Agonist trigger | 11 (73.33%) | 4 (26.67%) | ||
| Recombinant hCG | 142 (80.23%) | 35 (19.77%) | ||
| Urinary hCG | 13 (86.67%) | 2 (13.33%) | ||
| Embryo transfer day | D5a | 28 (59.57%) | 19 (40.43%) | 0.021a,d |
| D4b | 3 (60.00%) | 2 (40.00%) | ||
| D3c | 64 (71.11%) | 26 (28.89%) | ||
| D2d | 78 (82.98%) | 16 (17.02%) | ||
| Luteal estrogen | ( – ) | 53 (92.98%) | 4 (7.02%) | 0.001 |
| ( +) | 156 (72.22%) | 60 (27.78%) | ||
| Luteal Progesterone | Transvaginal + intramusculara | 2 (33.33%) | 4 (66.67%) | 0.039a |
| Transvaginal + oralb | 85 (70.25%) | 36 (29.75%) | ||
| Transvaginal progesteronec | 84 (77.78%) | 24 (22.22%) | ||
| Luteal GnRH analog | ( – ) | 104 (75.40%) | 34 (24.60%) | 0.462 |
| ( +) | 74 (71.15%) | 30 (28.85%) |
a, b, c, d indicate statistically significant differences between subgroups based on post-hoc pairwise comparisons
According to multivariable logistic regression analysis results, high total antral follicle count (OR: 1.093, 95% CI 1.030–1.160, p = 0.004), low ovulation trigger day LH level (OR: 0.740, 95% CI 0.593–0.923, p = 0.008), day five embryo transfer (OR: 2.370, 95% CI 1.167–4.812, p = 0.017) and luteal estrogen use (OR: 5.516, 95% CI 1.807–16.841, p = 0.003) were independently associated with clinical pregnancy (Table 5). Other variables included in the analysis, age (p = 0.123), total gonadotropin dose (p = 0.795), midluteal E2 level (p = 0.907), total oocyte number (p = 0.752), M2 oocyte number (p = 0.547), number of fertilized oocytes (p = 0.525), number of embryos (p = 0.394) and luteal progesterone use (p = 0.052) were found to be non-significant.
Table 5.
Significant factors independently associated with clinical pregnancy, multivariable logistic regression analysis
| β coefficient | Standard error | p | Exp (β) | 95% CI for Exp (β) | ||
|---|---|---|---|---|---|---|
| Total antral follicle count | 0.089 | 0.031 | 0.004* | 1.093 | 1.030 | 1.160 |
| Ovulation trigger day LH level (mIU/mL) | – 0.301 | 0.113 | 0.008* | 0.740 | 0.593 | 0.923 |
| Embryo transfer day, D5 | 0.863 | 0.361 | 0.017* | 2.370 | 1.167 | 4.812 |
| Luteal estrogen use, Yes | 1.708 | 0.569 | 0.003* | 5.516 | 1.807 | 16.841 |
| Constant | – 3.101 | 0.598 | < 0.001 | 0.045 | ||
Nagelkerke R2 = 0.206, CI Confidence interval
* indicates statistically significant difference at p 0.05
On the day the cyst was detected, the LH value was 3.92 mIU/mL (0.89–7.04) in the group with a cyst diameter of 10–15 mm, 2.71 mIU/mL (0.68–9.50) in the group with a cyst diameter of 16–20 mm, and 3.80 mIU/mL (0.66–15.20) in the group with a cyst diameter of > 21 mm (p = 0.030) (Table 6).
Table 6.
Comparison of biochemical parameters according to cyst diameter
| E2 level (pg/mL) | LH level (mIU/mL) | P4 level (ng/mL) | ||
|---|---|---|---|---|
| Median (min–max) | ||||
| Cyst diameter (mm) | 10–15 mm (a) (n = 44) | 51.5 (7.6–124) | 3.92 (0.89–7.04) | 0.32 (0.08–1.13) |
| 16–20 mm (b) (n = 24) | 52 (16–263) | 2.71 (0.68–9.50) | 0.41 (0.02–1.30) | |
| > 21 mm (c) (n = 13) | 71 (11.8–344) | 3.80 (0.66–15.20) | 0.46 (0.16–5.61) | |
| p | 0.535 | 0.030 | ||
| a > b | 0.418 | |||
When the correlation between cyst diameter and the values of E2, LH, and P4 was evaluated, a statistically significant correlation was found between the serum E2 value measured on the day the cyst was detected and the LH value (r = 0.316), between the serum E2 value measured on the day the cyst was detected and the P4 value (r = 0.257), and between the serum LH value measured on the day the cyst was detected and the P4 value (r = 0.335). Regarding the correlation between total antral follicle numbers and oocyte numbers according to cyst diameters, a significant correlation was observed between the total antral follicle number and oocyte number in the group with a cyst diameter of 10–15 mm (r = 0.626). A lower, yet still significant, correlation was found between the total antral follicle number and oocyte number in the group with a cyst diameter of 16–20 mm (r = 0.488) (Table 7).
