Fertility preservation in women with endometriosis: How,when,and for whom?

Abstract

Fertility preservation options, including cryopreservation of oocytes, embryos, and ovarian tissue, were initially focused on women undergoing gonadotoxic chemotherapy for oncologic treatment. The indications have expanded to include nonmalignant conditions that can also lead to follicular loss. Endometriosis is a chronic inflammatory, estrogen-dependent entity with a prevalence of 25%–50% in infertile patients. A reduction in the ovarian reserve among women with endometriosis may result either from the disease itself or from its surgical treatment. The aim of this editorial was to identify patients with endometriosis who may benefit from fertility preservation and discuss the available evidence.

Introduction

Fertility preservation options, including cryopreservation of oocytes, embryos, and ovarian tissue, ¹ were initially focused on women undergoing gonadotoxic chemotherapy for oncologic treatment. However, the indications have expanded to include nonmalignant conditions that can also lead to follicular loss, such as immunological, hematological, or genetic disorders; endometriosis; and age-related fertility decline.^2–4 According to the European Society of Human Reproduction and Embryology (ESHRE) guideline on female fertility preservation, oocyte cryopreservation is an effective and safe method. ⁵

Endometriosis is a chronic inflammatory, estrogen-dependent entity which is characterized by the presence of endometrial glands outside the uterus; it affects 10% of all women in the reproductive age group. ⁶ According to previous studies, the prevalence of endometriosis in infertile patients varies between 25% and 50% and is estimated to be 10 times higher in this subgroup than in the general population,^7–10 with a higher reported miscarriage rate. ¹¹ Many different mechanisms are involved in endometriosis-associated infertility, including mechanical factors such as pelvic adhesions, nonfunctional fallopian tubes, damage to the ovarian parenchyma due to endometriomas or iatrogenic during surgery, impaired endometrial receptivity, dyspareunia, and chronic inflammation in the pelvis and peritoneal fluid. ¹²

A reduction in the ovarian reserve among women with endometriosis may result either from the disease itself or its surgical treatment. Specifically, one meta-analysis has shown that women with endometriomas have lower anti-Müllerian hormone (AMH) levels than controls, whereas no significant differences were observed between women with endometriosis without ovarian involvement and those with early-stage disease. ¹³ In addition, a reduction in the ovarian reserve can also occur iatrogenically after surgery for ovarian endometrioma, particularly in women with recurrent or bilateral ovarian endometriomas.^14,15 Thus, various fertility preservation techniques have been proposed for women with endometriosis. The aim of this editorial was to identify patients with endometriosis who may benefit from fertility preservation and discuss the available evidence.

Fertility preservation interventions

Controlled ovarian stimulation (COS) and oocyte pick-up in endometriosis

Both oocyte and embryo cryopreservation begin with COS and oocyte pick-up, in which the ovaries are stimulated using injectable gonadotrophins to promote the recruitment and development of multiple follicles. Once matured, the follicles are aspirated transvaginally under ultrasound guidance. For fertility preservation in women with endometriosis, no specific COS protocol is currently recommended as the available evidence is limited and inconclusive regarding which protocol yields a higher number of retrieved oocytes.^16–18 A previous prospective study comparing progestin-primed ovarian stimulation (PPOS) with the antagonist protocol in women with endometriosis found comparable stimulation outcomes; however, in a cost-effectiveness analysis, the PPOS protocol was superior to the antagonist protocol. ¹⁸ From the perspective of endometriosis management, dienogest appears to be an ideal progestogen for PPOS as it is already used therapeutically for endometriosis and can be continued throughout the period of gonadotropin stimulation. ¹⁹ In an initial study, Iwami et al. compared the PPOS achieved using dienogest versus dydrogesterone, reporting fewer total oocytes but a higher proportion of mature (metaphase II (MII)) oocytes with dienogest. ²⁰ A 2025 study by Calero et al. that compared dienogest-based PPOS with that achieved using antagonist and agonist protocols found no significant differences in the outcomes. ²¹ These findings indicate that dienogest can be safely used for PPOS without clinical disadvantage; however, further randomized controlled trials and studies on perinatal and long-term health outcomes are required. Notably, dienogest exerts a stronger luteinizing hormone (LH)-suppressing effect than other progestogens commonly used in PPOS, suggesting that supplementation with human menopausal gonadotropin (hMG) or recombinant follicle stimulating hormone (rFSH) + recombinant LH (rLH) is necessary to ensure adequate final oocyte maturation. Moreover, prior use of dienogest before ovarian stimulation has been associated with increased melatonin levels in the follicular fluid, potentially offering antioxidant protection and improving oocyte quality. ²²

