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<p>Endometriosis</p><p>and Infertility</p><p>KRISTINJ.HOLOCH,MDandBRUCEA.LESSEY,MD,PHD</p><p>Department of Obstetrics and Gynecology, Greenville Hospital</p><p>System, Greenville, South Carolina</p><p>Abstract:Endometriosis is an enigmatic disease affect-</p><p>ing up to 10% of reproductive-aged women causing</p><p>pain and infertility. Up to 50% of women with</p><p>endometriosis are infertile, and agreement about</p><p>treatment options has been difficult to establish. The</p><p>association between endometriosis and infertility</p><p>is derived from comparisons of fertile and infertile</p><p>women, animal models, donor sperm studies, and</p><p>in vitro fertilization results. Diagnostic approaches</p><p>based on endometrial changes associated with endo-</p><p>metriosis are also providing insights into possible</p><p>mechanisms of infertility, especially in women with</p><p>milder forms of the disease. Treatment of endometrio-</p><p>sis, including surgical ablation or resection, is cost-</p><p>effective and offers the potential for improvement in</p><p>cycle fecundity. Medical management of endometrio-</p><p>sis-associated infertility has not been proven outside</p><p>of in vitro fertilization.</p><p>Key words: endometriosis, infertility, endometrium,</p><p>implantation, uterine receptivity</p><p>Introduction</p><p>Infertility is defined as the inability to</p><p>conceive after 1 year of unprotected inter-</p><p>course and is a problem confronted by 1</p><p>in 5 couples, estimated to affect up to 7.3</p><p>million couples in theUnited States alone.</p><p>The underlying causes of infertility are</p><p>multifactorial, involving both men and</p><p>women. Given the complexity of sexual</p><p>reproduction in humans coupled with the</p><p>myriad of disorders affecting both men</p><p>and women, the number of possible struc-</p><p>tural, hormonal, and physiologic factors</p><p>that contribute to a couple’s difficulty in</p><p>achieving or maintaining a pregnancy is</p><p>large.1 For practical purposes, there are 5</p><p>major categories that account for the in-</p><p>fertility in most couples seen in the clinic.</p><p>These include (1) male factor infertility,</p><p>(2) structural or biochemical problems</p><p>involving the cervix, (3) blocked or da-</p><p>maged fallopian tubes or abnormalities</p><p>within the uterus or endometrium, (4)</p><p>ovulatory dysfunction, and (5) peritoneal</p><p>factors including pelvic adhesions and</p><p>endometriosis. The goal of this paper is</p><p>to examine the contribution of endome-</p><p>triosis in the context of human fertility,</p><p>review its diagnosis and treatment, and</p><p>discuss how the heterogeneous nature</p><p>of this enigmatic disease has limited our</p><p>progress in establishing effective treat-</p><p>ment strategies for infertility.</p><p>Endometriosis is defined as the pre-</p><p>sence of endometrial epithelial and/or</p><p>stromal cells outside the uterine cavity.</p><p>The relationship between endometriosis</p><p>and infertility is generally accepted, but</p><p>the mechanism of action resulting in</p><p>www.clinicalobgyn.com | 429</p><p>Correspondence: Bruce A. Lessey, MD, PhD, Depart-</p><p>ment of Obstetrics and Gynecology, Greenville Hospital</p><p>System, Greenville, SC 29605. E-mail: blessey@ghs.org</p><p>CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 53 / NUMBER 2 / JUNE 2010</p><p>CLINICAL OBSTETRICS AND GYNECOLOGY</p><p>Volume 53, Number 2, 429–438</p><p>r 2010, Lippincott Williams & Wilkins</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p><p>decreased cycle fecundity remains unpro-</p><p>ven. Endometriosis is less common in</p><p>fertile women than those with infertility</p><p>and is found in 2% to 8% of the general</p><p>population. Endometriosis is present in</p><p>25% to 40% of women with infertility2,3</p><p>and 30% to 50% of women with endome-</p><p>triosis are infertile. Despite intense and</p><p>sustained research efforts, the associa-</p><p>tion between infertility and endometriosis</p><p>remains controversial. Although severe</p><p>endometriosis distorts pelvic anatomy</p><p>and reduces fertility by mechanical means,</p><p>mild endometriosis is commonly found</p><p>in female partners of couples with inferti-</p><p>lity. Tomany, it seems biologically implau-</p><p>sible that small surface implants of spent</p><p>endometrium would result in near com-</p><p>plete sterility. One of many obstacles to</p><p>the study of endometriosis has been its</p><p>heterogeneity and the variations in the</p><p>phenotype between women who have this</p><p>disorder. Although some women with en-</p><p>dometriosis conceive easily, others seem</p><p>completely sterile.