Treatment of symptomatic uterine fibroids with green tea extract: a pilot randomized controlled clinical study

Eman Roshdy, Veera Rajaratnam, Sarbani Maitra, Mohamed Sabry, Abdou S Ait Allah, Ayman Al-Hendy, Eman Roshdy, Veera Rajaratnam, Sarbani Maitra, Mohamed Sabry, Abdou S Ait Allah, Ayman Al-Hendy

Abstract

Background: Uterine fibroids (UFs, also known as leiomyoma) affect 70% of reproductive-age women. Imposing a major burden on health-related quality-of-life (HRQL) of premenopausal women, UF is a public health concern. There are no effective medicinal treatment options currently available for women with symptomatic UF.

Objectives: To evaluate the efficacy and safety of green tea extract (epigallocatechin gallate [EGCG]) on UF burden and quality of life in women with symptomatic UF, in a double-blinded, placebo-controlled randomized clinical trial.

Methods: A total of 39 reproductive-age women (age 18-50 years, day 3 serum follicle-stimulating hormone <10 \U/mL) with symptomatic UF were recruited for this study. All subjects had at least one fibroid lesion 2 cm(3) or larger, as confirmed by transvaginal ultrasonography. The subjects were randomized to oral daily treatment with either 800 mg of green tea extract (45% EGCG) or placebo (800 mg of brown rice) for 4 months, and UF volumes were measured at the end, also by transvaginal ultrasonography. The fibroid-specific symptom severity and HRQL of these UF patients were scored at each monthly visit, using the symptom severity and quality-of-life questionnaires. Student's t-test was used to evaluate statistical significance of treatment effect between the two groups.

Results: Of the final 39 women recruited for the study, 33 were compliant and completed all five visits of the study. In the placebo group (n = 11), fibroid volume increased (24.3%) over the study period; however, patients randomized to green tea extract (n = 22, 800 mg/day) treatment showed significant reduction (32.6%, P = 0.0001) in total UF volume. In addition, EGCG treatment significantly reduced fibroid-specific symptom severity (32.4%, P = 0.0001) and induced significant improvement in HRQL (18.53%, P = 0.01) compared to the placebo group. Anemia also significantly improved by 0.7 g/dL (P = 0.02) in the EGCG treatment group, while average blood loss significantly decreased from 71 mL/month to 45 mL/month (P = 0.001). No adverse effects, endometrial hyperplasia, or other endometrial pathology were observed in either group.

Conclusion: EGCG shows promise as a safe and effective therapeutic agent for women with symptomatic UFs. Such a simple, inexpensive, and orally administered therapy can improve women's health globally.

Keywords: EGCG; green tea; leiomyoma; pilot clinical study; quality of life; uterine fibroid.

Figures

Figure 1
Figure 1
Flowchart of participant recruitment and flow through randomized clinical epigallocatechin gallate (EGCG) treatment study. Only 39 of the 72 age eligible women consented during the enrollment phase. The ethical committee of the Faculty of Medicine, Sohag University approved the protocol. All consenting participants (n = 39) were confirmed by transvaginal ultrasonography to have uterine fibroids and randomized to treatment groups: 22 were randomized to receive green tea extract (EGCG, oral dose, 800 mg/day) and 17 to receive placebo capsules. The baseline characteristics of the two groups were well matched, with no significant difference (Table 1). After randomization and before any additional follow-up measures could be obtained, six patients dropped out of the placebo group. Compliance throughout the 4-month treatment period (visit 1 to visit 5) was high among the remaining patients in both treatment groups: EGCG (n = 22) and the placebo group (n = 11). Uterine fibroid volumes were measured again by transvaginal ultrasonography at the end of the 4-month treatment period (visit 5). * Signifies patients that dropped out after randomization. Abbreviation: UF, uterine fibroids.
Figure 2
Figure 2
Epigallocatechin gallate (EGCG) treatment decreases total uterine fibroid volume in patients. Fibroid volume decreased significantly with 4 months’ (visit 5 score t = 5.25; P < 0.0001) compared to the placebo group, for which mean fibroid volume increased by 24.25 (±38.09). A P-value of ≤0.05 was considered statistically significant and is indicated by the asterisk. The box plot shows the maximum and minimum values as well as the mean and the median. Mean values are indicated by the plus signs.
Figure 3
Figure 3
Epigallocatechin gallate (EGCG) treatment decreases symptom-severity (SS) score in patients with uterine fibroids. SS score dramatically decreased with 4 months’ (visit 5 [V5] score t = 5.22, P < 0.0001) compared to the placebo group, for which mean SS score was = 7.1 (±15.5). A P-value of ≤0.05 was considered statistically significant and is indicated by the asterisk. The box plot shows the maximum and minimum values as well as the mean and the median. Mean scores are indicated by plus signs.
Figure 4
Figure 4
Epigallocatechin gallate (EGCG) treatment increases health-related quality-of-life (HRQL) score in patients with uterine fibroids. HRQL score increased dramatically with 4 months’ (visit 5 [V5] score >visit 1 [V1] score) use of green tea extract (EGCG, oral dose, 800 mg/day). The mean increase in HRQL in the EGCG-treated group was 20.72 (±21.11) and significantly high (t = 1.25, P = 0.01) compared to the placebo group, for which the mean percentile increase in HRQL was only 2.19 (±17.42). A P-value of ≤0.05 was considered statistically significant and is indicated by the asterisk. The box plot shows the maximum and minimum values as well as the mean and the median. Mean scores are indicated by plus signs.
Figure 5
Figure 5
(A–D) Visit-to-visit quality-of-life improvement trends in response to epigallocatechin gallate (EGCG) treatment in patients with uterine fibroids. Oral dose (800 mg/day) of EGCG treatment dramatically increased health related quality-of-life (HRQL) score with every visit during the treatment period (visit 1 to visit 5, 4 months) while symptom severity scores decreased. The box plots show the 25th and 75th percentiles as well as the median, mean, and standard deviation (±standard deviation). Mean scores are indicated by plus signs.

