Abstract
Background:
There is a growing body of evidence that ovarian cystectomy may negatively impact ovarian reserve. However, it is unclear whether ovarian cyst surgery puts women at risk of future infertility. This study investigates whether surgery for benign ovarian cysts is associated with long-term infertility risk.
Methods:
Women aged 22–45 years (n = 1,537) were invited to participate in an interview about their reproductive histories, including whether they ever had infertility or ovarian cyst surgery. Each woman reporting cyst surgery was randomly matched to a comparison woman, who was assigned an artificial surgery age equal to that of her match. Matching was repeated 1,000 times. Adjusted Cox models were fit to examine time to infertility after surgery for each match. A subset of women was invited to participate in a clinic visit to assess markers of ovarian reserve (anti-Müllerian hormone [AMH], antral follicle count).
Results:
Approximately 6.1% of women reported cyst surgery. Infertility after surgery was more common for women reporting cyst surgery than those without surgery after adjusting for age, race, body mass index, cancer history, parity before assigned surgery age, history of infertility before surgery age, and endometriosis (median-adjusted hazard ratio 2.41, 95% simulation interval 1.03–6.78). The estimated geometric mean (95% confidence interval [CI]) AMH levels of those who reported a history of ovarian cyst surgery were 1.08 (95% CI: 0.57–2.05) times those of women who reported no history of surgery.
Conclusions:
Those with a history of ovarian cyst surgery were more likely to report having a history of infertility compared with age-matched women who reported no history of cyst surgery. It is possible that both ovarian surgery to remove cysts and the conditions that lead women to develop cysts requiring surgery may affect subsequent successful conception.
Keywords: cystectomy, infertility, ovarian cysts, ovarian reserve, ovarian surgery
Introduction
Benign ovarian cysts occur in ∼6.6% of women.1 “Ovarian cyst” encompasses many subtypes of benign cysts,2 some of which require surgical excision. The mainstay for treatment in reproductive-age women is ovarian-sparing surgery, usually by ovarian cystectomy with removal of the cyst from the surrounding ovarian cortex while preserving as much healthy ovarian tissue as possible.3 Ovarian cystectomy may have a detrimental effect on ovarian reserve (the quantity of oocytes remaining in the ovaries).4
Serum anti-Müllerian hormone (AMH) and ultrasonographic antral follicle count (AFC) are markers used to estimate the primordial follicle pool.5 Ovarian cystectomy may affect ovarian reserve by unintentional removal of some healthy ovarian cortex.6 While there is a growing body of evidence that cystectomy may negatively impact ovarian reserve, less is known about the effect of ovarian cyst surgery on fertility, since ovarian reserve itself does not appear to predict fertility.7,8
One study found that 48% of women who attempted to conceive after ovarian cyst surgery got pregnant within an 18-month time frame9; a separate study also reported a 50% pregnancy rate over the same time period after surgery, although a large proportion of women included in the study (70%) had been previously diagnosed with infertility.10 The majority of the current published data regarding fertility after ovarian cyst surgery focuses on response to assisted-reproductive technology (ART), was performed in women who were already infertile, or only has short-term follow-up.
The long-term effect of surgery for benign ovarian cysts on fertility remains unknown. While ovarian cyst surgery appears to lower markers of ovarian reserve, it is unclear whether ovarian cyst surgery puts women at risk of future infertility. The primary objective of this study was to compare the long-term risk of infertility between women with and without a history of surgery for benign ovarian cysts. In addition, we sought to compare markers of ovarian reserve between those with and without a history of ovarian cyst surgery.
Methods
Study population
The Furthering Understanding of Cancer, Health, and Survivorship in Adult (FUCHSIA) Women study is a population-based cohort study examining the effect of cancer during the reproductive years on future fertility. Female cancer survivors in the state of Georgia were identified in collaboration with the Georgia Cancer Registry (GCR).11 Survivors were invited to participate if they had been diagnosed between 1990 and 2009 with any reportable malignant cancer12 or ductal carcinoma in situ, were at least 2 years post-diagnosis.
