Main article: Endometriosis Overview

Updated: 16-August-2024

Treatment of Endometriosis

A cure for endometriosis is yet to be found however several treatment options, both conventional and natural, are available to relieve the symptoms and improving quality of life.

Conventional Treatment of Endometriosis

Conventional treatment options for women with endometriosis include:

• Medication
• Surgery

Of these 2 options, medication is always the first preference. However in cases where medication has failed, the doctor will recommend surgery.

Medication

Medication options for endometriosis include:

• Analgesics
• Hormonal
• Other medication (off label)

For some women, these medications can manage endometriosis related symptoms well enough that surgery is not necessary.¹

Analgesics

Analgesics (painkillers) such as paracetamol, ibuprofen and naproxen are sometimes recommended to women with endometriosis and minimal symptoms.

Ibuprofen and naproxen are both non-steroidal anti-inflammatory drugs (NSAIDs). However, naproxen offers a longer duration of pain relief compared to ibuprofen. Hence, naproxen is sometimes recommended to women with endometriosis who experience dysmenorrhea (period pain).² In 1985, Kauppila and Rönnberg reported that naproxen treatment provided complete or significant pain relief in approximately 80% of women with endometriosis.³ However, 20% of women are resistant to NSAIDs meaning some women will need to consider other management options.⁴ Nevertheless, women who do respond to NSAIDs report more effective control of symptoms (and reduction in lesion size) when combined with hormone therapy (Dydrogesterone).⁵ This is because NSAIDs do not cause endometriosis lesions to regress like some hormone treatments do. NSAIDs are also not without side effects, which can vary from mild (fatigue, dizziness) to serious (renal or heart failure).^6,7

Ongoing research suggests oxytocin receptor inhibitors may also be a viable option sometime in the future. Elevated oxytocin levels correlate positively with endometriosis associated pain.⁸ While animal studies report that oxytocin receptor inhibitors cause regression or complete resorption of endometroid lesions.⁹ Nevertheless, human trials are still needed to confirm these results and potential side effects.

Hormonal

Hormonal medications and contraceptives are utilised to inhibit ovulation, reduce hormone levels, and blood flow in the uterus which helps to decrease chronic pain levels in women with endometriosis.

This includes:

• Combined oral contraceptive pill
• Propgestin-only pill or intrauterine device
• Gonadotrophin-releasing hormone analogues

The Combined Oral Contraceptive Pill (COCP) containing both estrogen and progesterone derivatives is the most effective birth control pill for endometriosis.^10,11 This is because of evidence which suggests the addition of ethinyl estradiol (derivative of estradiol) to progestin only pills (such as desogestrel) increases the death of endometriosis cells.^12,13 A previous laboratory study reported this effect was dependent on endometriosis cells that expressed estrogen receptor alpha (which activated progesterone receptor B).¹⁴

Recent studies suggest the fourth-generation progestin named dienogest is highly effective at stopping the progress of endometriosis, inflammation and pain on its own,¹⁵ and may be somewhat better when combined with an estrogen derivative (i.e. estradiol valerate and ethinyl estradiol). Of these 2 potential combinations there is some evidence to suggest dienogest and ethinyl estradiol combined lowers estrogen levels significantly more than dienogest/estradiol valerate.^16,17 This is important to consider since endometriosis is an estrogen-dependent disease.

However this recommendation does not apply to women diagnosed with only ovarian endometriosis due to a different biology.^18,19 In these women, several studies report the best contraceptive pill is a progestogen-only pill (POP) such as dienogest.^20,21 Even though endometriomas do not grow during dienogest treatment, significant regression is uncommon and surgery may be required eventually.²² Post-surgery, a high rate of cystitis (bladder inflammation) has been observed with dienogest treatment.²³ Instead, experts recommend an intrauterine device (IUD) such as LNG-IUS after surgery because of its location, the set and forget nature of an IUD, and similar efficacy but less side effects long term.^24,25

Other potential side effects of the oral contraceptive pill includes venous or arterial thrombosis (up to 11 cases per 10,000 women a year) and decreased bone mineral density depending on the formulation.^26,27,28 Dienogest is also reported to significantly worsen the mood in some women leading to discontinuation.²⁹