References

    1. Merrill RM. Hysterectomy surveillance in the United States, 1997 through 2005. Med Sci Monit. 2008;14:CR24–CR31.
    1. Baird DD, Dunson DB, Hill MC, Cousins D, Schecctman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003;188:100–107.
    1. Shen SH, Fennessy F, McDannold N, Jolesz F, Tempany C. Image-guided thermal therapy of uterine fibroids. Semin Ultrasound CT MR. 2009;30:91–104.
    1. Othman EE, Al-Hendy A. Molecular genetics and racial disparities of uterine leiomyomas. Best Pract Res Clin Obstet Gynaecol. 2008;22:589–601.
    1. Al-Hendy A, Salama S. Gene therapy and uterine leiomyoma: a review. Hum Reprod Update. 2006;12:385–400.
    1. Ezzati M, Norian JM, Segars JH. Management of uterine fibroids in the patient pursuing assisted reproductive technologies. Womens Health (Lond Engl) 2009;5:413–421.
    1. Hassan MH, Othman EE, Hornung D, Al-Hendy A. Gene therapy of benign gynecological diseases. Adv Drug Deliv Rev. 2009;61:822–835.
    1. Attardi BJ, Burgenson J, Hild SA, Reel JR. In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone. J Steroid Biochem Mol Biol. 2004;88:277–288.
    1. Williams AR, Critchley HO, Osei J, et al. The effects of the selective progesterone receptor modulator asoprisnil on the morphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata. Hum Reprod. 2007;22:1696–1704.
    1. Yoshida S, Ohara N, Xu Q, et al. Cell-type specific actions of progesterone receptor modulators in the regulation of uterine leiomyoma growth. Semin Reprod Med. 2010;28:260–273.
    1. Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Rajaratnam V, Al-Hendy A. Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells. Fertil Steril. 2010;94:1887–1893.
    1. US Department of Agriculture USDA database for the flavonoid content of selected foods: release 2.1 2007Available from: Accessed May 10, 2013
    1. Khan N, Afag F, Saleem M, Ahmad N, Mukhtar H. Targeting multiple signaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallete. Cancer Res. 2006;66:2500–2505.
    1. Wolfram S. Effects of green tea and EGCG on cardiovascular and metabolic health. J Am Coll Nutr. 2007;26:373S–388S.
    1. Ahn WS, Yoo J, Huh SW, et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev. 2003;12:383–390.
    1. Chow HH, Hakim IA, Vining DR, et al. Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of polyphenon E in healthy individuals. Clin Cancer Res. 2005;11:4627–4633.
    1. Luo H, Tang L, Tang M, et al. Phase IIa chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: modulation of urinary excretion of green tea polyphenols and 8- hydroxydeoxyguanosine. Carcinogenesis. 2006;27:262–268.
    1. Zhang D, Al-Hendy M, Richard-Davis G, et al. Green tea extract inhibits proliferation of uterine leiomyoma cells in vitro and in nude mice. Am J Obstet Gynecol. 2010;202:e1–e9.
    1. Al-Hendy A, Salama SA. Catechol-O-methyltransferase polymorphism is associated with increased uterine leiomyoma risk in different ethnic groups. J Soc Gynecol Investig. 2006;13:136–144.
    1. Lu H, Meng X, Yang CS. Enzymology of methylation of tea catechins and inhibition of catechol-O-methyltransferase by (-)-epigallocatechin gallate. Drug Metab Dispos. 2003;31:572–579.
    1. Chen D, Wang CY, Lambert JD, Ai N, Welsh WJ, Yang CS. Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies. Biochem Pharmocol. 2005;69:1523–1531.
    1. Shixian Q, VanCrey B, Shi J, Kakuda Y, Jiang Y. Green tea extract thermogenesis-induced weight loss by epigallocatechin gallate inhibition of catechol-O-methyltransferase. J Med Food. 2006;9:451–458.
    1. Salama SA, Ho SL, Wang HQ, Tenhunen J, Tilgmann C, Al-Hendy A. Hormonal regulation of catechol-O-methyl transferase activity in women with uterine leiomyomas. Fertil Steril. 2006;86:259–262.
    1. Spies JB, Coyne K, Guaou Guaou N, Boyle D, Skyrnarz-Murphy K, Gonzalves SM. The UFS-QOL, a new disease-specific symptom and health-related quality of life questionnaire for leiomyomata. Obstet Gynecol. 2002;99:290–300.
    1. Wyatt KM, Dimmock PW, Walker TJ, O’Brien PM. Determination of total menstruation blood loss. Fertil Steril. 2001;76:125–131.
    1. Nair S, Al-Hendy A. Adipocytes enhance the proliferation of human leiomyoma cells via TNF-α proinflammatory cytokine. Reprod Sci. 2011;18:1186–1192.
    1. Serafini M, Del Rio D, Yao DN, Bettuzzi S, Peluso I. Health benefits of tea. In: Benzie IFF, Wachtel-Galor S, editors. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd ed. Boca Raton (FL): CRC Press; 2011. Chapter 12.
    1. Han SG, Han SS, Toborek M, Hennig B. EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes. Toxicol Appl Pharmacol. 2012;261:181–188.
    1. Hosokawa Y, Hosokawa I, Ozaki K, Nakanishi T, Nakae H, Matsuo T. Tea polyphenols inhibit IL-6 production in tumor necrosis factor superfamily 14-stimulated human gingival fibroblasts. Mol Nutr Food Res. 2010;54:S151–S158.
    1. Jiang J, Mo ZC, Yin K, et al. Epigallocatechin-3-gallate prevents TNF-alpha-induced NF-kappaB activation thereby upregulating ABCA1 via the Nrf2/Keap1 pathway in macrophage foam cells. Int J Mol Med. 2012;29:946–956.
    1. Loke WM, Proudfoot JM, Hodgson JM, et al. Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction. Arterioscler Thromb Vasc Biol. 2010;30:749–757.
    1. Ozdemir S, Celik C, Gezginc K, Kiresi D, Esen H. Evaluation of endometrial thickness with transvaginal ultrasonography and histopathology in premenopausal women with abnormal vaginal bleeding. Arch Gynecol Obstet. 2010;282:395–399.
    1. Maleki Z, Kim HS, Thonse VR, Judson K, Vinh TN, Vang R. Uterine artery embolization with trisacryl gelatin microspheres in women treated for leiomyomas: a clinicopathologic analysis of alterations in gynecologic surgical specimens. Int J Gynecol Pathol. 2010;29:260–268.
    1. Zhang Y, Peng W, Clarke J, Liu Z. Acupuncture for uterine fibroids. Cochrane Database Syst Rev. 2010;1:CD007221.
    1. Viswanathan M, Hartmann K, McKoy N, et al. Management of uterine fibroids: an update of the evidence. Evid Rep Technol Assess (Full Rep) 2007;154:1–122.
    1. Donnez J, Hervais Vivancos B, Kudela M, Audebert A, Jadoul P. A randomized, placebo-controlled, dose-ranging trial comparing fulvestrant with goserelin in premenopausal patients with uterine fibroids awaiting hysterectomy. Fertil Steril. 2003;79:1380–1389.
    1. Deligdisch L, Hirschmann S, Altchek A. Pathologic changes in gonadotropin releasing hormone agonist analogue treated uterine leiomyomata. Fertil Steril. 1997;67:837–841.
    1. Friedman AJ, Hoffman DI, Comite F, Browneller RW, Miller JD. Treatment of leiomyomata uteri with leuprolide acetate depot: a doubleblind, placebo-controlled, multicenter study. The Leuprolide Study Group. Obstet Gynecol. 1991;77:720–725.
    1. Khan KN, Kitajima M, Hiraki K, et al. Changes in tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma after GnRH agonist therapy. Hum Reprod. 2010;25:642–653.
    1. Palomba S, Russo T, Orio F, Jr, et al. Effectiveness of combined GnRH analogue plus raloxifene administration in the treatment of uterine leiomyomas: a prospective, randomized, single-blind, placebo-controlled clinical trial. Hum Reprod. 2002;17:3213–3219.
    1. Steinauer J, Pritts EA, Jackson R, Jacoby AF. Systematic review of mifepristone for the treatment of uterine leiomyomata. Obstet Gynecol. 2004;103:1331–1336.
    1. Donnez J, Tomaszewski J, Vasquez F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med. 2012;366:421–432.
    1. Donnez J, Tatarchuk TF, Bouchard P, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012;366:409–420.
    1. Surrey ES. Gonadotropin-releasing hormone agonist and add-back therapy: what do the data show? Curr Opin Obstet Gynecol. 2010;22:283–238.
    1. Spitz IM. Clinical utility of progesterone receptor modulators and their effect on the endometrium. Curr Opin Obstet Gynecol. 2009;21:318–324.
    1. Mavrelos D, Ben-Nagi J, Holland T, Hoo W, Naftalin J, Jurkovic D. The natural history of fibroids. Ultrasound Obstet Gynecol. 2010;35:238–242.
    1. Bukulmez O, Doody KJ. Clinical features of myomas. Obstet Gynecol Clin North Am. 2006;33:69–84.
    1. Carbonell Esteve JL, Riverón AM, Cano M, et al. Mifepristone 2.5 mg versus 5 mg daily in the treatment of leiomyoma before surgery. Int J Womens Health. 2012;4:75–84.
    1. Fiscella K, Eisinger SH, Meldrum S, Feng C, Fisher SG, Guzick DS. Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial. Obstet Gynecol. 2006;108:1381–1387.
    1. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry. 2008;65:220–231.
    1. Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet. 2010;375:686–695.
    1. Hirzel F, Hess T, Zollikofer C. Quality control and quality of life after uterine fibroid embolization: long-term results. Gynakol Geburtshilfliche Rundsch. 2008;48:84–93. German.
    1. Maheux-Lacroix S, Lemyre M, Laberge PY, Lamarre A, Bujold E. Uterine artery embolization complicated by uterine perforation at the site of previous myomectomy. J Minim Invasive Gynecol. 2012;19:128–130.
    1. Gupta JK, Sinha A, Lumsden MA, Hickey M. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2012;16:CD005073.
    1. Shen CL, Chyu MC, Pence BC, Yeh JK, Zhang Y, Felton CK. Green tea polyphenols supplementation and tai chi exercise for postmenopausal osteopenic women: safety and quality of life report. BMC Complement Altern Med. 2010;10:76.
    1. Matsuyama T, Tanaka Y, Kamimaki I, Nagao T, Taokimitsu I. Catechin safely improved higher levels of fatness, blood pressure, and cholesterol in children. Obesity (Silver Spring) 2008;16:1338–1348.
    1. Fiorini RN, Donovan JL, Rodwell D, et al. Short-term administration of (-)-epigallocatechin gallate reduces hepatic steatosis and protects against warm hepatic ischemia/reperfusion injury in steatotic mice. Liver Transpl. 2005;11:298–308.
    1. Nishikawa T, Nakajimi T, Moriguchi M, et al. A green tea polyphenol, epigalocatechin-3-gallate, induces apoptosis of human hepatocellular carcinoma, possibly through inhibition of Bcl-2 family proteins. J Hepatol. 2006;44:1074–1082.
    1. Bruno RS, Dugan CE, Smyth JA, DiNatale DA, Koo SI. Green tea extract protects leptin-deficient, spontaneously obese mice from hepatic steatosis and injury. J Nutr. 2008;138:323–331.
    1. Pisters KM, Newman RA, Coldman B, Shin DM, Khuri FR, Hong WK. Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol. 2001;19:1830–1838.
    1. Engman M, Granberg S, Williams AR, Meng CX, Lalitkumar PG, Gemzell-Danielsson K. Mifepristone for treatment of uterine leiomyoma. A prospective randomized placebo controlled trial. Hum Reprod. 2009;24:1870–1879.
    1. Chao MT, Wade CM. Socioeconomic factors and women’s use of complementary and alternative medicine in four racial/ethnic groups. Ethn Dis. 2008;18:65–71.

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