Information regarding cancer diagnosis and treatment, including gonadotoxic exposures, was abstracted from medical records and the GCR, and compared with self-reported exposures. Gonadotoxic treatment was defined as receipt of systemic chemotherapy, total body irradiation, or abdominal/pelvic radiation. Those with gonadotoxic exposure were excluded from this analysis. A group of comparison women with no history of cancer was also recruited to represent the general population.
Comparison women were identified using a purchased marketing list, and were frequency matched to the cancer survivors based on age and location of residence in Georgia. All participants were required to be 22–45 years at the time of enrollment in the study between 2012 and 2013, have a working telephone, and speak English. A subset of women with a uterus and at least one ovary was invited to participate in a clinical portion of the study to assess ovarian reserve.
Ethical approval
Informed consent was obtained from all participants. The Emory University and Georgia Department of Public Health Institutional Review Boards approved this study.
Procedures
Participants were invited to participate in a computer-assisted telephone interview to ascertain information regarding demographics; reproductive history including infertility; medical history (including chronic conditions [e.g., hypertension, thyroid disorders]); surgical history including prior ovarian cyst surgery; menstrual history; desire for future children; and lifestyle factors (e.g., tobacco use, alcohol intake). Women were also asked to report whether they had ever been diagnosed with either polycystic ovary syndrome (PCOS) or endometriosis.
Cancer survivors also answered questions regarding their cancer history. Women were asked, “Have you ever had surgery to remove ovarian cysts?” Those who responded yes were asked to provide the age at which they first had surgery to remove an ovarian cyst and why they had surgery (with options [1] Pain; [2] Cyst ruptured; [3] To improve the chance of pregnancy; [4] Endometriosis; and [5] Other).
Women who did not answer the question regarding ovarian cyst surgery or who were missing a surgery age were excluded. Women were asked whether they had had a hysterectomy; those who responded yes were asked the age at which the hysterectomy occurred. Those who reported a hysterectomy before or equal to the age at which they had surgery for ovarian cysts were excluded.
Participants answered questions regarding periods of infertility—specifically, whether they had a period during which they had regular (at least three times per month) unprotected sex with a male partner for ≥6 months without getting pregnant; those who responded yes were asked the age at which this subfertile period occurred, the length of time it continued, and whether they were trying to get pregnant during this period.
In addition, for each pregnancy that a participant reported, they were asked the age at which pregnancy occurred and the length of time before pregnancy for which they had been having regular unprotected sex. For analysis purposes, infertility was defined as 12 months of unprotected regular intercourse without getting pregnant.13 Infertility while trying to get pregnant was defined as 12 months of unprotected regular intercourse during which the participant stated she was explicitly trying to get pregnant. Women who reported never having sex with a male or who did not answer the question about a period of subfertility were excluded.
A subset of eligible participants (n = 514) was invited to attend a clinic visit at participating reproductive clinics across Georgia. Clinic visits included a blood draw and transvaginal ultrasound. A trained sonographer performed transvaginal ultrasounds and measured AFC (number of follicles sized 2–10 mm). Blood was drawn to measure serum AMH. AMH levels were measured in duplicate by ELISA (UltraSensitive AMH/MIS ELISA, Ansh Labs, USA). For participants whose AMH was undetectable by the UltraSensitive assay, AMH was measured in duplicate using the Ansh Labs picoAMH ELISA, with an assay sensitivity of 0.006 ng/mL.
Statistical analysis
Descriptive statistics were used to compare those who did and did not have a history of benign ovarian cyst surgery. To compare rates of infertility after ovarian cyst surgery, each participant with a history of ovarian cyst surgery was randomly matched with replacement to a participant with no history of ovarian cyst surgery. The participant without a history of ovarian cyst surgery was then assigned an artificial age at surgery equal to that of her match. Cox proportional hazard models were fit to examine the time from ovarian cyst surgery age to infertility.
