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Evidence linked treatment for endometriosis-associated infertility

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 commonlyassociated with infertility. The true prevalence remains obscure due to overall lack of well-designed epidemiologicstudies. The disease has an enigmatic and multifaceted pathology which remains elusive despite decades ofinvestigation. Despite all the uncertainties, it is established that treatment of endometriosis can improve fertility insome cases. Medical therapy although useful in reducing the severity of other symptoms of endometriosis such aspain and menstrual disorders, is not efficacious to improve fertility. Laparoscopic surgery apart from establishing thediagnosis, appears to be superior to expectant management or medical therapy. Controlled ovarian stimulation withintrauterine insemination is recommended in early stage and surgically corrected endometriosis when pelvic anatomyis normal. In advanced cases or moderate disease with associated tubal or male factors, in vitro fertilization isa treatment of choice. Despite all treatments, pregnancy rates remain lower in these women compared to disease-free 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 oftissue lesions or nodules that are histologically similar tothe endometrium, but are present at sites outside the uterus.1

It is a chronic, often recurring disease of complex andunclear aetiology. Endometriosis is a highly variable condi-tion in terms of age and mode of presentation, range ofsymptoms, anatomical sites, response to treatment and like-lihood of recurrence.

Infertility is defined as failure to conceive after regularunprotected sexual intercourse for 1e2 years.2 The inci-dence and prevalence of endometriosis cannot be accuratelydetermined due to uncertainties in making a definite diag-nosis without laparoscopy. It is thought to affect upto5e10% of women of reproductive age. Amongst thosewomen presenting with infertility, it can be detected inabout 30e50% of all cases.3

DOES ENDOMETRIOSIS AFFECTINFERTILITY?

Although it is not uncommon to find varying degree ofendometriosis in parous women, there is ample evidencein literature to implicate endometriosis contributing to infer-tility. When surgically investigated, infertile women havea much larger chance of having endometriosis (21%) incomparison to women undergoing sterilization (6%).4 Ifthere is associated moderate to severe dysmenorrhoeawith infertility, there is 50% of chance of women havingendometriosis.5

The most convincing evidence comes from a prospectivestudy of therapeutic donor insemination in which monthlyfecundity was 0.12 in women without endometriosis and0.036 in those with minimal endometriosis.6 Similar results

Senior Consultant, Obstetrician & Gynaecologist, Infertility & ART Specialist, Clinical & Academic Coordinator, Department of IVF, IndraprasthaApollo Hospitals, Sarita Vihar, New Delhi 110076, India.email: [email protected]: 9.6.2012; Accepted: 2.7.2012; Available online: 7.7.2012Copyright � 2012, Indraprastha Medical Corporation Ltd. All rights reserved.http://dx.doi.org/10.1016/j.apme.2012.07.001

Apollo Medicine 2012 SeptemberVolume 9, Number 3; pp. 184e192 Review Article

after donor as well as husband’s sperm insemination inwomen with minimal to mild endometriosis whencompared to these with a normal pelvis have been shownin various others studies.7

Reduced pregnancy rates have been reported in womenwith endometriosis undergoing In Vitro Fertilization(IVF). Barnhart et al (2002) in a meta-analysis of 22 pub-lished studies concluded that pregnancy rate is almosthalf in these women when compared with tubal factorinfertility.8

Donor oocytes from women with endometriosis havebeen reported to yield lower pregnancy rates that thosefrom the healthy donors.9

PATHOGENIC MECHANISM IN ENDOMETRI-OSIS-ASSOCIATED INFERTILITY

The exact cause of infertility remains elusive and contro-versial. The possible mechanisms may be anatomicaldisruption or physiological-hormonal, chemical or immu-nological alterations. All aspects of reproductiveprocess e oocyte development, ovulation process, fertiliza-tion, embryo quality and implantation have been reported tobe adversely affected by endometriosis.10 Several cyto-kines, interleukins, oxidative stress markers, cellular adhe-sion markers and immunomodulators are beinginvestigated to decode the mysterious role of endometriosisin causing infertility. The current literature suggests a multi-factorial mechanism.

POSSIBLE CAUSES OF REDUCED FERTILITYIN 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 envi-ronment in women with endometriosis and linked this topoor quality oocytes. Few of these reported markers are11,12:

- Increased progesterone concentration in follicularfluid

- Increased concentration of IL-6, IL-Ib, IL-8- Increased expression of the TNFa in the culturedgranulosa 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 medi-ated by elevated concentrations of soluble Fas ligandin serum and peritoneal fluid.