</p><p>There are general conclusions that have</p><p>emerged over the past 75 years of research</p><p>on endometriosis and infertility. First, the</p><p>effect on fertility seems to be dose depen-</p><p>dent, with more severe disease having a</p><p>more profound adverse effect. According</p><p>to Olive, expectant management alone</p><p>allows 50% of patients with mild disease</p><p>to conceive, whereas 25% with moderate</p><p>endometriosis and only a few with severe</p><p>disease are successful.4 Further, it is now</p><p>well established that in women with</p><p>endometriosis there are alterations in the</p><p>eutopic endometrium, suggesting that the</p><p>endometriotic implants somehow com-</p><p>municate with the native endometrium.</p><p>Specific defects in the eutopic endome-</p><p>trium of women with endometriosis may</p><p>be the smoking gun for its effect on ferti-</p><p>lity, especially in mild disease, and is</p><p>now the focus of exciting new research</p><p>on endometriosis.5,6 Furthermore, the</p><p>changes in the endometrium of women</p><p>with this disorder may contribute to the</p><p>pathophysiology of this disease and its</p><p>tendency to worsen or recur.</p><p>Risk Factors and</p><p>Endometriosis</p><p>Theories on the cause and pathogenesis</p><p>of endometriosis are numerous. The most</p><p>widely accepted is the transplantation</p><p>theory of retrograde menstruation. Most</p><p>women exhibit bloody peritoneal fluid</p><p>during their menstrual cycles suggesting</p><p>that retrograde efflux of menstrual blood</p><p>is common. When endometrial tissue</p><p>enters the pelvis through patent fallo-</p><p>pian tubes, viable cells can be deposited</p><p>onto gravity-dependent peritoneal sur-</p><p>faces and survive long enough to attach</p><p>and establish a blood supply. Although</p><p>most women have some reflux of men-</p><p>strual blood, not all develop endometrio-</p><p>sis. Endometrial cells and menstrual</p><p>debris that enter the pelvis must be re-</p><p>moved by the immune system, primarily</p><p>the macrophages; remaining endometrial</p><p>cells can remain on the peritoneal surface</p><p>or invade into the retroperitonal spaces.</p><p>Alternatively, the ovary is a rich source</p><p>of estrogen and also a favorite place</p><p>for endometriosis to become established.</p><p>In the ovary, cysts form that contain old</p><p>blood (endometriomas) that can rupture</p><p>and cause severe pain. These cysts may</p><p>interfere with normal ovulation and are</p><p>one type of endometriosis that is visible</p><p>on ultrasound.</p><p>Endometriosis is considered an in-</p><p>flammatory condition, supported by the</p><p>cascade of events after retrograde men-</p><p>struation, affecting nerves and causing</p><p>dysfunction of the bladder, gastrointest-</p><p>inal tract, and ovaries. Inflammatory</p><p>changes within the peritoneal fluid may</p><p>contribute to changes within the endome-</p><p>trium becoming detrimental to fertility.</p><p>Shed endometrium has been shown to</p><p>enter the lymphatics and vasculature.</p><p>Althoughmost endometriosis is relatively</p><p>430 Holoch and Lessey</p><p>www.clinicalobgyn.com</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p><p>noninvasive, other more aggressive forms</p><p>of endometriosis have been reported, re-</p><p>sembling the behavior of metastatic can-</p><p>cers. The types of implants that have been</p><p>described include the nearly invisible</p><p>and opague lesions, red or white lesions,</p><p>and the classic powderburn lesions and</p><p>alterations in the peritoneum, referred to</p><p>as ‘‘Allen Masters windows.’’ Endome-</p><p>triosis is capable of recruiting blood ves-</p><p>sels, a phenomenon that can sometimes</p><p>be useful for identifying subtle lesions at</p><p>laparoscopy.</p><p>The epidemiologic factors for the devel-</p><p>opment of endometriosis are numerous</p><p>(Table 1).7 Women at risk for endometrio-</p><p>sis include those with no prior pregnancy,</p><p>women with</p><p>a suboptimum immune re-</p><p>sponse, women with excessive vaginal</p><p>bleeding including short-cycle interval or</p><p>prolonged bleeding episodes and women</p><p>with obstruction of their cervical os. Ad-</p><p>ditionally, women with existing endome-</p><p>triosis seem to be at risk for recurrence or</p><p>exacerbation of their disease. Existing sites</p><p>of endometriosis may be those in which</p><p>newly deposited menstrual shedding can</p><p>attach and later invademore easily. Genet-</p><p>ics seem to play a role in the occurrence</p><p>of endometriosis. Reduced physical activ-</p><p>ity and higher body mass index (BMI) is</p><p>associated with endometriosis and higher</p><p>socioeconomic status. Certain psychologic</p><p>traits, race, and age also seem to influence</p><p>the incidence of this disease. Environmen-</p><p>tal exposures including dioxins have also</p><p>been implicated in endometriosis.