The standard treatments for endometriosis are a bit of a problem for women trying to conceive as there isn’t an ideal diagnosis or treatment option. Laparoscopy is the “Gold Standard” and only definitive diagnosis option, and surgical removal of superficial endometriosis and endometriomas is usually performed by laparoscopy at the time of diagnosis. However, it usually takes years to get the diagnosis, and the procedure is expensive and not universally available
The degree of endometriosis has a significant impact on fertility, and when there is no treatment: i
- About 50% of women with mild endometriosis conceive
- About 25% of women with moderate endometriosis can conceive
- Only a few of the women with severe forms of the disease can conceive
The standard treatment options for endometriosis are:
- Surgery
- Contraceptives
- GnRH agonists and antagonists
- Progestogens
- Aromatase inhibitors
- Painkiller medications (nonsteroidal anti-inflammatories or opioids)
A combination of surgery and postoperative hormonal treatment is the usual choice. However, hormone treatments have significant issues for women trying to conceive.
Surgery
Surgery is the preferred treatment option, but there’s debate over its use, especially for endometriomas of the ovary. Ovarian endometriosis is the type of endometriosis most commonly encountered, and as it’s either on or in the ovary, it can directly affect fertility.
In general, the recommendation is the complete removal of endometriomas while preserving the healthy tissue surrounding them. However, this can be challenging when the lesions are within the ovaries, and recommendations vary with endometrioma size.
Large endometriomas cause more physical damage by compressing follicles, hampering blood supply and creating fibrosis. Endometrioma size makes a significant difference to a range of outcomes in IVF/ICSI cycles, and when they’re over 3cm, fertility clinics experience: ii
- Fewer eggs retrieved
- Higher cancellation rates
- Lower implantation rates
- Lower pregnancy rates
These factors have led to different recommendations before IVF/ICSI cycles (or attempting to get pregnant naturally), depending on endometrioma size, and the current suggestion is:
- Have surgery to remove endometriomas over 3cm
- Postpone surgery when the endometrioma is less than 3cm
| Potential advantages of surgery | Potential disadvantages of surgery |
|---|---|
|
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Surgery is unavoidable in many circumstances, but the loss of ovarian tissue is often unavoidable when an endometrioma is removed, which inevitably hastens egg loss. Ovarian reserve is a more significant issue for some women than others, and a personalised approach is needed in all cases.
The recurrence of endometriosis following surgery is a significant issue as surgery does not remove the factors that cause the disease. There’s a wide range of estimates for recurrence depending on diagnosis methods, and somewhere between 20 – 44% after five years is a reasonable guess. iii
How surgery affects pregnancy
- 47% of “infertile” women with moderate or severe (Stage III or IV) endometriosis are likely to fall pregnant naturally within three years of the surgery iv
- 33% of “infertile” women with moderate endometriosis who don’t have any treatment are likely to fall pregnant naturally in those three years
- 0% of “infertile” women with severe endometriosis who don’t have any treatment are likely to fall pregnant naturally in those three years
Contraceptives
There are two options, both of which prevent pregnancy, so they’re not suitable for anyone trying to conceive. They work by preventing the release of Gonadotropin-releasing hormone (GnRH) from the hypothalamus, which would trigger the start of a new cycle and menstrual bleeding. However, treatment with the oral contraceptive pill is ineffective in 1/3rd of cases due to progesterone resistance. v
- Combination contraceptives contain synthetic estrogen and progesterone, the sex hormones from the ovaries that determine how the endometrium in the womb grows, becomes spongy and then sheds. By preventing this cycle of events, the hormones reduce the growth of endometriosis lesions.
