Endometriosis: Treatment of infertility in females

INTRODUCTION — Endometriosis, a disease characterized by ectopic endometrial implants throughout the pelvis, negatively impacts fertility. Although endometriosis impairs reproduction, it does not usually completely prevent pregnancy. A combination of surgery, superovulation with intrauterine insemination (IUI), and assisted reproductive technology (ART) can help these women conceive.

This topic will provide an approach to treatment of infertility in women with confirmed endometriosis. Other aspects of endometriosis are reviewed separately:

●(See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact".)

●(See "Endometriosis: Treatment of pelvic pain".)

●(See "Endometriosis: Surgical management of pelvic pain".)

●(See "Endometriosis: Management of ovarian endometriomas".)

In this topic, when discussing study results, we will use the terms "women" or "patients" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

PREVALENCE — Endometriosis has been estimated to affect 10 to 15 percent of women of reproductive age [1]. Of women with endometriosis, 30 to 50 percent are estimated to have infertility [2,3]. Of women who present with infertility, 25 to 50 percent are estimated to also have endometriosis [4,5]. (See "Female infertility: Causes" and "Female infertility: Evaluation".)

PATHOGENESIS OF INFERTILITY FROM ENDOMETRIOSIS — While endometriosis is known to impair fertility [6-8], mechanisms of infertility associated with endometriosis are uncertain and likely depend, in part, on the stage of disease [2]. Endometriosis is surgically staged using the American Society of Reproductive Medicine staging system (figure 1 and form 1). The spectrum of disease ranges from minimal presence of ectopic tissue (eg, 1 to 5 mm implants on the pelvic peritoneum) to severe anatomic distortion (deep ovarian endometriomas, major pelvic adhesions with obliteration of normal pelvic organ relationships). Mild disease appears to incite inflammatory pathways while advanced disease causes anatomic disruption in addition to the inflammatory response.

●Although stage I (minimal) or II (mild) endometriosis (figure 1) may be identified during an infertility evaluation, it is uncertain if early-stage disease is the cause of infertility. It is hypothesized that minimal/mild endometriosis is associated with an inflammatory response that results from overproduction of prostaglandins, metalloproteinases, cytokines, and chemokines [9], as well as macrophages and natural killer cells [10]. At least some of the inflammatory process appears to be reversed by lesion removal which suggests a cause and effect relationship between the lesions and markers of inflammation [11]. The resultant inflammatory process impairs ovarian, peritoneal, tubal, and endometrial function, and leads to defective folliculogenesis, fertilization, and/or implantation [12].

Additional support for this theory comes from studies reporting increased numbers of macrophages and cytokines in the peritoneal fluid of patients with endometriosis [13-15], and that their peritoneal fluid inhibits both sperm [16] and fallopian tube ciliary function in vitro [17]. In addition, eutopic endometrium may not function normally in women with endometriosis, which could impair implantation [18]. Progesterone resistance may also be involved and related to a reduction in the concentration of progesterone receptors and progesterone coactivators (eg, Hic-5) in the endometrium of women with endometriosis [19]. Animal studies (rodents and monkeys) show functional changes in the endometrium that are thought to reflect reduced implantation potential occur not long after induction of an endometriosis-like condition [20,21]. This data lends further credence to the idea that early-stage endometriosis may have a deleterious effect on embryo implantation.

●Advanced endometriosis (stage III or IV disease) (figure 1) is associated with distorted pelvic anatomy and adhesions. These changes can impair oocyte release or pick-up, alter sperm motility, cause disordered myometrial contractions, and impair fertilization and embryo transport [8]. The chemical and immunologic mechanisms discussed above for mild/moderate disease likely contribute as well. In a study of monkeys with experimentally induced endometriosis, the pregnancy rate was approximately 40 percent in normal controls, but only 12 percent in animals with advanced endometriosis and 0 percent if ovarian adhesions were present [22]. As a comparison, minimal endometriosis did not diminish the pregnancy rate.

Advanced endometriosis may also negatively impact the ovarian follicles. Compared with women who have mild endometriosis or tubal factor infertility, studies on women with advanced endometriosis have reported abnormal folliculogenesis [23] and reduced fertilization potential of oocytes [24].

OUR APPROACH — Infertility may be caused by endometriosis alone or endometriosis combined with other factors, both male and female. For patients who present with endometriosis symptoms or clinical signs on examination and infertility, we proceed with an infertility evaluation first (algorithm 1). We then assess the need to perform primary surgery for staging and treatment of endometriosis or repeat surgery to treat pain symptoms. Choice of infertility therapy is based on the combination of findings from the infertility evaluation and surgical staging.