</p><p>Signs and Symptoms</p><p>of Endometriosis</p><p>The association between endometriosis</p><p>and unexplained infertility is quite high.</p><p>The diagnosis of endometriosis is often</p><p>suspected when no other reason for infer-</p><p>tility can be established. Aside from in-</p><p>fertility, endometriosis can present with</p><p>dysmenorrhea or other pelvic symptoms,</p><p>typically before or at the onset of menses.</p><p>Symptoms include urinary frequency</p><p>or worsening irritable bowel syndrome-</p><p>related complaints. Abnormal spotting or</p><p>light bleeding days before the next anti-</p><p>cipated menstrual flow has been shown to</p><p>be associated with endometriosis. Dys-</p><p>pareunia or pain with bowel movement</p><p>(dyschezia) are other signs of this disease.</p><p>A delay in the diagnosis of endometrio-</p><p>sis is more common in the United States</p><p>than in other countries. This is important,</p><p>as treatments for infertility may not be</p><p>as effective in the presence of undiagno-</p><p>sed endometriosis. In vitro fertilization</p><p>(IVF), for example, is often not covered</p><p>by insurance and might be less effective in</p><p>couples in which the female partner has</p><p>undiagnosed and untreated endometrio-</p><p>sis.8 Paradoxically, when endometriosis is</p><p>discovered and resected in patients with</p><p>unexplained IVF failure, many of these</p><p>women conceive naturally without the</p><p>need for IVF. Understanding the cause</p><p>of painful symptoms or delayed fertility is</p><p>a key to the early identification and reso-</p><p>lution of this problem but also is psycho-</p><p>logically beneficial for infertile couples</p><p>who do not know what treatment to</p><p>try next.</p><p>Diagnosis of Endometriosis</p><p>Laparoscopy is currently the only reliable</p><p>method to diagnose endometriosis. The</p><p>decision to carry out laparoscopy can be</p><p>a challenge, as women without signs or</p><p>symptoms of endometriosis can still har-</p><p>bor the disease.9 In addition, endometrio-</p><p>sis canmasquerade as other entities, and is</p><p>commonly found in women who carry the</p><p>diagnosis of irritable bowel syndrome or</p><p>interstitial cystitis. The prevalence of en-</p><p>dometriosis depends on the clinical pre-</p><p>sentation, experience of the surgeon, year</p><p>of the surgery, type of equipment used,</p><p>and even time of the menstrual cycle</p><p>in which the surgery is carried out. The</p><p>Endometriosis and Infertility 431</p><p>www.clinicalobgyn.com</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p><p>likelihood of finding endometriosis is also</p><p>dependent on the clinical reasons for</p><p>the surgery. In general, endometriosis is</p><p>more frequently diagnosed in the setting</p><p>of pelvic pain and infertility.</p><p>There is growing evidence that subtle</p><p>lesions, red or opaque lesions, or even</p><p>invisible endometriotic implants can con-</p><p>tribute to infertility or pain. Red lesions</p><p>are now thought to constitute a more</p><p>active form of endometriosis than pow-</p><p>derburn lesions and these surface lesions</p><p>have direct contact with the peritoneal</p><p>milieu. Changes in peritoneal fluid (PF)</p><p>in endometriosis is the subject of over 100</p><p>studies, and could logically contribute to</p><p>infertility that accompanies mild endome-</p><p>triosis. There is also evidence that the infla-</p><p>mmatory environment of endometriosis</p><p>contributes to endometrial dysfunction</p><p>leading to the development of progester-</p><p>one resistance.</p><p>At surgery, the recognition of subtle or</p><p>mild endometriosis is influenced by the</p><p>experience and bias of the operator. Some</p><p>endometriosis can be almost invisible and</p><p>represents the far end of the continuum</p><p>between a normal pelvis and stage IV</p><p>disease.10 Several studies have suggested</p><p>that very mild disease is common in all</p><p>women but that increasing amounts may</p><p>be required to see effects on fertility.</p><p>Other diagnostic methods include a posi-</p><p>tive response toGnRH agonist therapy as</p><p>a nonsurgical indicator that endometriosis</p><p>is present. Various biomarkers have been</p><p>investigated for the nonsurgical diagnosis</p><p>of-endometriosis including CA-125, auto-</p><p>endometrial antibodies, and members</p><p>of the integrin family of proteins.11 The</p><p>TABLE 1. Risk Factors for Endometriosis in Reproductive Aged Women</p><p>Factor Category Proposed Mechanism</p><p>Exposure to dioxin, other</p><p>toxins</p><p>Environmental Alterations in steroid hormone effects/</p><p>estrogen action</p><p>Job/profession Environmental Exposures to environmental factors (?)