Nyas_1434007.dvi

Endometriosis and Infertility
Epidemiology and Evidence-based Treatments
EBIHA OZKAN,a WILLIAM MURK,b AND AYDIN ARICI
aDepartment of Obstetrics and Gynecology, Kocaeli University School of Medicine,
bDepartment of Obstetrics, Gynecology and Reproductive Sciences, Yale University
School of Medicine, New Haven, Connecticut 06520, USA
Endometriosis is an estrogen-dependent disorder defined as the presence of endometrial tis-
sue outside of the uterine cavity. A leading cause of infertility, endometriosis has a prevalence
of 0.5–5% in fertile and 25–40% in infertile women. The optimal choice of management for
endometriosis-associated infertility remains obscure. Removal or suppression of endometrial
deposits by medical or surgical means constitutes the basis of endometriosis management. Cur-
rent evidence indicates that suppressive medical treatment of endometriosis does not benefit
fertility and should not be used for this indication alone. Surgery is probably efficacious for
all stages of the disease. Controlled ovarian hyperstimulation with intrauterine insemination
is recommended in early-stage and surgically corrected endometriosis when pelvic anatomy is
normal. In advanced cases, in vitro fertilization is a treatment of choice, and its success may
be augmented with prolonged gonadotropin-releasing hormone analog treatment. Further ran-
domized clinical trials focusing on diverse etiopathogenic mechanisms and therapeutic innova-
tion are necessary to find more conclusive, evidence-based answers regarding this enigmatic
disease.
Key words: endometriosis; infertility; epidemiology; evidence-based treatments
sis improve fertility? What course of treatment is mostsuitable for a subfertile woman presenting with en- Infertility is a distressing and frustrating symptom dometriosis? Answers to these questions will define the associated with endometriosis, and the optimal choice primary scope of this review, but first we provide a brief of management in the context of this disease remains overview of the epidemiology of this perplexing disease obscure. Endometriosis, defined as the presence of en- and its relationship to infertility.
dometrial tissue outside the uterine cavity, is in itself anenigmatic and multifaceted pathology, a puzzle whose manifold pieces remain largely disconnected despitesome decades of investigation. Although infertility and endometriosis are clearly connected, uncertainty per- The true prevalence of endometriosis remains ob- sists over the causal relation between the two.
scure. Variations in patient populations, methods and It is somewhat easy to understand how moderate– criteria of diagnosis, and an overall lack of well- severe endometriosis is associated with infertility, as it designed epidemiologic studies have made it difficult is a destructive disorder that results in considerable to arrive at confident figures for this disease. Estimates pain and anatomical distortion of pelvic organs.1,2 Yet of prevalence range up to 10% among the general pop- it is less clear how mild–minimal endometriosis might ulation,9 and large-scale studies suggest a prevalence impair fertility without pelvic distortion,3–5 although of 0.5–5% in fertile and 25–40% in infertile women.10 a number of theories exist.6–8 To what extent can the Other studies quote figures of 5–50% among the infer- treatment of the clinical manifestations of endometrio- tile population,11 and it has been reported that infertilewomen are 6–8 times more likely than fertile womento have the disease.12 A review by D'Hooghe et al. Address for correspondence: Aydin Arici, M.D., Department of Ob- concluded that the prevalence of endometriosis is sig- stetrics, Gynecology & Reproductive Sciences, Yale University School of nificantly higher in infertile than fertile women, and Medicine, 333 Cedar Street, New Haven, CT 06520-8063. Voice: +1-203-785-4018; fax: +1-203-785-7134.