The follow-up period began at the reported surgery age for those who reported a history of ovarian cyst surgery or the assigned proxy age of surgery for those with no history of cyst surgery. The follow-up period lasted until the date of the study interview or censoring. Participants reporting a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation after their ovarian cyst surgery were censored at the age of the procedure. A total of 1,000 repeated matching simulations were conducted for all models. Overall estimates of effect were generated by averaging the results of all simulation trials. The median hazard ratios (HRs) and 95% simulation intervals (SIs) are reported.
The simulation was repeated using a model that adjusted for race, history of cancer, body mass index (BMI), parity at age of ovarian cyst surgery, and history of infertility before surgery. Additional simulations were performed adjusting for the previously listed covariates as well as self-reported history of endometriosis or PCOS. Further, sensitivity analyses were performed excluding women with PCOS and endometriosis, and excluding women who experienced infertility before cyst surgery. In addition, a subanalysis was performed, which included only participants who reported trying to get pregnant during this period.
To analyze clinical markers, AMH was log-transformed, and a linear model was fit to compare AMH between those with and without a history of ovarian cyst surgery, controlling for age at the clinic visit, cancer history, and endometriosis. An additional model was fit to compare AMH levels, which also adjusted for self-reported PCOS. AMH levels that were below the limit of detection (LOD) were assigned a value of LOD/√2. A negative log-binominal model was fit to determine whether the mean AFC values differed between those with and without a history of cyst surgery, controlling for the same previously listed confounders. Subanalyses of both AMH and AFC were performed, which excluded those with self-reported PCOS as well as PCOS using clinical criteria of ≥20 follicles per ovary.14
Results
Descriptive statistics
A total of 2,355 women participated in the FUCHSIA Women study. After excluding those who did not answer the question about ovarian cyst surgery (n = 5), did not report an ovarian cyst surgery age (n = 5), reported a hysterectomy before ovarian cyst surgery (n = 15), reported never having sex with a male or did not answer questions regarding a period of subfertility (n = 111), or reported a history of gonadotoxic cancer treatment (n = 682), there were 1,537 participants included in the analysis. Among those included, 94 (6.1%) reported a history of surgery for an ovarian cyst.
The characteristics of the sample stratified by history of ovarian cyst surgery are listed in Table 1. Those who reported prior ovarian cyst surgery were older than those who reported no prior surgery, with a median age at the interview of 40 (interquartile range [IQR]: 37–42) years in the surgery group compared with 38 (IQR: 35–41) years in the group with no prior ovarian surgery. Women with and without a history of ovarian cyst surgery were similar with regard to race, education, income, and health insurance status.
Table 1.
Demographic Characteristics of Women Who Participated in the Telephone Interview by Whether They Underwent Surgery for Ovarian Cysts, 2012–2013
| Surgery for ovarian cysts (n = 94) |
No surgery for ovarian cysts (n = 1,443) |
|||
|---|---|---|---|---|
| n | % | n | % | |
| Age at interview (years) | ||||
| 22–28 | 4 | 4.3 | 60 | 4.2 |
| 29–35 | 14 | 14.9 | 349 | 24.2 |
| 36–40 | 36 | 38.3 | 588 | 40.8 |
