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Endometriosis and Infertility

Endometriosis and infertility

Robert L Barbieri, MD

INTRODUCTION — It is relatively simple to identify the cause of infertility in women with ovulatory disorders or tubal disease and men with semen abnormalities. These categories identify the cause of infertility in approximately 75 percent of couples. Endometriosis and unexplained infertility account for most of the other 25 percent of couples in whom ovulation is occurring, fallopian tubes are patent on hysterosalpingogram and normal semen parameters are present. Endometriosis may be present in 40 percent of the female partners of these couples.

Endometriosis refers to the presence of endometrial tissue outside of the uterus. It is surgically staged using the American Society of Reproductive Medicine staging system . Although commonly associated with an increased risk of infertility, endometriosis does not usually completely prevent conception. The mechanism for impaired fertility may involve both anatomic distortion from pelvic adhesions and endometriomas and the production of substances (eg, prostanoids, cytokines, growth factors) which are "hostile" to normal ovulation, fertilization, and implantation. The treatment of infertility associated with endometriosis is a combination of medical therapy, surgery, and assisted reproduction techniques.

DEFINITIONS AND INCIDENCE — Fertility refers to the capacity to conceive and produce offspring; infertility results when this capacity is diminished, but not necessarily absent. In contrast to sterility, infertility is not an irreversible state. Clinically, a couple is considered infertile if they are unable to conceive after 12 months of frequent coitus. This clinical definition implies the existence of a dichotomous state: either a pregnancy is achieved (no infertility) or not achieved (infertility) within 12 months. Approximately 13 percent of married couples 15 to 44 years old in the United States reported that they were infertile in surveys conducted in 1965 and 1985 [1,2].

Fecundability, the probability of achieving a pregnancy in one menstrual cycle, better reflects the wide range of fertility potential in couples. In prospective studies of fecundability in young healthy couples, fecundability is approximately 0.30 during the first two months of observation (30 percent of the couples will conceive each month in the first two months) . The observed fecundability decreases to approximately 0.15 from months three to five and 0.04 for months nine to 12. After the first year of attempting conception, the fecundability of couples that had not yet conceived (17 percent of the starting cohort) is 0.03 per month [3]. Therefore, effective fertility treatments for endometriosis should demonstrate an increase in the pregnancy rate above this baseline fecundability rate of approximately 0.03.

OVERVIEW OF THE CAUSES OF INFERTILITY — Pregnancy is the result of successful completion of a complex series of physiological events occurring in both the male and female that allows the implantation of an embryo in the endometrium. At a minimum, pregnancy requires ovulation and the production of a competent oocyte, production of competent sperm, proximity of the sperm and oocyte in the reproductive tract, fertilization, transport of the embryo into the uterine cavity, and implantation of the embryo into the endometrium.

Many disorders can decrease fecundability. Conditions such as azoospermia or anovulation have an absolute cause-effect relationship between the disease and the infertility. For other disorders and exposures, such as early stage endometriosis or cigarette smoking, there is an observed decrease in fecundability in association with the disease or exposure, but the precise cause-effect relationship is not unequivocally established. Therefore, the attribution of causes of infertility to a couple is subjective and influenced by the clinician's opinion as to the diseases that can cause infertility.

The World health Organization (WHO) task force on Diagnosis and Treatment of Infertility conducted a study of 8500 couples using a standardized diagnostic protocol [4]. In developed countries, diseases that were identified as contributing to the infertile state were attributed to the female partner, male partner, or to combined male-female factors in 37, 8, and 35 percent of couples, respectively. Another five percent of couples had no identifiable cause of infertility (unexplained infertility); the remaining 15 percent became pregnant during the infertility evaluation.

Infertility-related disorders most often identified in female and male partners from two series totaling over 22,000 couples are listed in Table 2. As discussed above, endometriosis is present in 40 percent of infertile, ovulatory women with normal fallopian tubes and with male partners whose semen analysis is normal.