EFFECT ON ENDOMETRIAL RECEPTIVITY

Pellicer et al (2001)9 published a cross-over oocyte dona-tion study and concluded that it is the oocyte quality andnot endometrial receptivity, that plays a role in diminishedpregnancy rates in women with endometriosis. However,a study analyzing a cohort of 170 oocyte donors reportedno significant effects but a trend for reduced pregnancyrates in recipient cycles if the donor had endometriosisand a trend for reduced implantation rates in recipientswith endometriosis, suggesting a potential mild effect ofendometriosis on both the uterine environment and thequality of the oocyte.13

There is increasing evidence to support the hypothesesthat endometriosis is primarily an “endometrial” disease.Multiple functional and microanatomical abnormalitieshave been demonstrated within endometrium. The keyfunctional anomalies appear to be the expression of intra-cellular adhesions molecules, the presence of local aroma-tase enzyme activity, decreased apoptosis, increasedangiogenesis and increased neurogenesis.1

The available data suggests that both-development ofoocytes & embryos and endometrial receptivity can becompromised in women with endometriosis.

DIAGNOSIS OF ENDOMETRIOSIS IN INFER-TILE WOMEN

- The most common presenting complaints includechronic pelvic pain, dysmenorrhoea, dyspareunia, dys-chezia (pain on defecation) and low back pain. Onphysical examination localized pelvic tenderness withor without a mass/nodularity is often demonstrable.Uterus may be fixed and retroverted due to adhesions.

- Pelvic transvaginal ultrasound although limitedby its non-specificity, is very useful in detecting

Treatment for endometriosis-associated infertility Review Article 185

endometriomas (chocolate cyst) and in monitoring itssize in response to therapy.

- CT scan and MRI pelvis are other non-surgical diag-nostic tools used to identify the presence and theextent of deeply infiltrating lesions. These are espe-cially useful in detecting bowel and uretericinvolvement.

- The “gold standard” for diagnosis remains direct visu-alization of endometrial lesions using laparoscopy,ideally with histopathological confirmation by biopsyof excised endometriotic tissue. Classic lesions arered, blue-black powder burn appearance, white ornon-pigmented patches.

- Serum CA 125 levels may be elevated in endometri-osis. However, the test’s performance in diagnosingall disease stages is limited with an estimated sensi-tivity of only 28% and specificity of 90%. Comparedwith laparoscopy, measuring serum CA 125 levels,has no value as a diagnostic tool (Grade Arecommendation).

STAGING OF ENDOMETRIOSIS

Although various classification systems have beenproposed to standardise the criteria for severity of symp-toms, no system so far has received universal acceptance.Based on revised American Society for Reproductive Medi-cine (ASRM)14 (Fig. 1) endometriosis can be classified intofour different stages:Stage I (minimal) 1e5 (Revised ASRM scoring system)Stage II (mild) 6e15Stage III (moderate) 16e40Stage IV (severe) >40

EVIDENCE-BASED TREATMENT OFENDOMETRIOSIS-ASSOCIATEDINFERTILITY

A number of treatment options are available to treat infer-tility 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

EVIDENCE-BASED MEDICINE

Grade A recommendation is based on good evidence ob-tained from meta-analysis of randomized controlled trials(RCT) e Evidence level Ia or at least one RCT e Evidencelevel IB.15

Grade B recommendation is based on well controlledclinical studies (CT, cohort, case-control) but no RCT(Evidence levels IIa, IIb and III).

Grade C recommendation is based primarily onconsensus and expert opinion (evidence level IV).

Good practice point e Based on clinical experience ofthe guideline development group.

PROBLEMS IN THE EVALUATION OF TREAT-MENT OPTIONS FOR ENDOMETRIOSIS-ASSOCIATED INFERTILITY

- Any management should be compared to expectantmanagement

- The monthly fecundity rate (MFR) is more meaning-ful 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 womanachieving pregnancy in a given month, ranges from 0.15to 0.20 in normal couples and 0.02 to 0.10 in untreatedwomen with endometriosis.16

It is well known that monthly fecundity is lower inwomen with endometriosis than in women without thiscondition. The reduced fertility rates are shown in Table 1.17

As some women especially with mild to moderate endome-triosis will conceive spontaneously, when comparing theeffectiveness of any therapy for infertility, this needs tobe considered.