that infertile women are more likely to have advanced stages of the disease.13 Ann. N.Y. Acad. Sci. 1127: 92–100 (2008). C
2008 New York Academy of Sciences.
Ozkan et al.: Endometriosis-associated Infertility to altered risk of endometriosis. Smoking has been A growing body of evidence suggests that age, ge- found to create a hypoestrogenic state inversely re- netic factors, menstrual parameters, anthropometric lated with endometriosis,21 but others have found no measures, body habitus, lifestyle factors, environmen- association.16 Increased caffeine and alcohol consump- tal exposures, and a number of other characteristics tion has been associated with increased risk, whereas may play roles in the etiopathogenetic mechanisms of regular exercise reduces the risk of endometriosis.26 Although Signorello et al. did not find any relation- Endometriosis can be identified in women from ship to alcohol or smoking, they confirmed that exer- premenarche to postmenopause, and diagnoses have cising more than 4 h per week decreases the risk of been made in women ranging from 12 to 80 years of age. Regardless, endometriosis is foremost a disease of Exposure to polychlorinated biphenyl (PCB) and reproductive-age women, which may be explained by dioxin has been associated with endometriosis in stud- the estrogenic milieu strongly implicated in its patho- ies with rhesus monkeys, possibly through effects on the genesis, and it carries an average age of diagnosis of immune system.28 In humans, studies of toxin exposure 28 years.14 A positive correlation between age and risk as measured by serum levels have been contradictory.
of the disease has been noted, particularly at ages above Positive associations of PCB congeners, heavy metals, 30 and peaking in the early-to-mid 40s.15,16 chlorinated pesticides, and dioxin with endometriosis A genetic predisposition to endometriosis has been have been reported,29 although other studies found no supported by the high concordance of the disease association with organic pollutants,30 or found only among identical twins.17 A familial predisposition a nonsignificant doubling of risk with dioxin.31 In utero with no clear Mendelian inheritance, but rather with exposures may also determine a woman's risk of having multifactorial polygenic traits, has been identified endometriosis. Greater birth weight and breast-feeding in severe endometriosis,4 and a number of genetic were found to decrease endometriosis risk, while di- polymorphisms have been investigated.18,19 Although ethylstilbestrol exposure and multiple pregnancies in- Chatman et al. reported that there is no known racial or socioeconomic bias for the disease,20 it has been sug- Despite the fact that little is definitely known re- gested that Asian women are at higher risk than other garding the epidemiology of endometriosis, risk fac- races, with Black women at lower risk.16,21 However, tors for the disease appear to be related to increased this latter finding was attributed to a frequent misdiag- exposure to menstruation and body estrogen levels.
nosis of Black women as having pelvic inflammatory Further epidemiologic research is required to establish disease rather than endometriosis.22 new insights with respect to the etiopathogenesis of this Menstrual and reproductive factors associated with puzzling disorder.
increased risk of endometriosis include early menarche(≤11 years of age), short menstrual cycles (≤27 days), Endometriosis and Infertility heavy and long-lasting bleeding, reduced parity, and Although endometriosis is generally accepted to reduced lifetime duration of lactation.11,22,23 Cramer be related to infertility, its actual impact on fecundity and Missmer proposed a possible endometriosis phe- and the mechanisms underlying this effect are less notype of early menarche, short cycles, painful periods, clear. Unfortunately, well-designed scientific studies subfertility, and tall stature.11 are lacking on this issue.33 Fecundity, defined as the Taller and thinner women appear to have en- probability of a woman achieving a live birth in a dometriosis more frequently, consistent with higher given month, ranges from 0.15 to 0.20 in normal follicular-phase estradiol levels in taller women. Body couples and 0.02 to 0.10 in untreated women with weight, body mass index, and waist-to-hip ratio have endometriosis.34–36 Significantly lower 3-year cumu- been inversely correlated with endometriosis,22 al- lative conception rates in women with endometriosis though Missmer et al. did not find a relation with waist- compared with controls (36% vs. 54%),37 and reduced to-hip ratio.21 Interestingly, women with naturally red conception rates in women with endometriosis who hair may have an increased risk of endometriosis, pos- had donor inseminations to control for male and sibly associated with altered coagulation and immune coital factors have consistently shown a relation functions.24 Missmer et al. found no association with between decreased fertility and endometriosis.38 A red hair, although they concluded that this may de- variety of animal and human studies, including those pend on infertility status.25 involving assisted reproductive technology (ART), Lifestyle factors, such as smoking, exercise, and con- have also suggested lower pregnancy rates in cases of sumption of alcohol and caffeine, have been related endometriosis.39 A meta-analysis by Barnhart et al. Annals of the New York Academy of Sciences reported an endometriosis pregnancy rate that is half rupted pelvic anatomy have been reported to have that for tubal factor infertility.40 pregnancy rates near 0%; this disparity in fecundity Experience from IVF has indicated poor pregnancy between stages of endometriosis may confound the in- outcomes in endometriosis patients are associated with terpretation of various therapeutic modalities.
