Main article: Endometriosis Overview

Updated: 16-August-2024

How to get pregnant with Endometriosis

Women with endometriosis can become pregnant naturally or with medical assistance. Even though up to 40% of women with endometriosis are diagnosed with infertility,¹ the majority of women fall pregnant naturally in spite of endometriosis.

For this reason, doctors usually recommend women try to conceive naturally for at least 6 or more months so long as their menstrual cycles are regular and no other known causes of infertility (male or female) exist.

However, if the couple are still unsuccessful after 6 to 12 months, the doctor will suggest medically assisted reproduction.

Natural Conception with Endometriosis

Many women with endometriosis are able to get pregnant naturally which means expectant management (i.e. watchful waiting) may be a viable option.

However, women should consider the following beforehand:

• Age
• Comorbidities
• Pain
• Ovulation
• Fallopian tube patency
• Endometrial receptivity
• Sperm quality
• Diet
• Supplements

Age

According to the Endometriosis Fertility Index, women with endometriosis do not experience a natural decline in fertility until the age of 35.² This suggests the majority of women 30 years of age or younger with endometriosis can try to conceive naturally without worrying about their body clock.

However the natural fecundity (fertility) rate per month for women with endometriosis is significantly less than normal, between 2-10% depending on severity.³ This means it could take some women several years or longer to fall pregnant naturally which can strain the couples relationship. The only exception to this is rectosigmoid endometriosis, where 3 in 4 women conceive naturally in a median time of 10 months (range 2 to 34 months).⁴

Nevertheless, it’s also worth remembering that women with endometriosis experience natural menopause earlier than women without endometriosis.^5,6,7 Consequently, women 35 years of age or older with endometriosis have lower levels of AMH (ovarian reserve) compared to women without endometriosis which is known to decrease IVF success rates per cycle.^8,9

Comorbidities

Women with endometriosis are at higher risk of being diagnosed with other diseases (i.e. comorbidities). Some of these conditions are known to cause infertility independent of endometriosis.

This includes:

• Uterine fibroids ^10,11
• Endometrial polyps ^12,13
• Pelvic Inflammatory Disease (including endometritis) ^14,15,16,17
• Inflammatory Bowel Disease ^18,19
• Thyroid disorders (including Hashimoto thyroiditis) ^20,21
• Autoimmune disorders (specifically Rheumatoid Arthritis) ^22,23

Proper management of these other conditions should increase a woman’s fecundability however no relevant studies including women with endometriosis have been conducted to date.

Pain

Endometriosis-related pain (i.e. dyspareunia and chronic pelvic pain) can sometimes make trying to conceive naturally unbearable. Tajik et al. reported that changing sexual positions can significantly decrease this pain.²⁴ Presumably because some positions put less pressure on parts of the pelvis which contain endometrial tissue. However every woman is different so this will depend a lot on the location and severity of endometriosis.

Ovulation

Ovulation dysfunction occurs in 1 in 4 women diagnosed with endometriosis and infertility.²⁵

The most common type of ovulation dysfunction, LUFS (Luteinized Unruptured Follicle Syndrome), is prevalent in almost 75% of women with endometriosis depending on location and severity.^26,27,

²⁸ However, diagnosis of LUFS can only be made via ultrasound and not with blood tests (i.e. cycle day 21 progesterone levels).

Oligo-anovulation on the other hand appears as prevalent in women with endometriosis as those without endometriosis which suggests other causes.²⁹

Interestingly, Schliep et al. recently estimated that 1 in 50 women have endometriosis and PCOS, even though both conditions are thought to be diametric (opposite) disorders.³⁰

Fallopian Tube Patency

The majority of women with endometriosis have subtle fallopian tube abnormalities which could cause infertility.³¹ Meanwhile, at least one third of women with endometriosis have one blocked fallopian tube, and 1 in 10 have both fallopian tubes blocked.³² Mayrhofer et al. reports the risk of blocked fallopian tubes is higher according to the severity of endometriosis (rASRM stage III or IV).³³