Some women also gain weight when taking contraceptives due to its suppressive effect on testosterone.^30,31 A daily dose of DHEA helps maintain normal testosterone levels and regulate visceral fat.³²

However, in cases of severe pain or contraindications, gonadotrophin-releasing hormone (GnRH) analogues (i.e. agonists or antagonists) may be recommended to quickly induce a hypoestrogenic state in women with endometriosis. GnRH agonists (goserelin, leuprolide, nafarelin, buserelin, triptorelin) have been around for 30 years with well known side effects. This includes amenorrhea, vasomotor symptoms, sleep disturbance, urogenital atrophy, and accelerated bone loss. Consequently, the addition of add-back therapy (low-dose COCs, estrogen or progestins alone, bisphosphonates, tibolone or raloxifene) is standard practice when prescribing GnRH agonists. Experts report this can be a viable solution for up to 10 years.^33,34

On the other hand, GnRH antagonists (elagolix, relugolix, linzagolix) for endometriosis is a relatively new treatment option. The main advantages of GnRH antagonists is that it can be taken orally, has a very rapid effect, and is unlikely to cause severe hypoestrogenism. However, researchers have reported side effects, such as hot flashes, decrease in bone mineral density, increase in serum lipid levels (elagolix), and headaches or colds (relugolix).^35,36,37 For this reason, add-back therapy is also recommended with GnRH antagonists. Although preliminary studies are promising, researchers caution that larger studies are need to evaluate the efficacy and safety of GnRH antagonists compared to existing combined oral contraceptives and progestins.

Other medication

Depending on your individual circumstances the doctor may also recommend other medication commonly used to treat hyperprolactinemia or diabetes.

Women with endometriosis and elevated prolactin levels may benefit from dopamine agonists (bromocriptine, cabergoline, quinagolide).³⁸ In 2011, Gómez et al. reported that quinagolide treatment significantly reduced the size of lesions in women with endometriosis and hyperprolactinemia causing 1 in 3 to vanish completely by follow-up laparoscopy. Laboratory studies reveal dopamine agonists target angiogenesis, blocking proliferation and reducing lesion size, most notably by impairing VEGF (vascular endothelial growth factor).³⁹ A larger trial in women with deep infiltrating endometriosis, adenomyosis and or endometrioma also reported significant regression of lesions with quinagolide administered via a vaginal ring.⁴⁰ However, pending comparative studies, one study suggests a combination of dopamine and hormone therapy may be more effective.⁴¹

Similalrly, women with endometriosis and elevated glucose levels may benefit from taking metformin (Glucophage, Fortamet). Researchers reported that women with endometriosis experienced a noticeable decrease in their symptoms (dysmenorrhea, pelvic pain and dyspareunia) and inflammation during treatment with metformin.⁴² This finding is supported by several animal and laboratory studies which show metformin suppresses endometriosis growth and restores associated pathways.^43,44,45,46

Surgery

In many cases, surgery is eventually recommended to minimise endometriosis-related pain in patients.

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 obvious difference between excision vs. ablation is removed tissue can undergo histological examination (to confirm endometriosis). Excision is also more effective for deep infiltrating lesions, particularly when combined with near-infrared (NIR) fluorescence technology, to identify the border between lesions and healthy tissue, and to find hidden lesions.^47,48 Which probably explains why studies show that excision generally improves endometriosis-related pain significantly more than ablation.⁴⁹ However excision, specifically of endometriomas, may not be suitable for everyone depending on ovarian reserve and future family plans.⁵⁰ Instead the doctor will recommend conservative treatments such as aspiration followed by sclerotherapy or partial cystectomy, even though the likelihood of recurrence is higher.^51,52,53

The doctor will also advise that any surgery carries the risk of complications. This is especially true in cases of moderate to severe endometriosis and comorbidities such as adenomyosis.^54,55 Some women may also experience voiding dysfunction for up to 2 months after surgery.^56,57 However, studies show that nerve-sparing surgery eliminates this risk almost entirely, excluding of course women requiring bowel or urethral resection.^58,59 In these cases, sacral nerve stimulation may be a viable treatment option.⁶⁰

Long term, a follow-up study of 84,885 women who underwent surgery for endometriosis, reported that approximately 1 in 4 women who undergo minor endometriosis surgery, and 1 in 5 who undergo major conservative surgery with ovarian preservation, will require further endometriosis surgery in the following 10 years.⁶¹ For this reason, doctors strongly recommend hormone therapy after surgery to slow down the recurrence of endometriosis.

