Clinical trial NCT06611501: Glycemic Regulation as Endometriosis Adjunct Treatment
Official title: Glycemic Regulation as Endometriosis Adjunct Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pelvic Pain
Endometriosis
Keywords: Pelvic pain
Pain
Metformin
Chronic pain
Physiological Effects of Drugs
Endometriosis
Female Urogenital Diseases
Genital Diseases, Female
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
First posted: 2024-09-25
Enrollment: 14
Sex: FEMALE
Minimum age (years): 15
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed description: Endometriosis is a chronic illness defined by the presence of endometrial glands and stroma outside the uterine lining. While prevalence estimates vary depending on the population studied, endometriosis is thought to affect approximately one in ten reproductive aged women, up to 50% of women with infertility, and up to 70% of adolescents with chronic pelvic pain. Over 10 million women in the United States have endometriosis and incur significantly higher direct and indirect healthcare costs than those without. Annual health care costs are estimated at $100 billion in the United States alone. While the majority of patients report the onset of endometriosis symptoms during adolescence, delays in diagnosis are common and range from 7 to 12 years. During these delays, women may suffer from debilitating symptoms interfering with school and social activities, and commonly experience reduced health-related quality of life and work productivity. When left untreated, endometriosis can progress significantly in over 50% of patients and result in a higher stage of disease. Therefore, timely intervention and maintenance of therapy is critical for preventing the progression of disease and patient burden.

Therapeutic options for endometriosis include surgical and medical management. Because surgery is not curative, long-term medical therapy is often advised to prevent recurrence of symptoms and retard the progression of disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for endometriosis-related pain but do not remove or decrease deposits of ectopic endometrium. Hormonal therapies are the mainstay of medical therapy as they can inhibit prostaglandin production that contributes to pain, and cause decidualization and atrophy of ectopic endometrial tissue. Unfortunately, hormonal treatments have varied degrees of success and no data support one treatment over another. Additionally, the treatment choice may be limited to medication side effects, availability, costs, and contraceptive needs. Hormonal treatments do not cure endometriosis; 11-19% of women may not experience any relief with medical therapy, and up to a third of women experience recurrence of pain symptoms after treatment cessation. Additionally, as endometriosis is predominantly a disease of young reproductive-aged women, patients may desire a treatment with a different mechanism of action that does not impact ovarian function and fertility. There remains an unmet clinical need among women with endometriosis for effective and well-tolerated medical therapies.

Metformin, an insulin-sensitizing oral biguanide, is approved for the treatment of type 2 diabetes. Several published studies using in vitro and animal models have implicated metformin with a regression of endometriotic implants and reduction of inflammatory activity. Yet, the mechanisms of action of metformin remain to be further elucidated. Only one prospective study to date has investigated the use of metformin in humans as monotherapy for endometriosis; this study had substantial limitations. Further investigation will be improved with participant and provider blinding, use of validated pain measures, and inclusion of a broader population of patients affected by endometriosis. A randomized clinical trial is necessary to investigate the mechanisms and efficacy of metformin as an anti-endometriotic drug.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* Pre-menarche or post-menopause
* Diagnosis of Type 1 or Type 2 Diabetes Mellitus
* Severe renal dysfunction (creatinine \&gt;1.4 mg/dL or eGFR below 45 mL/minute/1.73 m2
* History of lactic acidosis or diabetic ketoacidosis
* ALT or AST \&gt; 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

Primary outcomes:
measure: Change in pain assessed by the Brief Pain Inventory Interference Scale (BPI) over 6 months
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Change in pain severity measured by Visual Analog Scale (VAS) over 6 months
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Change in emotional functioning assessed by Beck Depression Inventory-II (BDI) over 6 months
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Change in ratings of overall improvement assessed by the Patient Global Impression of Change scale (PGIC)
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
Secondary outcomes:
measure: Change in quality of life, measured via Endometriosis Health Profile-30 (EHP-30)
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Changes in sexual satisfaction for participants who are sexually active measured by the New Sexual Satisfaction Scale
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Complete health and medication history assessed by the World Endometriosis Research Foundation (WERF) questionnaire
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Changes in serum angiogenic/inflammatory markers
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
Other outcomes:
measure: Changes in school and/or work attendance
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Change in pregnancy status
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Changes in serum lactate levels
timeFrame: baseline, three and six months if needed
measure: Changes in pain
timeFrame: daily for 6 months
measure: Incidence of vaginal bleeding over six months
timeFrame: daily for 6 months
measure: Usage of any pain medications (both prescription and over the counter)
timeFrame: daily for 6 months
measure: Changes in height
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Changes in weight
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Changes in serum insulin c-peptide level
timeFrame: at baseline and 6 months
measure: Changes in hemoglobin and mean corpuscular volume
timeFrame: at baseline and 6 months
measure: Changes in vitamin B12 levels
timeFrame: at baseline and 6 months
measure: Changes in lipid levels
timeFrame: at baseline and 6 months
measure: Changes in hemoglobin A1c
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Changes in metabolic panel
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Changes in temperature
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Changes in heart rate
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
measure: Changes in blood pressure
timeFrame: once at each of the three visits (at baseline, 3 months, 6 months)
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
Study officials:
affiliation: Boston Children's Hospital
name: Jessica Shim, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994 Mar;23(2):129-38.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Olive DL. Medical therapy of endometriosis. Semin Reprod Med. 2003 May;21(2):209-22. doi: 10.1055/s-2003-41327.
citation: 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.
citation: 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.
citation: 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.
citation: Pugsley Z, Ballard K. Management of endometriosis in general practice: the pathway to diagnosis. Br J Gen Pract. 2007 Jun;57(539):470-6.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.