Hysterosalpingography (HSG) is a common procedure to check fallopian tube patency. Interestingly, studies show that the use of Lipiodol, an oil-based contrasting agent, during HSG significantly improves the uterine immune microenvironment of women with endometriosis for approximately 6 months and increases the likelihood of conceiving naturally by fourfold.^34,35,36,37 However the risk of developing subclinical hypothyroidism after this treatment is high and can negatively impact pregnancy success rates if not treated.^38,39

Endometrial Receptivity

Studies report women with endometriosis often display defective endometrial receptivity and progesterone resistance.⁴⁰ With significant differences in receptors (PR, LIF), genes (MIG-6, MUC-1, COX-2) and proteins (CFP1, NR4A1, SIRT1, MFG-E8).^{41,42,43,44,45,46,47,48,49} This causes the postovulatory endometrial tissue to be significantly out of phase in 60% of women with endometriosis.⁴⁰ Luteal support (e.g. progesterone), metformin and aspirin (pending human studies) is helpful in these cases.^50,51,52,53

However, studies also reveal that endometriosis causes changes in coagulation and fibrinolysis which impacts blastocyst implantation, remodeling of (decidualized) endometrial cells, trophoblast invasion and development of spiral arteries.^54,55 This means the risk of early pregnancy loss (including chemical pregnancy) is significantly higher among women with endometriosis and may require intervention if recurring. In severe cases endometriosis can also cause recurrent implantation failure during IVF treatment.⁵⁶

Sperm Quality

Endometriosis is reported to impact various sperm function (motility, velocity, sperm binding, acrosome reaction).^57,58,59,60 Endometriosis also disrupts normal uterine contractions (i.e. uterine peristalsis) during the peri-ovulatory phase which helps transport sperm towards the fallopian tubes and oocyte.⁶¹ As a result, researchers hypothesize male partners with below average sperm quality may unknowingly be affected by endometriosis.

Diet

The anti-inflammatory diet, according to the Dietary Inflammatory Index, may be helpful for some women with endometriosis.⁶² Studies suggest a link between the severity of endometriosis and inflammatory foods or diets.^63,64

In a controlled mouse study, endometriosis was shown to alter gut bacteria and short-chain fatty acids (specifically N-butyrate). N-butyrate is a short-chain fatty acid produced during the break down (fermentation) of dietary fibre. Meanwhile, mice that consumed n-butyrate for 21 days showed significantly fewer and smaller lesions than control mice.⁶⁵

Unfortunately, human studies are few and far between. In the only prospective study to date, consuming an anti-inflammatory diet before pregnancy significantly reduces the risk of preterm birth (< 34 week) and low birth weight (< 1500g) among women with endometriosis.⁶⁶

Supplements

Studies show women with endometriosis benefit from several natural supplements. In theory, some of these supplements should be helpful while trying to conceive however no endometriosis fertility studies exist.

• Ellagic acid
• Vitamin D
• Vitamin C and E
• N-acetyl cysteine

Ellagic acid

Ellagic acid (and ellagitannins), are a natural polyphenol found in numerous fruits and vegetables, including pomegranates (highest concentration), grapes, strawberries, red raspberries, blueberries, blackberries, walnuts and pecans.

Upon reaching the large intestine, this polyphenol is metabolized by the gut microflora to produce compounds known as Urolithins A and B.

In a mice study, urolithin A completely prevented the development of endometriosis like lesions while urolithin B significantly decreased implant volume, after surgically induced endometriosis.⁶⁷

However, non-endometriosis trials of urolithin A demonstrated that up to 60% of the population has gut microbiome not capable of producing urolithin A from natural sources (i.e. 240ml of pomegranate juice) after 24 hours.⁶⁸

This suggests that urolithin A and B supplementation may be required in some women with endometriosis if future human trials show similar results.