</p><p>Age General Incessant menstruation/ more opportunity</p><p>for retrograde menstruation</p><p>Higher socioeconomic status General Delayed or less frequent pregnancies/stress</p><p>or immune dysfunction</p><p>Psychologic traits General Stress/may relate to socioeconomic factors</p><p>Gynecologic procedures Iatrogenic Cervical treatments (LEEP/Cryotherapy/cold</p><p>knife cone) can cause cervical stenosis</p><p>Frequent or longer menstrual</p><p>cycles</p><p>Menstrual</p><p>characteristics/</p><p>Endocrine</p><p>Greater retrograde menstruation/higher risk</p><p>of exposure to menstrual blood</p><p>Low parity Menstrual</p><p>characteristics/</p><p>Endocrine</p><p>Less exposure to progesterone/more</p><p>menstrual cycles, less cervical dilation</p><p>Route of delivery</p><p>(C/S vs vaginal)</p><p>Menstrual</p><p>characteristics/</p><p>Endocrine</p><p>Less opportunity for cervical dilation/greater</p><p>retrograde menstruation</p><p>Reduced exercise/BMI Menstrual</p><p>characteristics/</p><p>Endocrine</p><p>Heavier or prolonged menses/anovulatory</p><p>bleeding (PCOS)</p><p>Genetics Systemic factors Unknown factor(s) related to genetics</p><p>Müllerian defects Systemic factors Abnormal muscle contraction/smaller or</p><p>stenotic cervical opening/greater retrograde</p><p>menstruation</p><p>Existing endometriosis Systemic factors Altered endometrial phenotype/pelvic</p><p>characteristics/aromatase production</p><p>432 Holoch and Lessey</p><p>www.clinicalobgyn.com</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p><p>endometrial integrin profile has been</p><p>used as a predictor of a woman’s ability</p><p>to conceive as well and the absence of</p><p>the a v/b 3 integrin suggests that implan-</p><p>tation defects may be related to mild</p><p>endometriosis. Finally proteomics and</p><p>genomics are now establishing the basis</p><p>for future biomarker development related</p><p>to endometriosis.5,6,12</p><p>Infertility and Mild</p><p>Endometriosis</p><p>In normal couples the probability of</p><p>achieving a pregnancy in any single</p><p>month is 15% to 20% [monthly cycle</p><p>fecundity rate (MFR) of 0.15 to 0.2],</p><p>whereas untreated women with endome-</p><p>triosis, conceive less frequentlywithMFR</p><p>less than 0.05.10,13 Efforts to develop sta-</p><p>ging systems that standardize the degree</p><p>of endometriosis have been faulted for</p><p>not predicting outcomes related to ferti-</p><p>lity. Recently, the factors that contribute</p><p>to the endometriosis-associated effects on</p><p>fertility have been formulated into a new</p><p>staging paradigm.14 Timewill tell whether</p><p>this system is reproducibly accurate and</p><p>clinically useful. Ongoing concerns with</p><p>any staging system have been the variable</p><p>effect of surgery on outcomes and the</p><p>vagueness related to laparoscopic find-</p><p>ings and treatments. Despite a lack of</p><p>solid epidemiologic evidence to support</p><p>an association between endometriosis and</p><p>infertility,15 several lines of evidence sup-</p><p>port its associationwith infertility,</p><p>even in</p><p>its mildest forms.</p><p>The first line of evidence that endo-</p><p>metriosis causes infertility was based on</p><p>prevalence data comparing endometriosis</p><p>in fertile controls and women with unex-</p><p>plained infertility.2,3 Women undergoing</p><p>tubal sterilization have been an ideal</p><p>fertile control group to study. D’Hooghe</p><p>pointed out that the prevalence of endo-</p><p>metriosis for fertile women was 4% com-</p><p>paredwith 33% in the infertile population.</p><p>Of those with the disease, 58% had mimi-</p><p>mal ormilddisease and32%hadmoderate</p><p>or severe endometriosis.9</p><p>The second line of evidence is based on</p><p>studies using animal models that replicate</p><p>this association between endometriotic</p><p>implants and subfertility.9,16 D’Hooghe</p><p>showed that MFR was lower in baboons</p><p>with mild, moderate, and severe endome-</p><p>triosis compared with animals that did</p><p>not harbor the disease. In prospectively</p><p>created endometriosis, researchers have</p><p>shown a rapid biochemical change in the</p><p>eutopic endometrium of baboons after</p><p>induction of endometriosis, suggesting a</p><p>possible communication between the ex-</p><p>trauterine and intrauterine environment.</p><p>These studies point toward endometrial</p><p>receptivity defects as the cause of de-</p><p>creased fecundity.</p><p>A third line of evidence is based on the</p><p>collective experience with donor sperm in</p><p>couples with severe male factor infertility.