Surgical management of endometriosis associated infertility: Time for a paradigm change

Laurie J. McKenzie is Director of Oncofertility at Houston IVF and Director of Houston Oncofertility Preservation and Education (H.O.P.E.), Texas. She is also a member of the Contemporary OB/GYN editorial board.

Endometriosis is one of the most challenging clinical entities for gynecologists. The resultant pain and infertility are often difficult to manage, and strategies are limited. I propose a more cautious approach to endometriosis-associated infertility, based on emerging evidence that “less is more” in surgical management of this problem.

A recent case highlights the clinical issues.

Case

J.E. is a 34-year-old P0 who initially presented in January 2014 after attempting pregnancy for 2 years. She reported a diagnosis of endometriosis as well as male-factor infertility. Her endometriosis was diagnosed via laparoscopy in December 2013 and her initial surgery was ablation of visible implants plus resection of a 4-cm endometrioma.

Prior fertility testing included a hysterosalpingogram obtained in November 2013, which demonstrated an occluded left Fallopian tube and an anti-Müllerian hormone (AMH) level that was reassuring at 1.6 ng per mL. Partner history was significant for a semen analysis that demonstrated 6 million sperm with 10% motility.

At J.E.’s initial infertility evaluation, a transvaginal ultrasound demonstrated suspected bilateral recurrent endometriomas measuring 5 and 10 cm. We discussed management options, including proceeding directly to in vitro fertilization (IVF) versus resection of the endometriomas. She was asymptomatic, but given the size of the endometriomas, I recommended repeat laparoscopy and resection of the endometriomas.

Four months postoperative, J.E.’s AMH was undetectable. Six months postoperative, she underwent an IVF. Despite an aggressive 16-day stimulation, no oocytes were recovered. Her AMH remains undetectable. She is now considering use of donor oocytes.

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Background

The prevalence of endometriosis is difficult to ascertain. The incidence of endometriosis in asymptomatic women undergoing tubal sterilization is reported to be 1%–7%, while the incidence of endometriosis in women undergoing laparoscopy for evaluation of infertility varies dramatically between 9% and 50%.^1,2

Risk factors for endometriosis include family history, low body mass index, current or past smoking history, alcohol use, white race, and early menarche or late menopause.^1,3

How endometriosis impacts fertility is unknown. Endometriotic implants may replace healthy normal ovarian tissue and exert a directly toxic effect. An inflammatory response to the endometriosis itself may affect fertility by increasing cytokine concentrations and other inflammatory mediators.

Endometriosis may disrupt normal anatomy-either by directly damaging the Fallopian tubes or via adhesion formation-resulting in impaired conception. Altered tubal transport has been documented. For a more detailed review of these proposed mechanisms see the Endometriosis and Infertility Committee Opinion by the American Society for Reproductive Medicine.⁴

Historical management

Despite the prevalence of endometriosis among infertile women, there is little consensus in regard to optimal treatment of an infertile patient with the condition.

Traditionally, endometriosis associated with infertility has been managed surgically. Surgical evaluation with histologic documentation of endometriosis is the only definitive way of diagnosing endometriosis. Goals of surgery include ablation or excision of all visible disease, prevention of adhesions, and restoration of normal anatomy.^5,6

If laparoscopy is performed, ablation or excision of visible endometriosis should be considered based on Level I evidence.4 In the presence of an endometrioma, excisional surgery is superior to drainage, because there is a high risk of recurrence if the cyst is merely drained.⁷

The benefit of surgery in improving pain in patients with endometriosis is undisputed. A Cochrane database review published in 2014 confirms that laparoscopic intervention for endometriosis and excision of endometriomas significantly improves pelvic pain.⁸

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However, the success rates for surgery to improve fertility in patients with endometriosis are modest at best. In asymptomatic patients undergoing laparoscopy to look for the presence of endometriosis, 40 laparoscopies would need to be performed to achieve one additional pregnancy over the course of 12 months.^4,8

From a risk-benefit standpoint, the scales clearly are not tipped toward surgical intervention. To take this discussion one step further: Are we causing more harm than benefit with our excisional or ablative techniques?

