Endometriosis and fertility
Endometriosis is found in 20% to 50% of infertile women. We theorize that it affects fertility by impairing oocyte development and/or quality, sperm penetration or fer-tilization, tubal function, and implantation. Without treatment, spontaneous monthly fecundity rates are between 2% and 3%.
Forget hormonal therapies. But that said, do not attempt medical suppression of endometriosis in women who hope to conceive. Hormonal therapies, such as danazol, progestins, and GnRH agonists, are ineffective despite their suppressive effect on endometriosis implants. They prevent ovulation and only further delay fertility.15,16 Surgery for endometriosis-associated infertility can modestly increase the monthly fecundity rate to under 5%.
Refer early to fertility specialists. Ovulation induction using clomiphene, coupled with intrauterine insemination, increases monthly fecundity rates to 9% and gonadotropin-controlled ovarian hyperstimulation further raises monthly fecundity rates to about 15%. In vitro fertilization has the highest monthly success rates in patients with endometriosis-associated infertility, reaching pregnancy rates of 30% to 50% per cycle, depending on age. Clearly, patients with endometriosis-associated infertility can benefit from early referral for infertility treatment.
Why do current medical and surgical procedures fail so often? And why do drugs fail to restore fertility? As we begin to understand more about the molecular and cellular defects in endometriosis, we have begun to explain these phenomena. The stem cell theory explains how endometriosis can be found remote from the peritoneal cavity, resist some treatments, and occasionally even occur after hysterectomy. Endometriosis has also found ways to avoid the normal hormonal restraints that we use to control it. By ex-pressing its own aromatase, endometriosis can make high local concentrations of estrogen and resist treatment with GnRH agonists. We have recently learned that in women with endometriosis, the progesterone response is blunted or undetectable, indicating a resistance to progesterone. Patients who fail conventional medical treatment likely have progesterone resistance. In the future, treatment options for endometriosis may need to target progesterone resistance.
Finally, we’ve recently shown that endometriosis induces epigenetic changes in the uterus that inhibit implantation. These changes involve DNA methylation and persist even after the endometriosis is removed. This finding helps to explain the continued infertility even after complete surgical resection of endometriosis. An understanding of the scientific basis of this enigmatic disease has and will continue to lead to novel and superior treatments for endometriosis.
Two important messages to keep in mind when treating patients with endometriosis: (1) recognize the treatment goal for each woman, whether it’s pain management or preserving or restoring fertility; (2) impress upon her that endometriosis is a disease that can be chronic and incurable. Fortunately, a broad and expanding armamentarium is available to treat these women.
DR. KULP is Instructor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT.
DR. TAYLOR is Professor of Obstetrics, Gynecology and Reproductive Sciences, and Director of Reproductive Endocrinology and Infertility at the Yale University School of Medicine. He is also Professor of Molecular, Cellular and Developmental Biology at Yale University and a recipient of eight National Institutes of Health research grants. Dr. Taylor is on the Speaker’s Bureau at Wyeth.
By: Jennifer L. Kulp, MD, Hugh S. Taylor, MD
1. Olive DL, Henderson DY. Endometriosis and mullerian anomalies. Obstet Gynecol. 1987;69(3 Pt 1):412-415.
2. Olive DL, Pritt EA. Treatment of endometriosis. N Engl J Med. 2001;345:266-275.
3. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25:2082-2086.
4. Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci. 2008;1127:106-115.
5. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292:81-85.
6. Sutton CJ, Ewen SP, Whitelaw N, et al. Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril. 1994;62:696-700.
7. Sutton CJ, Pooley AS, Ewen SP, et al. Follow-up report on a randomized controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal to moderate endometriosis. Fertil Steril. 1997;68:1070-1074.
8. Hart R, Hickey M, Maouris P, et al. Excisional surgery versus ablative surgery for ovarian endometriomata: a Cochrane Review. Hum Reprod. 2005;20:3000-3007.
9. Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91:16-24.
10. 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.
11. Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis? Fertil Steril. 2006;85:1307-1318.
12. Bulun SE. Endometriosis. N Engl J Med. 2009;360:268-279.
13. 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;19:160-167.
14. Kettel LM, Murphy AA, Morales AJ, et al. Treatment of endometriosis with the antiprogesterone mifepristone (RU486). Fertil Steril. 1996;65:23-28.
15. Yap C, Furness S, Farquhar C. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev. 2004(3):CD003678.
16. Hughes E, Fedorkow D, Collins J, et al. Ovulation suppression for endometriosis. Cochrane Database Syst Rev. 2003(3):CD000155.
17. Marcoux S, Maheux R, Be’rube’ S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med. 1997;337:217-222.
18. Lee B, Du H, Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80:79-85.
19. Wu Y, Halverson G, Basir Z, et al. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis. Am J Obstet Gynecol. 2005;193:371-380.
20. Kim JJ, Taylor HS, Lu Z, et al. Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod. 2007;13:323-332.