Perform infertility evaluation — We do not assume that endometriosis is the sole cause of the infertility. Couples who present with infertility proceed with evaluation for contributing male and female factors as reviewed in detail separately. (See "Female infertility: Evaluation" and "Approach to the male with infertility".)

Assess need for endometriosis surgery — Endometriosis is a chronic disease that requires life-long management with the goal of maximizing medical treatment and avoiding repeated surgery [25]. Primary laparoscopic surgery is indicated for staging and treating of endometriosis, improving fertility, and reducing pain. Indications for repeat surgical treatment are mainly severe recurrent pain symptoms that impair quality of life or treatment of a symptomatic endometrioma. Repeat surgery does not improve fertility.

A description of surgical techniques for treatment of endometriosis are found separately. (See "Endometriosis: Surgical management of pelvic pain", section on 'Surgical procedures'.)

Endometriosis symptoms — Non-infertile females with symptoms suggestive of endometriosis (eg, pain, dysmenorrhea, dyspareunia) who have not had primary surgical treatment are candidates for surgical diagnosis and resection. Examples include individuals who have had endometriosis visually diagnosed, but not treated, at a prior surgery (ie, appendectomy) or who have imaging or examination findings that are highly suggestive of endometriosis. (See "Endometriosis: Clinical features, evaluation, and diagnosis".)

For women with infertility and symptoms of endometriosis, primary surgery to resect or ablate endometriosis increases postoperative pregnancy rates compared with diagnostic laparoscopy only. A meta-analysis reported that operative laparoscopy nearly doubled the live birth or ongoing pregnancy rates (57 versus 34 total live births or pregnancies over 382 surgeries, odds ratio [OR] 1.94, 95% CI 1.20-3.16) [26]. Surgical treatment consists of both resection and ablation. A description of surgical techniques for treatment of endometriosis is presented separately. (See "Endometriosis: Surgical management of pelvic pain", section on 'Surgical procedures'.)

For women with continued severe pain and infertility after primary resection, repeat surgery can reduce pain but does not treat infertility. The major fertility benefit of surgical therapy is achieved shortly after the first procedure, and women who do not conceive after initial surgical treatment typically have worse disease and their pregnancy success is less, regardless of repeat surgical intervention. Clinicians must balance the limited benefits of second and third operative procedures to treat pain or other symptoms against the potential risks of major surgery and the lower likelihood of improved birth rate compared with assisted reproductive technology (ART) [27]. (See "Complications of laparoscopic surgery".)

Analysis of three observational studies that included 313 women reported lower pregnancy rates after repeat surgery compared with primary surgery for endometriosis (OR 0.44, 95% CI 0.28-0.68) [28]. In addition, the pregnancy rate for women undergoing in vitro fertilization (IVF) was similar to women undergoing repeat surgery (OR 1.51, 95% CI 0.58-3.91). Thus, for women who have failed to conceive after primary surgical resection of endometriosis, we proceed directly with infertility therapy. (See 'Infertility therapy' below.)

Endometrioma — Females with infertility and an asymptomatic endometrioma typically proceed with ART [29-35]. Management of endometriomas is presented separately. (See "Endometriosis: Management of ovarian endometriomas".)

Exceptions to the above include women with an endometrioma that is limiting oocyte retrieval during ART. Other indications for endometrioma resection are discussed separately. (See "Endometriosis: Management of ovarian endometriomas".)

Asymptomatic women — Women with asymptomatic endometriosis do not require surgical treatment, even if the endometriosis has not been previously surgically removed. As the impact of asymptomatic endometriosis on fertility is not known, the risks associated with surgical resection are not warranted [36].

Infertility therapy — Once the couple has completed an infertility evaluation and the woman has undergone laparoscopic evaluation and treatment of endometriosis, if indicated, the couple proceeds with infertility therapy. Infertility treatment is guided by the type and number of infertility factors identified during the evaluation. For women with no or reversible problems, reversible causes are treated when present, and subsequent therapy is guided by the stage of endometriosis. Women with nonreversible causes of infertility proceed directly with ART.

No or reversible infertility factors identified — All potentially treatable infertility factors are first addressed. (See "Female infertility: Treatments" and "Treatments for male infertility".)

