Glycemic Regulation as Endometriosis Adjunct Treatment

NCT06611501 | Recruiting Phase 2 FDA Drug

• 1 other identifier: IRB-P00049391
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this pilot trial is to learn if a novel non-hormonal treatment, metformin hydrochloride, works to treat pelvic pain in young women with endometriosis. The main questions it aims to answer are:

• Is metformin superior to placebo in alleviating pain symptoms in young women with endometriosis?
• Does metformin alter systemic inflammatory markers over 6 months in young women with endometriosis? Researchers will compare metformin to a placebo (a look-alike substance that contains no drug) to see if metformin works to treat pelvic pain. Participants will:
• Take drug metformin or a placebo every day for 6 months
• Visit the clinic three times: once at baseline (pre-treatment), once at 3 months, and once at 6 months
• Keep a daily symptom diary to track pain, bleeding, and usage of any pain medications

Conditions

Endometriosis; Pelvic Pain

Keywords

Pelvic pain; Pain; Metformin; Chronic pain; Physiological Effects of Drugs; Endometriosis; Female Urogenital Diseases; Genital Diseases, Female

Outcome Measures

Primary Outcomes (4)

• Change in pain assessed by the Brief Pain Inventory Interference Scale (BPI) over 6 months

  The BPI Interference Scale is a 7-item composite pain measurement. This self-report measure assesses the extent to which pain interferes with various components of physical and emotional functioning and sleep. The items in this scale can be grouped into those that assess physical functioning (general activity; walking ability; normal work, including both work outside the home and housework), those that assess emotional functioning (mood; relations with people; enjoyment of life), and a single item that assess the extent to which pain interferes with sleep. The arithmetic mean of the seven interference items can be used as a measure of pain interference. The BPI is anchored between a scale of zero (no pain/interference) to ten (maximum pain/interference). The magnitude of treatment-associated change in BPI Interference Scale scores in open-label and randomized clinical trials ranges from 1 to 3 points, depending on the specific pain conditions and treatments studied.

  once at each of the three visits (at baseline, 3 months, 6 months)

• Change in pain severity measured by Visual Analog Scale (VAS) over 6 months

  VAS: A measurement of pain intensity, assessed by a 0 to 10 numerical rating scale, to rate maximum and average pain intensity over the preceding 7 days. Higher scores indicate more severe pain intensity.

  once at each of the three visits (at baseline, 3 months, 6 months)

• Change in emotional functioning assessed by Beck Depression Inventory-II (BDI) over 6 months

  The BDI is a 21-item self-report instrument that provides a rapid assessment of depressive symptoms. BDI has been used in many studies of chronic pain, including chronic pelvic pain and endometriosis. Total scores on the BDI range from 0 to 63. The BDI takes about 5-10 minutes to complete. Scores below 13 should be considered to reflect "minimal or no" depression, with score ranges of 14 to 19, 20 to 28, and 29 to 63 reflect "mild to moderate," "moderate to severe," and "severe" depression, respectively.

  once at each of the three visits (at baseline, 3 months, 6 months)

• Change in ratings of overall improvement assessed by the Patient Global Impression of Change scale (PGIC)

  The PGIC is a seven-point single-item scale with options ranging from 'very much worse' to 'very much improved'. There has been widespread use of the PGIC in recent endometriosis clinical trials, as it readily interprets a person's evaluation of the importance of their improvement or worsening.

  once at each of the three visits (at baseline, 3 months, 6 months)

Secondary Outcomes (4)

• Change in quality of life, measured via Endometriosis Health Profile-30 (EHP-30)

  once at each of the three visits (at baseline, 3 months, 6 months)

• Changes in sexual satisfaction for participants who are sexually active measured by the New Sexual Satisfaction Scale

  once at each of the three visits (at baseline, 3 months, 6 months)

• Complete health and medication history assessed by the World Endometriosis Research Foundation (WERF) questionnaire

  once at each of the three visits (at baseline, 3 months, 6 months)

• Changes in serum angiogenic/inflammatory markers

  once at each of the three visits (at baseline, 3 months, 6 months)

Other Outcomes (17)

• Changes in school and/or work attendance

  once at each of the three visits (at baseline, 3 months, 6 months)

• Change in pregnancy status

  once at each of the three visits (at baseline, 3 months, 6 months)

• Changes in serum lactate levels

  baseline, three and six months if needed

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Placebo tablets orally daily for a total of 6 months of treatment.