| 40–45 | 49 | 42.6 | 446 | 30.9 |
| Race | ||||
| White | 65 | 69.9 | 1,011 | 70.5 |
| Black | 24 | 25.8 | 365 | 25.4 |
| Other racesa | 4 | 4.3 | 59 | 4.1 |
| Level of education | ||||
| High school or less | 7 | 7.5 | 77 | 5.3 |
| Some college | 23 | 24.5 | 346 | 24.0 |
| College graduate | 37 | 39.4 | 544 | 37.7 |
| Some grad school or grad degree | 27 | 28.7 | 476 | 33.0 |
| Location of residence at interview | ||||
| Metropolitan area | 82 | 87.2 | 1,308 | 90.6 |
| Nonmetropolitan area | 12 | 12.8 | 135 | 9.4 |
| Relationship status at interview | ||||
| Married, living with a partner, or in a committed relationship | 80 | 85.1 | 1,181 | 82.0 |
| Single | 14 | 14.9 | 253 | 17.6 |
| Otherb | 0 | 0 | 7 | 0.5 |
| Annual income | ||||
| >USD 50,000 | 67 | 72.8 | 1,039 | 72.7 |
| ≤USD 50,000 | 25 | 27.2 | 390 | 27.3 |
| Health insurance status at interview | ||||
| Insured | 85 | 90.4 | 1,298 | 90.0 |
| No insurance | 9 | 9.6 | 145 | 10.0 |
| Pregnancy history at interview | ||||
| Nulligravid | 19 | 20.4 | 247 | 17.1 |
| Gravid | 74 | 79.6 | 1,195 | 82.9 |
| Had at least one child by interview | ||||
| Yes | 66 | 70.2 | 1,125 | 78.0 |
| No | 28 | 29.8 | 318 | 22.0 |
| Ever 12 months infertile | ||||
| Yes | 41 | 43.6 | 491 | 34.0 |
| No | 53 | 56.4 | 952 | 66.0 |
| Ever 12 months infertile while trying | ||||
| Yes | 25 | 26.6 | 250 | 17.3 |
| No | 69 | 73.4 | 1,192 | 82.7 |
| Had a hysterectomy or bilateral oophorectomy by interview | ||||
| Yes | 25 | 26.6 | 165 | 11.4 |
| No | 69 | 73.4 | 1,278 | 88.6 |
| BMIc | ||||
| Underweight | 2 | 2.2 | 26 | 1.8 |
| Normal weight | 36 | 39.1 | 602 | 41.8 |
| Overweight | 29 | 31.5 | 400 | 27.8 |
| Obese | 25 | 27.2 | 411 | 28.6 |
| Cancer survivord | ||||
| Yes | 45 | 47.9 | 482 | 33.4 |
| No | 49 | 52.1 | 961 | 66.6 |
| Polycystic ovary syndrome | ||||
| Yes | 24 | 25.8 | 103 | 7.2 |
| No | 69 | 74.2 | 1,336 | 92.8 |
| Endometriosis | ||||
| Yes | 40 | 42.5 | 112 | 7.8 |
| No | 54 | 57.5 | 1,324 | 92.2 |
| Chronic medical conditione | ||||
| Yes | 64 | 68.1 | 784 | 54.3 |
| No | 30 | 31.9 | 659 | 45.7 |
Race category “other” includes: American Indian, Alaskan Native, Asian, Native Hawaiian, and Pacific Islander.
Relationship category “other” was reserved for women who felt the other listed options did not accurately reflect their relationship status.
BMI calculated by using self-reported weight in pounds and self-reported height in inches. Weight was converted to kilograms (kg). Height converted to meters (m). The formula kg/m2 was used to calculate BMI. Underweight: BMI <18.5; normal weight: 18.5 ≤ BMI <25; overweight: 25 ≤ BMI <30; obese: BMI ≥30.
Cancer survivors who received gonadotoxic treatment (e.g., pelvic radiation, chemotherapy with an alkylating agent) were excluded from this analysis.
Chronic medical conditions included hypertension, congestive heart failure, cardiomyopathy, previous myocardial infarction, diabetes, depression, osteoporosis or osteopenia, eating disorders, and thyroid disorders.
BMI, body mass index.
A larger proportion of those with a history of surgery for ovarian cysts had undergone a hysterectomy or bilateral oophorectomy by the interview compared with those with no history of surgery (26.6% vs. 11.3%). Those who reported a history of ovarian cyst surgery were also more likely to report being a cancer survivor (47.9%) and having a chronic medical condition (68.1%) compared with those with no history of surgery (33.4% and 54.3%, respectively). Endometriosis (42.6% vs. 7.8%) and PCOS (25.8% vs. 7.2%) were also more commonly reported among those who did versus did not have a history of ovarian cyst surgery.