</p><p>Normal annualized pregnancy rate using</p><p>donor insemination was reported to vary</p><p>by age but ranged from 54% to 75%with</p><p>an average MFR of 0.054% to 0.13%</p><p>with donor insemination. Uncontrolled</p><p>trials have reported a normal MFR of</p><p>0.20 and clinical pregnancy rate of 80%</p><p>in women with untreated endometriosis,</p><p>but prospective trials have been more</p><p>convincing that endometriosis causes</p><p>problems with fertility.9 For example, a</p><p>MFR of 0.12 was seen in normal women</p><p>compared with a 0.036 in women with</p><p>mild endometriosis receiving donor sperm.</p><p>Using frozen donor sperm in a prospective</p><p>randomized study design, others showed</p><p>that both intracervical and intrauterine</p><p>insemination was more successful in wo-</p><p>menwithout endometriosis comparedwith</p><p>those with this disease.</p><p>Data from Assisted Reproductive</p><p>Technologies (ART) including hyper-</p><p>stimulation and IVF provides the fourth</p><p>line of evidence for an association. In an</p><p>early meta-analysis, Hughes showed that</p><p>women with endometriosis had a worse</p><p>prognosis than women with male factor</p><p>Endometriosis and Infertility 433</p><p>www.clinicalobgyn.com</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p><p>infertility using gonadotropin hypersti-</p><p>mulation and IUI treatment.17 Surgical</p><p>treatment versus expectant management</p><p>provides a favorable outcome for women</p><p>with endometriosis receiving gonado-</p><p>trophins and intrauterine insemination</p><p>(IUI). In IVF, the reports have been mixed,</p><p>with some centers observing a detrimental</p><p>effect of endometriosis whereas others find</p><p>no adverse effect of endometriosis on suc-</p><p>cess rates.9 Meta-analyses suggests that</p><p>endometriosis has a dose effect, reducing</p><p>IVF success rates in a direct relationship to</p><p>stage of disease.18 Confounding these stu-</p><p>dies is the effect of downregulation of the</p><p>menstrual cycle before IVF using GnRH</p><p>analogs, as they might interfere with the</p><p>negative effect of endometriosis on cycle</p><p>outcome by suppressing the activity of the</p><p>disease.Long luteal suppressionwithGnRH</p><p>analogs before gonadotropins seem to be</p><p>an effective treatment and improves out-</p><p>comes compared with cycles in which</p><p>shorter courses of luteal suppression were</p><p>used.19</p><p>The association between endometriosis</p><p>and infertility or pregnancy loss seems to</p><p>depend on when the diagnosis is made.</p><p>For example, women with endometriosis</p><p>were more likely to have spontaneous</p><p>pregnancy loss, if the losses were assessed</p><p>before laparoscopy was carried out. After</p><p>diagnosis of endometriosis, no effect of</p><p>endometriosis on pregnancy loss was re-</p><p>ported. A second phenomenon related</p><p>to the decade that the study was con-</p><p>ducted.9,15 Surgeries carried out before</p><p>1985, before nonpigmented lesions were</p><p>recognized, might affect the estimate of</p><p>prevalence and association between endo-</p><p>metriosis and infertility, compared with</p><p>more recent studies carried out after 1987.</p><p>Studies involving endometriosis and</p><p>infertility are highly variable with regards</p><p>to the character of the control group.</p><p>Women with proven fertility under-</p><p>going tubal ligation are frequently chosen</p><p>as the controls. Since the time from last</p><p>pregnancy to the time of sterilization is</p><p>directly associated with the likelihood of</p><p>finding endometriosis, many controls</p><p>could have developed endometriosis if</p><p>the interval is sufficiently long and may</p><p>no longer reflect the general population</p><p>of fertile women. Patients with endome-</p><p>triosis after laparoscopy can be highly</p><p>variable with regards to residual disease</p><p>and not be the same as women who have</p><p>endometriosis but have not yet had la-</p><p>paroscopy. Recurrence rates of 20% to</p><p>80% have been described in women ear-</p><p>lier diagnosed with endometriosis, mak-</p><p>ing it difficult to assess the effect of</p><p>treatment going forward from the time</p><p>of treatment. Studies examining the effect</p><p>of prior laparoscopy or medical treat-</p><p>ments must take into consideration the</p><p>effect of time as an important variable</p><p>that can alter the outcome results.