Drug: Placebo

Metformin

EXPERIMENTAL

metformin hydrochloride 500 mg capsules daily for a total of 6 months of treatment

Drug: Metformin Hydrochloride

Interventions

Placebo DRUG

1 tablet orally with evening meal for 2 weeks, then 1 tablet twice daily for 2 weeks, then 3 tablets split twice daily for 2 weeks, then 4 tablets split twice daily, for a total of 6 months of treatment.

Also known as: Placebo capsule

Placebo

Metformin Hydrochloride DRUG

Metformin dosage titrated from 500 mg/daily for 2 weeks, then 1000 mg/daily for 2 weeks, 1500 mg/daily for 2 weeks, and then achieving 2000 mg/daily for a duration of 6 months of treatment.

Metformin

Eligibility Criteria

• Age: 15 Years - 35 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Female with surgically confirmed endometriosis, determined at laparoscopy
• Current use for at least 2 months duration of a consistent hormonal therapy for endometriosis (either combination hormonal contraceptives or progestin-only therapy)
• Current pelvic pain (score ≥ 3 on Visual Analog Scale) that has been present for at least 2 months prior to enrollment
• Age 15 years to 35 years and premenopausal
• Willingness to comply with visit schedule and protocol

You may not qualify if:

• Pre-menarche or post-menopause
• Diagnosis of Type 1 or Type 2 Diabetes Mellitus
• Severe renal dysfunction (creatinine \>1.4 mg/dL or eGFR below 45 mL/minute/1.73 m2
• History of lactic acidosis or diabetic ketoacidosis
• ALT or AST \> 2.5 times the upper limit of normal
• Significant mental or chronic systemic illness that might confound pain assessment or the inability to complete the study
• Current/planning pregnancy or breastfeeding
• Inability to read English

Sponsors & Collaborators

• Boston Children's Hospital: lead

Study Sites (1)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

Related Publications (86)

• Laufer MR, Goitein L, Bush M, Cramer DW, Emans SJ. Prevalence of endometriosis in adolescent girls with chronic pelvic pain not responding to conventional therapy. J Pediatr Adolesc Gynecol. 1997 Nov;10(4):199-202. doi: 10.1016/s1083-3188(97)70085-8.

  PMID: 9391902 BACKGROUND

• Nnoaham KE, Hummelshoj L, Webster P, d'Hooghe T, de Cicco Nardone F, de Cicco Nardone C, Jenkinson C, Kennedy SH, Zondervan KT; World Endometriosis Research Foundation Global Study of Women's Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011 Aug;96(2):366-373.e8. doi: 10.1016/j.fertnstert.2011.05.090. Epub 2011 Jun 30.

  PMID: 21718982 BACKGROUND

• Brown J, Crawford TJ, Allen C, Hopewell S, Prentice A. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2017 Jan 23;1(1):CD004753. doi: 10.1002/14651858.CD004753.pub4.

  PMID: 28114727 BACKGROUND

• Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Tamura R, Mori Y, Yamawaki K, Adachi S, Takahashi T, Kase H, Tanaka K, Yamamoto T, Motoyama T, Inoue I, Enomoto T. Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium. Cell Rep. 2018 Aug 14;24(7):1777-1789. doi: 10.1016/j.celrep.2018.07.037.

  PMID: 30110635 BACKGROUND

• Becker CM, Bokor A, Heikinheimo O, Horne A, Jansen F, Kiesel L, King K, Kvaskoff M, Nap A, Petersen K, Saridogan E, Tomassetti C, van Hanegem N, Vulliemoz N, Vermeulen N; ESHRE Endometriosis Guideline Group. ESHRE guideline: endometriosis. Hum Reprod Open. 2022 Feb 26;2022(2):hoac009. doi: 10.1093/hropen/hoac009. eCollection 2022.

  PMID: 35350465 BACKGROUND

• Hossain MM, Nakayama K, Shanta K, Razia S, Ishikawa M, Ishibashi T, Yamashita H, Sato S, Iida K, Kanno K, Ishikawa N, Kiyono T, Kyo S. Establishment of a Novel In Vitro Model of Endometriosis with Oncogenic KRAS and PIK3CA Mutations for Understanding the Underlying Biology and Molecular Pathogenesis. Cancers (Basel). 2021 Jun 25;13(13):3174. doi: 10.3390/cancers13133174.

