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Evidence linked treatment for endometriosis-associated infertility

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Endometriosis is conventionally defined as the presence of …

Endometriosis is conventionally defined as the presence of
tissue lesions or nodules that are histologically similar to
the endometrium, but are present at sites outside the uterus.It is a chronic, often recurring disease of complex and unclear aetiology. Endometriosis is a highly variable condition in terms of age and mode of presentation, range of symptoms, anatomical sites, response to treatment and likelihood of recurrence.

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  • 1. Evidence linked treatment for endometriosis-associated infertility
  • 2. Apollo Medicine 2012 September Volume 9, Number 3; pp. 184e192 Review Article Evidence linked treatment for endometriosis-associated infertility Sohani Verma ABSTRACT Endometriosis e defined as the presence of tissue similar to endometrium outside the uterine cavity, is commonly associated with infertility. The true prevalence remains obscure due to overall lack of well-designed epidemiologic studies. The disease has an enigmatic and multifaceted pathology which remains elusive despite decades of investigation. Despite all the uncertainties, it is established that treatment of endometriosis can improve fertility in some cases. Medical therapy although useful in reducing the severity of other symptoms of endometriosis such as pain and menstrual disorders, is not efficacious to improve fertility. Laparoscopic surgery apart from establishing the diagnosis, appears to be superior to expectant management or medical therapy. Controlled ovarian stimulation with intrauterine insemination is recommended in early stage and surgically corrected endometriosis when pelvic anatomy is normal. In advanced cases or moderate disease with associated tubal or male factors, in vitro fertilization is a treatment of choice. Despite all treatments, pregnancy rates remain lower in these women compared to diseasefree controls. Further well structured randomized clinical trials are necessary to reach any conclusive answers. Copyright © 2012, Indraprastha Medical Corporation Ltd. All rights reserved. Keywords: Infertility, Endometriosis, Treatment, Evidence linked Endometriosis is conventionally defined as the presence of tissue lesions or nodules that are histologically similar to the endometrium, but are present at sites outside the uterus.1 It is a chronic, often recurring disease of complex and unclear aetiology. Endometriosis is a highly variable condition in terms of age and mode of presentation, range of symptoms, anatomical sites, response to treatment and likelihood of recurrence. Infertility is defined as failure to conceive after regular unprotected sexual intercourse for 1e2 years.2 The incidence and prevalence of endometriosis cannot be accurately determined due to uncertainties in making a definite diagnosis without laparoscopy. It is thought to affect upto 5e10% of women of reproductive age. Amongst those women presenting with infertility, it can be detected in about 30e50% of all cases.3 DOES ENDOMETRIOSIS AFFECT INFERTILITY? Although it is not uncommon to find varying degree of endometriosis in parous women, there is ample evidence in literature to implicate endometriosis contributing to infertility. When surgically investigated, infertile women have a much larger chance of having endometriosis (21%) in comparison to women undergoing sterilization (6%).4 If there is associated moderate to severe dysmenorrhoea with infertility, there is 50% of chance of women having endometriosis.5 The most convincing evidence comes from a prospective study of therapeutic donor insemination in which monthly fecundity was 0.12 in women without endometriosis and 0.036 in those with minimal endometriosis.6 Similar results Senior Consultant, Obstetrician & Gynaecologist, Infertility & ART Specialist, Clinical & Academic Coordinator, Department of IVF, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110076, India. email: sohaniverma@hotmail.com Received: 9.6.2012; Accepted: 2.7.2012; Available online: 7.7.2012 Copyright Ó 2012, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2012.07.001
