Endometriosis with Concomitant Infertility: A Comprehensive Review

Endometriosis is a chronic gynecological disorder that affects approximately 10% of women of reproductive age. Characterized by the presence of endometrial-like tissue outside the uterine cavity — typically on the ovaries, fallopian tubes, pelvic peritoneum, and other organs — it causes a complex spectrum of symptoms, ranging from pelvic pain to gastrointestinal disturbances. However, one of the most challenging and emotionally taxing aspects of this condition is its frequent association with infertility.

Understanding the intersection between endometriosis and fertility requires an exploration into the pathophysiology of the disease, its stages, clinical manifestations, and available therapeutic strategies, particularly for women with advanced (stage 4) endometriosis.

Why Is It Difficult to Get Pregnant with Endometriosis?

The relationship between endometriosis and infertility is multifactorial and not entirely understood, but several mechanisms are known to contribute. In early stages of endometriosis, inflammatory processes may play a dominant role. The presence of ectopic endometrial tissue stimulates a pro-inflammatory environment in the pelvic cavity, which in turn increases the production of cytokines, prostaglandins, and other immune mediators. These molecules impair ovarian function, reduce oocyte quality, and interfere with fertilization and implantation.

In moderate to severe stages, especially stage 3 and stage 4 endometriosis, anatomical distortion becomes more evident. Adhesions may tether the ovaries and fallopian tubes in abnormal positions, obstructing the normal pick-up of the oocyte by the fimbriae. Endometriomas — cysts filled with old blood found on the ovaries — may reduce ovarian reserve and interfere with ovulatory function.

Moreover, endometriosis has been associated with altered hormonal profiles, including disruptions in estrogen metabolism, luteal phase defects, and progesterone resistance. These hormonal abnormalities can further compromise endometrial receptivity, making implantation of a fertilized egg less likely even if fertilization occurs.

How to Get Pregnant with Stage 4 Endometriosis?

Stage 4 endometriosis, classified by the American Society for Reproductive Medicine (ASRM), is the most severe form, marked by large endometriomas, dense adhesions, and extensive anatomical distortion. Achieving pregnancy in this context is indeed challenging, but not impossible.

The approach typically begins with a thorough evaluation of the woman’s ovarian reserve, partner’s sperm quality, and the degree of anatomical distortion. For some women, surgical intervention may be recommended. Laparoscopic excision of endometriotic lesions and adhesiolysis can significantly improve pelvic anatomy and has been shown to enhance spontaneous pregnancy rates in certain cases.

However, for many patients with stage 4 endometriosis, assisted reproductive technologies (ART) such as in vitro fertilization (IVF) represent the most effective path to conception. IVF bypasses many of the mechanical barriers created by endometriosis by retrieving eggs directly from the ovaries, fertilizing them in the laboratory, and transferring embryos into the uterus.

It's important to note that ovarian response during IVF may be impaired due to the presence of endometriomas and previous ovarian surgeries, which can deplete the follicular pool. Therefore, fertility preservation strategies, including egg freezing at a younger age, are sometimes advised for women diagnosed early with severe disease.

In some cases, a period of hormonal suppression using gonadotropin-releasing hormone (GnRH) agonists or antagonists prior to IVF may enhance uterine receptivity and improve outcomes. Yet, the optimal duration and protocol should be individualized based on the patient’s clinical profile.

Can Endometriosis Cause Ectopic Pregnancy?

Yes, endometriosis can increase the risk of ectopic pregnancy, although it is not the most common complication. The scarring and adhesions caused by endometriotic lesions can affect the structural and functional integrity of the fallopian tubes, impairing the transport of the fertilized egg to the uterus.

In particular, tubal endometriosis may lead to partial obstruction or dysfunction of ciliary movement within the tubes. This condition can result in the embryo implanting outside the uterine cavity, typically in the fallopian tube, constituting an ectopic pregnancy.

Women with a history of endometriosis should be closely monitored in early pregnancy. Prompt detection of an ectopic pregnancy is crucial, as it can pose serious health risks if left untreated. Early ultrasounds and monitoring of beta-hCG levels are essential in this population.

Is Endometriosis a High-Risk Pregnancy?

Endometriosis itself does not automatically categorize a pregnancy as high risk, but it does carry increased risks for certain complications. Studies have shown that women with endometriosis are at higher risk of first-trimester bleeding, miscarriage, placenta previa, preterm birth, and cesarean delivery.

In addition, the uterine environment in women with endometriosis may not support optimal placentation. Some researchers hypothesize that altered immune response and abnormal endometrial receptivity could contribute to issues like intrauterine growth restriction (IUGR) and preeclampsia.

Pain from active endometriosis may also persist or even exacerbate during pregnancy, although in many cases symptoms temporarily improve due to the hormonal milieu of gestation. Nonetheless, managing pregnancy in women with endometriosis requires vigilant prenatal care, ideally coordinated between obstetricians and reproductive endocrinologists familiar with the condition.

The Role of Danocrine (Danazol) in the Treatment of Endometriosis

Danocrine, known generically as danazol, is a synthetic androgen that has historically been used to treat endometriosis. Its mechanism involves the suppression of the hypothalamic-pituitary-ovarian (HPO) axis, leading to decreased levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and subsequently reducing estrogen production. The hypoestrogenic and mild androgenic environment it creates causes endometriotic lesions to shrink and become inactive.

Danazol induces a pseudo-menopausal state, often relieving pain symptoms associated with endometriosis. It is typically administered over a course of 3 to 6 months, depending on the severity of the disease and patient tolerance.

However, the use of Danocrine has significantly declined over the past two decades due to its side effect profile, which includes weight gain, acne, hirsutism, lipid abnormalities, and adverse effects on liver function. Furthermore, danazol is contraindicated in women attempting to conceive, as it can interfere with ovulation and poses teratogenic risks if pregnancy occurs during treatment.

Today, it has largely been replaced by newer agents such as GnRH agonists (e.g., leuprolide), GnRH antagonists (e.g., elagolix), and progestins (e.g., dienogest), which offer more targeted hormonal suppression with fewer androgenic effects. Nevertheless, danazol may still have a role in select cases where other medications are contraindicated or poorly tolerated.

Conclusion

Endometriosis with concomitant infertility represents a deeply complex medical and emotional challenge for many women. The condition affects nearly every facet of reproductive physiology, from ovulation and fertilization to implantation and gestation. While early stages may allow for conservative management and natural conception, severe forms such as stage 4 endometriosis often necessitate surgical and advanced reproductive interventions.

Despite the difficulties, many women with endometriosis do go on to have successful pregnancies. Advances in laparoscopic surgery, hormonal therapies, and ART have dramatically improved the outlook for fertility. Nonetheless, individualized treatment planning and multidisciplinary care are essential to optimize outcomes.

As research continues to unravel the intricate pathophysiology of endometriosis, the hope is for even more effective, less invasive, and better tolerated therapies to emerge — ones that not only alleviate pain but preserve and restore fertility.

Medically Reviewed by Dr. Faride Ramos, MD