Negative impact of surgery on ovarian reserve

The physiology of ovarian endometriomas differs vastly from that of traditional benign ovarian cysts. Their presence and certainly their resection may affect ovarian reserve much differently than the resection of benign ovarian cysts.

Recent evidence suggests that, in the absence of an anatomically identifiable plane of cleavage, adjacent healthy ovarian tissue is removed when a stripping technique is used to excise endometriomas. A retrospective study involving 35 patients with endometriomas found normal ovarian tissue in 97% of the specimens.⁹

Donnez et al. reported the presence of the oocytes in the vicinity of the endometrial stroma in biopsies from ovarian endometriomas, and cautioned against excision of the endometrioma wall secondary to the risk of removing ovarian cortex with the cyst wall.¹⁰

Excision of healthy ovarian tissue in endometrioma specimens has been documented in other studies.^11-14 Removal of the pseudo-cyst wall may excise the remaining primordial follicles and the coagulation required for hemostasis also may do irreversible damage to the blood supply.¹⁵

Several studies now suggest that surgery has adverse effects on ovarian reserve. Excision of endometriomas has been shown to reduce ovarian volume.¹⁶ A recent European study evaluated 411 women with histologically proven endometriosis and found no difference in AMH levels in women with endometriosis compared to controls. However, a significant difference was found in AMH values in women with endometriosis who had undergone previous endometrioma surgery.¹⁷

In another study, 65 women with known endometriosis were prospectively assessed for ovarian reserve markers following laparoscopic endometrioma stripping. A significant and progressive decline in AMH values was reported.¹⁸ A meta-analysis by Raffi et al. also documented a significant reduction of 38% in AMH levels after surgery, for a weighted mean difference of -1.13 ng/mL (95% confidence interval -1.88 to -0.37) after cyst excision.¹⁹

Repeat surgeries are worse; surgery for recurrent endometriomas is associated with increased loss of ovarian tissue, decreased antral follicle counts, and decreased ovarian volume compared with first-time surgery for endometriosis.²⁰

Assisted reproductive technologies

Removing endometriomas laparoscopically prior to IVF does not appear to improve fertility outcomes compared to proceeding directly to IVF,²¹ and ovarian endometriosis and surgical cystectomy are associated with decreased ovarian responsiveness to gonadotropins and diminished ovarian reserve.²² As a consequence, fewer embryos are available for transfer with IVF. Arguably, proceeding directly to IVF in women with asymptomatic endometriomas may reduce time to surgery, treatment cost, and risk of surgical complications.

In addition, there is no evidence to suggest that ovarian stimulation associated with IVF induces progression of endometriosis.²³

Use of ICSI on rise, but are outcomes better?

Take-home message

A recent national survey performed in the UK revealed that the majority of gynecologists there offer surgery primarily via cystectomy for endometriomas prior to using assisted reproductive technologies (ART), regardless of the presence of symptoms. This is despite the available evidence that surgery for endometriomas does not improve the outcome of ART and may damage ovarian reserve.¹⁹ Gynecologists in the United States seem to be following the same protocol.

Surgery for endometriosis is indicated in patients with pelvic pain and it has a role in the patient who wants a definitive diagnosis and is unhappy with the label “unexplained” infertility. Surgery also is reasonable if the location of the endometrioma precludes safe access to the ovary during anticipated oocyte harvest for planned IVF. What remains to be elucidated is the size beyond which endometriomas need resection.

As illustrated in the case of my patient J.E., resecting her 5- and 10-cm endometriomas resulted in a significant decline in ovarian function. Had they remained in situ, could I have safely accessed her ovaries? Would she have developed a postoperative infection? Would Lupron exposure have had a role in her pre-IVF management?

Many questions are yet to be answered. However, the paradigm in regard to endometriosis overall appears to be evolving toward a less invasive approach. As Shah eloquently asked in her review,²⁴ are we adding “insult upon injury” by operating (repeatedly) on these women?

References

1. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM, Hunter DJ. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol. 2004;160:784–796.

2. Verkauf BS. Incidence, symptoms, and signs of endometriosis in fertile and infertile women. J Fla Med Assoc. 1987;74:671–675.