poor sperm function, poor ovarian reserve, reducedoocyte retrieval, lower oocyte and embryo quality, im- Medical Treatment of paired implantation with decreased endometrial re- ceptivity, and luteinized unruptured follicles, particu- Medical treatment of endometriosis typically in- larly in advanced-stage disease.41–43 However, contra- volves hormonal manipulation of the menstrual cycle dictory studies exist.44–46 ART outcomes in patients to create an amenorrheic state, thus producing an en- with endometriosis are also contradictory, with some vironment unfavorable to endometrial tissue. Dana- reporting decreased numbers of preovulatory follicles, zol, progestational drugs, gestrinone, oral contracep- reduced embryo transfers, decreased fertility rates, and tives, and gonadotropin-releasing hormone (GnRH) increased miscarriages,47 whereas others suggest sim- agonists (GnRHa) are conventionally used medical ilar results with control cases.48 Additionally, adverse agents. In addition, experimental medications, such as pregnancy outcomes, such as pregnancy loss, preterm selective estrogen receptor modulators, selective pro- delivery, preeclampsia, and intrauterine growth restric- gesterone receptor modulators, aromatase inhibitors, tion, have been demonstrated to occur more frequently GnRH antagonists, pentoxifylline, tumor necrosis in subjects with endometriosis.49 factor-α inhibitors, angiogenesis inhibitors, and ma-trix metalloproteinase inhibitors, hold the potential forgreater efficacy and flexibility with fewer side effects.
Evidence-based Management in
Evidence to date indicates that medical therapy is not of benefit for endometriosis-associated infertility. Acomprehensive 2007 Cochrane review by Hughes et al. Primary aims of endometriosis treatment are the re- examining 24 randomized controlled trials (RCTs) con- moval or reduction of ectopic endometrial implants, cluded that pregnancy outcomes did not improve from restoration of normal anatomy, hindrance of disease treatment with ovulation-suppression agents (includ- progression, and alleviation of symptoms. A broad ing danazol, GnRHa, medroxyprogesterone, gestri- spectrum of therapeutic options, including expectant none, and oral contraceptives) compared to placebo management, medical and surgical interventions alone (odds ratio [OR]: 0.79, 95% confidence interval [CI]: or in combination, and ART, have been used to address 0.54–1.14, P = 0.21) or no treatment (OR: 0.80, 95% the clinical sequelae of endometriosis.2,50,51 However, CI: 0.51–1.24, P = 0.32), and that none of the med- the efficacy of these options with regard to achieving ical agents was more efficacious or better than any conception success in endometriosis-associated infertil- other.36 These drugs merely serve to delay fertility in- ity is considerably variable and remains inadequately stead of increasing pregnancy rates; further, they are, explored, as reviewed below.