Medical therapies

The medical treatment of endometriosis involves suppress-ing oestrogen/progesterone levels to prevent cyclicalchanges and menstruation. Depending upon their mode ofaction these agents can be classified under 3 categories(Table 2).18 Although these medical therapies are helpfulin reducing the severity of pain and menstrual disorders

186 Apollo Medicine 2012 September; Vol. 9, No. 3 Verma

Fig. 1


associated with endometriosis, these are not shown to beeffective in the treatment of infertility.

The value of ovarian suppression with danazol, medrox-yprogesterone acetate or gestrinone versus placebo/no treat-ment has been assessed in a Cochrane review.16 The oddsratio for pregnancy following ovulation suppression versusplacebo or no treatment was 0.74 (95% CI 0.48e1.15).These data were statistically homogeneous, despite theuse of a variety of suppression agents. The odds ratio forpregnancy following all agents versus danazol, the mostcommonly used agent prior to the advent of GnRHagonists, was 1.3 (95% CI 0.97e1.76).

Commonly used ovulation suppression agents have beenknown to cause significant adverse effects such as weightgain, hot flushes and bone loss.

Clearly, there is no evidence to support the use ofovarian suppression agents in the treatment of endometri-osis-associated infertility (Table 3). More harm than goodmay result from treatment, because of adverse effects andthe lost opportunity to conceive.

RecommendationsSuppression of ovarian function to improve fertility in min-imalemild endometriosis is not effective and should not beoffered for this indication alone. There is no evidence of itseffectiveness in more severe disease either (Grade ARecommendation).7,15

Surgical management

When endometriosis causes mechanical distortion of thepelvis, surgery is usually indicated to restore the normalpelvic anatomy. However, no RCTs are available to givea definitive answer whether surgery enhances the preg-nancy rates.

Laparoscopy is the preferred surgical approach due to40% lower risks than that of laparotomy.19 The goal ofsurgery is to remove endometriotic lesions as much aspossible, restore normal anatomy with adhesiolysis andoptimize ovarian and tubal preservation and integrity. Exci-sion or cystectomy is preferred over fenestration, drainageor ablation of the cyst lining for the treatment of an ovarianendometriomas.

There are several power sources used in endoscopicsurgery such as electrocautery (mono or bipolar), CO2 laser,Fibre lasers (KTP, argon, Nd YAG), diode laser, Harmonicscalpel or Helica thermal coagulator. No significant differ-ence in pregnancy rates using different power source hasbeen reported.19 Use of adhesion-prevention adjuncts may

Table 2 Medical therapy for endometriosis.18

Suppression of ovulation/oestrogen Direct action on endometriotic deposits Immunomodulation

Oral contraceptive pill Progesterone antagonists (Mifepristone, Onapristone) Inflammatory modulatorsDanazol SPRMs (Selective Progesterone Receptor Modulators) e

AsoprisnilMatrix metallo-proteinase inhibitors(MMP)

Gestrinone SERMs (Selective Oestrogen Receptor Modulators) eRaloxifene

Anti TNF Alfa Therapy (Pentoxi-fyllineetc.)

(GnRH) Gonadotrophin releasinghormoneagonists or antagonists

Aromatase inhibitors (Letrozole, Anastrozole)

Aromatase inhibitors ER ligands (Estrogen Receptor beta agonists)Progestogen & (Medroxyprogesteroneetc.)

Angiogenesis inhibitors

Table 3 Cumulative pregnancy rates following ovariansuppression for endometriosis (CPR).5

Notherapy

Ovariansuppression

Pvalue

Thomas et al., 1987 (RCT)(Gestrinone)

24% 25% NS

Bayer et al., 1988 (RCT)(Danazol)

57.4% 37.2% NS

Telimaa et al., 1988 (RCT)(Danazol)

46% 33% NS

Telimaa et al., 1988 (RCT)(MPA)

46% 42% NS

Fedele et al., 1992 (RCT)(Buserelin)

61% 37% NS

Table 1 Spontaneous conception in women withendometriosis.17

Degree ofendometriosis

Cumulative preg-nancy rate (CPR)

Monthly fecundityrate (MFR)

Mild 52.9% 5.7%Moderate 25% 3.2%Severe 0% 0%All cases 24.4% 3.1%


help to reduce adhesion formation but improvement infertility is unknown.20

Recommendations- Ablation of endometriotic lesions plus adhesiolysis toimprove fertility in minimalemild endometriosis iseffective compared with diagnostic laparoscopy alone(Grade A Recommendation).

- The role of surgery in improving pregnancy rates formoderate to severe disease is uncertain (Grade BRecommendation).

- There is no universal consensus, but generally cystec-tomy for ovarian endometriomas is considered betterthan drainage and coagulation (Grade A recommen-dation) and has less chance of recurrence.