If there are no identified causes or if the woman does not conceive after treatment of reversible causes (eg, intrauterine polyps or fibroids), subsequent infertility treatment is then based upon the surgical stage of endometriosis and patient age. Endometriosis is surgically staged using the revised American Society of Reproductive Medicine staging system. Cost, treatment availability, and patient preference also play a major role in the selection of treatment. (See "Unexplained infertility" and "Unexplained infertility", section on 'Our approach'.)

Minimal or mild endometriosis — Women with stage I/II endometriosis have the options of natural conception, superovulation and intrauterine insemination (IUI), and ART, which includes in vitro fertilization (IVF) and intracytoplasmic sperm injection.

There is no consensus as to the optimal approach. ART is more effective but more costly and not always available or acceptable to the patient, while superovulation and intrauterine insemination (IUI) is less expensive, but when ineffective delays conception. While the selection of infertility treatment is based on medical indications, factors such as patient age, patient preference, procedure risk, birth rate, insurance coverage, and cost must also be considered. As an example, we would typically offer a patient younger than age 35 clomiphene superovulation and IUI because of the low risk of the treatment, low cost, and reasonable chance of conception. However, an identical patient may prefer to go directly to IVF to maximize chance of a live birth despite the higher cost and invasive technique compared with superovulation and IUI.

●For patients younger than 35 years who desire a trial of natural conception, we advise six months of timed intercourse. If conception does not occur within six months, or if the patient elects treatment, we offer mild superovulation with clomiphene citrate and IUI.

●For patients younger than 35 years who prefer infertility treatment (rather than a trial of natural conception as above), or who do not conceive naturally, we advise proceeding with mild superovulation with clomiphene citrate (CC) or letrozole (which is not FDA approved for infertility) plus IUI. The intent of ovulation induction plus IUI is to enhance follicular development, ovulation, and luteal progesterone levels (to offset the associated progesterone resistance) while placing large numbers of motile sperm high in the reproductive tract (and thus bypassing possible cervical factors) to facilitate fertilization.

Evidence from randomized trials shows that mild superovulation and IUI should be used together [37], and that this combined therapy improves fecundability in women with early stage endometriosis [36,38-40]. Women who do not conceive after three cycles of CC/IUI are typically referred for ART. (See "Overview of ovulation induction" and "Procedure for intrauterine insemination (IUI) using processed sperm".)

CC has the advantages of being an oral agent, easy to use, low-cost, and less likely to result in multiple gestation compared with gonadotropin mild superovulation [41]. Cumulative pregnancy rates of nearly 40 percent have been reported with this combination [42]. (See "Ovulation induction with clomiphene citrate".)

●For patients ≥35 years of age, we often proceed with ART but also offer clomiphene if ART is not possible (eg, insurance, financial restraints). Advancing directly to ART has been shown to shorten the time to pregnancy (median time to pregnancy 8 and 11 months, respectively) [43]. In addition, ART offers the option of freezing excess embryos for future use.

Historically, these patients were offered gonadotropin mild superovulation and IUI [39,44,45]. The use of gonadotropin/IUI has fallen out of favor because of the increased rate of multiple gestations, including a rate of twin pregnancies of up to 20 percent [39]. During ART, the number of embryos transferred into the uterus is controlled by the clinician.

For couples who do not desire or are unable to proceed with ART, we offer three to four cycles of CC or an aromatase inhibitor such as letrozole, as clinically indicated, with IUI. The use of aromatase inhibitors in infertility therapy is discussed separately. (See "Overview of ovulation induction", section on 'Gonadotropin therapy' and "Overview of ovulation induction", section on 'Letrozole'.)

In contrast to this sequential approach, some clinicians may proceed directly to ART rather than attempt natural conception or superovulation, despite the higher cost, because at least one study has reported that superovulation does not perform better than attempted natural conception. In this retrospective cohort study of 96 women who underwent operative laparoscopy for endometriosis, 12-month cumulative pregnancy rates did not statistically differ between natural and ovarian stimulation cycles (45 versus 42 percent for stage I/II endometriosis and 20 and 10 percent for stage III/IV endometriosis) [38]. (See 'Nonreversible infertility factors' below.)

Moderate to severe endometriosis — Women with surgically staged moderate (stage III) to severe (stage IV) endometriosis, including those with endometriomas, benefit from ART [27,46-48]. There does not appear to be a role for superovulation in these women unless they are unable to access or decline ART [36,40]. Repeat surgery does not improve fertility because even aggressive lysis of adhesions is accompanied by adhesion re-formation that may block normal tubal function and ovum pickup. Repeat surgery is only performed to treat persistent symptoms, such as severe pain. (See 'Endometriosis symptoms' above.)