in themselves, detrimental for fecundity and carry sig-nificant costs and side effects. Therefore, they should Expectant Management be discouraged in the management of endometriosis- In spite of a significantly impaired pregnancy rate in associated infertility, with the possible exception of use comparison with the general population, patients with in in vitro fertilization (IVF). European Society of Hu- early-stage endometriosis without severe pelvic adhe- man Reproduction and Embryology (ESHRE) guide- sions are able to conceive spontaneously. A prospec- lines for the treatment of endometriosis-associated in- tive multicenter cohort study assessing 168 patients fertility state that hormonal suppression of ovarian with endometriosis undergoing expectant manage- function does not improve fertility in minimal–mild ment found that the monthly fecundity rate of 2.52 or more severe endometriosis, and should not be of- per 100 person-months did not differ significantly from fered for this reason alone (recommendation grade A, the fecundity of 263 women with unexplained infertil- evidence level 1a).57 ity.52 Other studies have found monthly fecundity rates Experimental medications that do not inhibit ovu- ranging between 0.14 and 0.45.53–55 Hull et al. reported lation can be used without a delay of attempted a cumulative pregnancy rate of 55% in 56 cases of conception. Pentoxifylline is a phosphodiesterase in- minimal–mild endometriosis after an expectant man- hibitor with anti-inflammatory properties and has agement of 18 months.56 However, cases of advanced- been investigated in infertile women with endometrio- stage endometriosis complicated with extremely dis- sis. A single small-scale RCT with 60 cases reported Ozkan et al.: Endometriosis-associated Infertility a nonsignificant increase in pregnancy rates with that a structural normalization of severely distorted pentoxifylline use (31% vs. 18.5% with placebo in a pelvic anatomy can improve conception outcomes, 12-month period),58 whereas a prospective, double- as supported by the above studies. Future RCTs are blind, randomized, placebo-controlled study did not needed to reach definitive answers on the efficacy of find any fertility improvement with the same med- surgery in advanced endometriosis.
ication.59 This latter study concluded that pentoxi-fylline did not enhance fertility or lessen recurrence in any stage of endometriosis. Other emerging drugs The value of surgical treatment in minimal–mild en- that do not suppress ovarian function and instead dometriosis is more controversial. In a Canadian RCT selectively target endometriotic lesions may yet hold of 341 infertile women (20–39 years of age) with stage promise, but current evidence based on the established I–II disease, 169 underwent diagnostic laparoscopy pharmacopoeia indicates that medical treatment of with no treatment and 172 underwent operative la- endometriosis-associated infertility is not effective and paroscopy with ablation or excision of endometrial should not be pursued.
implants. Subjects were followed up for 36 weeks post-operatively and for up to 20 weeks of gestation if they Surgical Treatment in conceived.54 The cumulative pregnancy rates and fe- cundity rates were found to be significantly higher in Restoration of disrupted pelvic anatomy is the main- surgically managed patients (30.7% vs. 17.7% for those stay of surgical treatment of endometriosis-associated with no treatment, OR: 1.7, CI: 1.2–2.6 and 4.7% vs.
infertility and involves the destruction of endometriotic 2.4%, OR: 1.9, CI: 1.2–3.1, respectively). There was deposits, removal of endometriomas, and adhesiolysis.
no evidence that outcomes were affected by method Laparotomy and laparoscopy are efficacious routes of of ablation by electrosurgery or laser delivery systems.
access for surgery, but laparoscopy has shorter hospi- However, contradictory conclusions were made by an talization, recovery, and return-to-work times, fewer Italian study, which involved a similar design but exam- adhesions, and greater patient comfort.60,61 Surgery is ined a smaller number of early-stage patients (n = 101), usually the treatment of choice to restore disrupted and followed pregnancies 1 year after laparoscopic in- pelvic anatomy and remove endometriomas in ad- tervention proceeding to live births.68 Live birth rates vanced stages,62,63 whereas the question of optimal were comparable in surgically treated and nontreated treatment remains more controversial in early stages subjects (19.6% vs. 22.2%, respectively). Neither of of the disease without anatomical distortion.