HOW DOES ENDOMETRIOSIS CAUSE INFERTILITY? — Endometriosis is a heterogeneous disease spanning a spectrum from minimal disease (Stage I, characterized by small 1 to 5 mm implants on the pelvic peritoneum) to severe disease (Stage IV, characterized by obliteration of the cul-de-sac, deep ovarian endometriosis cysts and major pelvic adhesions).

Early stage endometriosis — Women with infertility and early stage endometriosis (minimal or mild disease) appear to have decreased fecundability, in the range of 0.03 (3 percent per cycle pregnancy rate). However, early stage disease has not been scientifically established as a definitive cause of infertility.

Functional abnormalities in peritoneal, tubal, and endometrial function are a potential mechanism linking infertility and minimal or mild endometriosis. Studies have shown that women with endometriosis have an increased volume of peritoneal fluid [5], increased peritoneal fluid concentration of activated macrophages [6], and increased peritoneal fluid concentration of prostaglandin, interleukin-1, tumor necrosis factor, and proteases [7]. These abnormalities in the peritoneal environment may impair gamete, embryo, and fallopian tube function. For example, peritoneal fluid from women with endometriosis has been reported to inhibit sperm function [8] and ciliary function [9], thereby possibly reducing fertility. This is also likely to occur in women with early stage disease.

Other studies have found elevated levels of anti-endometrial antibodies in women with endometriosis; these antibodies may impair endometrial function [10,11]. In addition, some women with early stage endometriosis have luteal phase dysfunction [12], abnormal follicle growth [13], multiple premature LH surges [14], and luteinized unruptured follicle syndrome, all of which may diminish fertility.

Lastly, eutopic endometrium may be abnormal in women with endometriosis and a müllerian tract "field defect" may be present. In one study, for example, endometrial expression of beta-3 integrin was significantly suppressed in women with stage I and II endometriosis [15]. Normal beta-3 integrin expression appears to be required for proper interaction between the embryo and endometrium; thus, abnormal expression of beta-3 integrin may be associated with reduced fertility.

Advanced stage endometriosis — Advanced endometriosis (moderate and severe disease, Stage III and Stage IV disease) has been demonstrated to cause infertility in laboratory animals. As an example, in one study the fertility of monkeys with experimentally induced endometriosis was compared to controls with adipose tissue autografts [16]. The pregnancy rate was similar in control monkeys and monkeys with minimal endometriosis (42 and 35 percent, respectively). By comparison, the pregnancy rate was reduced to 12 percent in animals with advanced endometriosis. Furthermore, the presence of ovarian adhesions lowered the pregnancy rate to 0. The major pelvic adhesions caused by advanced endometriosis may contribute to reduced fecundability by impairing egg release from the ovary, blocking sperm entry into the peritoneal cavity, and inhibiting tubal pickup of the oocyte.

In addition, the functional mechanisms discussed above probably also contribute to impaired fertility in women with advanced stage disease.

APPROACH TO TREATMENT OF WOMEN WITH EARLY STAGE ENDOMETRIOSIS AND INFERTILITY — Women with early stage (minimal or mild, Stage I or II) endometriosis and infertility have a baseline fecundability of approximately 0.03 (3 percent per cycle pregnancy rate). Numerous randomized studies have demonstrated that a step-wise approach to treatment can increase the fecundability of women with early stage endometriosis.

Step one — Identify and treat all reversible causes of infertility in the couple.

Step two — Consider a laparoscopic surgical procedure to ablate or excise endometriosis implants and adhesions and to attempt to restore the pelvis to normal. In one randomized prospective trial, 341 women with early stage endometriosis were randomly assigned to a diagnostic laparoscopy combined with surgical resection or ablation of endometriosis lesions or a diagnostic laparoscopy only [17]. During 36 weeks of postoperative follow-up, the fecundability was significantly higher in the group that underwent surgical resection or ablation of endometriosis lesions compared to the control group (0.047 versus 0.024). The cumulative pregnancy rates over the 36 weeks of follow-up in the treatment and control groups were 31 and 18 percent, respectively. In contrast, a clinical trial with approximately 100 women did not observe a difference in fecundability between diagnostic laparoscopy alone and laparoscopy plus excision or ablation of endometriosis lesions [18]. However, this trial did not have sufficient statistical power to detect clinically meaningful differences between the surgery and control treatment arms.