</p><p>Heterogeneity of the observers is an-</p><p>other problem with studies involving</p><p>endometriosis. It is difficult to control</p><p>for operator experience, expertise, or</p><p>bias. Learned attitudes about what con-</p><p>stitutes ‘‘active’’ endometriosis can alter</p><p>the reporting of disease or influence how</p><p>aggressively endometriosis is excised or</p><p>cauterized. Methods for removing endo-</p><p>metriosis and ability of the operators also</p><p>vary. Centers with greater proficiency at</p><p>complete resection of implants including</p><p>removal of both deep nodular endome-</p><p>triosis and active red or nonpigmented</p><p>lesions will likely report different out-</p><p>comes compared with centers in which</p><p>only surface lesions are ablated or cauter-</p><p>ized.When comparing the effectiveness of</p><p>surgery, information on methodology, or</p><p>completeness of resection is not generally</p><p>available. If a small amount of endome-</p><p>triosis causes infertility, as some studies</p><p>suggest, then leaving a small amount</p><p>of endometriosis behind might be equiva-</p><p>lent to not carrying out the surgery</p><p>at all. Perhaps this is why recent studies</p><p>in which all endometriosis was completely</p><p>removed at the time of surgery8 report</p><p>better results than some larger studies that</p><p>434 Holoch and Lessey</p><p>www.clinicalobgyn.com</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p><p>did not use red or active lesions as entry</p><p>criteria in the study.20</p><p>Finally, the role of expectant manage-</p><p>ment is often not perceived as important.</p><p>Tanahatoe et al21 found no difference</p><p>in pregnancy outcome when comparing</p><p>laparoscopy (L/S) versus intrauterine</p><p>insemination (IUI) in women with un-</p><p>explained infertility. Almost 50% of pa-</p><p>tients that underwent IUI before L/S</p><p>conceived before surgery. Would the re-</p><p>sults have been different if the group that</p><p>conceived with expectant management</p><p>had been excluded before the initiation</p><p>of the study? Nowroozi et al,22 conducted</p><p>a study on L/S only after 8 months of</p><p>expectant management. They reported a</p><p>much greater benefit of L/S on fertility</p><p>than many other studies, illustrating the</p><p>importance of taking away those that</p><p>conceive easily. By excluding those that</p><p>do not really need surgery in the first place,</p><p>Nowrooziwas able to showa greater bene-</p><p>fit with fewer patients than other laparo-</p><p>scopic studies.20</p><p>This heterogeneity of response to en-</p><p>dometriosis and its variable effect on fer-</p><p>tility has also been a major obstacle when</p><p>comparing the effect of medical manage-</p><p>ment on endometriosis and infertility.</p><p>As reported earlier,19 medical treatment of</p><p>endometriosis has not been shown to have</p><p>a benefit for treating infertility. For mild</p><p>disease, it has been repeatedly showed</p><p>that about 50% of women will conceive</p><p>without therapy (similar to the report by</p><p>Tanahatoe et al above). When studies</p><p>using suppressive medications like GnRH</p><p>agonists are considered, the 6 months of</p><p>therapy will prevent pregnancy in those</p><p>that might otherwise have conceived on</p><p>their own with expectant management,</p><p>even if it was helpful for those that were</p><p>otherwise sterile. Thus, although 50% of</p><p>the patients may experience improvement</p><p>in cycle fecundity, the other 50% will</p><p>experience delay in the time to pregnancy.</p><p>As in the Nowroozi example provided</p><p>above, if the selection could be made</p><p>to include only those who are the most</p><p>affected by their endometriosis, a more</p><p>accurate assessment of medical therapies</p><p>might be possible. Surrey, using this ap-</p><p>proach in IVF failure patients showed</p><p>benefit, perhaps by excluding those that</p><p>did not need the treatment before entry</p><p>into the study.1 Thus the dogmatic conclu-</p><p>sion that medical therapy is not useful</p><p>might still be wrong.</p><p>How Does Endometriosis</p><p>Cause Infertility?</p><p>Despite a strong association between en-</p><p>dometriosis and infertility, a true cause</p><p>and effect relationship has yet to be estab-</p><p>lished. It seems implausible that mild</p><p>endometriosis could be the sole cause</p><p>of long-standing infertility. Furthermore,</p><p>diagnostic accuracy and effectiveness of</p><p>resection varies widely between operators</p><p>and between patients, resulting in a wide</p><p>range of reports related to the benefits of</p><p>treatment. The actual presence or absence</p><p>of disease is sometimes not well documen-</p><p>ted, and cannot always be adjudicated by</p><p>histologic confirmation, as pathologic</p><p>diagnosis frequently does not correlate</p><p>with laparoscopic findings.9Womenwith</p><p>endometriosis and infertility may be</p><p>subjected to sequential or combination</p><p>strategies. Outcomes may differ when</p><p>surgery is followed by ovulation induc-</p><p>tion, compared with expectant manage-</p><p>ment alone after surgery. During IVF</p><p>cycles, outcome might be affected by pro-</p><p>longed use of GnRH agonists or oral</p><p>contraceptives before the start of the</p><p>cycle. As a recurring disease, the effect</p><p>of any treatment might only be tempo-</p><p>rary, making conclusions difficult to</p><p>establish over time after treatment if the</p><p>disease recurs.