  PMID: 34202354 BACKGROUND

• Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, Amadiume SC, Goncalves MD, Hodakoski C, Lundquist MR, Bareja R, Ma Y, Harris EM, Sboner A, Beltran H, Rubin MA, Mukherjee S, Cantley LC. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018 Aug;560(7719):499-503. doi: 10.1038/s41586-018-0343-4. Epub 2018 Jul 4.

  PMID: 30051890 BACKGROUND

• Qiang P, Shao Y, Sun YP, Zhang J, Chen LJ. Metformin inhibits proliferation and migration of endometrial cancer cells through regulating PI3K/AKT/MDM2 pathway. Eur Rev Med Pharmacol Sci. 2019 Feb;23(4):1778-1785. doi: 10.26355/eurrev_201902_17140.

  PMID: 30840303 BACKGROUND

• Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, Burchard EG, Brett CM, Giacomini KM. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007 May;117(5):1422-31. doi: 10.1172/JCI30558.

  PMID: 17476361 BACKGROUND

• Oner G, Ozcelik B, Ozgun MT, Serin IS, Ozturk F, Basbug M. The effects of metformin and letrozole on endometriosis and comparison of the two treatment agents in a rat model. Hum Reprod. 2010 Apr;25(4):932-7. doi: 10.1093/humrep/deq016. Epub 2010 Feb 3.

  PMID: 20133323 BACKGROUND

• Yilmaz B, Sucak A, Kilic S, Aksakal O, Aksoy Y, Lortlar N, Sut N, Gungor T. Metformin regresses endometriotic implants in rats by improving implant levels of superoxide dismutase, vascular endothelial growth factor, tissue inhibitor of metalloproteinase-2, and matrix metalloproteinase-9. Am J Obstet Gynecol. 2010 Apr;202(4):368.e1-8. doi: 10.1016/j.ajog.2009.10.873. Epub 2009 Dec 29.

  PMID: 20035912 BACKGROUND

• Zhang H, Xue J, Li M, Zhao X, Wei D, Li C. Metformin regulates stromal-epithelial cells communication via Wnt2/beta-catenin signaling in endometriosis. Mol Cell Endocrinol. 2015 Sep 15;413:61-5. doi: 10.1016/j.mce.2015.06.011. Epub 2015 Jun 24.

  PMID: 26116230 BACKGROUND

• Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-2701. doi: 10.2337/dci18-0033. Epub 2018 Oct 4.

  PMID: 30291106 BACKGROUND

• Rowan JA, Hague WM, Gao W, Battin MR, Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008 May 8;358(19):2003-15. doi: 10.1056/NEJMoa0707193.

  PMID: 18463376 BACKGROUND

• Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994 May;43(5):647-54. doi: 10.1016/0026-0495(94)90209-7.

  PMID: 8177055 BACKGROUND

• Jackson RA, Hawa MI, Jaspan JB, Sim BM, Disilvio L, Featherbe D, Kurtz AB. Mechanism of metformin action in non-insulin-dependent diabetes. Diabetes. 1987 May;36(5):632-40. doi: 10.2337/diab.36.5.632.

  PMID: 3552795 BACKGROUND

• Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Manneras-Holm L, Stahlman M, Olsson LM, Serino M, Planas-Felix M, Xifra G, Mercader JM, Torrents D, Burcelin R, Ricart W, Perkins R, Fernandez-Real JM, Backhed F. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017 Jul;23(7):850-858. doi: 10.1038/nm.4345. Epub 2017 May 22.

  PMID: 28530702 BACKGROUND

• Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, Maggo J, Gray V, De Berardis G, Ruospo M, Natale P, Saglimbene V, Badve SV, Cho Y, Nadeau-Fredette AC, Burke M, Faruque L, Lloyd A, Ahmad N, Liu Y, Tiv S, Wiebe N, Strippoli GF. Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis. JAMA. 2016 Jul 19;316(3):313-24. doi: 10.1001/jama.2016.9400.

  PMID: 27434443 BACKGROUND

• Takemura Y, Osuga Y, Yoshino O, Hasegawa A, Hirata T, Hirota Y, Nose E, Morimoto C, Harada M, Koga K, Tajima T, Yano T, Taketani Y. Metformin suppresses interleukin (IL)-1beta-induced IL-8 production, aromatase activation, and proliferation of endometriotic stromal cells. J Clin Endocrinol Metab. 2007 Aug;92(8):3213-8. doi: 10.1210/jc.2006-2486. Epub 2007 May 15.