Step three — Try a course of clomiphene plus intrauterine insemination (IUI). The intent of this therapy is to develop multiple follicles and induce multiple ovulation. In addition, placing a large number of motile sperm high in the reproductive tract by IUI facilitates fertilization by avoiding the need for sperm to travel through the vagina, cervix, and lower portion of the uterus. These two interventions improve fecundability in women with early stage endometriosis.

Step four — Try a course of gonadotropin injections plus IUI. The rationale of this therapy is the same as discussed in step three. In one study, 40 women with early stage endometriosis were randomly assigned to treatment with three cycles of gonadotropin injections plus IUI or no treatment [19]. The fecundability was significantly higher in the treatment group (0.15 versus 0.045). Similar findings have been reported by others [20-22].

In a large clinical trial sponsored by the National Institutes of Health, 932 infertile couples (most of whom carried the diagnosis of early stage endometriosis or unexplained infertility) were randomly assigned to one of four treatment groups [23]:

   Intracervical insemination of sperm (ICI)

   Intrauterine insemination of sperm (IUI)

   FSH injections plus ICI

   FSH injections plus IUI.

The purpose of IUI was to place a large number of sperm high in the reproductive tract, while ICI was used as a control treatment that mimicked natural intercourse. FSH injections were administered to stimulate multiple follicular development and ovulation, thereby increasing the number of oocytes available for fertilization in a single cycle.

Fecundability of the treatments were: IUI alone (0.05), FSH plus ICI (0.04), FSH plus IUI (0.09), and for the control group, ICI (0.02). Fecundability after FSH plus IUI was significantly higher than with ICI or IUI alone.

In this trial, the main complication of this approach to treatment of infertility in women with early stage endometriosis was an increase in the rate of multiple gestations. Among the ongoing pregnancies in the groups receiving FSH injections, 3 percent were quadruplets, 5 percent were triplets, and 20 percent were twins.

The per cycle pregnancy rate appears to drop significantly after three or four cycles of clomiphene plus IUI or gonadotropin injections plus IUI. Therefore, after three cycles of treatment at Step three or Step four, the clinician should review the advantages of proceeding to Step five (treatment with in vitro fertilization) with the couple [24].

Step five — Consider treatment with in vitro fertilization (IVF).There are no prospective, large scale, randomized trials that demonstrate the efficacy of IVF in the treatment of infertility caused by endometriosis. However, the baseline fecundability of women with endometriosis and infertility is approximately 0.03 and observational series have shown that IVF procedures in these women routinely result in a treatment cycle pregnancy rate of approximately 0.30 [25-27]. However, a meta-analysis of observational studies found that women with endometriosis-related infertility undergoing IVF were less likely to achieve pregnancy than women with tubal factor infertility (OR 0.56, 95 percent CI 0.44 to 0.70) [28]. In addition, pregnancy rates after IVF were lower in women with severe compared to mild endometriosis (OR 0.60, 95 percent CI 0.42 to 0.87). The success of IVF is highly influenced by the age of the female partner.

APPROACH TO TREATMENT OF WOMEN WITH ADVANCED ENDOMETRIOSIS (STAGE III AND IV) AND INFERTILITY — A step-wise approach to treatment is also warranted in women with advanced endometriosis (moderate or severe, Stage III, or IV) and infertility.

Step one — Identify and correct all reversible causes of infertility.

Step two — Surgically resect ovarian endometriosis, peritoneal endometriosis, and pelvic adhesions to restore pelvic anatomy and function. There are no randomized prospective studies that demonstrate the efficacy of surgery in the treatment of advanced endometriosis. However, most authorities believe that surgery improves fertility in affected women. One retrospective study analyzed 130 infertile women treated with expectant management, surgery, or both [29]. No pregnancies occurred among 32 women with advanced endometriosis observed over 231 months of cumulative follow-up, while 10 pregnancies occurred in 34 women with advanced endometriosis treated with conservative surgery during 702 months of follow-up.