</p><p>Some of the mechanisms that account</p><p>for the adverse effect endometriosis has</p><p>on fertility are listed in Table 2, and</p><p>includes altered folliculogenesis or ovula-</p><p>tion, defects in luteal phase function,</p><p>Endometriosis and Infertility 435</p><p>www.clinicalobgyn.com</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p><p>mechanical distortion of pelvic anatomy,</p><p>impaired oocyte release or pickup, altered</p><p>sperm quality or function, decreased em-</p><p>bryo quality, and disturbances in uterine</p><p>contractility. Peritoneal factors are dra-</p><p>matically altered in the presence of endo-</p><p>metriosis including inflammatory effects</p><p>associated with activated macrophages or</p><p>alteration of immune function or cytokine</p><p>production. PF factors have been shown</p><p>to adversely affect ovulation, fertililiza-</p><p>tion, embryo quality, and implantation.</p><p>Altered endocrine/cytokine milieu and</p><p>a new focus on progesterone resistance</p><p>has been reported in the endometrium of</p><p>women with endometriosis providing a</p><p>logical explanation for both the fertility</p><p>problems associated with endometriosis</p><p>and its pathophysiology.6 Progesterone is</p><p>a brake on the actions of estrogen and</p><p>is essential for the success of pregnancy;</p><p>progesterone resistance would account</p><p>for suspected implantation failure in wo-</p><p>men with infertility and endometriosis.</p><p>Structural and biochemical alterations in</p><p>the endometrium of women with endome-</p><p>triosis have also been described that support</p><p>these concepts. An increased proliferative</p><p>phenotype seen in the eutopic endome-</p><p>trium of women with endometriosis and</p><p>defects in apoptosis or programmed cell</p><p>death is consistent with a defect in pro-</p><p>gesterone action in affected individuals.</p><p>Future studies on the mechanisms of pro-</p><p>gesterone resistance are ongoing and focus</p><p>on the paracrine relationships and steroid</p><p>hormone signaling in women with endo-</p><p>metriosis.</p><p>Treatment of Infertility</p><p>and Endometriosis</p><p>As discussed above, the role of treatment</p><p>for infertility associated with endometrio-</p><p>sis remains controversial and should</p><p>begin with evidenced-based medicine.23 In</p><p>an early meta-analyses of cohort studies,</p><p>Adamson and Pasta reported that surgical</p><p>management seemed to have benefit for</p><p>the treatment of infertility,24 later con-</p><p>firmed by Hughes et al.13 Randomized</p><p>controlled trials (RCTs) have not showed</p><p>benefit for medical management of the</p><p>infertile women with endometriosis.19</p><p>Olive followed 123 patients with endome-</p><p>triosis and found that 45% conceived</p><p>TABLE 2. Proposed Mechanisms of Endometriosis on Fertility</p><p>Disruption Point of Action Proposed Mechanism</p><p>Oocyte production/</p><p>ovulation</p><p>Ovary/peritoneal fluid (PF) Mechanical or inflammatory effects</p><p>within the ovary of endometriomas</p><p>Gamete transport</p><p>or oocyte pickup</p><p>Peritoneal fluid/fallopian</p><p>tube function</p><p>Cytokine disturbances, expression difference</p><p>in factors that regulate tubal function</p><p>Embryo toxicity Inflammatory or toxic</p><p>effects of the PF on</p><p>gametes or embryos</p><p>Inflammation, hormonal disruption,</p><p>LH concentrations, macrophage activation</p><p>Sperm quality</p><p>or function</p><p>Peritoneal fluid or</p><p>fallopian tube</p><p>Inflammatory or toxic effects of the PF or</p><p>macrophages on sperm number or function</p><p>Disordered</p><p>myometrial</p><p>contractions</p><p>Uterus or fallopian tubes Gamete transport or embryo placement</p><p>Pelvic distortion</p><p>of anatomy</p><p>Uterus, tubes, ovaries, cervix Mechanical disruptions preventing sperm, egg</p><p>transport, fertilization, and embryo</p><p>transport</p><p>Luteal phase defect Endocrine Ovulatory dysfunction, progesterone</p><p>resistance</p><p>Endometrial</p><p>receptivity</p><p>Endocrine, inflammatory</p><p>cytokines</p><p>Progesterone resistance, aromatase</p><p>expression, other causes?