these studies was free of confounding factors. In theCanadian study, subjects were informed about the ran- Advanced Endometriosis domization, 10% of women in each group received Although few RCTs have examined the efficacy of fertility treatment or adhesiolysis, pregnancy rates in surgical approaches in advanced endometriosis, some control cases were lower than expected, the follow-up evidence indicates that surgery can be of value. Sev- period was less than 1 year, no distinction was made be- eral nonrandomized trials involving cases of severe en- tween active red lesions and nonactive black or fibrotic dometriosis have found a rise in pregnancy rates after white lesions, vascularization and mitotic activity were reparative surgery compared with rates of approxi- not taken into account, and mapping of lesions was mately 0% in untreated cases.64,65 A meta-analysis of not considered in the selection at the time. The Italian one quasi-randomized and five cohort studies reported study had a lower statistical power because its series that surgery may be of value to improve pregnancy was small (n = 54 operative surgeries vs. n = 47 diag- rates compared with no treatment or medical therapy, nostic laparoscopies), with patients distributed among but the heterogeneity of these studies unfortunately re- seven different centers. The patients had a longer du- duces the confidence of such a conclusion.35 Moreover, ration of infertility and slightly more extensive disease; two prospective randomized studies by Busacca et al. histologic confirmation was not requested; rates of and Soong et al. concluded that operative laparoscopy red, white, or black lesions were not recorded; and was beneficial for infertile women with advanced-stage vascularization and mitotic activity were not consid- endometriosis, although the latter study found a re- ered. Regardless, a meta-analysis of these two studies duced postoperative conception rate in women with concluded that surgery was of significant benefit in stage IV compared with stage III disease.66,67 ESHRE infertile patients with early-stage endometriosis (OR: guidelines state that data are insufficient regarding the 1.7, 95%, CI: 1.1–2.5).69 However, the degree of the efficacy of surgical treatment in cases of moderate– conferred benefit appears to be small: the number of severe endometriosis.57 Regardless, it seems intuitive women who must undergo surgery to achieve a single Annals of the New York Academy of Sciences additional pregnancy in these cases has been calcu- tive than expectant management in improving fertility lated as 7.7, which may be unacceptably high for some for endometriosis-associated infertility (recommenda- patients. ESHRE guidelines state that endometriotic tion grade A, evidence level 1b).57,75,77–79 lesion ablation with adhesiolysis improves fertility in Thus, it appears that no qualified evidence indicates minimal–mild endometriosis compared with diagnos- that fertility is enhanced by combination surgery with tic laparoscopy alone (recommendation grade A, evi- either preoperative or postoperative medical therapy, dence level 1a).57,70 and the conversion of theoretical advantages into prac-tical outcomes has hitherto been unfruitful. As with Combined Medical and Surgical Therapies medical treatment alone, medication combined with in Endometriosis-associated Infertility surgery may only serve to delay fertility.
Surgery combined with pre- and postoperative med- ical therapy represents a growing field of drug appli- Assisted Reproductive Technologies cation. Theoretically, preoperative medication may re- in Endometriosis-associated Infertility duce inflammation, vascularization, and implant size, Controlled Ovarian Hyperstimulation With or making for faster, easier, less traumatic surgery, with Without Intrauterine Insemination the possibility of surgical scheduling in any time of A number of randomized trials assessing the ef- cycle and the potential for complete eradication of ficacy of ovulation induction with or without in- the disease and decreased risk of postoperative ad- trauterine insemination (IUI) have found that ovu- hesions. However, drawbacks of combined therapy in- lation induction enhances fertility rates in cases of clude drug costs, side effects, and temporary regression endometriosis-associated infertility without distorted of endometrial foci allowing escape from laparoscopic pelvic anatomy or male factor infertility.4,53,80–82 recognition and ablation.