Combined medical & surgical therapy

Surgery combined with pre and postoperative medicaltherapy represents a growing field of drug application.Theoretically, preoperative medication may reduce inflam-mation, vascularization, and implant size, making thesurgery faster, easier and less traumatic, and the potentialfor complete eradication of the disease and decreased riskof postoperative adhesions.

However, drawbacks of combined therapy include drugcosts, side effects, and temporary regression of endometrialfoci allowing escape from laparoscopic recognition andablation.21

Preoperative medical therapyThe preoperative use of medication may be useful forreducing the severity of endometriosis. A prospectivemulticenter clinical trial by Audebert et al21 reported reduc-tions in severity with preoperative compared with postoper-ative GnRHa treatment, although surgical feasibility did notdiffer significantly. Nasal application of GnRHa hasrevealed decreased inflammation, vascularization, severity,and endometrioma growth. However, in the absence ofconvincing evidence of improvements in surgical feasibilityand in fertility rate, the use of preoperative medication iscontroversial.

Postoperative medical therapyPostoperative medical therapy is another option incombined therapy, aiming to achieve resorption of residualdeposits that cannot be surgically removed, destruction ofmicroscopic implants, and reduction of disease dissemina-tion in case of endometrioma rupture. Few studies haveevaluated the use of postoperative medical therapy with

GnRHa. None of these studies reported increased fertilityrates with postoperative medication. ESHRE guidelinesconclude that postoperative danazol or GnRHa treatmentis not more effective than expectant management inimproving fertility for endometriosis-associated infertility(Grade A recommendation, Evidence level 1b).7

Sandwich therapyd Medical-surgical-medical therapy

Recommendations

- Cochrane review 2007 documents no benefit ofhormonal suppression before or after surgery.16

- The opinion on pre-surgical medical therapy iscontroversial.21 In some reports pre-surgical medicaltherapy showed a significant improvement in preg-nancy rates.22,23

- Post-surgical hormonal suppression has no beneficialeffect on pregnancy rates after surgery15 (Grade Arecommendation).

Combined ovarian stimulation (COS) with orwithout Intrauterine Insemination (IUI)

- Several RTCs have shown significant higher clinicalpregnancy rates with COS & IUI treatment comparedto no treatment.7 However the presence of endometri-osis is shown to reduce treatment effectiveness of IUIby approximately half (OR 0.45), when comparedwith similar treatment in disease-free women.24

- In general, repetitive COS þ IUI cycles showa plateau effect after 3e4 cycles, therefore patientsmust be counselled to switch to IVF after 3e4cycles.7

- IUI plus gonadotrophins have been shown to signifi-cantly increase live birth rates in at least two RCTs.One RCT2 reported 29% live birth rates with IUIand gonadotrophins in comparison to 8% with notreatment. The other cross-over RCT2 found thatalternate cycles of gonadotrophins plus IUI had19% pregnancy rates versus 0% with IUI alone.

Recommendation- Treatment with IUI improves fertility in minimal tomild endometriosis. IUI with ovarian stimulation iseffective but the role of unstimulated IUI is uncertain(Grade A recommendation).


Assisted Reproduction Techniques (ART)

In Vitro Fertilization (IVF) is appropriate treatment, espe-cially if tubal function is compromised, if there is alsomale factor infertility and/or other treatments have failed(Grade B recommendation). It represents an effectivemeans to bypass the hostile peritoneal environment andanatomic distortion associated with endometriosis.However, a meta-analysis of published studies suggeststhat IVF pregnancy rates are lower in patients with endome-triosis than in those with tubal infertility.8 The reviewincluded 22 studies, consisting of 2377 cycles in womenwith 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, implan-tation rate, mean number of oocytes retrieved and peak oes-tradiol concentrations were also significantly lower inendometriosis group.

Although both GnRH antagonist and GnRH-analogueprotocols for IVF/ICSI are equally effective in terms ofimplantation and clinical pregnancy rates, GnRH-analoguemay be preferred because of the availability of more M IIoocyts and embryos.25

Use of ultralong (3e6 months) prior to IVF in a group ofpatients with significantly high proportion patients classi-fied as moderate to severe endometriosis, showed higherpregnancy rates23 (Grade A recommendation).

SURGERY FOR ENDOMETRIOMA-BEFOREART RECOMMENDED OR NOT?

The presence of an endometriotic cyst in women under-going ART supposedly has a negative influence on theresults although the literature is far from consistent onthis point.7 The advantage of surgery has to be weighedagainst the disadvantage of the loss of ovarian tissue con-taining follicles close to the cyst.