Complementary Treatment of Endometriosis

Complementary (natural) treatment options for women with endometriosis include:

• Anti-inflammatory diet
• Vitamin D
• Vitamin C and E
• N-acetyl cysteine
• Garlic
• Ellagic acid
• Alpha-lipoic acid

Anti-inflammatory diet

Studies suggest a link between the severity of endometriosis and inflammatory foods or diets.^62,63 Consequently, researchers believe the anti-inflammatory diet, according to the Dietary Inflammatory Index, may be beneficial for some women with endometriosis.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. Subsequent experiments showed that mice which consume n-butyrate had significantly fewer and smaller lesions than control mice.⁶⁵

More recently, the same researchers also identified 5 metabolites that are significantly higher in feces of mice with endometriosis. In vitro and in vivo analysis revealed that quinic acid significantly supports endometriotic lesion growth (more than the other 4 metabolites) but not the establishment of lesions.⁶⁶ Human studies are next on the list to confirm these findings.

Vitamin D

Vitamin D or Calcitriol, (the hormonally active form of vitamin D with progesterone-like activity), has anti-proliferative and anti-inflammatory effects.^67,68

Observational studies suggest a link between vitamin D and endometriosis exist.^69,70 In the laboratory, Miyashita et al. demonstrated that vitamin D significantly modulates inflammation and proliferation of endometriotic cells.⁷¹

In human studies, Yarmolinskaya et al. reported that endometrial vitamin D receptor (VDR) expression is significantly higher in women with endometriosis and does not increase as expected during the luteal phase. Interestingly, hormone therapy decreases VDR expression in endometriosis tissue which causes a non-significant increase in serum vitamin D levels.⁷² This would explain why some observational studies fail to report a clear link between vitamin D serum levels and endometriosis.^73,74 Nevertheless, hormone therapy plus vitamin D supplementation eliminated endometriosis-related pain more so than either treatment alone.⁷⁵ This is most likely helpful for women with vitamin D insufficiency (20-30 ng/mL) or deficiency (<20 ng/mL) however more studies are needed to understand the relationship between vitamin D and endometriosis.

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 endometriosis-related symptoms (dysmenorrhea, dyspareunia and chronic pelvic pain) after just 8 weeks.⁷⁶

This reaffirms an earlier study which also reported a significant improvement in endometriosis-related symptoms after vitamin C and E supplementation.⁷⁷ Preliminary studies in the laboratory show vitamin C significantly suppresses implantation of endometriosis lesions and even causes regression.^78,79

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.⁸⁰ A second 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 NAC treatment.⁸¹

Researchers believe this effect is due to NAC ability to inhibit ferroptosis, and VEGFA and IL8 secretion, caused by iron overload in endometriotic cysts.⁸² Nevertheless, no comparative studies exist to recommend NAC over current hormone based treatment options.

Garlic

Garlic, one of nature’s superfoods, has antiproliferative, anti-inflammatory, antiangiogenic, and antioxidant effects.⁸³

In the only human study to date, 1100μg of allicin (garlic extract) daily for 3 months significantly decreased the severity of endometriosis-related pain (pelvic pain, back pain, dysmenorrhea, dyspareunia). ⁸⁴

This result is consistent with a prior laboratory study that reported aged garlic extract as a possible treatment for endometriosis.⁸⁵ This could be a result of S-allyl cysteine (SAC) and N-acetyl cysteine (NAC) which is found in garlic extract and shown to have anti-proliferative effects on endometriosis.⁸⁶

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 controlled mice study, urolithin A completely prevented the development of endometriosis like lesions while urolithin B significantly decreased implant volume, after surgically induced endometriosis.⁸⁷

Although, 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 (e.g. pomegranate juice) after 24 hours.⁸⁸

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

Alpha-lipoic acid

Alpha-lipoic Acid (ALA) is a natural compound with broad antioxidant and anti-inflammatory effects that is mostly obtained through a balanced diet.⁸⁹

In a laboratory study, alpha-lipoic acid (ALA) significantly reduced expression of estrogen receptor-β and inflammasome NALP-3 in cultured endometriosis cells causing a decrease in inflammation (IL-1β, IL-18).⁹⁰ Cellular adhesion and migration was also inhibited with significantly reduced levels of ICAM-1, MMP-2 and MMP-9 suggesting ALA may potentially be able to block the progression of endometriosis, in future human trials.