- Progestin-only contraceptives only contain synthetic progesterone, a heating hormone that counter-balances estrogen to suppress endometriosis lesion growth. However, they also thicken cervical mucus, increase the risks of ovarian cysts, liver and heart problems, and some cancers, and reduce bone density.
| Oral contraceptive pill | Potential side effects |
|---|---|
Combination contraceptives
Progestin-only contraceptives
|
|
Progestogen drugs
Progestogens (or “gestogens”) are synthetic steroids that mimic progesterone, and in this scenario, they’re used to reduce the estrogens that promote endometriosis. However, treatment with progestogens is ineffective in 1/3rd of cases due to progesterone resistance. vi
| Progesterone derivatives | Potential side effects |
|---|---|
Nortestosterone derivatives
|
These drugs (gestagens) also affect a variety of metabolic processes:
|
Combining buserelin (a GnRH agonist) and dienogest (a gestagen) after surgery for endometriosis-related infertility has shown promising clinical outcomes and fewer side effects than a GnRH agonist alone. The combination of buserelin and dienogest was highly effective in reducing the endometriosis symptoms; pelvic pains, period pain, pain on urinating and bleeding, plus pregnancy rates and outcomes were also measured: vii
| Buserelin alone | Buserelin + dienogest | |
|---|---|---|
| Pregnancy rates | 54.7% | 53.3% |
| Adverse effects | 92% | 16% |
| Undeveloped pregnancies | 17.3% | 9.3% |
| Live birth rate | 82.7% | 90.7% |
Gonadotropin-releasing hormone agonists (GnRH agonist)
GnRH agonists may improve the ability of those who are infertile to get pregnant, and they are usually prescribed following surgery to remove lesions.
| GnRH analogues | Potential side effects |
|---|---|
|
|
Aromatase inhibitors
Aromatase inhibitors (AI) prevent the action of the enzyme “aromatase”, which transforms testosterone into estradiol (E2). Endometriosis lesions have high levels of aromatase, but it’s absent in the endometrium of the uterus. viii Testosterone inhibits the growth of endometriosis, while estradiol promotes it.
AIs have been used for years to treat estrogen-sensitive cancers, and research has shown it’s effective in managing the symptoms of endometriosis when combined with gestagens, contraceptives or GnRH agonists. ix
However, despite several studies into AI use to improve fertility following surgery for endometriosis, there isn’t sufficient evidence of any significant improvement in live birth rates. x-xi
| Aromatase inhibitors | Potential side effects |
|---|---|
|
|
Painkillers
Nonsteroidal anti-inflammatories (NSAIDs) are the first-line option, and if these don’t work, mild opioids may be prescribed, but gastric ulcers and addiction are significant factors in their use.
| Nonsteroidal anti-inflammatory drugs (NSAID) | Potential side effects |
|---|---|
|
|
| Opioids | Potential side effects |
|---|---|
|
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i Olive DL, Stohs GF, Metzger DA, Franklin RR. Expectant management and hydrotubations in the treatment of endometriosis-associated infertility. Fertil Steril. 1985;44:35–41.
ii Nadeem Faiyaz Zuberi and Rehana Rehman, “Subfertility; Recent Advances for Management and Prevention” Book. Elsevier. 2020. https://doi.org/10.1016/C2019-0-02584-8
iii Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15:441–61. doi: 10.1093/humupd/dmp007.
iv Vercellini P, Fedele L, Aimi G, De Giorgi O, Consonni D, Crosignani PG. Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classification system. Hum Reprod. 2006;21:2679–85
v Donnez, J.; Dolmans, M.-M. Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review. J. Clin. Med. 2021, 10, 1085. https://doi.org/10.3390/jcm10051085
vi Donnez, J.; Dolmans, M.-M. Endometriosis and Medical Therapy: From Progestogens to Progesterone Resistance to GnRH Antagonists: A Review. J. Clin. Med. 2021, 10, 1085. https://doi.org/10.3390/jcm10051085
vii Artymuk N.V., Danilova L.N., Tachkova O.A. Possibilities of a combined approach to treating endometriosis-associated infertility, Obstetrics and Gynegology 2019, 10
viii Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98:511–519.
ix Nawathe A, Patwardhan S, Yates D, et al. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG. 2008;115:818–822.
x Słopień R, Męczekalski B. Aromatase inhibitors in the treatment of endometriosis. Prz Menopauzalny. 2016;15(1):43-47. doi:10.5114/pm.2016.58773
xi Abu Hashim H. Aromatase Inhibitors for Endometriosis-Associated Infertility; Do We Have Sufficient Evidence?. Int J Fertil Steril. 2016;10(3):270-277. doi:10.22074/ijfs.2016.5040