Vitamin D

Vitamin D or calcitriol (the hormonally active form of vitamin D with progesterone-like activity) has anti-proliferative and anti-inflammatory effects.⁶⁹

Research suggest vitamin D deficiency increases the risk of endometriosis (or at least its progression).⁷⁰ While laboratory studies show vitamin D inhibits NF-κB signalling and decreases PHH3 protein levels, which is elevated among women with endometriosis.^71,72

Moreover, experts believe vitamin D provides essential support from the luteal phase onwards for implantation and pregnancy similar to progesterone.⁶⁸ In fact, a recent IVF study reported that vitamin D deficiency significantly impairs embryo quality and success rates in women with endometriosis.⁷³ Overall, vitamin D appears to be an essential vitamin for managing endometriosis and fertility.

Please note vitamin D supplements should only be taken as directed. Experts report that any deficiency or excess of vitamin D (or calcium) negatively impacts a woman’s fertility.⁷⁴

Vitamin C and E

Vitamin C and E are two of the most prominent antioxidants. In a placebo controlled trial, taking vitamin C (1000mg/day) and E (800IU/day) together causes a significant reduction in oxidative stress levels (and reactive oxygen species) in women with endometriosis after just 8 weeks.⁷⁵ Experts believe oxidative stress is a likely cause of infertility in women with minimal or mild endometriosis.⁷⁶

However, a study in 2008 reported that vitamin C (343mg/day) and E (84mg/day) supplementation for 6 months only caused a non-significant increase in the natural pregnancy rate among women with minimal or mild endometriosis.⁷⁷ Researchers suggest this is most likely due to lower dose of both vitamins although further studies are required to confirm this.⁷⁸

N-acetyl cysteine

N-acetyl cysteine (NAC) is an antioxidant and precursor to glutathione. Studies show N-acetyl cysteine has a positive effect on ovarian endometriomas.

In 2013, Porpora et al. reported that NAC (600mg three times a day, three consecutive days a week) reduced cyst mean diameter (-1.5mm) compared to untreated patients (+6.6mm) after 3 months.⁷⁹ Researchers believe this effect is due to NAC ability to inhibit ferroptosis, and VEGFA and IL8 secretion, caused by iron overload in endometriotic cysts.⁸⁰

Similarly, another study in a different group of women also reported a significant reduction in cyst mean diameter (-3.5mm), symptoms of pain, and CA-125 levels after 3 months of N-acetyl cysteine treatment. In this study, 39/52 women trying to conceive also fell pregnant (spontaneously) within 6 months of starting treatment, however there was no control group to compare with.⁸¹

Medically Assisted Reproduction

Medically assisted reproduction (MAR) describes a variety of methods used to help infertile couples conceive.

In women diagnosed with endometriosis and infertility, medically assisted reproduction consists of surgery and or assisted reproductive technologies (IUI/IVF).

With so many options, doctors and patients often refer to the ESHRE guidelines to assist in the decision making process.⁸²

Surgery

Surgical treatment of endometriosis involves destroying or removing peritoneal and deep endometriotic lesions, along with any endometriomas and separation of adhesions to restore normal pelvis anatomy.

Surgical techniques including excision (cutting) with diathermy scissors (or similar) or ablation (destroying) by laser or diathermy. The main advantages of excision vs. ablation is removed tissue can undergo histological examination (to confirm endometriosis). Excision is also more effective for deep infiltrating lesions, especially when combined with near-infrared (NIR) fluorescence technology, to identify the border between lesions and healthy tissue, and also hidden lesions.^83,84 Although a previous study reported that CO₂ laser vaporization of endometriosis results in significantly higher rates of pregnancy compared to monopolar electrocoagulation,⁸⁵ there is still a lack of studies to support one technique over another for surgeons regarding fertility outcomes.