References

1. Vannuccini S, et al. (2021). Hormonal treatments for endometriosis: The endocrine background. https://link.springer.com/article/10.1007/s11154-021-09666-w ↩︎
2. Brown J, et al. (2017). Nonsteroidal anti‐inflammatory drugs for pain in women with endometriosis. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004753.pub4/full ↩︎
3. Kauppila A and Rönnberg L, et al. (1985). Naproxen sodium in dysmenorrhea secondary to endometriosis. https://pubmed.ncbi.nlm.nih.gov/3883265/ ↩︎
4. Oladosu F A, et al. (2017). NSAID resistance in dysmenorrhea: epidemiology, causes, and treatment. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839921/ ↩︎
5. Xue H L, et al. (2023). A comparative study between Dydrogesterone alone and combined with Non-Steroidal Anti-Inflammatory Drugs in the treatment of Mild Endometriosis. https://www.pjms.org.pk/index.php/pjms/article/view/7138 ↩︎
6. Kleinknecht D, (1995). Interstitial nephritis, the nephrotic syndrome, and chronic renal failure secondary to nonsteroidal anti-inflammatory drugs. https://pubmed.ncbi.nlm.nih.gov/7631049/ ↩︎
7. Arfè A, et al. (2016). Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. https://www.bmj.com/content/354/bmj.i4857.long ↩︎
8. Yarmolinskaya M, et al. (2020). The potentialities of oxytocin receptor inhibitors for endometriosis therapy. https://www.tandfonline.com/doi/full/10.1080/09513590.2020.1816722 ↩︎
9. Simsek Y, et al. (2012). Therapeutic efficiency of Atosiban, an oxytocin receptor blocking agent in the treatment of experimental endometriosis. https://link.springer.com/article/10.1007/s00404-012-2390-7 ↩︎
10. Troia L and Luisi S, et al. (2022). Estro-Progestins and Pain Relief in Endometriosis. https://www.mdpi.com/2673-396X/3/2/28 ↩︎
11. Reis F, et al. (2020). Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure. https://academic.oup.com/humupd/article/26/4/565/5837503 ↩︎
12. Sophonsritsuk A, et al. (2021). Effects of Ethinyl Estradiol in Combined Oral Contraceptives on Cell Proliferation and Apoptosis in Ectopic Endometrial Tissue: A Randomized Controlled Study. https://doi.org/10.18502/jfrh.v15i1.6077 ↩︎
13. Waiyaput W, et al. (2021). Effect of combined contraceptive pill on immune cell of ovarian endometriotic tissue. https://ovarianresearch.biomedcentral.com/articles/10.1186/s13048-021-00819-8 ↩︎
14. Bono Y, et al. (2014). Concurrent estrogen action was essential for maximal progestin effect in oral contraceptives. https://www.fertstert.org/article/S0015-0282(14)00143-5/fulltext ↩︎
15. Ajdary M, et al. (2024). NLRP3 concentration, oxidants, and antioxidants in plasma of endometriosis patients undergoing treatment with dienogest. https://www.sciencedirect.com/science/article/pii/S2468784724000230 ↩︎
16. Endrikat J, et al. (2012). Pituitary, ovarian and additional contraceptive effects of an estradiol-based combined oral contraceptive: results of a randomized, open-label study. https://www.contraceptionjournal.org/article/S0010-7824(12)00674-9/abstract ↩︎
17. Vandever M A, et al. (2008). Evaluation of pituitary-ovarian axis suppression with three oral contraceptive regimens. https://www.contraceptionjournal.org/article/S0010-7824(07)00502-1/abstract ↩︎
18. Kalkan U, et al. (2022). T-Cadherin, E-Cadherin, PR-A, and ER-α Levels in Deep Infiltrating Endometriosis. https://pubmed.ncbi.nlm.nih.gov/35149616/ ↩︎
19. Biyik I, et al. (2021). The deep infiltrating endometriosis tissue has lower T-cadherin, E-cadherin, progesterone receptor and oestrogen receptor than endometrioma tissue. https://www.sciencedirect.com/science/article/pii/S102845592100257 ↩︎