Table 7.
Evaluation of the correlation between cyst diameter and total antral follicle number
| Total antral follicle diameter | r | p | |
|---|---|---|---|
| Cyst diameter (mm) |
10–15 mm n = 86 |
0.626 | < 0.001 |
|
16–20 mm n = 30 |
0.488 | 0.006 | |
|
> 21 mm n = 13 |
0.366 | 0.219 |
In the cyst group, the mean serum E2 value on the day of ovulation trigger was 1582.8 ± 951.0 in the group without cycle cancellation and 858.9 ± 574.3 in the group with cycle cancellation and was found to be significantly lower in the group with cycle cancellation (p < 0.001) (Table 8).
Table 8.
Evaluation of the effect of cyst diameter on cycle cancellation
| Cycle cancellation | p | ||
|---|---|---|---|
| ( – ) | ( +) | ||
| Cyst diameter (mm) | 15.29 ± 7.17 | 18.95 ± 10.79 | 0.054 |
| Maximum E2 level (pg/mL) | 1582.8 ± 951.0 | 858.9 ± 574.3 | < 0.001* |
All values are expressed as mean ± standard deviation, number or %
There was a significant relationship between serum E2 on the ovulation trigger day and cycle cancellation, with an area under the curve (AUC) value of 0.741 (p = 0.028). The value was calculated using the Youden Index and 1253 pg/mL was determined as the cut-off value (Fig. 1).
Fig. 1.
Relationship between serum E2 values and cycle cancellation
There was a significant relationship between cyst diameter and cycle cancellation, and the AUC value was determined as 0.693 (p = 0.006). The value was calculated using the Youden Index and 14 mm was determined as the cut-off value (Fig. 2).
Fig. 2.
Relationship between cyst diameter and cycle cancellation
Discussion
The effect of ovarian cysts detected on the day of basal USG before the start of an IVF cycle on the outcome of IVF treatment is controversial. Although some authors state that simple cysts detected at the beginning do not cause a negative effect [13], some authors report worse results [14]. In our study, when the patient groups with and without cysts are compared, there was no statistically significant difference in terms of clinical pregnancy results. In the ROC analysis performed for cycle cancellation, the cut-off value determined for cyst diameter values was found as 14 mm. In addition, the clinical pregnancy rate was higher in the group with high midluteal serum E2 values.
Ovarian cysts detected on basal USG performed before the IVF cycle may be the reason for cycle cancellation. The concerns that cause physicians to cancel cycles are that the cyst may grow, torsion, rupture, and not allowing follicular development due to the mechanical pressure effect. It is thought that the most important factor in this group is the mechanical effect. Waiting for the cyst to regress spontaneously or with combined oral contraceptive (COC) treatment and postponing the treatment during this process is a great cause of hopelessness and disappointment especially in patients aged over 35 years. Because the patient is financially and emotionally ready to start the treatment. In a study conducted by Levi et al. in 2003 [15], the results of patients with and without ovarian cysts at the beginning of an IVF cycle after the application of GnRH analogs were compared. Three hundred fifty-six patients who started IVF cycles were included. The total gonadotropin dose was found to be significantly higher in the group with cysts. In our study, the duration of stimulation was longer in the control group, the total gonadotropin dose used was higher, and the number of oocytes retrieved was lower. This may be because we started higher gonadotropin doses in these patient groups due to the fact that the causes of infertility were decreased ovarian reserve, advanced maternal age and multiple causes, and the cycle cancellation rate was higher in the group with cysts.
The maximum E2 level was found to be lower in the control group, in line with the data mentioned above. The low peak E2 level shows that the ovarian reserve is worse. There was no difference between the cyst and control groups in terms of the number of embryos transferred, endometrial thickness on the day of transfer, baby gestational age, and birth weight. In the study conducted by Keltz et al. [16], there was no significant difference between the causes of infertility in the groups with and without cysts, consistent with our study. There was also no difference between the two groups in terms of number of PN and embryo quality, again consistent with our study.