  PMID: 17504902 BACKGROUND

• Nodler JL, DiVasta AD, Vitonis AF, Karevicius S, Malsch M, Sarda V, Fadayomi A, Harris HR, Missmer SA. Supplementation with vitamin D or omega-3 fatty acids in adolescent girls and young women with endometriosis (SAGE): a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2020 Jul 1;112(1):229-236. doi: 10.1093/ajcn/nqaa096.

  PMID: 32453393 BACKGROUND

• DiVasta AD, Stamoulis C, Gallagher JS, Laufer MR, Anchan R, Hornstein MD. Nonhormonal therapy for endometriosis: a randomized, placebo-controlled, pilot study of cabergoline versus norethindrone acetate. F S Rep. 2021 Jul 24;2(4):454-461. doi: 10.1016/j.xfre.2021.07.003. eCollection 2021 Dec.

  PMID: 34934987 BACKGROUND

• Yanovski JA, Krakoff J, Salaita CG, McDuffie JR, Kozlosky M, Sebring NG, Reynolds JC, Brady SM, Calis KA. Effects of metformin on body weight and body composition in obese insulin-resistant children: a randomized clinical trial. Diabetes. 2011 Feb;60(2):477-85. doi: 10.2337/db10-1185. Epub 2011 Jan 12.

  PMID: 21228310 BACKGROUND

• Adeyemo MA, McDuffie JR, Kozlosky M, Krakoff J, Calis KA, Brady SM, Yanovski JA. Effects of metformin on energy intake and satiety in obese children. Diabetes Obes Metab. 2015 Apr;17(4):363-70. doi: 10.1111/dom.12426. Epub 2015 Jan 11.

  PMID: 25483291 BACKGROUND

• Srinivasan S, Ambler GR, Baur LA, Garnett SP, Tepsa M, Yap F, Ward GM, Cowell CT. Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab. 2006 Jun;91(6):2074-80. doi: 10.1210/jc.2006-0241. Epub 2006 Apr 4.

  PMID: 16595599 BACKGROUND

• Mauras N, DelGiorno C, Hossain J, Bird K, Killen K, Merinbaum D, Weltman A, Damaso L, Balagopal P. Metformin use in children with obesity and normal glucose tolerance--effects on cardiovascular markers and intrahepatic fat. J Pediatr Endocrinol Metab. 2012;25(1-2):33-40. doi: 10.1515/jpem-2011-0450.

  PMID: 22570948 BACKGROUND

• Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, Haythornthwaite JA, Jensen MP, Kerns RD, Ader DN, Brandenburg N, Burke LB, Cella D, Chandler J, Cowan P, Dimitrova R, Dionne R, Hertz S, Jadad AR, Katz NP, Kehlet H, Kramer LD, Manning DC, McCormick C, McDermott MP, McQuay HJ, Patel S, Porter L, Quessy S, Rappaport BA, Rauschkolb C, Revicki DA, Rothman M, Schmader KE, Stacey BR, Stauffer JW, von Stein T, White RE, Witter J, Zavisic S. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008 Feb;9(2):105-21. doi: 10.1016/j.jpain.2007.09.005. Epub 2007 Dec 11.

  PMID: 18055266 BACKGROUND

• Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clin J Pain. 2004 Sep-Oct;20(5):309-18. doi: 10.1097/00002508-200409000-00005.

  PMID: 15322437 BACKGROUND

• Smarr KL, Keefer AL. Measures of depression and depressive symptoms: Beck Depression Inventory-II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D), Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9). Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S454-66. doi: 10.1002/acr.20556. No abstract available.

  PMID: 22588766 BACKGROUND

• Pokrzywinski R, Soliman AM, Surrey E, Snabes MC, Coyne KS. Psychometric assessment of the PROMIS Fatigue Short Form 6a in women with moderate-to-severe endometriosis-associated pain. J Patient Rep Outcomes. 2020 Oct 27;4(1):86. doi: 10.1186/s41687-020-00257-y.

  PMID: 33108543 BACKGROUND

• Bourdel N, Chauvet P, Billone V, Douridas G, Fauconnier A, Gerbaud L, Canis M. Systematic review of quality of life measures in patients with endometriosis. PLoS One. 2019 Jan 10;14(1):e0208464. doi: 10.1371/journal.pone.0208464. eCollection 2019.

  PMID: 30629598 BACKGROUND

• Vitonis AF, Vincent K, Rahmioglu N, Fassbender A, Buck Louis GM, Hummelshoj L, Giudice LC, Stratton P, Adamson GD, Becker CM, Zondervan KT, Missmer SA; WERF EPHect Working Group. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: II. Clinical and covariate phenotype data collection in endometriosis research. Fertil Steril. 2014 Nov;102(5):1223-32. doi: 10.1016/j.fertnstert.2014.07.1244. Epub 2014 Sep 22.