When considering oocyte cryopreservation, the associated risks must be carefully evaluated. In 2018, Seyhan et al. reported that endometrioma volume increased by approximately 10% during stimulation, particularly in larger cysts. ²³ Follicular aspiration also carries higher risks of bleeding and infection due to distorted anatomy.^24,25 Intra-abdominal hemorrhage following ultrasound-guided transvaginal oocyte retrieval is a rare (0.1%–0.5%) but potentially life-threatening complication. In some cases when there is an expanding intra-abdominal hematoma, surgical intervention is required. However, such procedures are associated with an additional risk of ovarian reserve and fertility compromise. ²⁶ Pelvic infection after oocyte retrieval is estimated to have an incidence of 0.03%–0.24%. When surgical management is required, it may be particularly challenging due to extensive pelvic adhesions, increasing the risk of inadvertent removal of healthy ovarian tissue or ovarian damage due to excessive coagulation and hemostasis. ²⁷ Endometriomas should not be aspirated, and if punctured accidentally, antibiotic therapy—such as cefuroxime (1.5 mg intravenous (IV)/intramuscular (IM) for up to 4 days)—should be considered. ²⁸ A previous study has shown that ovarian pick-up in women with endometrioma is associated with more contamination of the follicular fluid and incomplete aspiration; ²⁸ however, a more recent study found that the complications between the two groups were comparable. ²⁹

Oocyte cryopreservation

After oocyte retrieval, the cumulus cells are removed from the oocytes and are cryopreserved at low temperatures to maintain their genetic stability and metabolic inactivity. ³⁰ The first birth from a cryopreserved oocyte was reported in 1986. ³¹ Approximately 3 decades later, the American Society for Reproductive Medicine (ASRM) approved the procedure for women undergoing gonadotoxic treatments in 2012 and later for all women in 2014. ³² Since then, advances in vitrification and clinical experience have driven a steady rise in fertility preservation. The first case of oocyte cryopreservation in a woman with endometriosis was reported in 2009 in a 25-year-old nulliparous patient who underwent multiple surgeries, including right oophorectomy. ³³

A recent systematic review including 10 studies involving a total of 1110 patients with endometriosis showed that the total number of oocytes retrieved ranged between 5.0 (median) and 9.5 (mean) per cycle. The number of MII oocytes retrieved varied between 3.0 (median) and 7.2 (mean) per cycle, while the maturation rate ranged from 58.3% to 79.5%. The number of oocytes cryopreserved varied between 4 (median) and 5.5 (mean) per cycle. ³⁴ The review also demonstrated that the number of oocytes retrieved was negatively correlated with age and was significantly higher in patients who had not previously undergone surgery. ³⁴ The number of oocytes retrieved was comparable between patients with endometrioma and those with other types of cysts; however, it was significantly lower in women with endometrioma than in patients without cysts. ³⁴

The return rate ranged from 1.37% (2/146) to 46.5% (485/1044) across the available studies; however, only one of these studies reported the follow-up duration.^34,35 The reported data on conception outcomes are limited as no study has included information on natural conception after oocyte cryopreservation, and only two studies have reported the outcomes of in vitro fertilization (IVF). Santulli et al. noted that two patients returned for oocyte warming, both of whom achieved live births, ³⁶ whereas Cobo et al. reported a 46.4% live birth rate among women who returned for IVF. Women who were aged <35 years at the time of oocyte cryopreservation had higher chances of achieving a live birth. ³⁵

Embryo cryopreservation

Embryo cryopreservation involves fertilization of oocytes with sperm from either a male partner or sperm donor. The main advantage of this technique is the slightly higher survival rate of embryos compared with that of oocytes. ³⁷ However, one major limitation is the use of the partner’s genetic material, which may lead to ethical and legal challenges in cases of death or separation before fertility treatment. ³⁸ In some European countries, such as Switzerland, explicit banking of embryos is not allowed, whereas in other countries, such as Turkey, it is the only fertility preservation option for married couples.