Where endometriosis involves the ovaries, known as endometriomas, surgical removal of the endometriotic cyst (ovarian cystectomy) irrespective of size, number and bilaterality increases the probability of spontaneous pregnancy, improves symptoms of pain and reduces the likelihood of recurrence.⁸⁶ The probability of being pregnant after cystectomy (or ablation) is 18% in the first year after surgery.⁸⁷ Predictably, increasing age, recurrence of endometrioma and adhesions negatively impacts the probability of spontaneous pregnancy.⁸⁸

A partial cystectomy significantly lessens the impact on AMH compared to total cystectomy (-25% vs. -35%).⁹⁰ If AMH levels are very low, leaving the endometrioma in situ and opting for IVF is sometimes a viable option.⁹¹ Alternatively, Vaduva et al. reported that aspiration followed by sclerotherapy has no effect on AMH levels.⁹² However, no fertility outcomes or the likelihood of (endometrioma) recurrence was reported following partial cystectomy or sclerotherapy.

A previous study, featuring women with minimal or mild endometriosis, reported a significant increase in the cumulative probability of pregnancy, 20 weeks post-laparoscopy, between surgical laparoscopy (31%) and diagnostic laparoscopy (18%).^93,94

Likewise, a more recent study of 174 women, with moderate to severe endometriosis, also revealed improved fertility outcomes post-surgery, with 55% of women conceiving naturally and another 23% following IVF.⁹⁵ Experts suggest this improvement in fertility depends on whether or not endometriosis is still active at the time of surgery.⁹⁶

However, surgery of moderate to severe endometriosis carries a higher risk of complications especially among comorbid women (i.e. adenomyosis).^97,98 Nonetheless, complications do not appear to affect pregnancy or live birth rates, and time to pregnancy.^99,100

Overall, 30-70% of women become pregnant naturally within 12-18 months post-surgery. Research suggests this natural fertility window post-surgery varies according to the severity of endometriosis and tubal quality.^101,102,103

However postoperatively women with a pre-surgery EFI score ≥ 5 were also found more likely to have a spontaneous pregnancy, rather than assisted (ART) conception, over a 36-month period. On the other hand, women with a pre-surgery EFI score ≤ 4 showed a significantly higher cumulative pregnancy rate via ART.¹⁰⁴ This suggests that women with EFI ≥ 4 (and time on their side) may be better off trying to conceive naturally post-surgery for 12-24 months, while women with EFI ≤ 3 should seek ART shortly after surgery.¹⁰⁵

However hormone therapy is not normally prescribed to women trying to conceive. Nevertheless, Deng et al. reported that dydrogesterone (synthetic progesterone) can be a viable option if taken in the second half of the menstrual cycle to simultaneously manage endometriosis, boost progesterone levels, correct luteal phase defects, and support ongoing pregnancy.¹⁰⁶

Researchers also believe that dopamine agonists (bromocriptine, cabergoline, quinagolide) could have a potential role in the treatment of endometriosis and infertility sometime in the near future.¹⁰⁷ Dopamine agonists significantly regulate the Serpin-1 gene, responsible for the availability of plasminogen activator inhibitor 1 (PAI-1), which enhances fibrinolysis (enzymatic breakdown of fibrin) and regression of lesions.¹⁰⁸ This research explains the results of a previous clinical trial involving Pentoxifylline, a routine drug that acts as a PAI-1 inhibitor. Creus et al. reported women with mild and moderate endometriosis had significantly higher cumulative pregnancy rates after surgery with Pentoxifylline treatment compared to placebo during a 6 month preliminary trial.¹⁰⁹

Assisted Reproductive Technologies

Couples with compromised tubal function, male factor subfertility, or post-surgery infertility may be advised to utilise assisted reproductive technologies.

This involves ‘in vivo’ conception with superovulation and intrauterine insemination (SO/IUI), or ‘in vitro’ conception commonly known as in-vitro fertilization (IVF).