Similar results were reported in a meta-analysis of the impact of surgery on fertility in women with endometriosis [30]. These studies suggest that expectant management is not warranted in the treatment of infertility associated with advanced endometriosis. Surgical treatment appears to improve fecundability, especially in the six to 18 months after the surgical procedure. If pregnancy does not occur after the first surgery, the clinician should move on to Step three in the treatment algorithm.

  Reoperation — After the first infertility operation, additional surgical procedures have not been demonstrated to be effective in increasing fecundability. For example, one retrospective study of infertile women with advanced endometriosis found two cycles of IVF treatment was associated with a higher cumulative pregnancy rate than reoperation (69 and 24 percent, respectively) [31]. Physicians should carefully weigh the limited benefits of second and third operative procedures to enhance fertility against the potential risks of major surgery.

Steps three and four should not be recommended for women with tubal blockage, or dense ovarian adhesions. If pelvic adhesions are severe, clinicians may choose to move directly from Step two to Step five, in vitro fertilization.

Step three — Try empirical use of clomiphene plus IUI. Most of the clinical trials evaluating the use of clomiphene plus IUI or gonadotropin injections plus IUI (step four) have focused on women with early stage endometriosis However, many authorities believe the benefits of these steps, which have been clearly demonstrated in clinical trials in women with infertility and early stage endometriosis, probably also extend to women with advanced disease.

Step four — Try empirical use of human gonadotropin injections plus IUI. The benefits of treating advanced endometriosis (Stage III and IV) with the GnRH agonist decapeptyl for more than one month prior to initiating gonadotropin injections plus IUI was evaluated in a small clinical trial [32]. The pregnancy rate in women treated with decapeptyl for more than one month was 50 percent (10/20 women) compared to 19 percent (4/21) in those treated for less than one month prior to gonadotropin-IUI therapy [32]. The use of a GnRH agonist prior to initiating gonadotropin-IUI therapy in women with advanced endometriosis requires additional study before general clinical use.

Step five — Consider in vitro fertilization-embryo transfer (IVF-ET). There are no large, randomized controlled clinical trials that definitively demonstrate that IVF increases fecundability in women with advanced endometriosis. One small randomized study of 21 women with endometriosis and infertility evaluated treatment with IVF (N=15) versus expectant management (N=6) [33]. None of the women in the expectantly managed group became pregnant, whereas five of 15 women treated with IVF became pregnant. However, this study did not have sufficient statistical power to detect true differences between the two groups because of the small sample size. As discussed above, a meta-analysis of observational studies found that women with endometriosis-related infertility undergoing IVF were less likely to achieve pregnancy than women with tubal factor infertility (OR 0.56, 95 percent CI 0.44 to 0.70) [28]. In addition, pregnancy rates after IVF were lower in women with severe compared to mild endometriosis (OR 0.60, 95 percent CI 0.42 to 0.87).

A history of previous bilateral ovarian surgery may influence the success of IVF in women with advanced endometriosis; those with a previous oophorectomy and a contralateral ovarian cystectomy appear to have poor responses to ovarian stimulation and a low pregnancy rate [34-36]. Reduced pregnancy rates for women with advanced endometriosis (compared to women with early stage endometriosis or tubal factor infertility) [28] may be due to premature depletion of the ovarian follicle pool [34], abnormal folliculogenesis [35], and/or reduced fertilization potential of oocytes in these women [36].

Cost effectiveness — An analysis of the cost effectiveness of various infertility treatments found that for infertile women with advanced endometriosis, rapid progression through the steps to IVF was the most cost effective treatment algorithm [37]. Based upon data from 1993, the cost of IVF per live birth was in the range of 22,000 to 43,000 dollars, depending upon the clinical characteristics of the infertile couples [38]. These costs are within the range of current costs for adopting a child. Furthermore, IVF success rates have increased [39] and costs per cycle have decreased since 1993.