Recommendations

- NICE guidelines 20042 e if endometrioma <3 cmwith reasonable amount of normal ovarian stromaand antral follicles e it should be left alone andIVF 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 ovariancystectomy before IVF is recommended for

endometriomas �4 cm in diameter. Women shouldbe counselled regarding the risks of reduced ovarianfunction after surgery.

- ESHERE guidelines 2008 e laparoscopic ovariancystectomy in patients with unilateral endometriomasbetween 3 and 6 cm in diameter before IVF/ICSI candecrease ovarian response without improving cycleoutcome e (Evidence level IB).

- As per the evidence available, there is no significantdifference in the clinical pregnancy rate by adoptingno intervention or medical or surgical option inwomen with endometriomas.27

Based on above reports, there is insufficient evidence torecommend surgical treatment of endometriomas beforeIVF/ICSI cycles.

There are exceptions e such as pelvic pain (possibilityof intensifying during COHS), presence of hydrosalpingsand large endometriomas especially when doubts existabout their exact nature, where surgery before ART shouldbe undertaken.28

Large randomized trials are needed. In the meantimedecisions need to be taken on a comprehensive and individ-ualised basis.

Aspiration of endometrioma prior to IVF remains anothercontroversial issue. Traditionally it has been advised to avoidaspiration due to risk of infection, however, Suganuma et al(2002) compared the aspiration to surgery and no treatmentand found higher fertilization rate in aspiration group.29

SUMMARY

Based on currently available evidence, the stage wise treat-ment of endometriosis associated with infertility can besummarized as given below:

Management of minimal to mild endometriosiswith infertility

- Ablation of endometriotic lesions plus adhesiolysis atthe time of diagnostic laparoscopy is recommended(Grade A Recommendation).

- Suppression of ovarian function using drugs (OCpills, progestational agents, danazol, GnRH agonists)is of no benefit to infertile woman and delays poten-tial conceptions (Grade A Recommendation).

- Considering age, ovarian reserve and excluding maleand tubal factors, option to try naturally for 3e6cycles can be offered.

- Treatment with IUI is shown to improve fertility inminimal to mild endometriosis. Therefore controlled


ovarian Stimulation and IUI is recommended for 3e4cycles. If there is still no conception e IVF/ICSIshould be advised.

- In older patients, reduced ovarian reserve or associ-ated male/tubal factor e early resort to IVF/ICSI isadvised.

Management of moderate to severe endome-triosis with infertility

- Medical therapy alone is ineffective in restoring thefertility in women with endometriosis (Grade Arecommendation).

- The role of surgery in improving pregnancy rates formoderate to severe disease is uncertain (Grade Brecommendation).

- Laparoscopic cystectomy for ovarian endometriomais better than drainage and coagulation (Grade Arecommendation). However, loss of normal ovariantissue should be minimized.

- Laparoscopy surgery to assess exact extent of thedisease and surgical excision (drainage and excisionof pseudo-cyst wall) as best as possible with ablationand adhesiolysis should be considered.

- The role of preoperative hormonal therapy iscontroversial.

- Postoperative hormonal treatment has no beneficialeffect on pregnancy rates after surgery (Grade Arecommendation).

- IVF is an effective treatment of infertility in thesewomen and this should be offered at an early stagewhile ovarian reserve is still optimal. However,patients must be counselled for lower rate of preg-nancy as compared to non-disease IVF patients.

- Young patients with good ovarian reserve and nomale or tubal factor should be offered 2e3 cyclesof COS þ IUI before proceeding to IVF/ICSI.

Management of severe/deep infiltrating endo-metriosis or recurrent endometriosis followingprevious surgery with infertility

- GnRH agonist depot for 3e6 months followed by IVF/ICSI (Ultralong protocol) is shown to increase the rateof clinical pregnancy (Grade A Recommendation).

CONCLUSION

Endometriosis is commonly associated with infertility. Theexact pathogenic mechanism remains elusive and current

literature suggests a multifactorial mechanism. In theabsence of any clear understanding or cure for this enigmaticmedical disorder, it is important to be flexible in diagnosticas well as therapeutic approach. Expectant management maybe a reasonable approach in younger patients with earlystage disease and a shorter duration of infertility. The coupleshould be involved in decision making at all stages and treat-ment must be individualized taking into account all medicaland surgical therapeutic available options. Further RCTs arenecessary to find more conclusive answers and remedies totreat this challenging disorder.

CONFLICTS OF INTEREST

The author has none to declare.

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