  PMID: 25256930 BACKGROUND

• Othman Eel-D, Hornung D, Salem HT, Khalifa EA, El-Metwally TH, Al-Hendy A. Serum cytokines as biomarkers for nonsurgical prediction of endometriosis. Eur J Obstet Gynecol Reprod Biol. 2008 Apr;137(2):240-6. doi: 10.1016/j.ejogrb.2007.05.001. Epub 2007 Jun 19.

  PMID: 17582674 BACKGROUND

• Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, Attaran M, Nelson DR, Agarwal A. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod. 2002 Feb;17(2):426-31. doi: 10.1093/humrep/17.2.426.

  PMID: 11821289 BACKGROUND

• Xavier P, Belo L, Beires J, Rebelo I, Martinez-de-Oliveira J, Lunet N, Barros H. Serum levels of VEGF and TNF-alpha and their association with C-reactive protein in patients with endometriosis. Arch Gynecol Obstet. 2006 Jan;273(4):227-31. doi: 10.1007/s00404-005-0080-4. Epub 2005 Oct 6.

  PMID: 16208475 BACKGROUND

• Karbalaee-Hasani A, Khadive T, Eskandari M, Shahidi S, Mosavi M, Nejadebrahimi Z, Khalkhali L, Sangdari A, Mohammadi D, Soltani A, Khodabandehloo H, Hosseini H, Koushki M. Effect of Metformin on Circulating Levels of Inflammatory Markers in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Ann Pharmacother. 2021 Sep;55(9):1096-1109. doi: 10.1177/1060028020985303. Epub 2021 Jan 7.

  PMID: 33412927 BACKGROUND

• Seifarth C, Schehler B, Schneider HJ. Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes. 2013 Jan;121(1):27-31. doi: 10.1055/s-0032-1327734. Epub 2012 Nov 12.

  PMID: 23147210 BACKGROUND

• Kujawska-Luczak M, Musialik K, Szulinska M, Swora-Cwynar E, Kargulewicz A, Grzymislawska M, Pupek-Musialik D, Bogdanski P. The effect of orlistat versus metformin on body composition and insulin resistance in obese premenopausal women: 3-month randomized prospective open-label study. Arch Med Sci. 2017 Jun;13(4):725-731. doi: 10.5114/aoms.2016.62014. Epub 2016 Aug 29.

  PMID: 28721138 BACKGROUND

• DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995 Aug 31;333(9):541-9. doi: 10.1056/NEJM199508313330902.

  PMID: 7623902 BACKGROUND

• Reese KA, Reddy S, Rock JA. Endometriosis in an adolescent population: the Emory experience. J Pediatr Adolesc Gynecol. 1996 Aug;9(3):125-8. doi: 10.1016/s1083-3188(96)70021-9.

  PMID: 8795787 BACKGROUND

• Fujita Y, Inagaki N. Metformin: New Preparations and Nonglycemic Benefits. Curr Diab Rep. 2017 Jan;17(1):5. doi: 10.1007/s11892-017-0829-8.

  PMID: 28116648 BACKGROUND

• Kashi Z, Mahrooz A, Kianmehr A, Alizadeh A. The Role of Metformin Response in Lipid Metabolism in Patients with Recent-Onset Type 2 Diabetes: HbA1c Level as a Criterion for Designating Patients as Responders or Nonresponders to Metformin. PLoS One. 2016 Mar 15;11(3):e0151543. doi: 10.1371/journal.pone.0151543. eCollection 2016.

  PMID: 26978661 BACKGROUND

• Abrao MS, Podgaec S, Filho BM, Ramos LO, Pinotti JA, de Oliveira RM. The use of biochemical markers in the diagnosis of pelvic endometriosis. Hum Reprod. 1997 Nov;12(11):2523-7. doi: 10.1093/humrep/12.11.2523.

  PMID: 9436699 BACKGROUND

• May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010 Nov-Dec;16(6):651-74. doi: 10.1093/humupd/dmq009. Epub 2010 May 12.

  PMID: 20462942 BACKGROUND

• Pizzo A, Salmeri FM, Ardita FV, Sofo V, Tripepi M, Marsico S. Behaviour of cytokine levels in serum and peritoneal fluid of women with endometriosis. Gynecol Obstet Invest. 2002;54(2):82-7. doi: 10.1159/000067717.

