Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists
- Mark D Hornstein, MD
Mark D Hornstein, MD
- Professor of Obstetrics, Gynecology & Reproductive Biology
- Harvard Medical School
- William E Gibbons, MD
William E Gibbons, MD
- Division of Reproductive Endocrinology
- Department of Obstetrics and Gynecology
- Baylor College of Medicine
- Chief of Reproductive Medicine for the Pavilion for Women
- Texas Children's Hospital
Pelvic pain due to endometriosis can be treated with medical therapy, surgical intervention, or a combination of both. In most cases, women with chronic pelvic pain (CPP) thought to be due to endometriosis are initially treated empirically with nonsteroidal anti-inflammatory drugs (NSAIDS) and combined estrogen-progestin contraceptives. (See "Treatment of chronic pelvic pain in women".)
If these medications do not resolve the pain, laparoscopy is usually performed to determine a definitive diagnosis. If the diagnosis of endometriosis is confirmed at laparoscopy, conservative surgery involving excision, fulguration, or laser vaporization of endometriotic implants and adhesiolysis is often attempted. (See "Endometriosis: Surgical management of pelvic pain".)
Pain can continue after conservative surgery. Recurrence of endometriosis is estimated as 21.5 percent at two years and 40 to 50 percent at five years after surgery . For women with persistent pain or selected patients who have not responded to empiric treatment with NSAIDs or oral contraceptives , administration of a gonadotropin releasing hormone (GnRH) agonist is usually effective.
Side effects of GnRH agonists, such as vasomotor symptoms and accelerated bone loss, limit treatment duration to six months. However, treatment can be extended beyond six months if add-back therapy is combined with the GnRH agonist.
BASIS FOR HORMONAL TREATMENT
Compared to eutopic endometrium, endometriotic implants are characterized by overproduction of prostaglandins and local production of estrogens and cytokines, which synergize the activities of each other, promote implantation of ectopic endometrium, and cause the pain associated with endometriosis . In addition, aromatase overactivity results in increased COX2 expression favoring prostaglandin E production, which, in turn, upregulates estrogen synthesis pathways. Interventions that reduce ovarian estrogen production reduce this synergistic process, thereby reducing or eliminating endometriosis-related pain. (See "Endometriosis: Pathogenesis, clinical features, and diagnosis".)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update 2009; 15:441.
- Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol 1999; 93:51.
- Bulun SE. Endometriosis. N Engl J Med 2009; 360:268.
- Ranney B. Endometriosis. 3. Complete operations. Reasons, sequelae, treatment. Am J Obstet Gynecol 1971; 109:1137.
- Gray LA. Endometriosis of the bowel: role of bowel resection, superficial excision and oophorectomy in treatment. Ann Surg 1973; 177:580.
- Hammond CB, Rock JA, Parker RT. Conservative treatment of endometriosis: the effects of limited surgery and hormonal pseudopregnancy. Fertil Steril 1976; 27:756.
- Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogues. N Engl J Med 1991; 324:93.
- Levine D, Kaufman L, Cuenca VG, Badawy SZ. Cell growth effects of leuprolide on cultured endometrioma cells. J Reprod Med 2007; 52:581.
- Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol 1998; 91:16.
- Dlugi AM, Miller JD, Knittle J. Lupron depot (leuprolide acetate for depot suspension) in the treatment of endometriosis: a randomized, placebo-controlled, double-blind study. Lupron Study Group. Fertil Steril 1990; 54:419.
- FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and Notification to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of Diabetes and Certain Cardiovascular Diseases http://www.fda.gov/Drugs/DrugSafety/ucm229986.htm (Accessed on October 21, 2010).
- Henzl MR, Corson SL, Moghissi K, et al. Administration of nasal nafarelin as compared with oral danazol for endometriosis. A multicenter double-blind comparative clinical trial. N Engl J Med 1988; 318:485.
- Barbieri RL. New therapy for endometriosis. N Engl J Med 1988; 318:512.
