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"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Pain aside, for many women of reproductive age the fear of infertility is the most distressing aspect of endometriosis.

In fact, the monthly fecundity rate in endometriosis-affected couples is estimated at compared with 15-20% of fertile couples. (Cycle fecundity is the probability that a single cycle will result in a live birth.)

The relationship between /the mechanisms by which endometriosis can contribute to infertility are complex. For instance, while 50% of women with infertility are found to have endometriosis, not all women with endometriosis are necessarily infertile, said Tommaso Falcone, MD, chief of staff and medical director of Cleveland Clinic London. "We can't predict which women with endometriosis are infertile, but couples should not automatically assume they need treatment."

The Impact of Disease

Even small amounts of endometriosis, however, can impair fertility at the molecular level, owing to the presence of chemicals in pelvic fluid that are toxic to sperm, eggs, and embryo. "A couple can overcome these challenges, but it takes more time to get pregnant," Falcone explained. "In patients with advanced endometriosis – involving, that is, distortion of the pelvic anatomy – the risk of infertility is much greater and often requires corrective surgery or other infertility treatments."

This systemic inflammatory condition has a broad overall impact on the reproductive organs -- "by this I mean the uterus, ovaries," Falcone said. While some reproductive-system consequences of endometriosis may be asymptomatic, "sometimes there are obvious symptoms such as pain from an ovarian cyst or pain on sexual intercourse."

Multiple Mechanisms

Falcone outlined the multiple mechanisms by which endometriosis can impair fertility:

• Anatomical changes: Moderate or severe disease will often lead to peritubal or periovarian adhesions, compromising tubal motility and ovum capture

• Immunological factors: The peritoneal fluid of women with endometriosis has an abnormally high level of pro-inflammatory cytokines, prostaglandins, growth factors, and other inflammatory cells, which likely participate in the etiology or sustenance of endometrial implants. These alterations negatively affect sperm motility, ovaries, fertilization, embryo survival, and tubal function

• Impact on sperm: Cytokines secreted in the pelvis bathe the distal tube and negatively affect sperm motility and the ability to fertilize an egg

• Implantation: Gene profiling studies have found that progesterone resistance (demonstrated molecularly by blunted decidualization and altered endometrial receptivity) at the level of the endometrium can negatively impact

• Elevated cytokines in the peritoneal fluid of patients can be embryotoxic

Can Hormone-suppressing Therapy Enhance Fertility After Cessation?

"This is controversial, but in my opinion hormone-suppressive therapy for pain does not improve fertility," said Falcone. "These drugs are designed to improve quality of life and decrease pelvic pain, menstrual pain, and pain with sexual intercourse. The only treatment for infertility associated with endometriosis is surgery or assisted reproductive treatment [ART]."

As for the return to fertility after suppressive therapy, that depends on several factors, said Kamaria Cherise Cayton Vaught, MD, of Johns Hopkins Medicine in Baltimore. "With oral contraceptives, we can see a return to fecundity by the next menstrual cycle. But if the patient has been on injections of a gonadotropin-releasing hormone (GnRH) agonist like leuprolide [Lupron], for example, it will take longer from the last treatment -- maybe 3 months," she said.

What Do Recent Treatment Studies Show?

Falcone noted that recent studies have focused on hormone-suppressive therapy for the treatment of endometriosis-associated pain, and, as noted, suppressive therapy does not improve fertility. Most studies focus on surgery or ART. "What we have learned from the surgery trials is that operating on the ovary requires skill, because you can damage it and reduce fertility," he said.

According to the of the European Society of Human Reproduction and Embryology (ESHRE) the extended administration of a GnRH agonist before ART to improve the live birth rate in infertile endometriosis patients requires additional prospective clinical trials to determine effectiveness in improving implantation, clinical pregnancy, and live birth rates.

What Happens to Symptoms When Hormone Suppression Stops?

Usually symptoms will not return immediately after a woman ceases suppressive therapy, Falcone said.

"So if a woman is undergoing IVF, she comes off suppressive therapy and goes immediately to IVF," he said. "So really, there's no time for most symptoms to recur. It's when a patient wants to try for a spontaneous pregnancy that there is a problem, because it may take 9 to 12 months of suppressive therapy before she achieves pregnancy."

In general, he added, studies have shown no worsening of endometriosis with the ovarian stimulation protocols used in infertility treatment.

Fertility Treatments

Therapy depends on the stage of endometriosis, Falcone noted. "Severe endometriosis always requires IVF. In the early stages, some patients do clomiphene ovulatory stimulation and intrauterine injection, especially if they can't afford IVF. Ovulation induction and intrauterine insemination do improve pregnant rates; IVF, however, is the most effective."

In those undergoing IVF, endometriosis does not appear to impact embryo transfer. A found no difference in pregnancy outcomes in endometriosis patients compared with two control groups – women undergoing IVF for male factor infertility and non-infertile patients undergoing preimplantation genetic testing for monogenic disorders.

What Are the Overall Chances of Successful Pregnancy?

The overall chances for successful pregnancy are very high with appropriate treatment, Falcone said. "Couples should be very optimistic as surgery or ART can result in pregnancy in over 80% of couples. It all depends on how easily we can restore normal anatomy. It also depends on whether the ovaries are significantly involved."