Nonreversible infertility factors — For couples with nonreversible infertility factors (eg, significant male factor component, decreased ovarian reserve), we generally proceed directly with ART rather than less invasive treatments, such as superovulation and IUI, because ART is more likely to result in pregnancy. Other variables that impact this decision are the cost of treatment and extent of fertility coverage.

INTERACTION OF ENDOMETRIOSIS AND ART

Impact of endometriosis on ART — The impact of endometriosis on assisted reproductive technology (ART) outcomes varies by degree of disease.

●Stage I/II disease – Stage I/II (mild) disease does not appear to negatively impact ART outcomes [49,50]. While a 2002 meta-analysis of 22 studies reported worsened in vitro fertilization (IVF) outcomes for patients with mild endometriosis compared with other infertile women [51], subsequent larger meta-analyses have consistently reported that women with minimal to mild endometriosis have similar live birth rates after IVF compared with women without endometriosis (relative risk [RR] 0.99, 95% CI 0.29-1.06 [52] and RR 0.94, 95% CI 0.84-1.06 [53]). There was approximately 50 percent overlap in the included studies [52,53]. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'Live birth and IVF'.)

Alternatively, the above study results may reflect changes in clinical recognition of stage I/II endometriosis owing to changing laparoscopy patterns over time rather than the disease’s clinical impact. Laparoscopy is required to diagnose stage I/II disease. When laparoscopy was routinely used in the evaluation of patients without evidence of male, tubal, uterine cavity, or ovulatory factors, endometriosis was diagnosed in 25 to 50 percent, or more, of patients with infertility [4,5]. By contrast, in the 2019 US Assisted Reproductive Technology Fertility Clinic and National Summary Report, only 7 percent of patients had endometriosis as an ART treatment indication [54]. The large reduction in endometriosis prevalence likely reflects a drop in diagnosis as laparoscopy is no longer a routine part of an infertility evaluation, which, in turn, has likely has resulted in a failure to recognize the disease in many patients with stage I/II disease. An additional confounder is that patients who were diagnosed, often because of pain symptoms, would largely have had surgery and resection of at least some of the lesions. These changes in clinical practice would clearly skew towards the null the outcome of any more recent study of stage I/II endometriosis on IVF outcomes

●Stage III/IV disease – In contrast to mild endometriosis, the negative effects of stage III/IV disease are not as controversial. Three systematic reviews of 22 [51], 27 [55], and 36 [53] studies (with approximately 50 percent overlap between two of the studies [53,55]) reported lower oocyte retrieval, implantation, and pregnancy rates for women with advanced endometriosis undergoing IVF compared with women with mild endometriosis. In contrast, a much larger meta-analysis of 78 studies comprising over 20,000 women reported no difference among women with stage I/II endometriosis and stage III/IV endometriosis in live birth rate (RR 0.94, 95% CI 0.80 to 1.11) and clinical pregnancy rate (RR 0.90, 95% CI 0.82 to 1.00) [52]. However, women with advanced disease, particularly those with endometriomas, often have lower ovarian reserve and produce fewer oocytes for recovery, which reduces ART success [50]. The impact of diminished ovarian reserve becomes more pronounced in women of older age whose declining egg quality is associated with greater embryo aneuploidy. In women with poor ovarian reserve, such as those with advanced age and severe endometriosis, we discuss the option to pursue ART with donor oocytes.

Impact of ART on endometriosis — There is no evidence that ART increases the recurrence of endometriosis [36]. In addition, the use of ART in women with endometriosis does not appear to increase the risk of poor birth outcome, particularly preterm birth [56].

INEFFECTIVE THERAPY — Medical therapy, including hormonal suppression, Chinese herbal medicine, nutritional supplements, and complementary/alternative medicine have not been shown to improve pregnancy rates in women with endometriosis-related infertility [36,57,58]. Randomized clinical trials consistently report that hormone therapy with agents such as danazol or gonadotropin-releasing hormone agonists for suppression of endometriosis does not improve fertility or pregnancy rates [36,59-63]. The lack of improvement applies to women treated with medical therapy alone, as well as those treated with combined medical and surgical therapy versus surgery alone. In contrast, for women whose treatment goal is pain reduction, hormonal suppression is an effective treatment. (See "Endometriosis: Treatment of pelvic pain".)