Ovarian tissue cryopreservation

Ovarian tissue cryopreservation has primarily been employed for oncological patients who are scheduled to undergo gonadotoxic treatments and cannot delay therapy for COS. This technique can be performed at any time during the menstrual cycle and does not require ovarian stimulation. However, it involves two surgical procedures: the first for harvesting the ovarian tissue and the second for transplanting it either orthotopically to the remaining ovary or the peritoneum of the ovarian fossa or heterotopically to another site. Orthotopic transplantation may allow spontaneous conception. ³⁹

Data on ovarian tissue cryopreservation in women with endometriosis remain limited. In 2005, Donnez et al. reported two cases of fresh ovarian tissue orthotopic transplantation in patients with severe endometriosis who underwent left oophorectomy for recurrent disease; one of these patients conceived following IVF. ⁴⁰ Since endometriosis is a benign condition that usually allows sufficient time to plan optimal fertility preservation, ovarian tissue cryopreservation may be considered primarily in cases requiring urgent surgery, such as those with bowel obstruction or hydronephrosis with coexistent ovarian involvement. Additionally, it is noteworthy that in cases of severe endometriosis, tubal motility is usually impaired, making subsequent spontaneous conception impossible. If, in these cases, only preserved ovarian tissue is available, for retransplantation of the tissue, a site is selected that would be easily accessible for transvaginal follicular aspiration (in the case of future ovarian stimulation treatment and IVF).

Discussion

Generally, age and ovarian reserve are key determinants of fertility preservation outcomes. A woman’s age at the time of oocyte retrieval is strongly associated with the likelihood of achieving a live birth following elective oocyte cryopreservation. Younger women with the same number of retrieved oocytes have significantly higher chances of live birth than older women. ⁴¹

In a previous study, women aged <35 years who had endometriosis demonstrated better outcomes, and the gain per additional oocyte was greater in younger patients. For example, among women with 10 cryopreserved oocytes, the cumulative live birth rate was 41.8% in the younger group compared with 24.3% in the older group (p = 0.007). ³ The cumulative live birth rates in that study were comparable across different oocyte ranges between women with and without endometriosis. ³ The age at which women choose to have children has increased, and the number of women who have children at ≥40 years of age has more than doubled in the past 20 years. Therefore, during fertility preservation counseling, it is crucial to emphasize on the differences in success rates according to the patient’s age at the time of egg retrieval. ⁴² In women with severe endometriosis who have a strong prospective desire to have children, fertility preservation should be offered because younger patient age during fertility preservation is directly proportional to better outcomes. ⁴³

Ovarian reserve, characterized as the functional potential of the ovary, is related to reproductive aging. The constant decline in ovarian reserve is a process that spans decades, starting from fetal life and ending at menopause. The most common use of the ovarian reserve is to predict the response to ovarian stimulation; however, it can also be used for women with endometriosis to guide treatment planning as both endometriosis and ovarian surgery can influence the ovarian reserve. Patients with ovarian endometriosis exhibit lower AMH levels than those without endometriomas (mean difference (MD): −0.84, 95% confidence interval (CI): −1.16 to −0.52); ³³ in addition, surgical treatments of ovarian endometrioma such as cystectomy and ablation reduce the ovarian reserve (MD: −1.26, 95% CI: −1.64 to −0.88, I²: 45% and MD: −0.70, 95% CI: −1.07 to −0.32, I² = 0%, respectively). ⁴⁴ A recent meta-analysis reported a statistically significant decline in the AMH levels postoperatively at multiple time points: up to 6 weeks (−1.39 ng/mL, 95% CI: −2.01 to −0.76), from 7 weeks to 6 months (−1.13 ng/mL, 95% CI: −1.40 to −0.87), and from 6 to 18 months (−2.12 ng/mL, 95% CI: −2.61 to −1.63). These data suggest a partial rebound of AMH in the medium-term period, followed by a more pronounced decline in the long term, indicating a sustained negative impact on the ovarian reserve. ⁴⁵ A meta-analysis has shown comparable baseline AMH levels between women with unilateral and bilateral endometriomas; however, the postoperative reduction in AMH levels was significantly greater in the bilateral group. ⁴⁶ Alternative techniques with less or no detrimental effect on the ovarian reserve, such as alcohol sclerotherapy and laser ablation, should be considered in the treatment of endometrioma. ⁴⁷ Studies are in concordance that women who have undergone cystectomy for ovarian endometrioma have fewer oocytes retrieved compared with women who have not undergone surgery;^33,35 therefore, when technically feasible, fertility preservation should be considered prior to endometrioma surgery. Regarding peritoneal endometriosis, a previous study has shown that women with this condition had AMH levels comparable to those of controls. ⁴⁸ In terms of evaluating the ovarian reserves in women with endometriosis who are scheduled for surgery, an online questionnaire study among gynecologists in France has shown that 78% of practitioners assessed AMH preoperatively, whereas only 37.3% assessed it postoperatively. ⁴⁹ Patient-specific characteristics which could influence the decision of fertility preservation in women with endometriosis are age, reduced ovarian reserves, presence of bilateral endometriomas, risk or history of repeated surgeries due to compromised ovarian function, and relationship status. According to a previous study, fertility preservation for women with endometriosis is increasingly integrated into clinical practice, with 74% of specialists routinely recommending it—particularly for patients with bilateral (77%) or recurrent (96%) ovarian endometriomas. Oocyte cryopreservation is reported as the most used method for fertility preservation by 87% of practitioners, with patient age identified as the primary factor influencing the decision. ⁴⁹