Superovulation and Intrauterine Insemination

ESHRE guidelines recommend women with minimal or mild endometriosis try to conceive using SO/IUI with controlled ovarian stimulation first.⁸¹ This improves ovulation and reduces the impact of endometriosis on sperm motility and potential fecundability.⁵⁶

One of the first randomised controlled trials showed that SO/IUI increased the live birth rate to 11% per cycle, from a live birth rate of only 2% in the no treatment group.¹¹⁰ A later study also reported that if SO/IUI is started within 7 months of laparoscopic surgery (treating minimal or mild endometriosis), the clinical pregnancy rate per cycle is almost doubled (minimal = 21%, mild = 18.9%).¹¹¹ This study and others suggest laparoscopic surgery of endometriosis restores the clinical pregnancy rate to the same level as women with unexplained infertility undergoing SO/IUI.¹¹²

To date the choice of induction agent (clomiphene citrate, letrozole, human menopausal gonadotropins) shows no clear advantage or disadvantage on final outcomes, needing much larger RCT studies to answer this question.¹¹³

In-Vitro Fertilisation

In-Vitro Fertilisation (IVF) is the most effective treatment for patients with infertility due to endometriosis. IVF helps identify oocyte or sperm defects and bypasses the fallopian tubes which is helpful for women with moderate to severe endometriosis and or damaged pelvic anatomy (e.g. hydrosalpinx).^114,115 Nevertheless, women diagnosed with comorbidities (e.g. adenomyosis, Hashimoto thyroiditis) require tailored treatment plans to maximise IVF success rates.^116,117,20

Despite some evidence that endometriosis (or vitamin D deficiency¹¹⁸) affects embryo quality, IVF PGT studies, comparing women with and without endometriosis, reported no difference in the mean euploid blastocyst rate, live birth rate, gestational or neonatal outcomes.¹¹⁹ Non-PGT studies did show a small decrease in the median number of retrieved oocytes (8 vs 10) for women with endometriosis aged ≤35, however embryo grades, fertilisation rates, clinical pregnancy and ongoing pregnancy rates were all similar.¹²⁰

In a similar but much larger retrospective study, oocyte morphology was shown to be no different for women with endometriosis using the Average Oocyte Quality Index (AOQI) and metaphase II oocyte morphological scoring system (MOMS). However cumulative implantation rates (0.23 vs. 0.34) and clinical pregnancy rates (36% vs. 58%) was significantly lower.¹²¹ This difference in outcomes further supports the claim by most experts that women with endometriosis have impaired endometrial receptivity (i.e. progesterone resistance).

In fact, women with endometriosis need almost 4 times the normal levels of mid-luteal phase progesterone, as women without endometriosis, to significantly improve IVF treatment outcomes.¹²²

Interestingly, women with stage III-IV endometriosis and basal serum testosterone levels below 0.305 ng/mL experience lower clinical pregnancy and live birth rates in their first IVF/ICSI cycle, even though miscarriage or preterm birth rates were similar.¹²³
_{Source: Huang L, et al. (2021)}

DHEA supplementation is reported to be beneficial in such cases however no high-quality endometriosis only studies have been conducted to date.¹²⁴

Surgical treatment of endometriosis following recurrent implantation failures significantly improves cumulative live birth rates by 15–25% and decreases time to live birth by as much as 9 months, compared to women who elect to continue IVF and not undergo surgery.¹²⁵

In women with an endometrioma or adenomyosis, the use of GnRH agonists for 3 to 6 months prior to fertility treatment (IVF / ICSI) significantly increases the odds of clinical pregnancy by (4x) fourfold. However, such a delay in fertility treatment needs to be considered carefully alongside the woman’s age to optimise treatment success.¹²⁶

Even though surgical treatment of endometriomas (ovarian cystectomy) prior to IVF/ICSI treatment may not significantly increase pregnancy rates,^127,128 surgery is still recommended whenever endometriosis type pain exists or access to ovaries for egg collection is compromised.

For women with endometriosis related pain, new Progestin-primed ovarian stimulation (PPOS) protocols, using Dienogest or Dydrogesterone, allows for the simultaneous treatment of endometriosis and infertility, during the stimulation phase of treatment.¹²⁹ Although the authors did note that a future randomized control trial is required to confirm the more effective progestin of the two.

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