20. Angioni S, et al. (2019). Is dienogest the best medical treatment for ovarian endometriomas? Results of a multicentric case control study. https://www.tandfonline.com/doi/full/10.1080/09513590.2019.1640674 ↩︎
21. Wattanayingcharoenchai R, et al. (2021). Postoperative hormonal treatment for prevention of endometrioma recurrence after ovarian cystectomy: a systematic review and network meta-analysis. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.16366 ↩︎
22. Malik R and Mann M K, (2021). Role of Dienogest in Endometriosis in Young Women. https://link.springer.com/article/10.1007/s13224-021-01483-0 ↩︎
23. Krakhotkin D V, et al. (2022). The dienogest-related cystitis in women with endometriosis: a prospective, controlled, comparative study. https://www.tandfonline.com/doi/pdf/10.1080/01443615.2022.2081492 ↩︎
24. Kim H, et al. (2022). Long-term efficacy and safety of levonorgestrel-releasing intrauterine system as a maintenance treatment for endometriosis. https://journals.lww.com/md-journal/fulltext/2022/03110/long_term_efficacy_and_safety_of.28.aspx ↩︎
25. Lee K H, et al. (2018). Comparison of the efficacy of diegnogest and levonorgestrel-releasing intrauterine system after laparoscopic surgery for endometriosis. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.13703 ↩︎
26. de Bastos M, et al. (2014). Combined oral contraceptives: venous thrombosis. https://doi.org/10.1002/14651858.CD010813.pub2 ↩︎
27. Therapeutic Goods Administration, (2021). Update – Dienogest and risk of venous thromboembolism. https://www.tga.gov.au/news/safety-updates/update-dienogest-and-risk-venous-thromboembolism ↩︎
28. Ebert A D, et al. (2017). Dienogest 2 mg Daily in the Treatment of Adolescents with Clinically Suspected Endometriosis: The VISanne Study to Assess Safety in ADOlescents. https://www.jpagonline.org/article/S1083-3188(17)30036-0/fulltext ↩︎
29. Dietrich H, et al. (2023). Endometriosis features and dienogest tolerability in women with depression: a case-control study. https://www.tandfonline.com/doi/full/10.1080/13625187.2023.2199899 ↩︎
30. Zimmerman Y, et al. (2014). The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis. https://academic.oup.com/humupd/article/20/1/76/887764 ↩︎
31. Janssen I, et al. (2009). Testosterone and Visceral Fat in Midlife Women: The Study of Women’s Health Across the Nation (SWAN) Fat Patterning Study. https://onlinelibrary.wiley.com/doi/10.1038/oby.2009.251 ↩︎
32. Coelingh Bennink H, et al. (2016). Maintaining physiological testosterone levels by adding dehydroepiandrosterone to combined oral contraceptives: I. Endocrine effects. https://www.sciencedirect.com/science/article/pii/S001078241630141X ↩︎
33. Bedaiwy M and Casper R, (2006). Treatment with leuprolide acetate and hormonal add-back for up to 10 years in stage IV endometriosis patients with chronic pelvic pain. https://www.fertstert.org/article/S0015-0282(06)00550-4/fulltext ↩︎
34. Mitwally M, et al. (2002). Prevention of bone loss and hypoestrogenic symptoms by estrogen and interrupted progestogen add-back in long-term GnRH-agonist down-regulated patients with endometriosis and premenstrual syndrome. https://journals.lww.com/menopausejournal/abstract/2002/07000/prevention_of_bone_loss_and_hypoestrogenic.4.aspx ↩︎
35. Surrey E, et al. (2018). Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies. https://journals.lww.com/greenjournal/abstract/2018/07000/long_term_outcomes_of_elagolix_in_women_with.22.aspx ↩︎
36. Giudice L C, et al. (2022). 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). https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00622-5/ ↩︎