  PMID: 12566749 BACKGROUND

• Ohata Y, Harada T, Miyakoda H, Taniguchi F, Iwabe T, Terakawa N. Serum interleukin-8 levels are elevated in patients with ovarian endometrioma. Fertil Steril. 2008 Oct;90(4):994-9. doi: 10.1016/j.fertnstert.2007.07.1355. Epub 2008 Jul 16.

  PMID: 18635170 BACKGROUND

• Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohi J, Simon C. The follicular and endocrine environment in women with endometriosis: local and systemic cytokine production. Fertil Steril. 1998 Sep;70(3):425-31. doi: 10.1016/s0015-0282(98)00204-0.

  PMID: 9757870 BACKGROUND

• Stulhofer A, Busko V, Brouillard P. Development and bicultural validation of the new sexual satisfaction scale. J Sex Res. 2010 Jul;47(4):257-68. doi: 10.1080/00224490903100561.

  PMID: 19629836 BACKGROUND

• van de Burgt TJ, Hendriks JC, Kluivers KB. Quality of life in endometriosis: evaluation of the Dutch-version Endometriosis Health Profile-30 (EHP-30). Fertil Steril. 2011 Apr;95(5):1863-5. doi: 10.1016/j.fertnstert.2010.11.009. Epub 2010 Dec 3.

  PMID: 21122838 BACKGROUND

• Jones G, Kennedy S, Barnard A, Wong J, Jenkinson C. Development of an endometriosis quality-of-life instrument: The Endometriosis Health Profile-30. Obstet Gynecol. 2001 Aug;98(2):258-64. doi: 10.1016/s0029-7844(01)01433-8.

  PMID: 11506842 BACKGROUND

• Waller KG, Shaw RW. Endometriosis, pelvic pain, and psychological functioning. Fertil Steril. 1995 Apr;63(4):796-800. doi: 10.1016/s0015-0282(16)57484-6.

  PMID: 7890065 BACKGROUND

• Kames LD, Rapkin AJ, Naliboff BD, Afifi S, Ferrer-Brechner T. Effectiveness of an interdisciplinary pain management program for the treatment of chronic pelvic pain. Pain. 1990 Apr;41(1):41-46. doi: 10.1016/0304-3959(90)91107-T.

  PMID: 2352765 BACKGROUND

• Vincent K, Kennedy S, Stratton P. Pain scoring in endometriosis: entry criteria and outcome measures for clinical trials. Report from the Art and Science of Endometriosis meeting. Fertil Steril. 2010 Jan;93(1):62-7. doi: 10.1016/j.fertnstert.2008.09.056. Epub 2008 Nov 5.

  PMID: 18990378 BACKGROUND

• Raichle KA, Osborne TL, Jensen MP, Cardenas D. The reliability and validity of pain interference measures in persons with spinal cord injury. J Pain. 2006 Mar;7(3):179-86. doi: 10.1016/j.jpain.2005.10.007.

  PMID: 16516823 BACKGROUND

• Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.

  PMID: 8080219 BACKGROUND

• Bourdel N, Alves J, Pickering G, Ramilo I, Roman H, Canis M. Systematic review of endometriosis pain assessment: how to choose a scale? Hum Reprod Update. 2015 Jan-Feb;21(1):136-52. doi: 10.1093/humupd/dmu046. Epub 2014 Sep 1.

  PMID: 25180023 BACKGROUND

• Siavash M, Tabbakhian M, Sabzghabaee AM, Razavi N. Severity of Gastrointestinal Side Effects of Metformin Tablet Compared to Metformin Capsule in Type 2 Diabetes Mellitus Patients. J Res Pharm Pract. 2017 Apr-Jun;6(2):73-76. doi: 10.4103/jrpp.JRPP_17_2.

  PMID: 28616428 BACKGROUND

• Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013 Feb 15;5(1):6. doi: 10.1186/1758-5996-5-6.

  PMID: 23415113 BACKGROUND

• Reiser E, Lanbach J, Bottcher B, Toth B. Non-Hormonal Treatment Options for Regulation of Menstrual Cycle in Adolescents with PCOS. J Clin Med. 2022 Dec 21;12(1):67. doi: 10.3390/jcm12010067.

  PMID: 36614868 BACKGROUND

• Flyckt R, Kim S, Falcone T. Surgical Management of Endometriosis in Patients with Chronic Pelvic Pain. Semin Reprod Med. 2017 Jan;35(1):54-64. doi: 10.1055/s-0036-1597306. Epub 2017 Jan 3.