3. Hadfield RM, Mardon HJ, Barlow DH, Kennedy SH. Endometriosis in monozygotic twins. Fertil Steril. 1997;68(5):941-942.

4. Pfeifer S, Fritz M, Goldberg J, et al. Endometriosis and infertility: a committee opinion. Practice Committee of the American Society for Reproductive Medicine. 2012;98(3):591-598.

5. Yeung P Jr. The laparoscopic management of endometriosis in patients with pelvic pain. Obstet Gynecol Clin North Am. 2014;41(3):371-83.

6. Johnson NP, Hummelshoj L. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552-1568.

7. Hart RJ, Hickey M, Maouris P, Buckett W. Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev. 2008;(2):CD004992.

8. Brown J, Farquhar C. Endometriosis: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2014. See comment in PubMed Commons: Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Farquhar C Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database Syst Rev. 2002;(4).

9. Roman H, Tarta O, Pura I, et al. Direct proportional relationship between endometrioma size and ovarian parenchyma inadvertently removed during cystectomy, and its implication on the management of enlarged endometriomas. Hum Reprod. 2010;25(6):1428-1432.

10. Donnez J, Nisolle M, Gillet N, Smets M, Bassil S, Casanas-Roux F. Large ovarian endometriomas. Hum Reprod. 1996;11(3):641-646.

11. Muzii L, Bianchi A, Croce C, Manci N, Panici PB. Laparoscopic excision of ovarian cysts: is the stripping technique a tissue-sparing procedure? Fertil Steril. 2002;77:609–614.

12. Muzii L, Bellati F, Palaia I, et al. Laparoscopic stripping of endometriomas: a randomized trial on different surgical techniques. Part I: clinical results. Hum Reprod. 2005;20:1981–1986.

13. Muzii L, Bianchi A, Bellati F, et al. Histologic analysis of endometriomas: what the surgeon needs to know. Fertil Steril. 2007;87:362–366.

14. Muzii L, Marana R, Angioli R, et al. Histologic analysis of specimens from laparoscopic endometrioma excision performed by different surgeons: does the surgeon matter? Fertil Steril. 2011;95:2116–2119.

15. Kuroda M, Kuroda K, Arakawa A, et al. Histological assessment of impact of ovarian endometrioma and laparoscopic cystectomy on ovarian reserve. J Obstet Gynaecol Res. 2012;38(9):1187-1193.

16. Exacoustos C, Zupi E, Amadio A, et al. Laparoscopic removal of endometriomas: sonographic evaluation of residual functioning ovarian tissue. Am J Obstet Gynecol. 2004;191(1):68-72.

17. Streuli I, de Ziegler D, Gayet V, et al. In women with endometriosis anti-Müllerian hormone levels are decreased only in those with previous endometrioma surgery. Hum Reprod. 2012;27(11):3294-3303.

18. Celik HG, Dogan E, Okyay E, at al. Effect of laparoscopic excision of endometriomas on ovarian reserve: serial changes in the serum antimüllerian hormone levels. Fertil Steril. 2012;97(6):1472-1478.

19. Raffi F, Shaw RW. National survey of the current management of endometriomas in women undergoing assisted reproductive treatment. Hum Reprod. 2012;27(9):2712-2719.

20. Muzii L, Achilli C, Lecce F, et al. Second surgery for recurrent endometriomas is more harmful to healthy ovarian tissue and ovarian reserve than first surgery. Fertil Steril. 2015;103(3):738-743.

21. Garcia-Velasco JA, Mahutte NG, Corona J, et al. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study. Fertil Steril. 2004;81:1194–1197.

22. Matalliotakis IM, Cakmak H, Mahutte N, Fragouli Y, Arici A, Sakkas D. Women with advanced-stage endometriosis and previous surgery respond less well to gonadotropin stimulation, but have similar IVF implantation and delivery rates compared with women with tubal factor infertility. Fertil Steril. 2007;88(6):1568–1572.

23. Benaglia L, Somigliana E, Santi G, Scarduelli C, Ragni G, Fedele L. IVF and endometriosis-related symptom progression: insights from a prospective study. Hum Reprod. 2011;26(9):2368-2372.

24. Shah DK. Diminished ovarian reserve and endometriosis: insult upon injury. Semin Reprod Med. 2013;31(2):144-149.