FERTILITY PRESERVATION — As endometriosis can be associated with ovarian depletion and infertility, fertility preservation therapies such as embryo, oocyte, and ovarian tissue freezing have been proposed for women diagnosed with endometriosis [64]. These technologies, especially embryo and oocyte freezing, have proven efficacy for women planning treatment with gonadotoxic medications, such as chemotherapy. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery", section on 'Fertility preservation'.)

However, offering all women diagnosed with endometriosis additional fertility preservation treatment would be extremely expensive and place a significant strain on global health care costs without providing a clear advantage, as many of these women will conceive without intervention or with a combination of the treatments reviewed above. Women who may benefit from this approach include those with bilateral endometriomas, prior ovarian surgery, and young age at diagnosis. More data are needed before a recommendation can be made regarding fertility preservation treatment in women with endometriosis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Endometriosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Endometriosis (The Basics)")

●Beyond the Basics topic (see "Patient education: Endometriosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – The pathogenesis of infertility with endometriosis varies by the stage of the disease, with mild disease inciting inflammatory pathways and advanced disease involving anatomic disruption in addition to inflammation. (See 'Pathogenesis of infertility from endometriosis' above.)

●Approach to evaluation – For patients who present with endometriosis and infertility, we proceed with an infertility evaluation. We do not assume the endometriosis is the cause of infertility. We then assess the need to perform primary endometriosis surgery. (See 'Our approach' above.)

•For patients with significant symptoms suggestive of endometriosis (eg, pain, dysmenorrhea, dyspareunia) who have not had primary surgical treatment, we recommend operative laparoscopy with ablation or excision of endometriosis implants as the first step in management after the infertility evaluation is complete (Grade 1B). Operative treatment is associated with improved pregnancy rates and reduced pain symptoms compared with diagnostic surgery alone. (See 'Endometriosis symptoms' above.)

•For patients who have previously undergone primary surgical treatment of endometriosis, we suggest not repeating surgical removal of endometriosis for the treatment of infertility unless there is significant pain (Grade 2C). Repeat surgery does not improve fertility, although it can reduce pain. Thus, clinicians must balance the limited benefits of second and third operative procedures to treat pain or other symptoms against the potential risks of major surgery and the lower likelihood of improved birth rate compared with assisted reproductive technology (ART). (See 'Endometriosis symptoms' above.)

•For patients with infertility and an asymptomatic presumed endometrioma, we generally proceed with ART and observation of the endometrioma rather than surgical removal.

-(See 'Endometrioma' above.)

-(See "Endometriosis: Management of ovarian endometriomas".)

•For patients with endometriosis who have no symptoms other than infertility, surgical treatment to improve fertility is not indicated, even if the endometriosis has not been previously removed. As the impact of asymptomatic endometriosis on fertility is not known, the risks associated with surgical resection are not warranted. (See 'Asymptomatic women' above.)

●Infertility treatment – Infertility therapy is guided by the combination of findings from the infertility evaluation and surgical staging of endometriosis as well as patient age. Cost and patient preferences also play a major role in treatment decisions. (See 'Infertility therapy' above.)

•Patients with no or reversible infertility factors, minimal to mild endometriosis (stage I/II), and age younger than 35 years are usually offered a trial of natural conception or continued infertility treatment with superovulation and intrauterine insemination (IUI). For women ≥35 years of age with stage I/II endometriosis, we often proceed directly with ART because of the shortened time to pregnancy. (See 'Minimal or mild endometriosis' above.)

•Patients with no or reversible infertility factors and/or those with advanced endometriosis (stage III/IV) are suggested to proceed directly with ART, typically in vitro fertilization when available. (See 'Moderate to severe endometriosis' above.)

•For patients with nonreversible infertility factors (eg, significant male factor component, decreased ovarian reserve), we generally proceed directly with ART, including in vitro fertilization, rather than less invasive treatments because ART is more likely to result in pregnancy. (See 'Nonreversible infertility factors' above.)

●Impact of endometriosis on assisted reproductive technology – The impact of endometriosis on ART outcomes is variable. The effects of mild endometriosis (ie, stage I/II disease) on ART are controversial. By contrast, there is consensus that stage III/IV disease can negatively impact outcomes, with one important mechanism being decreased ovarian reserve. (See 'Impact of endometriosis on ART' above.)