Among those reporting surgery, the median age at the time of surgery was 25 (IQR: 20–31) years. The median time from ovarian cyst surgery to the interview among those who reported surgery was 12 (IQR: 6–19) years. The most common reason for ovarian cyst surgery among those reporting a history of surgery was pain (50.5%) (Table 2).
Table 2.
Reasons for Ovarian Cyst Surgery Among Women Who Self-Reported a History of Surgery for Ovarian Cysts
| N | % | |
|---|---|---|
| Pain | 47 | 50.5 |
| Cyst ruptured | 9 | 9.7 |
| To improve the chance of pregnancy | 7 | 7.5 |
| Endometriosis | 5 | 5.4 |
| Other | 25 | 26.9 |
| Did not answer | 1 |
Risk of infertility
A similar proportion of women in the surgery (20.4%) versus no surgery group (17.1%) reported never being pregnant although a smaller proportion of those in the surgery group (70.2%) reported having at least one child by the interview compared with the women with no history of surgery (78.0%). Of those with a history of ovarian cyst surgery reporting at least one pregnancy, 50% reported pregnancy occurring after ovarian cyst surgery.
A larger proportion of women who reported a history of ovarian cyst surgery reported ever having a 12-month period of infertility (43.6%) compared with those with no history of surgery (34.0%); this difference remained true among those who reported infertility while specifically trying to get pregnant (26.6% [surgery] vs. 17.3% [no surgery]). Some women reported having been diagnosed with an underlying cause of their infertility; these reasons are listed in Table 3.
Table 3.
Infertility Diagnoses Among Women by Whether they Underwent Surgery for Ovarian Cystsa
| Surgery for ovarian cysts (n = 94) |
No surgery for ovarian cysts (n = 1,443) |
|||
|---|---|---|---|---|
| n | % | n | % | |
| Endometriosis | 10 | 10.6 | 29 | 2.0 |
| Anovulation | 9 | 9.6 | 49 | 3.4 |
| Male factor | 4 | 4.3 | 38 | 2.6 |
| Diminished ovarian reserve | 6 | 6.4 | 12 | 0.8 |
| Fibroids or uterine factor | 11 | 11.7 | 20 | 1.4 |
| Tubal factor | 6 | 6.4 | 11 | 0.8 |
| Problems with cervix or cervical mucous | 2 | 2.1 | 11 | 0.8 |
| Menopause | 0 | 0.0 | 0 | 0.0 |
Categories were not mutually exclusive. Women were asked to report all diagnoses related to infertility that they had received from a medical professional.
Women with prior ovarian cyst surgery were more likely to experience infertility after surgery compared with women without prior ovarian cyst surgery (median HR: 1.91, 95% SI: 1.15–3.74) (Fig. 1). After adjusting for age, race, BMI, cancer history, parity before surgery age, and history of infertility, this relationship remained (median-adjusted HR [aHR]: 2.11, 95% SI: 1.09–4.98). After adding endometriosis to the adjustment variable set, the relationship remained with a similar effect size (median aHR: 2.41, 95% SI: 1.03–6.78). When history of PCOS was also added to the model, the relationship remained (median aHR: 2.33, 95% SI: 0.99–7.35).
FIG. 1.
Unadjusted and adjusted median HRs and 95% SI examining time from ovarian cyst surgery age to infertility after surgery comparing those who reported a history of ovarian cyst surgery and those assigned a proxy age of surgery who reported no history of ovarian cyst surgery, censored at age of hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or study interview. BMI, body mass index; HR, hazard ratio; PCOS, polycystic ovary syndrome; SI, simulation interval.
After adjusting for age, race, BMI, cancer history, parity before surgery, history of infertility, and history of chronic illness including endometriosis, the median aHR was 2.07 (95% SI: 1.05–5.08). When infertility was restricted to those attempting pregnancy, the association between risk of infertility and ovarian cyst surgery was more marked, but less precise (aHR: 3.09, 95% SI: 1.10–15.58; adjusted for age, race, BMI, cancer history, parity before surgery age, history of infertility, and endometriosis).