  • 3. Treatment for endometriosis-associated infertility after donor as well as husband’s sperm insemination in women with minimal to mild endometriosis when compared to these with a normal pelvis have been shown in various others studies.7 Reduced pregnancy rates have been reported in women with endometriosis undergoing In Vitro Fertilization (IVF). Barnhart et al (2002) in a meta-analysis of 22 published studies concluded that pregnancy rate is almost half in these women when compared with tubal factor infertility.8 Donor oocytes from women with endometriosis have been reported to yield lower pregnancy rates that those from the healthy donors.9 Review Article 185 - Increased progesterone concentration in follicular fluid - Increased concentration of IL-6, IL-Ib, IL-8 - Increased expression of the TNFa in the cultured granulosa cells - Lower levels of cortisol - Lower concentrations of IGFBP-I - Lower levels of HCG receptors in granulosa cells - Increased rate of apoptosis in granulosa cells mediated by elevated concentrations of soluble Fas ligand in serum and peritoneal fluid. EFFECT ON ENDOMETRIAL RECEPTIVITY PATHOGENIC MECHANISM IN ENDOMETRIOSIS-ASSOCIATED INFERTILITY The exact cause of infertility remains elusive and controversial. The possible mechanisms may be anatomical disruption or physiological-hormonal, chemical or immunological alterations. All aspects of reproductive process e oocyte development, ovulation process, fertilization, embryo quality and implantation have been reported to be adversely affected by endometriosis.10 Several cytokines, interleukins, oxidative stress markers, cellular adhesion markers and immunomodulators are being investigated to decode the mysterious role of endometriosis in causing infertility. The current literature suggests a multifactorial mechanism. POSSIBLE CAUSES OF REDUCED FERTILITY IN WOMEN WITH ENDOMETRIOSIS (i) Tubal adhesions (ii) Impaired gamete interaction (iii) Reduced functional ovarian tissue (ovarian reserve) by endometriosis or surgery (iv) Poor quality of oocytes (v) Impaired fertilization (vi) Lower quality embryos with a reduced ability to implant (vii) Impaired implantation POOR QUALITY OF OOCYTES Several investigators have reported altered follicular environment in women with endometriosis and linked this to poor quality oocytes. Few of these reported markers are11,12: Pellicer et al (2001)9 published a cross-over oocyte donation study and concluded that it is the oocyte quality and not endometrial receptivity, that plays a role in diminished pregnancy rates in women with endometriosis. However, a study analyzing a cohort of 170 oocyte donors reported no significant effects but a trend for reduced pregnancy rates in recipient cycles if the donor had endometriosis and a trend for reduced implantation rates in recipients with endometriosis, suggesting a potential mild effect of endometriosis on both the uterine environment and the quality of the oocyte.13 There is increasing evidence to support the hypotheses that endometriosis is primarily an “endometrial” disease. Multiple functional and microanatomical abnormalities have been demonstrated within endometrium. The key functional anomalies appear to be the expression of intracellular adhesions molecules, the presence of local aromatase enzyme activity, decreased apoptosis, increased angiogenesis and increased neurogenesis.1 The available data suggests that both-development of oocytes & embryos and endometrial receptivity can be compromised in women with endometriosis. DIAGNOSIS OF ENDOMETRIOSIS IN INFERTILE WOMEN - The most common presenting complaints include chronic pelvic pain, dysmenorrhoea, dyspareunia, dyschezia (pain on defecation) and low back pain. On physical examination localized pelvic tenderness with or without a mass/nodularity is often demonstrable. Uterus may be fixed and retroverted due to adhesions. - Pelvic transvaginal ultrasound although limited by its non-specificity, is very useful in detecting
  • 4. 186 Apollo Medicine 2012 September; Vol. 9, No. 3 endometriomas (chocolate cyst) and in monitoring its size in response to therapy. - CT scan and MRI pelvis are other non-surgical diagnostic tools used to identify the presence and the extent of deeply infiltrating lesions. These are especially useful in detecting bowel and ureteric involvement. - The “gold standard” for diagnosis remains direct visualization of endometrial lesions using laparoscopy, ideally with histopathological confirmation by biopsy of excised endometriotic tissue. Classic lesions are red, blue-black powder burn appearance, white or non-pigmented patches. - Serum CA 125 levels may be elevated in endometriosis. However, the test’s performance in diagnosing all disease stages is limited with an estimated sensitivity of only 28% and specificity of 90%. Compared with laparoscopy, measuring serum CA 125 levels, has no value as a diagnostic tool (Grade A recommendation). STAGING OF ENDOMETRIOSIS Although various classification systems have been proposed to standardise the criteria for severity of symptoms, no system so far has received universal acceptance. Based on revised American Society for Reproductive Medicine (ASRM)14 (Fig. 1) endometriosis can be classified into four different stages: Stage Stage Stage Stage I (minimal) II (mild) III (moderate) IV (severe) 1e5 (Revised ASRM scoring system) 6e15 16e40 >40 EVIDENCE-BASED TREATMENT OF ENDOMETRIOSIS-ASSOCIATED INFERTILITY A number of treatment options are available to treat infertility in women with endometriosis. (i) Expectant management (ii) Medical therapy (iii) Surgical treatment (iv) Combined medical and surgical therapy (v) Controlled ovarian stimulation (COS) with or without Intrauterine Insemination (IUI) (vi) Assisted reproduction techniques Verma EVIDENCE-BASED MEDICINE Grade A recommendation is based on good evidence obtained from meta-analysis of randomized controlled trials (RCT) e Evidence level Ia or at least one RCT e Evidence level IB.15 Grade B recommendation is based on well controlled clinical studies (CT, cohort, case-control) but no RCT (Evidence levels IIa, IIb and III). Grade C recommendation is based primarily on consensus and expert opinion (evidence level IV). Good practice point e Based on clinical experience of the guideline development group. PROBLEMS IN THE EVALUATION OF TREATMENT OPTIONS FOR ENDOMETRIOSISASSOCIATED INFERTILITY - Any management should be compared to expectant management - The monthly fecundity rate (MFR) is more meaningful than the pregnancy rate (PR) - Few studies are controlled - Few studies report the fecundity rate - Techniques/skills differ - Recognition of “atypical” lesions Expectant management in endometriosis The fecundity defined as the probability of a woman achieving pregnancy in a given month, ranges from 0.15 to 0.20 in normal couples and 0.02 to 0.10 in untreated women with endometriosis.16 It is well known that monthly fecundity is lower in women with endometriosis than in women without this condition. The reduced fertility rates are shown in Table 1.17 As some women especially with mild to moderate endometriosis will conceive spontaneously, when comparing the effectiveness of any therapy for infertility, this needs to be considered. Medical therapies The medical treatment of endometriosis involves suppressing oestrogen/progesterone levels to prevent cyclical changes and menstruation. Depending upon their mode of action these agents can be classified under 3 categories (Table 2).18 Although these medical therapies are helpful in reducing the severity of pain and menstrual disorders
  • 5. Treatment for endometriosis-associated infertility Fig. 1 Review Article 187
  • 6. 188 Apollo Medicine 2012 September; Vol. 9, No. 3 Table 1 Spontaneous endometriosis.17 Degree of endometriosis Mild Moderate Severe All cases conception in women Verma with Cumulative pregnancy rate (CPR) Monthly fecundity rate (MFR) 52.9% 25% 0% 24.4% 5.7% 3.2% 0% 3.1% Table 3 Cumulative pregnancy rates following ovarian suppression for endometriosis (CPR).5 associated with endometriosis, these are not shown to be effective in the treatment of infertility. The value of ovarian suppression with danazol, medroxyprogesterone acetate or gestrinone versus placebo/no treatment has been assessed in a Cochrane review.16 The odds ratio for pregnancy following ovulation suppression versus placebo or no treatment was 0.74 (95% CI 0.48e1.15). These data were statistically homogeneous, despite the use of a variety of suppression agents. The odds ratio for pregnancy following all agents versus danazol, the most commonly used agent prior to the advent of GnRH agonists, was 1.3 (95% CI 0.97e1.76). Commonly used ovulation suppression agents have been known to cause significant adverse effects such as weight gain, hot flushes and bone loss. Clearly, there is no evidence to support the use of ovarian suppression agents in the treatment of endometriosis-associated infertility (Table 3). More harm than good may result from treatment, because of adverse effects and the lost opportunity to conceive. Recommendations Suppression of ovarian function to improve fertility in minimalemild endometriosis is not effective and should not be offered for this indication alone. There is no evidence of its effectiveness in more severe disease either (Grade A Recommendation).7,15 No therapy Thomas et al., 1987 (RCT) (Gestrinone) Bayer et al., 1988 (RCT) (Danazol) Telimaa et al., 1988 (RCT) (Danazol) Telimaa et al., 1988 (RCT) (MPA) Fedele et al., 1992 (RCT) (Buserelin) Ovarian suppression P value 24% 25% NS 57.4% 37.2% NS 46% 33% NS 46% 42% NS 61% 37% NS Surgical management When endometriosis causes mechanical distortion of the pelvis, surgery is usually indicated to restore the normal pelvic anatomy. However, no RCTs are available to give a definitive answer whether surgery enhances the pregnancy rates. Laparoscopy is the preferred surgical approach due to 40% lower risks than that of laparotomy.19 The goal of surgery is to remove endometriotic lesions as much as possible, restore normal anatomy with adhesiolysis and optimize ovarian and tubal preservation and integrity. Excision or cystectomy is preferred over fenestration, drainage or ablation of the cyst lining for the treatment of an ovarian endometriomas. There are several power sources used in endoscopic surgery such as electrocautery (mono or bipolar), CO2 laser, Fibre lasers (KTP, argon, Nd YAG), diode laser, Harmonic scalpel or Helica thermal coagulator. No significant difference in pregnancy rates using different power source has been reported.19 Use of adhesion-prevention adjuncts may Table 2 Medical therapy for endometriosis.18 Suppression of ovulation/oestrogen Oral contraceptive pill Danazol Gestrinone Direct action on endometriotic deposits Progesterone antagonists (Mifepristone, Onapristone) SPRMs (Selective Progesterone Receptor Modulators) e Asoprisnil SERMs (Selective Oestrogen Receptor Modulators) e Raloxifene Aromatase inhibitors (Letrozole, Anastrozole) (GnRH) Gonadotrophin releasing hormone agonists or antagonists Aromatase inhibitors ER ligands (Estrogen Receptor beta agonists) Progestogen & (Medroxyprogesterone Angiogenesis inhibitors etc.) Immunomodulation Inflammatory modulators Matrix metallo-proteinase inhibitors (MMP) Anti TNF Alfa Therapy (Pentoxi-fylline etc.)
  • 7. Treatment for endometriosis-associated infertility help to reduce adhesion formation but improvement in fertility is unknown.20 Recommendations - Ablation of endometriotic lesions plus adhesiolysis to improve fertility in minimalemild endometriosis is effective compared with diagnostic laparoscopy alone (Grade A Recommendation). - The role of surgery in improving pregnancy rates for moderate to severe disease is uncertain (Grade B Recommendation). - There is no universal consensus, but generally cystectomy for ovarian endometriomas is considered better than drainage and coagulation (Grade A recommendation) and has less chance of recurrence. Combined medical & surgical therapy Surgery combined with pre and postoperative medical therapy represents a growing field of drug application. Theoretically, preoperative medication may reduce inflammation, vascularization, and implant size, making the surgery faster, easier and less traumatic, and the potential for complete eradication of the disease and decreased risk of postoperative adhesions. However, drawbacks of combined therapy include drug costs, side effects, and temporary regression of endometrial foci allowing escape from laparoscopic recognition and ablation.21 Preoperative medical therapy The preoperative use of medication may be useful for reducing the severity of endometriosis. A prospective multicenter clinical trial by Audebert et al21 reported reductions in severity with preoperative compared with postoperative GnRHa treatment, although surgical feasibility did not differ significantly. Nasal application of GnRHa has revealed decreased inflammation, vascularization, severity, and endometrioma growth. However, in the absence of convincing evidence of improvements in surgical feasibility and in fertility rate, the use of preoperative medication is controversial. Postoperative medical therapy Postoperative medical therapy is another option in combined therapy, aiming to achieve resorption of residual deposits that cannot be surgically removed, destruction of microscopic implants, and reduction of disease dissemination in case of endometrioma rupture. Few studies have evaluated the use of postoperative medical therapy with Review Article 189 GnRHa. None of these studies reported increased fertility rates with postoperative medication. ESHRE guidelines conclude that postoperative danazol or GnRHa treatment is not more effective than expectant management in improving fertility for endometriosis-associated infertility (Grade A recommendation, Evidence level 1b).7 Sandwich therapy d Medical-surgical-medical therapy Recommendations - Cochrane review 2007 documents no benefit of hormonal suppression before or after surgery.16 - The opinion on pre-surgical medical therapy is controversial.21 In some reports pre-surgical medical therapy showed a significant improvement in pregnancy rates.22,23 - Post-surgical hormonal suppression has no beneficial effect on pregnancy rates after surgery15 (Grade A recommendation). Combined ovarian stimulation (COS) with or without Intrauterine Insemination (IUI) - Several RTCs have shown significant higher clinical pregnancy rates with COS & IUI treatment compared to no treatment.7 However the presence of endometriosis is shown to reduce treatment effectiveness of IUI by approximately half (OR 0.45), when compared with similar treatment in disease-free women.24 - In general, repetitive COS þ IUI cycles show a plateau effect after 3e4 cycles, therefore patients must be counselled to switch to IVF after 3e4 cycles.7 - IUI plus gonadotrophins have been shown to significantly increase live birth rates in at least two RCTs. One RCT2 reported 29% live birth rates with IUI and gonadotrophins in comparison to 8% with no treatment. The other cross-over RCT2 found that alternate cycles of gonadotrophins plus IUI had 19% pregnancy rates versus 0% with IUI alone. Recommendation - Treatment with IUI improves fertility in minimal to mild endometriosis. IUI with ovarian stimulation is effective but the role of unstimulated IUI is uncertain (Grade A recommendation).
  • 8. 190 Apollo Medicine 2012 September; Vol. 9, No. 3 Assisted Reproduction Techniques (ART) In Vitro Fertilization (IVF) is appropriate treatment, especially if tubal function is compromised, if there is also male factor infertility and/or other treatments have failed (Grade B recommendation). It represents an effective means to bypass the hostile peritoneal environment and anatomic distortion associated with endometriosis. However, a meta-analysis of published studies suggests that IVF pregnancy rates are lower in patients with endometriosis than in those with tubal infertility.8 The review included 22 studies, consisting of 2377 cycles in women with endometriosis and 4383 in women without the disease. After adjusting for confounding variables, there was a 35% reduction in the chance of achieving pregnancy (OR 0.63). Other outcome parameters such as fertilization rate, implantation rate, mean number of oocytes retrieved and peak oestradiol concentrations were also significantly lower in endometriosis group. Although both GnRH antagonist and GnRH-analogue protocols for IVF/ICSI are equally effective in terms of implantation and clinical pregnancy rates, GnRH-analogue may be preferred because of the availability of more M II oocyts and embryos.25 Use of ultralong (3e6 months) prior to IVF in a group of patients with significantly high proportion patients classified as moderate to severe endometriosis, showed higher pregnancy rates23 (Grade A recommendation). Verma endometriomas 4 cm in diameter. Women should be counselled regarding the risks of reduced ovarian function after surgery. - ESHERE guidelines 2008 e laparoscopic ovarian cystectomy in patients with unilateral endometriomas between 3 and 6 cm in diameter before IVF/ICSI can decrease ovarian response without improving cycle outcome e (Evidence level IB). - As per the evidence available, there is no significant difference in the clinical pregnancy rate by adopting no intervention or medical or surgical option in women with endometriomas.27 Based on above reports, there is insufficient evidence to recommend surgical treatment of endometriomas before IVF/ICSI cycles. There are exceptions e such as pelvic pain (possibility of intensifying during COHS), presence of hydrosalpings and large endometriomas especially when doubts exist about their exact nature, where surgery before ART should be undertaken.28 Large randomized trials are needed. In the meantime decisions need to be taken on a comprehensive and individualised basis. Aspiration of endometrioma prior to IVF remains another controversial issue. Traditionally it has been advised to avoid aspiration due to risk of infection, however, Suganuma et al (2002) compared the aspiration to surgery and no treatment and found higher fertilization rate in aspiration group.29 SUMMARY SURGERY FOR ENDOMETRIOMA-BEFORE ART RECOMMENDED OR NOT? The presence of an endometriotic cyst in women undergoing ART supposedly has a negative influence on the results although the literature is far from consistent on this point.7 The advantage of surgery has to be weighed against the disadvantage of the loss of ovarian tissue containing follicles close to the cyst. Recommendations - NICE guidelines 20042 e if endometrioma <3 cm with reasonable amount of normal ovarian stroma and antral follicles e it should be left alone and IVF carried out. - ASRM-200626 e if bilateral large endometriomas 4 cm counsel for surgical excision prior to IVF/ICSI. - RCOG Guidelines No 2415 e laparoscopic ovarian cystectomy before IVF is recommended for Based on currently available evidence, the stage wise treatment of endometriosis associated with infertility can be summarized as given below: Management of minimal to mild endometriosis with infertility - Ablation of endometriotic lesions plus adhesiolysis at the time of diagnostic laparoscopy is recommended (Grade A Recommendation). - Suppression of ovarian function using drugs (OC pills, progestational agents, danazol, GnRH agonists) is of no benefit to infertile woman and delays potential conceptions (Grade A Recommendation). - Considering age, ovarian reserve and excluding male and tubal factors, option to try naturally for 3e6 cycles can be offered. - Treatment with IUI is shown to improve fertility in minimal to mild endometriosis. Therefore controlled
  • 9. Treatment for endometriosis-associated infertility ovarian Stimulation and IUI is recommended for 3e4 cycles. If there is still no conception e IVF/ICSI should be advised. - In older patients, reduced ovarian reserve or associated male/tubal factor e early resort to IVF/ICSI is advised. Management of moderate to severe endometriosis with infertility - Medical therapy alone is ineffective in restoring the fertility in women with endometriosis (Grade A recommendation). - The role of surgery in improving pregnancy rates for moderate to severe disease is uncertain (Grade B recommendation). - Laparoscopic cystectomy for ovarian endometrioma is better than drainage and coagulation (Grade A recommendation). However, loss of normal ovarian tissue should be minimized. - Laparoscopy surgery to assess exact extent of the disease and surgical excision (drainage and excision of pseudo-cyst wall) as best as possible with ablation and adhesiolysis should be considered. - The role of preoperative hormonal therapy is controversial. - Postoperative hormonal treatment has no beneficial effect on pregnancy rates after surgery (Grade A recommendation). - IVF is an effective treatment of infertility in these women and this should be offered at an early stage while ovarian reserve is still optimal. However, patients must be counselled for lower rate of pregnancy as compared to non-disease IVF patients. - Young patients with good ovarian reserve and no male or tubal factor should be offered 2e3 cycles of COS þ IUI before proceeding to IVF/ICSI. Management of severe/deep infiltrating endometriosis or recurrent endometriosis following previous surgery with infertility - GnRH agonist depot for 3e6 months followed by IVF/ ICSI (Ultralong protocol) is shown to increase the rate of clinical pregnancy (Grade A Recommendation). CONCLUSION Endometriosis is commonly associated with infertility. The exact pathogenic mechanism remains elusive and current Review Article 191 literature suggests a multifactorial mechanism. In the absence of any clear understanding or cure for this enigmatic medical disorder, it is important to be flexible in diagnostic as well as therapeutic approach. Expectant management may be a reasonable approach in younger patients with early stage disease and a shorter duration of infertility. The couple should be involved in decision making at all stages and treatment must be individualized taking into account all medical and surgical therapeutic available options. Further RCTs are necessary to find more conclusive answers and remedies to treat this challenging disorder. CONFLICTS OF INTEREST The author has none to declare. REFERENCES 1. Fraser Ian S. Recognizing, understanding and managing endometriosis. J Hum Reprod Sci. 2008;1(2):56e64. 2. NICE Clinical GuidelinesFertility Assessment and Treatment to People with Fertility Problems. 2004;33. 73, 77. 3. Werbrouck E, Spiessens C, Meuleman C, D’Hooghe T. Surgical treatment of early endometriosis, unexplained infertility and fertility treatment outcomes. Fertil Steril. 2006;86:556e571. 4. Mahmoud, Templeton. Prevalence and genesis of endometriosis. Hum Reprod. 1991;6(4):544e549. 5. D’Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis and subfertility: is the relationship resolved? Semin Reprod Med. 2003;21:243e254. 6. Jansen RP. Minimal endometriosis and reduced fecundability: prospective evidence from an artificial insemination by donor programme. Fertil Steril. 1986;46(1):141e143. 7. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698e2704. 8. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77:1148e1155. 9. Pellicer A, Navarro J, Bosch E. Endometrial quality in infertile women with endometriosis. Ann N Y Acad Sci. 2001 Sep;943: 122e130. 10. Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A. Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril. 2008;90:247e257. 11. Bergquist A, Hooghe TD. Mini symposium on pathogenesis of endometriosis and treatment of endometriosis-associated subfertility. Hum Reprod Update. 2002;8(1):79e83. 12. Iwabe T, Harada T, Terakuwa N. Role of cytokines in endometriosis-associated infertility. Gynecol Obstet Invest. 2002;53:19e25.