Stimulation with cysts at the beginning had a significantly lower pregnancy rate than those without cysts. In our study, no significant difference was found between the two groups in terms of clinical pregnancy rates. Consistent with the study by Levi et al., there was no difference between the number of oocytes retrieved and the number of embryos transferred between the groups with and without cysts. In our study, although clinical pregnancy reached a higher percentage in the control group, it was not statistically significant. This result is consistent with both studies. Penzias et al. compared patients with and without cysts and reported no difference in stimulation quality or pregnancy rates [13]. In our study, no significant difference was found in clinical pregnancy rates between the cyst and control groups. In the study by Goldberg et al. [17], the serum peak E2 level was significantly lower in the cyst group, but this difference disappeared when only the cycles without cancellation were considered.
In our study, the cycle cancellation rate was 14.6% in the cyst group and 11.8% in the non-cyst group. Although the result does not seem statistically significant, it appears that the group with cysts had a higher rate of cycle cancellation. This is one of the hypotheses of our study. In the study by Goldberg et al., the cycle cancellation rate was 43.5% in the cyst group and 28% in the non-cyst group, and this difference was significant. This situation is explained in the article by the fact that most cancellations are due to dominant follicles or low E2 values. The lack of statistical significance in our study may be due to the small number of patients. This rate can be achieved with increasing patient numbers.
In the present study, no difference was found between the cyst and control groups in terms of embryo grade, clinical pregnancy rate, and miscarriage rate. The live birth rate was higher in the control group. The decrease in pregnancy rates in cycles with basal cysts may be attributed to two potential factors. The first involves the tendency for cyst formation in patients expected to have a poor ovarian response to luteal phase GnRH analog administration. Cycles in which cysts occurred were associated with older patients and patients with higher follicle-stimulating hormone (FSH) levels, suggesting that cystic production is not random and may be related to patients at risk for poor response cycles. The second factor is the negative impact of ovarian cysts on folliculogenesis and IVF-ET outcome. Ron-El et al. found no difference in pregnancy rates, and fewer oocytes were retrieved in cycles with basal ovarian cysts [14]. Our study found no difference in the number of oocytes retrieved. Biljan et al. [5] performed a prospective study on 48 patients in which the time to achieve pituitary suppression was prolonged, gonadotropin requirements increased, and embryo quality was reduced in the cyst group. However, no negative effect was found on clinical pregnancy rates. In our study, the clinical pregnancy rate was found as 22.63% in the group with cysts and 24.26% in the group without cysts. Although the percentage of clinical pregnancy was higher in the group without cysts, this was not a statistically significant result. This may be because the number of patients in our study was much higher than in that of Biljan et al.
If we evaluate all participants according to the clinical pregnancy status that we took as the primary result of our study, age, total antral follicle count, total gonadotropin dose, serum LH level on the ovulation trigger day and midluteal serum E2 level were statistically significant in patients with clinical pregnancy. The pregnancy rate decreased as the woman’s age increased, in line with the literature. The increase in the clinical pregnancy rate as the total antral follicle count increases is also an expected situation and gives basic information about the woman’s ovarian reserve. The total gonadotropin dose was significantly lower in patients with clinical pregnancy. This is because these women had good ovarian reserve, and we started the stimulation with a lower dose of gonadotropin.
The serum LH level on the day of ovulation trigger was found to be significantly lower in the clinical pregnancy group. The absence of pregnancy due to low midluteal serum E2 is consistent with the literature. In the clinical pregnancy group, the number of oocytes retrieved, the number of M2 oocytes, the number of PN and the number of embryos were found to be significantly higher, as expected. However, no difference was found in the number of embryos transferred and endometrial thickness on the embryo transfer day in women with and without clinical pregnancy. In women with clinical pregnancy, reasons for infertility, especially multiple reasons, unexplained infertility, seem to be significantly less frequent, and anovulation (polycystic ovary syndrome (PCOS)) is significantly more frequent. The number of patients with PCOS in our study was insufficient to make a meaningful comment. No significant relationship was found between clinical pregnancy and the stimulation protocol, the type of gonadotropins, and the ovulation trigger agent.
In terms of cyst sizes, the clinical pregnancy rate of patients with cysts between 10–15 mm in the cyst group was found as 22.47%, and the clinical pregnancy rate of patients with cysts between 16–20 mm was 24.24%. The total number of patients with a cyst diameter of 21 mm and above was 15 and the clinical pregnancy rate was 20%. It is difficult to comment on the group with cysts of 21 mm and above due to both the small number of patients and the pressure effect of the cysts on the ovary. D2 transfer was most frequently performed in women without clinical pregnancy, and D5 transfer was most frequently performed in women with clinical pregnancy. In addition, luteal estrogen and progesterone were also seen to be significant among these groups. The clinical pregnancy rate in D2 transfer was 17.02%, 28.89% in D3 transfer, and 40.43% in D5 transfer. There was a selection bias in this regard because we perform D2 transfer in patients with insufficient embryos and poor ovarian reserve, and we generally find clinical pregnancy rates to be low. Because we can perform D5 transfer in patients with sufficient and good quality embryos, the clinical pregnancy rate was higher in this group.