In a sensitivity analysis where women who reported PCOS or a history of endometriosis were excluded from the analysis (n = 254), 1,283 participants remained; 43 (3.4%) of whom reported a history of surgery for an ovarian cyst. After excluding those with PCOS and endometriosis, the HR for infertility was 2.08 (95% SI: 0.87–6.26). In a separate sensitivity analysis that excluded those who reported a history of infertility before ovarian cyst surgery age (or assigned proxy age), the HR for risk of infertility was 1.93 (95% SI: 1.20–3.47).
Clinical markers of ovarian reserve
Of the 514 women who participated in a clinic visit to evaluate ovarian reserve, 28 (5.4%) reported a history of ovarian cyst surgery. The age and race distributions comparing those who did and did not have surgery for ovarian cysts among women who participated in a clinic visit were similar to the distributions observed in Table 1 (Supplementary Table S1). Those who reported a history of ovarian cyst surgery were less likely to have had a child by the time of the clinic visit (57.1%) compared with those with no history of ovarian cyst surgery (76.5%).
A substantially larger proportion of women with a history of ovarian cyst surgery who visited clinic reported having endometriosis or PCOS compared with those with no history of ovarian cyst surgery. Four women (0.8%) did not have AMH performed due to difficult intravenous access. Fourteen women (2.7%) did not have an ultrasound performed or had uninterpretable ultrasound reports. Of the women with a history of ovarian cyst surgery, 7.4% had an AMH level below the LOD compared with 3.1% of those who reported no prior ovarian cyst surgery. Among women with prior surgery for an ovarian cyst, the median time from surgery to AMH measurement was 9.3 (IQR: 6.4–16.7) years.
A multivariable model was fit to examine the association between log-transformed AMH and history of ovarian cyst surgery. After adjusting for age at the clinic visit, history of cancer, and endometriosis, the estimated geometric mean (95% confidence interval [CI]) AMH levels of those who reported prior ovarian cyst surgery were 1.06 (95% CI: 0.56–2.01) times those of women who reported no history of surgery. When women who reported a history of PCOS were excluded, predicted AMH levels for those who reported a history of ovarian cyst surgery were 1.18 (95% CI: 0.57–2.45) times those of women who reported no cyst surgery.
Figure 2 depicts the predicted mean and 95% CI for AMH levels using the model adjusted for age at the clinic visit, history of cancer, and endometriosis. Despite excluding cancer survivors who received gonadotoxic treatments, cancer survivorship appeared to be a strong confounder of AMH results, while adjusting for endometriosis changed results minimally.
FIG. 2.
Adjusted estimates and 95% CI for geometric mean values of AMH and AFC comparing women who reported a history of surgery for ovarian cysts versus no history of surgery for ovarian cysts. AFC, antral follicle count; AMH, anti-Müllerian hormone; CI, confidence interval.
Women with no history of cancer or endometriosis who reported a history of ovarian cyst surgery had predicted AMH levels at age 38 years of 1.57 ng/mL (95% CI: 0.79–3.12), which were comparable with women with no history of cancer or endometriosis who did not have a history of ovarian cyst surgery (1.48 ng/mL, 95% CI: 1.15–1.91). Among those who reported endometriosis but no history of cancer, the predicted AMH levels were similar for those who did (1.11 ng/mL, 95% CI: 0.58–2.13) and did not (1.05 ng/mL, 95% CI: 0.63–1.75) report a history of ovarian cyst surgery. The pattern of AMH levels for cancer survivors who did and did not report endometriosis and ovarian cyst surgery was similar to that of women with no history of cancer.
AFC data were also compared for those with and without a history of ovarian cyst surgery. Those with prior ovarian cyst surgery had estimated AFC values that were 1.20 (95% CI: 0.92–1.57) times those of women without a history of cyst surgery after adjusting for age at the clinic visit. The predicted value of AFC for a 38-year-old woman with no history of cancer or endometriosis was higher in those reporting a history of ovarian cyst surgery (19.7, 95% CI: 14.3–27.1) than in those who did not have cyst surgery (14.0, 95% CI: 12.4–15.7). A supplemental subanalysis was performed accounting for those with self-reported PCOS (Supplementary Results S1); when PCOS was addressed in multiple ways, results were unchanged.