Guzick compared fecundity rates after randomizingpatients into intracervical insemination (ICI), IUI, Preoperative Medical Therapy gonadotropin induction/ICI, and gonadotropin in- The preoperative use of medication may be useful duction/IUI.83 Monthly fecundity rates were high- for reducing the severity of endometriosis. A prospec- est in the gonadotropin induction/IUI group (0.09), tive multicenter clinical trial by Audebert et al. re- followed by IUI (0.05), gonadotropin induction/ICI ported reductions in severity with preoperative com- (0.04), and ICI (0.02). A study by Adamson et al. re- pared with postoperative GnRHa treatment, although ported that monthly fecundity in infertile couples with surgical feasibility did not differ significantly.71 Nasal endometriosis was doubled with clomiphene citrate to application of GnRHa has revealed decreased inflam- approximately 7% per month, and quadrupled with mation, vascularization, severity, and endometrioma menotropins to 15%, compared with no treatment.84 growth,72 and a study by Muzii et al. found that preop- However, RCTs assessing superovulation with IUI in erative GnRHa can improve surgical performance.73 advanced-stage endometriosis are lacking. ESHRE However, in the absence of convincing evidence of im- guidelines conclude that IUI with ovarian stimulation provements in surgical feasibility and in fertility rate, improves fertility in minimal–mild endometriosis, but preoperative medication appears to be unjustified, as the effect of unstimulated IUI is not clear (recommen- the theoretical benefits do not seem to outweigh the dation grade A, evidence level 1b).57,81 It is important increased costs and rates of morbidity.
to note that, because ovarian stimulation may lead tothe progression of ovarian endometriosis, controlled Postoperative Medical Therapy ovarian hyperstimulation (COH) with IUI should be Postoperative medical therapy is another option in limited to a maximum of three to four cycles, and IVF- combined therapy, aiming to achieve resorption of embryo transfer should be preferred.85 residual deposits that cannot be surgically removed,destruction of microscopic implants, and reduction of Assisted Reproductive Technologies disease dissemination in case of endometrioma rup- in Endometriosis-associated Infertility ture. Three studies have evaluated the use of postopera- The impact of endometriosis on IVF outcomes re- tive medical therapy with GnRHa and raloxifene,74–76 mains uncertain. Some studies have reported IVF and other randomized trials have examined postopera- success rates in cases of endometriosis comparable tive ovarian suppression.73–75,77–79 None of these stud- with those of unexplained or tubal factor infertil- ies reported increased fertility rates with postoperative ity48,86,87 or improved outcomes with increasing dis- medication. ESHRE guidelines conclude that postop- ease stage,41 whereas other studies have found re- erative danazol or GnRHa treatment is not more effec- duced success rates.1,43,88 These inconsistent results Ozkan et al.: Endometriosis-associated Infertility may be attributable to laparoscopic oocyte retrieval rent medical therapy is not efficacious, and its use and inferior laboratory methodologies used in early should be discouraged as it may only serve to post- studies.4 A meta-analysis involving 22 nonrandomized pone conception. Laparoscopic surgery appears to be studies of IVF outcome found lower pregnancy rates in superior to expectant management or medical ther- patients with endometriosis compared with those with apy in minimal–mild endometriosis and may also be tubal factor infertility; it was reported that women with of benefit for patients with advanced endometriosis.
severe endometriosis were less likely to achieve preg- The quality of available evidence supporting the use nancy success than those with mild disease.40 Reduced of preoperative or postoperative medication combined oocyte retrieval, fertilization, and implantation rates with surgery is too poor to make a recommendation were also associated with endometriosis, and it has on such regimens. COH/IUI is a good option in mild been suggested that lower implantation rates in en- and surgically corrected disease. In patients with early- dometriosis may be attributable to diminished ovarian stage endometriosis, IVF outcomes are similar to those reserve rather than embryo quality or uterine receptiv- with unexplained or tubal factor infertility, and Gn- ity.89 An analysis of the Human Fertilisation and Em- RHa treatment combined with IVF may be useful for bryology Authority database suggested that IVF live more advanced disease.
birth rates are not adversely affected by endometriosis Further RCTs with rigorous scientific designs are compared with unexplained infertility.90 No evidence needed to establish a comprehensive evidence-based shows adverse effects of endometriosis on implantation approach to deciding among management strategies and pregnancy rates in patients undergoing intracyto- for endometriosis-associated infertility.
plasmic sperm injection.91 Several studies suggest that long-term treatment Conflicts of Interest
with GnRHa before IVF may improve fertility rates inadvanced-stage endometriosis by means of increased The authors declare no conflicts of interest.
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