- Barbieri RL. Comparison of the pharmacology of nafarelin and danazol. Am J Obstet Gynecol 1990; 162:581.
- Prentice A, Deary AJ, Goldbeck-Wood S, et al. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev 2000; :CD000346.
- Shaw, RW. Goserelin depot preparation of LHRH analogue used in the treatment of endometriosis. In: Current concepts in endometriosis, Chadha, DR Buttram, VC (Eds), Alan R. Liss, New York 1990. p.323.
- Cirkel, U, Schweppe, KW, Ochs, H, et al. Effects of LHRH agonist therapy in the treatment of endometriosis. In: Gonadotropin down-regulation in gynecological practice. Vol 225, Chadha, DR, Willemsen, WNP (Eds). Aln R Liss, New York 1986. p. 189.
- Li Y, Zhu HL, Liang XD, et al. [Outcome analysis of stage III - IV endometriosis after conservative surgery]. Zhonghua Fu Chan Ke Za Zhi 2007; 42:92.
- Evers JL. The second-look laparoscopy for evaluation of the result of medical treatment of endometriosis should not be performed during ovarian suppression. Fertil Steril 1987; 47:502.
- Evers JL, Dunselman GA, Land JA, Bouckaert PX. Is there a solution for recurrent endometriosis? Br J Clin Pract Suppl 1991; 72:45.
- Tandoi I, Somigliana E, Riparini J, et al. High rate of endometriosis recurrence in young women. J Pediatr Adolesc Gynecol 2011; 24:376.
- Szendei G, Hernádi Z, Dévényi N, Csapó Z. Is there any correlation between stages of endometriosis and severity of chronic pelvic pain? Possibilities of treatment. Gynecol Endocrinol 2005; 21:93.
- Hornstein MD, Hemmings R, Yuzpe AA, Heinrichs WL. Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis. Fertil Steril 1997; 68:860.
- Vercellini P, Crosignani PG, Somigliana E, et al. Medical treatment for rectovaginal endometriosis: what is the evidence? Hum Reprod 2009; 24:2504.
- Zupi E, Marconi D, Sbracia M, et al. Add-back therapy in the treatment of endometriosis-associated pain. Fertil Steril 2004; 82:1303.
- Guzick DS, Huang LS, Broadman BA, et al. Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain. Fertil Steril 2011; 95:1568.
- Küpker W, Felberbaum RE, Krapp M, et al. Use of GnRH antagonists in the treatment of endometriosis. Reprod Biomed Online 2002; 5:12.
- Hurst BS, Gardner SC, Tucker KE, et al. Delayed oral estradiol combined with leuprolide increases endometriosis-related pain. JSLS 2000; 4:97.
- Surrey ES, Hornstein MD. Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: long-term follow-up. Obstet Gynecol 2002; 99:709.
- Irahara M, Uemura H, Yasui T, et al. Efficacy of every-other-day administration of conjugated equine estrogen and medroxyprogesterone acetate on gonadotropin-releasing hormone agonists treatment in women with endometriosis. Gynecol Obstet Invest 2001; 52:217.
- Pierce SJ, Gazvani MR, Farquharson RG. Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up. Fertil Steril 2000; 74:964.
- Franke HR, van de Weijer PH, Pennings TM, van der Mooren MJ. Gonadotropin-releasing hormone agonist plus "add-back" hormone replacement therapy for treatment of endometriosis: a prospective, randomized, placebo-controlled, double-blind trial. Fertil Steril 2000; 74:534.
- DiVasta AD, Feldman HA, Sadler Gallagher J, et al. Hormonal Add-Back Therapy for Females Treated With Gonadotropin-Releasing Hormone Agonist for Endometriosis: A Randomized Controlled Trial. Obstet Gynecol 2015; 126:617.
- Howell R, Edmonds DK, Dowsett M, et al. Gonadotropin-releasing hormone analogue (goserelin) plus hormone replacement therapy for the treatment of endometriosis: a randomized controlled trial. Fertil Steril 1995; 64:474.