Discussion
Women who reported prior ovarian cyst surgery were more likely to report subsequent infertility compared with women with no prior ovarian cyst surgery. This finding remained after adjusting for age, race, BMI, cancer history, parity before surgery age, and endometriosis. In addition, when history of infertility before age (or proxy age) of ovarian cyst surgery was controlled for, our results did not change. Among women who had a clinic visit, a higher proportion of women with a history of ovarian cyst surgery had an AMH level below the LOD, but overall those with and without a history of ovarian cyst surgery had no difference in AMH after adjusting for age.
The decrease in ovarian reserve after benign cystectomy is hypothesized to be due to unintentional removal of some healthy ovarian tissue adjacent to the cyst.6 A unilateral oophorectomy also decreases ovarian tissue. A previous study found that fertility is conserved after unilateral oophorectomy.15 We found that similar proportions of women who did and did not have surgery for ovarian cysts reported having never been pregnant by the time of the interview and reported having at least one child. While this is reassuring, it is possible that ovarian cystectomy may impact time to pregnancy.
Prior studies indicate that ovarian cyst surgery appears to affect short-term ovarian reserve. One meta-analysis evaluating the effect of ovarian cystectomy on AMH levels found a 38% fall in AMH for those undergoing surgery for endometriomas16; this conclusion was supported by a separate systematic review.17 A larger effect on markers of ovarian reserve has been seen in those undergoing surgery for bilateral ovarian cysts compared with unilateral surgery.18,19 Most studies, however, looked at relatively short-term effects of cystectomy on ovarian reserve (6–24 months).
In our study, there were similar values of predicted AMH among those with and without a history of ovarian cyst surgery. Our median time from ovarian cyst surgery to clinic visit was 9.3 years (IQR: 6.4–16.7) among those who reported a history of ovarian cysts. It is possible that the initial decline in ovarian reserve after cystectomy is less marked with the passage of time. We acknowledge that our sample size of women who visited a clinic and reported a history of ovarian cyst surgery was small, so our AMH and AFC estimates are imprecise.
We were able to find previously published studies that had conflicting results for AMH and AFC. Celik et al. noted that AMH declined 26% at 6 weeks postoperatively and 61% at 6 months postoperatively when compared with preoperative levels, but that AFC was noted to have increased at the postoperative assessment.19 A separate meta-analysis also concluded that ovaries that underwent an operation did not show a decreased AFC compared with preoperative values.20,21
It is possible that the type of benign ovarian cyst matters.22 Endometriomas may show a more significant decline in postoperative AMH compared with other benign cysts.23–25 Those undergoing cystectomy for a mature teratoma may also be at increased risk of a larger decline in AMH compared with other histological cyst subtypes.26 While we asked women whether they had a cystectomy for endometriosis or had a known history of endometriosis, this information was based on self-report, and we were unable to further categorize type of cyst removed. In addition, when excluding those with self-reported endometriosis from the analysis, the relationship between history of surgery for an ovarian cyst and subsequent infertility remained, although the estimate was less precise.
Our study has many strengths. We were able to include a moderate number of women who reported surgery for ovarian cysts. Most studies evaluating the effects of ovarian cysts on fertility in the past have been smaller. In addition, we were able to compare those with a history of cyst surgery with women with no history of ovarian cyst surgery by creating a proxy surgery age among those who reported no history of surgery. The median time from ovarian cyst surgery to the interview among those who reported surgery was 12 (IQR 6–19) years, allowing sufficient time for individuals to be at risk of infertility after surgery.
We were able to control for many possible confounding factors associated with infertility to account for groups that may have differential risk. This study is also strengthened by the fact that we evaluated a general cohort of women rather than just an infertile population. Most published research regarding cystectomy and fertility was performed in infertile populations undergoing ART rather than unassisted conception after surgery. These studies may be subject to selection bias and may not be representative of women with ovarian cysts who are trying to conceive naturally. Finally, we were able to include information related to ovarian reserve to further enrich our discussion of how ovarian cyst surgery may affect reproductive potential.