  PMID: 28049215 BACKGROUND

• Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann Intern Med. 2016 Jun 7;164(11):740-51. doi: 10.7326/M15-2650. Epub 2016 Apr 19.

  PMID: 27088241 BACKGROUND

• Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995 Aug 31;333(9):550-4. doi: 10.1056/NEJM199508313330903.

  PMID: 7623903 BACKGROUND

• LaMoia TE, Shulman GI. Cellular and Molecular Mechanisms of Metformin Action. Endocr Rev. 2021 Jan 28;42(1):77-96. doi: 10.1210/endrev/bnaa023.

  PMID: 32897388 BACKGROUND

• Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017 Sep;60(9):1577-1585. doi: 10.1007/s00125-017-4342-z. Epub 2017 Aug 3.

  PMID: 28776086 BACKGROUND

• Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006 Jun;21(6):1416-25. doi: 10.1093/humrep/del025. Epub 2006 Feb 24.

  PMID: 16501038 BACKGROUND

• Khattab S, Fotouh IA, Mohesn IA, Metwally M, Moaz M. Use of metformin for prevention of ovarian hyperstimulation syndrome: a novel approach. Reprod Biomed Online. 2006 Aug;13(2):194-7. doi: 10.1016/s1472-6483(10)60614-1.

  PMID: 16895631 BACKGROUND

• Hostalek U, Campbell I. Metformin for diabetes prevention: update of the evidence base. Curr Med Res Opin. 2021 Oct;37(10):1705-1717. doi: 10.1080/03007995.2021.1955667. Epub 2021 Jul 28.

  PMID: 34281467 BACKGROUND

• Praharaj SK, Jana AK, Goyal N, Sinha VK. Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis. Br J Clin Pharmacol. 2011 Mar;71(3):377-82. doi: 10.1111/j.1365-2125.2010.03783.x.

  PMID: 21284696 BACKGROUND

• Sivalingam VN, Myers J, Nicholas S, Balen AH, Crosbie EJ. Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications. Hum Reprod Update. 2014 Nov-Dec;20(6):853-68. doi: 10.1093/humupd/dmu037. Epub 2014 Jul 10.

  PMID: 25013215 BACKGROUND

• Arslanian S, Bacha F, Grey M, Marcus MD, White NH, Zeitler P. Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association. Diabetes Care. 2018 Dec;41(12):2648-2668. doi: 10.2337/dci18-0052. No abstract available.

  PMID: 30425094 BACKGROUND

• Yari S, Khoei HH, Saber M, Esfandiari F, Moini A, Shahhoseini M. Metformin attenuates expression of angiogenic and inflammatory genes in human endometriotic stromal cells. Exp Cell Res. 2021 Jul 15;404(2):112659. doi: 10.1016/j.yexcr.2021.112659. Epub 2021 May 19.

  PMID: 34022204 BACKGROUND

• Stochino-Loi E, Major AL, Gillon TER, Ayoubi JM, Feki A, Bouquet de Joliniere J. Metformin, the Rise of a New Medical Therapy for Endometriosis? A Systematic Review of the Literature. Front Med (Lausanne). 2021 May 11;8:581311. doi: 10.3389/fmed.2021.581311. eCollection 2021.

  PMID: 34046415 BACKGROUND

• Kimber-Trojnar Z, Dluski DF, Wierzchowska-Opoka M, Ruszala M, Leszczynska-Gorzelak B. Metformin as a Potential Treatment Option for Endometriosis. Cancers (Basel). 2022 Jan 24;14(3):577. doi: 10.3390/cancers14030577.

  PMID: 35158846 BACKGROUND

• Hopkins BD, Goncalves MD, Cantley LC. Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol. 2020 May;16(5):276-283. doi: 10.1038/s41574-020-0329-9. Epub 2020 Mar 3.

  PMID: 32127696 BACKGROUND

• Dinulescu DM, Ince TA, Quade BJ, Shafer SA, Crowley D, Jacks T. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med. 2005 Jan;11(1):63-70. doi: 10.1038/nm1173. Epub 2004 Dec 26.