- Fuldeore MJ, Marx SE, Chwalisz K, et al. Add-back therapy use and its impact on LA persistence in patients with endometriosis. Curr Med Res Opin 2010; 26:729.
- Tanaka T. Effects of herbal medicines on menopausal symptoms induced by gonadotropin-releasing hormone agonist therapy. Clin Exp Obstet Gynecol 2001; 28:20.
- Surrey ES. Add-back therapy and gonadotropin-releasing hormone agonists in the treatment of patients with endometriosis: can a consensus be reached? Add-Back Consensus Working Group. Fertil Steril 1999; 71:420.
- www.Reprotox.com (Accessed April 10, 2009).
- Kim NY, Ryoo U, Lee DY, et al. The efficacy and tolerability of short-term low-dose estrogen-only add-back therapy during post-operative GnRH agonist treatment for endometriosis. Eur J Obstet Gynecol Reprod Biol 2011; 154:85.
- Hornstein MD, Yuzpe AA, Burry KA, et al. Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain. Fertil Steril 1995; 63:955.
- Mitwally MF, Gotlieb L, Casper RF. 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. Menopause 2002; 9:236.
- Bedaiwy MA, Casper RF. Treatment with leuprolide acetate and hormonal add-back for up to 10 years in stage IV endometriosis patients with chronic pelvic pain. Fertil Steril 2006; 86:220.
- Hull ME, Barbieri RL. Nafarelin in the treatment of endometriosis. Dose management. Gynecol Obstet Invest 1994; 37:263.
- Tahara M, Matsuoka T, Yokoi T, et al. Treatment of endometriosis with a decreasing dosage of a gonadotropin-releasing hormone agonist (nafarelin): a pilot study with low-dose agonist therapy ("draw-back" therapy). Fertil Steril 2000; 73:799.
- Uemura T, Shirasu K, Katagiri N, et al. Low-dose GnRH agonist therapy for the management of endometriosis. J Obstet Gynaecol Res 1999; 25:295.
- Tse CY, Chow AM, Chan SC. Effects of an extended-interval dosing regimen of triptorelin depot on the hormonal profile of patients with endometriosis: prospective observational study. Hong Kong Med J 2000; 6:260.
- Kang JL, Wang XX, Nie ML, Huang XH. Efficacy of gonadotropin-releasing hormone agonist and an extended-interval dosing regimen in the treatment of patients with adenomyosis and endometriosis. Gynecol Obstet Invest 2010; 69:73.
- Soysal S, Soysal ME, Ozer S, et al. The effects of post-surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Hum Reprod 2004; 19:160.
- Vercellini P, Frontino G, De Giorgi O, et al. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003; 80:305.
- Abou-Setta AM, Al-Inany HG, Farquhar CM. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database Syst Rev 2006; :CD005072.
- Ferreira RA, Vieira CS, Rosa-E-Silva JC, et al. Effects of the levonorgestrel-releasing intrauterine system on cardiovascular risk markers in patients with endometriosis: a comparative study with the GnRH analogue. Contraception 2010; 81:117.
- Gomes MK, Rosa-e-Silva JC, Garcia SB, et al. Effects of the levonorgestrel-releasing intrauterine system on cell proliferation, Fas expression and steroid receptors in endometriosis lesions and normal endometrium. Hum Reprod 2009; 24:2736.
- BASIS FOR HORMONAL TREATMENT
- PHARMACOLOGY OF GnRH AGONISTS
- Side effects
- Gonadotropin releasing hormone agonists after conservative surgery
- Recurrence of symptomatic endometriosis
- Symptomatic rectovaginal endometriosis
- GnRH WITH ADD-BACK THERAPY
- GnRH antagonists
- - Progestin-only add-back
- - Estrogen plus progestin add-back
- - Nonsteroidal add-back
- - Other
- Concurrent versus delayed initiation of hormonal add-back
- Duration of therapy
- LOW DOSE GNRH
- Titration method
- Longer interval method
- Addition of an aromatase inhibitor
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS