Evidence linked treatment for endometriosis-associated infertility

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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.

Transcript of Evidence linked treatment for endometriosis-associated infertility

  • 1.Evidence linked treatment for endometriosis-associated infertility

2. Apollo Medicine 2012 September Volume 9, Number 3; pp. 184e192Review ArticleEvidence linked treatment for endometriosis-associated infertility Sohani VermaABSTRACT Endometriosis e dened 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 efcacious 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 linkedEndometriosis is conventionally dened 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 dened 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 denite 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.3DOES ENDOMETRIOSIS AFFECT INFERTILITY? Although it is not uncommon to nd 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 resultsSenior Consultant, Obstetrician & Gynaecologist, Infertility & ART Specialist, Clinical & Academic Coordinator, Department of IVF, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110076, India. email: [email protected] Received: 9.6.2012; Accepted: 2.7.2012; Available online: 7.7.2012 Copyright 2012, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2012.07.001 3. Treatment for endometriosis-associated infertilityafter donor as well as husbands 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.9Review Article185- Increased progesterone concentration in follicular uid - 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 uid.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 implantationPOOR 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 signicant 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 xed and retroverted due to adhesions. - Pelvic transvaginal ultrasound although limited by its non-specicity, is very useful in detecting 4. 186Apollo Medicine 2012 September; Vol. 9, No. 3endometriomas (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 inltrating 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 conrmation 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 tests performance in diagnosing all disease stages is limited with an estimated sensitivity of only 28% and specicity 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 classication 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 classied into four different stages: Stage Stage Stage StageI (minimal) II (mild) III (moderate) IV (severe)1e5 (Revised ASRM scoring system) 6e15 16e40 >40EVIDENCE-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 techniquesVermaEVIDENCE-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 F