SUPPRESSIVE HORMONE THERAPY DOES NOT IMPROVE FECUNDABILITY IN WOMEN WITH ENDOMETRIOSIS — Clinical trials have shown that suppressive hormone therapy of endometriosis, with agents such as danazol or GnRH agonists, does not improve fertility. The first prospective randomized trial of danazol (N=37) or no treatment (N=36) of endometriosis in infertile women was performed in couples with one year of failure to conceive, a normal basic infertility examination, and laparoscopic evidence of minimal endometriosis [40]. During one year of follow-up, 35 percent of the danazol-treated women and 47 percent of the untreated women became pregnant. The fecundability in the danazol and control groups was 0.035 and 0.051, respectively. This study demonstrated that danazol treatment of endometriosis lesions did not improve fecundability in women with infertility and early-stage endometriosis.

Another report also showed that suppressive hormone treatment of endometriosis with the GnRH agonist buserelin did not improve fertility [41]. Women with early stage endometriosis were randomly assigned to six months of suppressive hormone treatment with buserelin or to a no treatment group. Median follow-up was approximately 18 months after completion of assigned therapy. The one and two year actuarial pregnancy rates were similar in both groups (30 and 37 percent at one year, 61 and 60 percent at two years). Using the two year pregnancy rate, the fecundability in both groups was approximately 0.04 (4 percent per cycle). These data demonstrate that in women with endometriosis, treatment with buserelin does not improve fertility.

IMPACT OF AGE ON TREATMENT DECISIONS — A critical determinant of fecundability is the age of the female partner. An immutable feature of ovarian physiology is that the number of oocytes and follicles is fixed in-utero and declines, following an exponential curve, beginning in the second trimester. During reproductive life, it appears that the follicles most sensitive to the growth promoting effects of FSH are the first to be recruited and selected to become the dominant follicle. As the ovary ages, the follicles that are relatively resistant to FSH populate the residual follicular pool. These aging follicles contain oocytes that are less likely to result in a successful pregnancy, due to chromosomal damage and cytoplasmic deficiency of critical factors. It is likely that the decrease in fecundability associated with female aging is due to a decline in both the quantity and quality of the oocytes.

One approach to understanding the relative impact of ovarian aging on fertility is to study infertile couples in whom the male partner has no sperm and the female partner is being treated with donor sperm. In these studies, women over 35 years of age have approximately one-half the fecundability of women younger than age 30. As an example, in one study the fecundability of women treated with donor sperm who were either over age 35 or younger than age 30 was 0.06 (6 percent per cycle pregnancy rate) and 0.10 (10 percent per cycle pregnancy rate) respectively [42].

The age of the female partner plays an important role in clinical decision making regarding the treatment of infertility associated with endometriosis. For women less than 32 years of age, a deliberate progression through the step-wise approach to fertility treatment is warranted. However, rapid progression through the step-wise approach to fertility treatment is warranted for women over 37 years of age to reduce the risks of decreasing ovarian function before a successful pregnancy can be established.

KEY POINTS

   A step-wise approach to the treatment of infertility associated with endometriosis balances the cost of the intervention with the efficacy of the treatment. Less resource intensive treatments are first used in the step-wise approach. The more resource intensive treatments, such as IVF, are reserved for later treatment cycles.

   The age of the female partner is an important determinant of the pace at which the couple should proceed through the step-wise approach to treatment. For women over 37 years of age, rapid progression through the steps is warranted to ensure that if IVF is necessary, the treatment will be started before the ovarian follicle pool wanes and the success of IVF decreases. For women under 32 years of age, progress through the step-wise approach to treatment can occur at a measured pace.

   Gonadotropin injections plus IUI has been demonstrated to improve fecundability in women with early stage endometriosis. However, gonadotropin treatment is associated with an increased risk of twin and triplet pregnancy. Some authorities prefer skipping this step and moving directly from clomiphene plus IUI treatment to IVF. In IVF, it is conceptually possible to reduce the rate of triplet pregnancy by transferring no more than two embryos.

REFERENCES