  • 10. 192 Apollo Medicine 2012 September; Vol. 9, No. 3 13. Katsoff B, Check JH, Davies E, Wilson C. Evaluation of the effect of endometriosis on oocyte quality and endometrial environment by comparison of donor and recipient outcomes following embryo transfer in a shared oocyte program. Clin Exp Obstet Gynecol. 2006;33(4):201e202. Pubmed ID: 17214020. 14. Revised American Society for Reproductive Medicine classification of endometriosis. Fertil Steril. 1997;67:817e821. 15. Royal College of Obstetrician and Gynaecologists. The Investigation and Management of Endometriosis (Green Top Guidelines No. 24). London: RCOG; October 2008. 16. Hughes E, Fedorkow D, Collins J, Vandekerckhove P. Ovulation suppression for endometriosis. Cochrane Database Syst Rev; 2002 (4):CD001398. 17. Olive DL, Pritis EA. Treatment of endometriosis. N Engl J Med. 2001;345:265e275. 18. Panay N. Advances in medical management of endometriosis. BJOG. 2008;115:814e817. 19. Marcoux S, Maheux R, Bérubé S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med. 1997;337:217e222. 20. DeWilde RL, Trew RG. Post operative abdominal adhesions and their prevention in gynaecological surgery. Expert consensus position. Part 2 e steps to reduce adhesions. Gynecol Surg. 2007;4:243e253. 21. Ozkan S, Murk W, Arici A. Endometriosis and infertility. Ann N Y Acad Sci. 2008;1127:92e100. Verma 22. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. Effect of prolonged gonadotropin e releasing hormone agonist therapy on the outcome in vitro fertilization-embryo transfer in patients with endometriosis. Fertil Steril. 2002;78:699e704. 23. Sallam HN, Gar cia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006 Jan 25 (1):CD004635. 24. Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum Reprod. 1997;12:1865e1872. 25. Pabuccu R, Onalan G, Goktolga U, Kucuk T, Orhon E, Ceyhan T. Aspiration of ovarian endometriomas before intracytoplasmic sperm injection. Fertil Steril. 2004;82:705e711. 26. Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril. 2006;86(5 suppl I):156e160. 27. 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;81:1194e1197. 28. Somigliana E, Vercellini P, Vigano, et al. Should endometriomas be treated before IVF-ICSI cycles? Hum Reprod Update. 2006;12:57e64. 29. Suganuma N, Wakahara Y, Ishiada D, et al. Pretreatment for ovarian endometrial cyst before in vitro fertilization. Gynecol Obstet Invest. 2002;54:36e40.
  • 11. A o oh s i l ht:w wa o o o p a . m/ p l o p a : t / w .p l h s i lc l ts p / l ts o T ie: t s / ie. m/o p a A o o wt rht :t t r o H s i l p l t p /w t c ts l Y uu e ht:w wy uu ec m/p l h s i ln i o tb : t / w . tb . a o o o p a i a p/ o o l ts d F c b o : t :w wfc b o . m/h A o o o p a a e o k ht / w . e o k o T e p l H s i l p/ a c l ts Si s ae ht:w wsd s aen t p l _ o p a l e h r: t / w .i h r.e/ o o H s i l d p/ le A l ts L k d : t :w wl k d . m/ mp n /p l -o p a i e i ht / w . e i c c a y o oh s i l n n p/ i n no o a l ts Bo : t :w wl s l e l . / l ht / w . t a h a hi g p/ e tk t n