Endometriosis Part 2: Implications for Infertility

Dr. Bethany Mattson, ND

Endometriosis is a complex condition and can include profound fertility complications. As high as 30-50% of patients with infertility have a diagnosis of endometriosis and about 50% of patients with endometriosis struggle with infertility. 

There are several proposed mechanisms for the link between endometriosis and infertility including: 

• Structural complications:
  • Pelvic adhesions
  • Impaired ovum release/pick-up
  • Distorted myometrial contractions
• Increased inflammation and immune activity
• Hyperprolactinemia
• Corpus Luteum Defect

1) Structural Complications:

The most common reasons for infertility in a patient with endometriosis are pelvic adhesions and inflammation leading to the excess production of cytokines, prostaglandins, and macrophage activity. These excess substances disrupt normal ovulation, implantation, and sperm motility. Endometriosis adhesions can cause occlusion of the fallopian tubes and decreased sperm motility. Additionally, impaired ovum release and pick-up can be altered and distorted myometrial contractions can occur. Fimbriae movement is essential for transport of the oocyte from the ovary to the uterus and the adhesions can block or interfere with that coordinated movement. Finally, lack of space and decreased healthy ovarian tissue due to adhesions and ectopic tissue can decrease ovulation of healthy oocytes and increase ovulation of immature oocytes instead.

2) Immune and Inflammation Implications:

An increased immune response in endometriosis can cause a build-up of inflammatory cytokines, prostaglandins, and increased macrophage activity. Examination of both peritoneal and follicular fluid have shown altered composition with increased prostaglandins and cytokines in patients with endometriosis. These prostaglandins may alter tubal motility and the chronic inflammation from excess cytokines and macrophages may contribute to additional endometrioma formation. In addition, particular cytokines such as interleukin-6 may alter sperm motility, damage DNA, and interfere with implantation. The increased inflammation can also affect the quality and production of oocytes. A newer and equally important addition to this theory is the role that reactive oxygen species (ROS) play in the pathophysiology of endometriosis and infertility. ROS also cause an inflammatory response, which increase cell proliferation and affect similar outcomes seen with increased prostaglandin, cytokine, and macrophage activity.

3) Hyperprolactinemia:

Prolactin is secreted by the anterior pituitary gland and can suppress ovulation. Although the direct link between prolactin levels and endometriosis is still unclear, associations do exist. Studies have found a positive correlation between prolactin levels and endometriosis stage as well as higher prolactin levels found in endometriosis patients who could not achieve pregnancy. A study completed in 2006 found that serum prolactin and cortisol were both elevated in patients with endometriosis. The study compared 21 infertile women with endometriosis and 18 infertile women without endometriosis and examined prolactin and cortisol levels in serum, peritoneal fluid, and follicular fluid. No statistically significant difference was found in the peritoneal fluid and follicular fluid levels, but the serum levels were significantly different between the groups.

4) Corpus Luteum Defect:

A final proposed mechanism of action for infertility in patients with endometriosis is a corpus luteum defect. The corpus luteum is formed after ovulation and secretes progesterone throughout the second half of the menstrual cycle (the luteal phase). There are two types of luteal cells including small (theca) and large (granulosa) cells. Defects can occur in one or both types of cells. Small cells are luteinizing hormone (LH) receptive and secrete progesterone and the large cells are estradiol receptive during the first half of the menstrual cycle (follicular phase). Decreased progesterone levels are often seen in luteal phase defects and is often found in patients with endometriosis. There is a correlation between endometriosis and pituitary-ovarian dysfunction, which may be explained by both hyperprolactinemia and a corpus luteum defect. 

*One case-control study compared 24 patients with mild endometriosis and found that the infertile patients had statistically significant lower progesterone levels and significantly lower follicular phase estradiol levels compared to fertile patients. Because infertile endometriosis patients had lower progesterone secretion in the late luteal phase and lower estradiol levels in the follicular phase, both small and large luteal cell defects are possible.

Conventional Management: 

Treating endometriosis and infertility concomitantly can be difficult due to the wide variety in pathophysiology for each condition. One big challenge of trying to achieve pregnancy in a patient with endometriosis is that conventional medical treatment for endometriosis often includes hormonal contraceptives or other substances that suppress ovulation and implantation. Progesterone supplementation is often used to suppress the menstrual cycle and decrease dysmenorrhea. Continuous combined oral contraceptives and the Mirena IUD are also frequently used to manage pain and heavy bleeding. The best conventional treatment option for a patient with endometriosis and infertility is surgical laparoscopic management. Although the literature does show increased pregnancy rates after surgery, there are associated risks including reduced ovarian reserve and decreased ovarian response to gonadotropin. The literature is mixed on the efficacy of surgery before assisted reproductive technology (ART) and in vitro fertilization (IVF) procedures are performed. A patient-centered approach may help guide decision making for treatment options. If a patient is older or already has a decreased ovarian reserve, surgery may not be beneficial and ART may be a better starting place. However, if the patient has severe pelvic pain and large endometriomas, surgery is likely the best starting place. The staging and severity of endometriosis also changes the appropriate treatment options. Ovulation induction with clomiphene citrate and intrauterine insemination can be utilized in minimal or mild endometriosis. Moderate to severe endometriosis is often better managed with ART and one trial of surgery.

Endometriosis and infertility are two complex and frustrating conditions for patients to manage and the overlap and interactions between the two are still lacking in both knowledge and treatment options. Helping a patient with endometriosis achieve pregnancy is an important goal and an area of research that needs more attention.