The progesterone value on the ovulation trigger day was 0.97 ± 1.18 ng/mL in the clinical pregnancy group and 1.70 ± 9.24 ng/mL in the group without clinical pregnancy. In studies, serum progesterone levels on the ovulation trigger day were associated with lower live birth rates [18]. Midluteal serum E2 was found as 761.54 pg/mL in the clinical pregnancy group and 495.74 pg/mL in the group without clinical pregnancy. Midluteal serum P4 was found as 33.14 ng/mL in the clinical pregnancy group and 20.32 ng/mL in the group without clinical pregnancy. The clinical pregnancy rate was higher in the group with high midluteal serum E2 and P4 values. The mean E2, LH, and P4 values of the cyst group participants were examined. The mean serum E2 on the day the cyst was detected was 65.12 ± 49.21 pg/mL, the mean LH was 4.13 ± 2.58 mIU/mL, and the mean P4 was 0.48 ± 0.63 ng/mL. It is important that P4 was below 1 ng/mL among these values measured on the menstruation. If these cysts had corpus luteum persistence, the serum P4 level would have been much higher. According to the Pearson correlation table, there is no correlation between the cyst diameter and the E2, LH and P4 values on the basal USG. However, there was a statistically significant correlation between serum E2 value and serum LH value (r = 0.316), between serum E2 value and serum P4 value (r = 0.257), and between serum LH and serum P4 value (r = 0.335).
By grouping the cyst structures into < 10 mm, 10–14 mm, 15–19 mm, and 20–22 mm groups, a progressive deterioration in clinical pregnancy outcomes was observed with progressively larger basal cysts. When an ROC analysis of cyst size and pregnancy outcome was performed with these data, it was shown that it was more accurate to exclude cystic structures ≤ 14 mm and include structures ≥ 15 mm as cysts. According to Keltz et al., based on ROC analysis, ≥ 15 mm can be used as a cut-off value for cysts. In our study, the cut-off value determined using ROC analysis with cycle cancellation of cyst diameter values was found as 14 mm. In the study by Hornstein et al., consistent with our study, no difference was found between two groups in terms of peak serum E2, the number of follicles 10 mm and above on the day of hCG administration, the number of oocytes retrieved, and the number of embryos transferred [19]. Again, consistent with our study, there was no difference between the two groups in terms of cycle cancellation rates and pregnancy rates. Hornstein et al. concluded that small ovarian follicles did not negatively affect the ovulation stimulation parameters and pregnancy rates in IVF cycles that had started (19). To determine which threshold values they indicated with small ovarian cysts, we performed ROC analysis in our study and found the cut-off value of 14 mm. Because our study included patients who were relatively older and had worse ovarian reserve compared with the literature, our clinical pregnancy rates are low. The strengths of the study are that it has a larger patient population compared with other studies in the literature. The study also includes many different data from the beginning of the IVF cycle to clinical pregnancy. The limitations of our study are that we could not obtain every biochemical value from every patient because it was not prospective. This study can be planned prospectively and more meaningful results can be obtained by also looking at FSH values. AMH data for all patients are not available in our study. The number of patients with cysts of 21 mm and above is too limited to make meaningful comments.
Conclusion
Whether the presence of an ovarian cyst before starting an in vitro fertilization cycle affects clinical pregnancy outcomes remains controversial. According to our findings, the cycle can be started without hesitation with < 14 mm follicles. Serum E2 level on the ovulation trigger day, which greatly affects pregnancy outcomes, is also important. Clinical pregnancy outcomes are lower in patients with cysts, but not statistically significantly. Although the pregnancy rate decreases slightly in patients with a cyst diameter of 21 mm and above, the difference is statistically insignificant. IVF treatment can be started by also taking into account the number of antral follicles around the cyst. Prospective randomized controlled studies with high patient numbers are needed on this subject.
Acknowledgements
The authors would like to express their sincere gratitude to Prof. Dr. E. Dogan and Dr. E. Ozgozen their valuable guidance, support, and insightful contributions throughout the course of this study.
Author contribution
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Begum Ertan, Ufuk Atlihan and Cemal Posaci. The first draft of the manuscript was written by Begum Ertan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding was received for conducting this study. The authors have no financial or proprietary interests in any material discussed in this article.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.