Our study has some limitations. Our cyst data and report of infertility are based on self-report from an interview, which may lead to misclassification; however, participants were asked about history of ovarian cysts requiring surgery, not just a history of a spontaneously resolved cyst, making them less likely to misremember having had an operation. It is also possible that differential misclassification exists if women who report a history of ovarian cyst surgery were more likely to recall an infertile period.
We were unable to verify patient's report of their infertility history with a more objective medical record. Although women were slightly older in the cyst surgery group at the time of the interview than the women with no history of ovarian cyst surgery, this difference was small and still gave a similar length of time after surgery age (or proxy surgery age) to be at risk of infertility. We accounted for PCOS in our analysis, as this condition may affect both infertility and ovarian reserve markers; however, it is possible that a diagnosis of PCOS may affect women's reporting of surgery for an ovarian cyst, or conversely that surgery for an ovarian cyst may affect women's report of having PCOS despite the two conditions having different etiologies.
We were unable to evaluate the histological cyst type among those reporting a history of ovarian cyst surgery. It is possible that there may be confounding, as conditions that cause women to have cysts might also affect fertility. Endometriosis is such a condition, as it is often diagnosed surgically. We were able to adjust for self-reported endometriosis, but there is likely residual confounding by other conditions resulting in cysts that require surgery and affect fertility.
When those with a history of endometriosis were excluded, there remained a relationship between history of cyst surgery and infertility, although the estimate was less precise. Therefore, we cannot separate the effect of the surgery from the effects of these conditions. It is also possible that different operative techniques have a differential impact on ovarian reserve.20,27–29 We were unable to compare operative reports to parse out whether surgical technique had an effect on ovarian reserve or on risk of infertility.
Finally, this study was a secondary analysis of a larger population-based study originally designed to compare cancer survivors with comparison women. Cancer survivors included in this analysis mostly had a history of cancer not thought to affect reproductive potential. However, it is possible that there remains some ascertainment bias where cancer survivors may be more likely to be recommended for surgery for ovarian cysts out of concern for this history of malignancy.
While we notably excluded all women with a history of gonadotoxic exposure due to cancer treatment and adjusted for cancer survivorship status with all analyses, it is possible that this affects the generalizability of our results. However, a subanalysis was also performed excluding all cancer survivors, and our results did not change (data not shown), but estimates became less precise.
Similar proportions of women with and without a history of ovarian cyst surgery reported having never been pregnant and reported having had a child by the time of the interview. However, those with a history of ovarian cyst surgery were more likely to report having a history of infertility after cyst surgery compared with age-matched women who reported no history of cyst surgery.
Previous studies investigating the effect of ovarian cystectomy on fertility focus primarily on surrogate markers of fertility, such as ovarian reserve, are limited to an infertile population, and have short-term follow-up. Our study was population based and may reflect a more general impact of ovarian cyst surgery on subsequent fertility. It is possible that both ovarian surgery to remove cysts and the conditions that lead women to develop cysts requiring surgery may affect subsequent successful conception.
Supplementary Material
Authors' Contributions
L.M.S. designed conceptualization, data curation, methodology, formal analysis, writing—original draft; J.B.S. contributed to conceptualization, data curation, writing—review and editing; L.M.K. performed methodology and formal analysis; B.H. assisted with conceptualization, writing—original draft, review and editing; A.C.M. contributed to data curation, writing—review and editing; P.P. H. developed conceptualization, data curation, methodology, formal analysis, writing—original draft, funding acquisition, and supervision.
Author Disclosure Statement
Conflicts of Interest: L.M.S., J.B.S., L.M.K., B.H., and A.C.M. have nothing to disclose. P.P.H. reports a grant from NICHD 1R01HD066059 during the conduct of the study.
Funding Information
Funding for this research was provided by The Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant 1R01HD066059.
Supplementary Material
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