37. Donnez J, et al. (2024). Linzagolix therapy versus a placebo in patients with endometriosis-associated pain: a prospective, randomized, double-blind, Phase 3 study (EDELWEISS 3). https://academic.oup.com/humrep/article/39/6/1208/7656387 ↩︎
38. Mendoza-Torreblanca J G, et al. (2023). Antiangiogenic Effect of Dopamine and Dopaminergic Agonists as an Adjuvant Therapeutic Option in the Treatment of Cancer, Endometriosis, and Osteoarthritis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10299003/ ↩︎
39. Pellicer N, et al. (2021). Use of dopamine agonists to target angiogenesis in women with endometriosis. https://academic.oup.com/humrep/article/36/4/850/6045346 ↩︎
40. Pellicer A, et al. (2024). O-021 Magnetic Resonance Imaging (MRI) evaluation of Quinagolide Vaginal Ring (QVR) treatment on endometrioma, Deep Infiltrating Endometriosis (DIE), and adenomyosis lesion characteristics: QLARITY trial results. https://academic.oup.com/humrep/article/39/Supplement_1/deae108.021/7703299 ↩︎
41. Yarmolinskaya M, et al. (2020). Dopamine agonists as genital endometriosis target therapy. https://www.tandfonline.com/doi/full/10.1080/09513590.2020.1816720 ↩︎
42. Foda A and Aal I, et al. (2012). Metformin as a new therapy for endometriosis, its effects on both clinical picture and cytokines profile. https://www.sciencedirect.com/science/article/pii/S1110569012000957 ↩︎
43. Xie Y, et al. (2023). Metformin Inhibits the Estrogen-mediated Epithelial-Mesenchymal Transition of Ectopic Endometrial Stromal Cells in Endometriosis. https://iv.iiarjournals.org/content/37/6/2490 ↩︎
44. Sönmez Ünal G, et al. (2023). Effects of metformin and ganirelix on subcutaneous endometriosis in a mouse model of autophagy-related cell death. https://tjoddergisi.org/articles/doi/tjod.galenos.2023.85616 ↩︎
45. Mashayekhi P, et al. (2022). Metformin as a potential agent for modulating the faulty endometriotic mesenchymal stem cells: A case-control study. https://kneopen.com/ijrm/article/view/12270/ ↩︎
46. Cheng J, et al. (2022). Metformin Alleviates Endometriosis and Potentiates Endometrial Receptivity via Decreasing VEGF and MMP9 and Increasing Leukemia Inhibitor Factor and HOXA10. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.750208/full ↩︎
47. Turco L C, et al. (2021). Near-Infrared Imaging With Indocyanine Green for the Treatment of Endometriosis: Results From the Gre-Endo Trial. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.737938/full ↩︎
48. Kanno K, et al. (2021). Clinical use of indocyanine green during nerve-sparing surgery for deep endometriosis. https://www.fertstert.org/article/S0015-0282(21)00219-3/fulltext ↩︎
49. Pundir J, et al. (2017). Laparoscopic Excision Versus Ablation for Endometriosis-associated Pain: An Updated Systematic Review and Meta-analysis. https://www.jmig.org/article/S1553-4650(17)30263-7/abstract ↩︎
50. Tsolakidis D, et al. (2010). The impact on ovarian reserve after laparoscopic ovarian cystectomy versus three-stage management in patients with endometriomas: a prospective randomized study. https://www.fertstert.org/article/S0015-0282(09)00264-7/ ↩︎
51. Vaduva C C, et al. (2023). Ovarian reserve after treatment of ovarian endometriomas by ethanolic sclerotherapy compared to surgical treatment. https://www.europeanreview.org/article/32795 ↩︎
52. Javaheri A, et al. (2021). Ovarian reserve in women with endometriosis under total cystectomy compared to partial cystectomy: A randomized clinical trial. https://knepublishing.com/index.php/ijrm/article/view/9472 ↩︎