If a woman has achieved a pregnancy spontaneously after surgery or with ART, then the couple should be optimistic about future pregnancy because the treatment worked. "But women should understand that pregnancy is not a cure for endometriosis," he cautioned.

If surgery is the choice, then an expert surgeon is needed, since surgery can worsen fertility. There is controversial regarding removal of endometriomas, owing to the potential impact on ovarian reserve. Cayton Vaught agreed that a is a threat to egg supply and quality: "A patient's egg supply and other risk factors should be evaluated at the outset," she said.

If ART is the choice, then there are nuances of treatment that also require an expert, Falcone said.

Implications for the Future

Fertility management will require the removal of social/behavioral factors that make the peritoneal environment worse such as smoking and poor nutrition, Falcone said. These increase the peritoneal inflammation of endometriosis.

"Both of these habits reduce fertility dramatically – in everyone, but especially in endometriosis patients," he said.

Conversations With Patients

Patients should never automatically conclude that a woman with endometriosis will be infertile, Falcone stressed. "If a woman is experiencing infertility, physicians should communicate optimism, because the treatments are very effective -- but, again, they require experts."

In addition to reviewing adverse behaviors such as smoking and pro-inflammatory nutrition, physicians should also discuss whether endometriotic pain is preventing successful sexual intercourse.

Endometriosis in Pregnancy

Mark D. Hornstein, MD, director of the Reproductive Endocrinology Division of Brigham and Women's Hospital and Harvard Medical School in Boston, agreed that the chances of successful pregnancy and a healthy birth are high, but he, too, stressed that an endometriosis patient will need more time to conceive: "So as a rule of thumb, I recommend cutting the usual wait time in half before referral to a fertility specialist. If a patient is under 35, I suggest cutting the period of unprotected intercourse from a year to 6 months from 12, and if the patient is over 35, from 6 to 3 months," he said.

Though not considered high-risk, pregnant endometriosis patients should be followed carefully, he added, since recent – but not robust – suggest a possible increased risk of complications. These include preterm birth, low-for-gestational-age weight, miscarriage, premature rupture of the membranes, placenta previa, and gestational diabetes.

Some studies have noted an increase in pregnancy-induced hypertension, as well as prenatal and postnatal hemorrhage. found that endometriosis was associated with a somewhat greater risk of spontaneous abortion, ectopic pregnancy, gestational diabetes, and hypertensive disorders of pregnancy.

"Overall, the data are not very strong, and a weak correlation does not mean it will happen," Hornstein said. "I'm going to make up a number and say the risk is 1%, which would be statistically but not clinically significant. While that risk is unlikely to deter women from getting pregnant, I think the reasonable thing is to follow these patients closely."

A 2022 French however, found no increased risk of preterm birth in women with endometriosis and suggested that no changes in management strategies are warranted. But the ESHRE guideline notes that though complications in pregnancy are rare, clinicians should be aware of a possible increased risk of first-trimester miscarriage and ectopic pregnancy in the endometriosis patient.

How Does Pregnancy Affect Endometriosis?

While pregnancy is not a cure for endometriosis, pregnancy generally relieves endometriosis symptoms owing to the elevated progesterone levels, which oppose the high estrogen levels that drive endometriosis.

"Pregnancy can be great for endometriosis," Hornstein said. "About 98% of pregnant patients are substantially or completely better. The hormonal environment of pregnancy is like being on multiple doses of progesterone-dominant combination birth control pills at the same time." Progesterone alone is a good first-line medical therapy approach for endometriosis, he added.

However, the ESHRE guideline advises that patients should not become pregnant with the sole purpose of treating endometriosis.

The Odds: Bottom Line

"Overall, endometriosis patients have a great chance of getting pregnant, but in addition to taking longer, conception is more likely to require fertility therapy," Hornstein said. "The women who have a markedly decreased chance of pregnancy are those who have had extensive surgery on their ovaries," Falcone sad.

Without alarming endometriosis patients about the increased risks of complications, obstetricians should follow them more closely, Hornstein said. "And even if they've had a successful first pregnancy, when they want a second pregnancy, they should be treated as infertile and referred for fertility therapy."

Breastfeeding

Lactation also produces a favorable hormonal environment, because it suppresses GnRH, luteinizing hormone, and follicle-stimulating hormone, thereby leading to low estrogen levels. "Once a woman stops breastfeeding, there's a variable length of time to the return of endometriosis symptoms," Hornstein noted.

Non-medical Approaches

There is no clear evidence that non-medical interventions will increase the chance of pregnancy, according to the ESHRE. "No recommendation can be made to support any non-medical interventions (nutrition, Chinese medicine, electrotherapy, acupuncture, physiotherapy, exercise, and psychological interventions) to increase fertility in women with endometriosis. The potential benefits and harms are unclear," the guidelines state.

In conclusion, reproductive assistance for endometriosis patients is effective, and the outlook for having a safe pregnancy and a healthy baby is good.

Read previous installments of this series:

Part 1: Endometriosis: Understanding the Pathogenesis and Pathophysiology

Part 2: Diagnosing Endometriosis

Part 3: Managing Endometriosis: Research and Recommendations

Part 4: Case Study: Endometriosis or Hernia?