The return rate for women with cryopreserved oocytes varies widely, ranging from 1.37% to 46.5%.^35,36 These discrepancies may be due to differences in the follow-up duration, which was not reported in either study, and differences in patient characteristics; for example, Cobo et al. included infertile patients. ³⁵ The mean storage time reported by Cobo et al. was 1.7 ± 0.4 years. ³⁵

Although fertility preservation techniques can help mitigate the effects of age-related fertility decline and socioeconomic factors, thereby providing reproductive autonomy to women, the decision regarding fertility preservation and its timing remains complex and is associated with several limitations, including psychological impact, cost, and realistic expectations regarding reproductive outcomes and success rates. ⁵⁰ According to a previous study that developed an online decision-aid tool, women who used this tool experienced lower decisional conflict. ⁵¹

A multidisciplinary approach is increasingly being adopted in endometriosis treatment, with many specialized centers holding multidisciplinary team meetings to develop holistic strategies for managing complex cases. ⁵² A recent European survey on fertility preservation counseling for women with endometriosis revealed that most centers reserved fertility preservation counseling for severe cases, such as large endometriomas with or without deep endometriosis. Routine fertility preservation counseling for all endometriosis patients was standard practice in only 32.8% of the surveyed centers, whereas 15.5% did not offer any fertility preservation options. ⁵³

The cost-effectiveness of fertility preservation and the assessment of related expenses by health insurance providers should not be overlooked as fertility preservation for endometriosis is generally not covered under insurance in most countries. Some European nations—such as Italy, France, Finland, and Sweden—do, however, offer partial or full reimbursement. ⁵³ The significant variation in fertility preservation strategies across Europe may be attributed to several factors, including limited access to surgical or fertility centers, insufficient awareness or expertise, inadequate familiarity with the available techniques, and unclear or inconsistent regulations and guidelines. ⁵³

Given the numerous challenges associated with infertility and reduced reproductive potential, discussions about fertility preservation are crucial—particularly in adolescents and very young women. A recent survey conducted in 13 European countries, encompassing 58 fertility centers and hospitals, reported that most centers (51.7%) offered fertility counseling primarily to patients with severe endometriosis, including those with large endometriomas with or without deep endometriosis. Notably, 15.5% of centers did not provide fertility preservation options to women with endometriosis, whereas routine fertility counseling for all affected patients was implemented at 32.8% of the participating centers. ⁵³

Conclusion

Considering that endometriosis is associated with infertility and diminished reproductive potential, it is essential that practitioners treating women with this condition are aware of and able to counsel patients appropriately—ideally preoperatively—about the available fertility preservation techniques considering the severity of endometriosis and patients’ reproductive expectations. Various surgical and fertility preservation options, including cryopreservation of oocytes, embryos, or ovarian tissue, can provide women with endometriosis the opportunity to preserve their reproductive autonomy. As treatment decisions in these cases are often complex, it is crucial that patients receive individualized counseling and care through an interdisciplinary approach involving gynecologic surgeons and fertility specialists. Given the rising maternal age and increased need for fertility treatment, proactive counseling and performance of fertility preservation are essential.