53. Hart R J, et al. (2008). Excisional surgery versus ablative surgery for ovarian endometriomata. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004992.pub3/full ↩︎
54. Gracia M, et al. (2022). Adenomyosis is an independent risk factor for complications in deep endometriosis laparoscopic surgery. https://www.nature.com/articles/s41598-022-11179-8 ↩︎
55. Kondo W, et al. (2010). Complications after surgery for deeply infiltrating pelvic endometriosis. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2010.02774.x ↩︎
56. Imboden S, et al. (2021). Predictive Factors for Voiding Dysfunction after Surgery for Deep Infiltrating Endometriosis. https://www.jmig.org/article/S1553-4650(21)00037-6/abstract ↩︎
57. Dior U P, et al. (2021). Urinary Function after Surgery for Deep Endometriosis: A Prospective Study. https://www.jmig.org/article/S1553-4650(21)00410-6/abstract ↩︎
58. Puntambekar S P, et al. (2023). Endometriosis Resection Using Nerve Sparing Versus Non-nerve Sparing Surgical Techniques. https://link.springer.com/article/10.1007/s13224-023-01794-4 ↩︎
59. Laterza R M, et al. (2022). Is the Deep Endometriosis or the Surgery the Cause of Postoperative Bladder Dysfunction? https://www.jmig.org/article/S1553-4650(21)01340-6/abstract ↩︎
60. Aublé A, et al. (2023). Evaluation of the efficacy of sacral neuromodulation in the treatment of voiding dysfunction after endometriosis surgery. https://www.sciencedirect.com/science/article/pii/S1166708723002919 ↩︎
61. Bougie O, et al. (2021). Long-term follow-up of endometriosis surgery in Ontario: a population-based cohort study. https://www.ajog.org/article/S0002-9378(21)00467-1/abstract ↩︎
62. Herup-Wheeler T, et al. (2023). High-fat diets promote peritoneal inflammation and augment endometriosis-associated abdominal hyperalgesia. https://www.biorxiv.org/content/10.1101/2023.11.09.566474v1.full ↩︎
63. Shafrir A L, et al. (2018). Risk for and consequences of endometriosis: A critical epidemiologic review. https://www.sciencedirect.com/science/article/pii/S1521693418301093 ↩︎
64. Shivappa N, et al. (2014). Designing and developing a literature-derived, population-based dietary inflammatory index. https://www.cambridge.org/core/journals/public-health-nutrition/article/designing-and-developing-a-literaturederived-populationbased-dietary-inflammatory-index/30BE2C2295CE93DC6B54F9F9AD50CC68 ↩︎
65. Chadchan S B, et al. (2021). Gut microbiota–derived short-chain fatty acids protect against the progression of endometriosis. https://www.life-science-alliance.org/content/4/12/e202101224 ↩︎
66. Chadchan S B, et al. (2023). Gut microbiota and microbiota-derived metabolites promotes endometriosis. https://www.nature.com/articles/s41420-023-01309-0 ↩︎
67. Monastra G, et al. (2018). Vitamin D: a steroid hormone with progesterone-like activity. https://www.europeanreview.org/article/14845 ↩︎
68. Krishnan A V and Feldman D, (2011). Mechanisms of the Anti-Cancer and Anti-Inflammatory Actions of Vitamin D. https://www.annualreviews.org/content/journals/10.1146/annurev-pharmtox-010510-100611 ↩︎
69. Delbandi A A, et al. (2020). Vitamin D deficiency as a risk factor for endometriosis in Iranian women. https://www.sciencedirect.com/science/article/pii/S016503782030187X ↩︎
70. Kalaitzopoulos D R, et al. (2020). Association between vitamin D and endometriosis: a systematic review. https://link.springer.com/article/10.1007/s42000-019-00166-w ↩︎
71. Miyashita M, et al. (2016). Effects of 1,25-Dihydroxy Vitamin D3 on Endometriosis. https://academic.oup.com/jcem/article/101/6/2371/2804763 ↩︎