  PMID: 15619626 BACKGROUND

• Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noe M, Horlings HM, Lum A, Jones S, Senz J, Seckin T, Ho J, Wu RC, Lac V, Ogawa H, Tessier-Cloutier B, Alhassan R, Wang A, Wang Y, Cohen JD, Wong F, Hasanovic A, Orr N, Zhang M, Popoli M, McMahon W, Wood LD, Mattox A, Allaire C, Segars J, Williams C, Tomasetti C, Boyd N, Kinzler KW, Gilks CB, Diaz L, Wang TL, Vogelstein B, Yong PJ, Huntsman DG, Shih IM. Cancer-Associated Mutations in Endometriosis without Cancer. N Engl J Med. 2017 May 11;376(19):1835-1848. doi: 10.1056/NEJMoa1614814.

  PMID: 28489996 BACKGROUND

• Becker CM, Gattrell WT, Gude K, Singh SS. Reevaluating response and failure of medical treatment of endometriosis: a systematic review. Fertil Steril. 2017 Jul;108(1):125-136. doi: 10.1016/j.fertnstert.2017.05.004.

  PMID: 28668150 BACKGROUND

• Olive DL. Medical therapy of endometriosis. Semin Reprod Med. 2003 May;21(2):209-22. doi: 10.1055/s-2003-41327.

  PMID: 12917790 BACKGROUND

• Shim JY, Laufer MR. Adolescent Endometriosis: An Update. J Pediatr Adolesc Gynecol. 2020 Apr;33(2):112-119. doi: 10.1016/j.jpag.2019.11.011. Epub 2019 Dec 5.

  PMID: 31812704 BACKGROUND

• Hoshiai H, Ishikawa M, Sawatari Y, Noda K, Fukaya T. Laparoscopic evaluation of the onset and progression of endometriosis. Am J Obstet Gynecol. 1993 Sep;169(3):714-9. doi: 10.1016/0002-9378(93)90649-4.

  PMID: 8372885 BACKGROUND

• DiVasta AD, Vitonis AF, Laufer MR, Missmer SA. Spectrum of symptoms in women diagnosed with endometriosis during adolescence vs adulthood. Am J Obstet Gynecol. 2018 Mar;218(3):324.e1-324.e11. doi: 10.1016/j.ajog.2017.12.007. Epub 2017 Dec 13.

  PMID: 29247637 BACKGROUND

• Pugsley Z, Ballard K. Management of endometriosis in general practice: the pathway to diagnosis. Br J Gen Pract. 2007 Jun;57(539):470-6.

  PMID: 17550672 BACKGROUND

• Ballweg ML. Big picture of endometriosis helps provide guidance on approach to teens: comparative historical data show endo starting younger, is more severe. J Pediatr Adolesc Gynecol. 2003 Jun;16(3 Suppl):S21-6. doi: 10.1016/s1083-3188(03)00063-9. No abstract available.

  PMID: 12742183 BACKGROUND

• Simoens S, Hummelshoj L, D'Hooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update. 2007 Jul-Aug;13(4):395-404. doi: 10.1093/humupd/dmm010.

  PMID: 17584822 BACKGROUND

• Soliman AM, Surrey E, Bonafede M, Nelson JK, Castelli-Haley J. Real-World Evaluation of Direct and Indirect Economic Burden Among Endometriosis Patients in the United States. Adv Ther. 2018 Mar;35(3):408-423. doi: 10.1007/s12325-018-0667-3. Epub 2018 Feb 15.

  PMID: 29450864 BACKGROUND

• Bulletti C, Coccia ME, Battistoni S, Borini A. Endometriosis and infertility. J Assist Reprod Genet. 2010 Aug;27(8):441-7. doi: 10.1007/s10815-010-9436-1. Epub 2010 Jun 25.

  PMID: 20574791 BACKGROUND

• Shafrir AL, Farland LV, Shah DK, Harris HR, Kvaskoff M, Zondervan K, Missmer SA. Risk for and consequences of endometriosis: A critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol. 2018 Aug;51:1-15. doi: 10.1016/j.bpobgyn.2018.06.001. Epub 2018 Jul 3.

  PMID: 30017581 BACKGROUND

MeSH Terms

Conditions

Pelvic Pain; Endometriosis; Pain; Chronic Pain; Female Urogenital Diseases; Genital Diseases, Female

Interventions

Metformin

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Jessica Shim, MD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mari Garza, BA

CONTACT

6173557648; GYNResearch@childrens.harvard.edu

Jessica Shim, MD

CONTACT

6173557648; GYNResearch@childrens.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Division of Gynecology

Study Record Dates

• First Submitted: September 10, 2024
• First Posted: September 25, 2024
• Study Start: May 22, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)