</p><p>436 Holoch and Lessey</p><p>www.clinicalobgyn.com</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p><p>with EM after diagnosis of mild disease</p><p>but found only 20% conceive with</p><p>stage III disease and none with stage IV</p><p>endometriosis. Two RCTs to evaluate</p><p>pregnancy after laparoscopy were divided</p><p>in their findings, but meta-analysis sug-</p><p>gests a modest benefit of surgery on ferti-</p><p>lity for women with mild endometriosis.20</p><p>Controlled ovarian hyperstimulation</p><p>improves the chances for pregnancy in</p><p>women with endometriosis. Although</p><p>systematic reviews of 6 RCTs have shown</p><p>that intrauterine insemination (IUI) with</p><p>clomiphene citrate is superior to inter-</p><p>course in a natural cycle, IUI works best</p><p>for women with ovulatory problems but</p><p>is least successful in women with endo-</p><p>metriosis. Endometriosis has been listed</p><p>among the unfavorable predictors of</p><p>pregnancy in several large IUI studies.17</p><p>This was also showed in studies using</p><p>donor sperm for male factor infertility</p><p>comparing women with and without this</p><p>disease9 as discussed earlier in the chapter.</p><p>In general, IVF has proven benefit over</p><p>all other treatments. Although sporadic</p><p>reports suggested that endometriosis re-</p><p>duced the success rates in IVF, many</p><p>other reports found no effect on preg-</p><p>nancy or implantation rates. Barnhart</p><p>et al,18 conducted meta-analysis of IVF</p><p>and endometriosis and showed that only</p><p>severe endometriosis altered the outcome</p><p>of IVF treatments. Nevertheless, unex-</p><p>plained repetitive IVF failures sporadi-</p><p>cally occur and whereas they seem to be</p><p>associated with endometriosis, this may</p><p>affect the population unequally.8 No one</p><p>can tell which patients will be affected,</p><p>making the decision to carry out IVF</p><p>seem reasonable. In couples contemplat-</p><p>ing IVF, surgical diagnosis and correction</p><p>is probably indictated before any ART</p><p>procedure, although cost analyses dis-</p><p>agree. In women with repetitive IVF fail-</p><p>ure at least one study showed benefit to</p><p>laparoscopy, with many of these patients</p><p>conceiving without IVF once their endo-</p><p>metriosis had been treated.8 Conclusions</p><p>about the role of L/S before IVF seem</p><p>to depend on the point of view of the</p><p>observer and in many cases evidence in</p><p>the scientific literature will be found to</p><p>support all opinions.</p><p>Summary</p><p>The role of endometriosis in inferti-</p><p>lity remains controversial. Evidence from</p><p>many sources find that endometriosis,</p><p>even in its mildest forms can compromise</p><p>fertility. In contrast, expectant manage-</p><p>ment can result in pregnancy, albeit at a</p><p>lower cycle fecundity rate. On the basis of</p><p>best evidence, it would seem that endome-</p><p>triosis should be diagnosed and treated</p><p>when empiric or expectant management</p><p>fails orwhen other advanced reproductive</p><p>methods have not been successful. In-</p><p>creasing awareness of subtle forms of</p><p>endometriosis is providing greater insight</p><p>into the impact of mild disease on</p><p>reproductive health. Evidence for a bio-</p><p>chemical effect of endometriosis on the</p><p>endometrium resulting in resistance to</p><p>progesterone is providing a roadmap to</p><p>study the biologic mechanisms of endo-</p><p>metriosis and infertility. Future studies</p><p>must pay closer attention to the partici-</p><p>pants and their control groups, taking</p><p>into account the effect of heterogeneity</p><p>on treatments and outcomes. Biomarkers</p><p>that define subsets of patients affected</p><p>by endometriosis will likely improve our</p><p>ability to show the role of endometriosis</p><p>on fertility in women and further clarify</p><p>the mechanisms involved and direct</p><p>future therapies.</p><p>References</p><p>1. Strauss JF III, Lessey BA. The structure,</p><p>function and evaluation of the female re-</p><p>productive tract. In: Strauss JF III, Barbieri</p><p>RL, eds.Reproductive Endocrinology: Phy-</p><p>siology, Pathophysiology and Clinical Man-</p><p>agement. 6th Edition ed. New York: W.B.</p><p>Saunders Co; 2009: 191–233.</p><p>Endometriosis and Infertility 437</p><p>www.clinicalobgyn.com</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p><p>2. Strathy JH, Molgaard CA, Coulam CB,</p><p>et al. 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Am J Obstet Gynecol. 1994;171:</p><p>1488–1504.</p><p>438 Holoch and Lessey</p><p>www.clinicalobgyn.com</p><p>D</p><p>ow</p><p>nloaded from</p><p>http://journals.lw</p><p>w</p><p>.com</p><p>/clinicalobgyn by B</p><p>hD</p><p>M</p><p>f5eP</p><p>H</p><p>K</p><p>av1zE</p><p>oum</p><p>1tQ</p><p>fN</p><p>4a+</p><p>kJLhE</p><p>Z</p><p>gbsIH</p><p>o4X</p><p>M</p><p>i0</p><p>hC</p><p>yw</p><p>C</p><p>X</p><p>1A</p><p>W</p><p>nY</p><p>Q</p><p>p/IlQ</p><p>rH</p><p>D</p><p>3i3D</p><p>0O</p><p>dR</p><p>yi7T</p><p>vS</p><p>F</p><p>l4C</p><p>f3V</p><p>C</p><p>4/O</p><p>A</p><p>V</p><p>pD</p><p>D</p><p>a8K</p><p>2+</p><p>Y</p><p>a6H</p><p>515kE</p><p>=</p><p>on 09/16/2024</p>