72. Matasariu D R, et al. (2023). Vitamin D and Mitosis Evaluation in Endometriosis: A Step toward Discovering the Connection? https://www.mdpi.com/2227-9059/11/8/2102 ↩︎
73. Ursache A, et al. (2024). Vitamin D—The Iceberg in Endometriosis—Review and Meta-Analysis. https://www.mdpi.com/2075-4426/14/1/119 ↩︎
74. Lopes V M, et al. (2017). Highly prevalence of vitamin D deficiency among Brazilian women of reproductive age. https://www.scielo.br/j/aem/a/sPvXzYbkGqfXgyDDKHfP3pq/ ↩︎
75. Yarmolinskaya M et al. (2021). Vitamin D significance in pathogenesis of endometriosis. https://www.tandfonline.com/doi/full/10.1080/09513590.2021.2006516 ↩︎
76. Amini L, et al. (2021). The Effect of Combined Vitamin C and Vitamin E Supplementation on Oxidative Stress Markers in Women with Endometriosis: A Randomized, Triple-Blind Placebo-Controlled Clinical Trial. https://onlinelibrary.wiley.com/doi/10.1155/2021/5529741 ↩︎
77. Santanam N, et al. (2012). Antioxidant supplementation reduces endometriosis-related pelvic pain in humans. https://www.translationalres.com/article/S1931-5244(12)00160-0/abstract ↩︎
78. Erten O U, et al. (2016). Vitamin C is effective for the prevention and regression of endometriotic implants in an experimentally induced rat model of endometriosis. https://www.sciencedirect.com/science/article/pii/S1028455916000371 ↩︎
79. Durak Y, et al. (2013). Effect of vitamin C on the growth of experimentally induced endometriotic cysts. https://obgyn.onlinelibrary.wiley.com/doi/10.1111/jog.12050 ↩︎
80. Porpora M G, et al. (2013). A Promise in the Treatment of Endometriosis: An Observational Cohort Study on Ovarian Endometrioma Reduction by N-Acetylcysteine. https://onlinelibrary.wiley.com/doi/10.1155/2013/240702 ↩︎
81. Anastasi E, et al. (2023). Efficacy of N-Acetylcysteine on Endometriosis-Related Pain, Size Reduction of Ovarian Endometriomas, and Fertility Outcomes. https://www.mdpi.com/1660-4601/20/6/4686 ↩︎
82. Li G, et al. (2022). Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis. https://www.nature.com/articles/s41420-022-00821-z ↩︎
83. Meresman G F, et al. (2020). Plants as source of new therapies for endometriosis: a review of preclinical and clinical studies. https://academic.oup.com/humupd/article/27/2/367/5943557 ↩︎
84. Amirsalari S, et al. (2021). The Effect of Garlic Tablets on the Endometriosis-Related Pains: A Randomized Placebo-Controlled Clinical Trial. https://onlinelibrary.wiley.com/doi/10.1155/2021/5547058 ↩︎
85. Kim K H, et al. (2013). Hexane extract of aged black garlic reduces cell proliferation and attenuates the expression of ICAM-1 and VCAM‑1 in TNF-α-activated human endometrial stromal cells. https://www.spandidos-publications.com/10.3892/ijmm.2013.1362 ↩︎
86. Park W, et al. (2024). Therapeutic effects of S-allyl-L-cysteine in a mouse endometriosis model and its immunomodulatory effects via regulation of T cell subsets and cytokine expression. https://link.springer.com/article/10.1007/s43440-024-00625-1 ↩︎
87. Mc Cormack B A, et al. (2021). Effect of urolithins A and B on ectopic endometrial growth in a murine model of endometriosis. https://pubs.rsc.org/en/content/articlelanding/2021/fo/d1fo01702k ↩︎
88. Singh A, et al. (2021). Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population. https://www.nature.com/articles/s41430-021-00950-1 ↩︎
89. Di Nicuolo F, et al. (2021). α-Lipoic Acid and its Role on Female Reproduction. https://www.eurekaselect.com/article/118608 ↩︎
90. Di Nicuolo F, et al. (2021). Alpha-Lipoic Acid Plays a Role in Endometriosis: New Evidence on Inflammasome-Mediated Interleukin Production, Cellular Adhesion and Invasion. https://www.mdpi.com/1420-3049/26/2/288 ↩︎