Evidence - Diagnostic laparoscopy endometriosis treatment

Endometriosis is a chronic, benign, and estrogen-dependent condition where endometrial glandular tissue and stroma grow outside the uterine cavity. These ectopic endometriosis lesions are most commonly found in the pelvic area but can also affect other body regions such as the intestines, diaphragm, or pleural cavity.

Although endometriosis is a non-malignant condition, the displaced tissue can trigger an inflammatory response, leading to severe pain, adhesions, and infertility. The most common symptoms are dysmenorrhea (painful menstruation), dyspareunia (pain during intercourse), chronic pelvic pain, and fertility issues. The severity of symptoms varies greatly—while some affected individuals have few symptoms, the condition can lead to significant impairments in quality of life for others.

Endometriosis affects women in all hormonal life stages, including premenarchal, reproductive, and postmenopausal periods. As it is hormone-dependent, the condition may remain inactive during pregnancy or under hormonal therapies but can flare up again after discontinuing therapy.

The exact cause of endometriosis is not yet fully understood, but hormonal, immunological, and genetic factors play a role. Despite its high prevalence, diagnosis is often delayed because the symptoms are nonspecific and not always directly associated with the condition.

Locations of endometriosis in decreasing frequency

1. Pelvic peritoneum – most common location, affects the peritoneum of the pelvis.
2. Ovaries (endometriomas / chocolate cysts) – often associated with adhesions.
3. Uterosacral ligaments (pelvic ligaments) – deep infiltrating endometriosis often occurs here.
4. Rectovaginal septum / posterior vaginal fornix – can lead to pain during intercourse (dyspareunia) and bowel movements (dyschezia).
5. Rectosigmoid (bowel endometriosis) – commonly affected in deep infiltrating endometriosis.
6. Bladder and ureters (ureteral endometriosis) – can lead to urinary obstruction and kidney damage.
7. Uterus (adenomyosis) – endometriosis within the uterine wall, causes heavy bleeding.
8. Fallopian tubes (tubal endometriosis) – can lead to tubal occlusions and infertility.
9. Diaphragm (diaphragmatic endometriosis) – rare, but can lead to cyclic shoulder pain.
10. Extragenital endometriosis (e.g., appendix, navel, skin scars, thorax, lung, brain) – very rare, but possible.

Reference:

1. Ulrich U, Buchweitz O, Greb R et al (2014) German and Austrian Societies for Obstetrics and Gynecology. National German Guideline (S2k): Guideline for the Diagnosis and Treatment of Endometriosis: Long Version – AWMF Registry No. 015–045. Geburtshilfe Frauenheilk 74:1104–1118

The basic principle of hormonal treatment is to suppress estrogen production to prevent the growth of ectopic endometrium.

First-line Therapy

Progestins, e.g., Dienogest

• Inhibit the growth of endometriosis lesions through decidualization and atrophy.
• Long-term pain reduction with continuous intake.
• Fewer side effects than other hormonal preparations.
• Examples: Dienogest, Norethisterone acetate, Medroxyprogesterone acetate.

Second-line Therapy

Combined Oral Contraceptives

• Reduction of dysmenorrhea and chronic pelvic pain.
• Most effective with continuous intake (long cycle) without pill break.
• Off-label use, but clinical evidence of effectiveness is available.

GnRH Analogues (with Add-Back Therapy)

• Block estrogen production at the pituitary level.
• Significant pain reduction and inhibition of endometriosis.
• High rate of side effects (hot flashes, osteoporosis, loss of libido).
• Use is usually limited to 3–6 months, longer use only with add-back therapy to avoid estrogen deficiency symptoms.

GnRH Antagonists (Elagolix, Relugolix Combination Therapy)

• Relugolix is approved in Germany in combination with Estradiol and Norethisterone acetate (Ryeqo®).
• Elagolix was approved in the USA in 2018 but is not primarily recommended in Europe.
• Directly effective, no initial hormone fluctuations compared to GnRH analogues.
• Less pronounced side effects than GnRH analogues due to accompanying add-back therapy.
• Reduction of dysmenorrhea and chronic pelvic pain confirmed in clinical studies.

Intrauterine Devices (IUD) with Levonorgestrel

• Direct effect on the endometrium through local hormone release.
• Especially suitable for long-term therapy in adenomyosis.

Aromatase Inhibitors

• Inhibit local estrogen production in endometriosis tissue.
• Due to strong side effects (osteoporosis, muscle pain), only recommended in studies for therapy-resistant endometriosis.

Reference:

1. Nagandla K, Idris N, Nalliah S, Sreeramareddy CT, George SRK, Kanagasabai S. Hormonal treatment for uterine adenomyosis. Cochrane Database of Systematic Reviews 2014, DOI: 10.1002/14651858.CD011372
2. Ferrero S, Barra F, Leone Roberti Maggiore U. Current and Emerging Therapeutics for the Management of Endometriosis. Drugs 2018, DOI: 10.1007/s40265-018-0928-0: 1‐18
3. Takaesu Y, Nishi H, Kojima J, Sasaki T, Nagamitsu Y, Kato R, Isaka K. Dienogest compared with gonadotropin-releasing hormone agonist after conservative surgery for endometriosis. The journal of obstetrics and gynaecology research 2016; 42: 1152-1158
4. Strowitzki T, Faustmann T, Gerlinger C, Schumacher U, Ahlers C, Seitz C. Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program. Int J Womens Health 2015; 7: 393-401
5. Lee KH, Jung YW, Song SY, Kang BH, Yang JB, Ko YB, Lee M, Han HY, Yoo HJ. Comparison of the efficacy of diegnogest and levonorgestrel-releasing intrauterine system after laparoscopic surgery for endometriosis. Journal of obstetrics and gynaecology research 2018, DOI: 10.1111/jog.13703
6. Brown J, Farquhar C. Endometriosis: an overview of Cochrane Reviews. The Cochrane database of systematic reviews 2014, DOI: 10.1002/14651858.CD009590.pub2: Cd009590
7. Houda MR, Grant NH. Gonadotrophin antagonists for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2014, DOI: 10.1002/14651858.CD011446
8. Wu D, Hu M, Hong L, Hong S, Ding W, Min J, Fang G, Guo W. Clinical efficacy of add-back therapy in treatment of endometriosis: a meta-analysis. Archives of gynecology and obstetrics 2014; 290: 513-523
9. Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, Diamond MP, Surrey E, Johnson NP, Watts NB, et al. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. New England journal of medicine 2017; 377: 28‐40
10. Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2) Giudice, Linda C et al. The Lancet, Volume 399, Issue 10343, 2267 - 2279
11. Harada T, Osuga Y, Suzuki Y, Fujisawa M, Fukui M, Kitawaki J. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study. Fertil Steril. 2022 Mar;117(3):583-592. doi: 10.1016/j.fertnstert.2021.11.013. Epub 2021 Dec 8. PMID: 34895700.
12. Harada T, Osuga Y, Suzuki Y, Fujisawa M, Fukui M, Kitawaki J. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study. Fertil Steril. 2022 Mar;117(3):583-592. doi: 10.1016/j.fertnstert.2021.11.013. Epub 2021 Dec 8. PMID: 34895700.