Kaylen M. Silverberg and Thomas C. Vaughn
Table Of Contents
Kaylen M. Silverberg, MD
Thomas C. Vaughn, MD
Infertility is generally defined as the inability to conceive following 1 year of unprotected intercourse. This definition is often modified in couples in which the female partner is 35 years of age or older, such that an infertility evaluation may be encouraged following only 6 months of unsuccessful attempted conception. Up to 30% of couples presenting with this chief complaint are eventually diagnosed as having unexplained infertility.1 Couples with unexplained infertility are thought to represent either a subpopulation of patients in the lower extreme end of the normal distribution of fertility or a group of patients with a defect in fecundity not detected by the routine infertility evaluation.2 When compared with “normal, fertile” patients, couples with unexplained infertility demonstrate both diminished and delayed fecundity. Untreated, their pregnancy rates have been reported to be 34% within 6 months, 76% within 2 years, and 87% within 5 years.3 In a review of previously published prospective randomized trials, Guzick and colleagues observed that cycle fecundity in couples with unexplained infertility managed expectantly ranges between 0.013 and 0.041, compared with a generally accepted 0.20 cycle fecundity in proven fertile couples.4
This chapter provides a critical, evidence-based review of both the diagnosis and the treatment of unexplained infertility.
Traditionally, a diagnosis of unexplained infertility is made only when the basic infertility evaluation fails to reveal an obvious abnormality. This diagnosis therefore implies that a couple has evidence of normal, timely ovulation, adequate sperm production, fallopian tube patency, normal integrity of the endometrial cavity, adequate cervical mucus production, timely development of endometrial secretory change, and no evidence of pelvic endometriosis. Until recently, the basic infertility workup included basal body temperature charting, a semen analysis, a hysterosalpingogram (HSG), a postcoital test (PCT), an endometrial biopsy (EMB), and a diagnostic laparoscopy.
Over the past several years, both the PCT and the EMB have fallen into disfavor. Two studies in particular helped diminish the importance of the PCT. In the early 1980s, a group of investigators performed midcycle intracervical insemination in a group of infertile women, followed a few hours later by laparoscopy.5 During the surgical procedure, samples of cervical mucus and fluid surrounding the distal fallopian tubes were collected and analyzed for the presence of motile and nonmotile sperm. The investigators were unable to correlate the findings in the cervical mucus with the findings in the peritoneal fluid surrounding the tubes and ovaries. In 1984, Collins and coworkers followed a large group of patients who had discontinued their infertility treatment.6 Pregnancy rates observed over a subsequent 2-year period were correlated with results obtained from PCT performed during their evaluations. No statistically significant differences in pregnancy rates were observed in these couples, despite PCT results that varied widely, from more than 11 motile sperm observed per high-power microscope field to no sperm seen at all. These observations and the evolution of contemporary treatments for unexplained infertility that typically employ intrauterine insemination (IUI) or assisted reproductive technologies (ART; in vitro fertilization [IVF]) challenge the results of a PCT in all but a very few women. Some physicians still use the PCT to evaluate cervical mucus production in women under treatment with clomiphene citrate (CC) to determine whether IUI should be included in the treatment regimen, but many have eliminated the test from their evaluation algorithm altogether.
Routine EMB is also no longer universally recommended in the contemporary infertility evaluation. Initially proposed as the optimal way to assess the synchrony between the development of the endometrium and the embryo, the utility of the EMB has been undermined by observations that interpretation varies widely among examiners and that up to 30% of normal ovulatory women may exhibit delayed endometrial development, at least on occasion.7 Whereas false-positive EMB results may be reduced substantially if biopsy is performed only in women who exhibit a grossly short luteal phase duration (fewer than 11 days of luteal phase basal body temperature elevation or onset of menses less than 13 days after detection of a midcycle urinary luteinizing hormone [LH} surge), many physicians regard such observations alone as diagnostic of luteal phase deficiency (LPD) and as an indication for treatment without need for a corroborating EMB. Although LPD is still considered as an important cause of recurrent early spontaneous abortion, the weight of currently available evidence suggests that it is neither a common nor an important cause of infertility.8
The role of routine laparoscopy continues to be a source of much controversy, just like the association between endometriosis and infertility. Although most investigators recognize a strong correlation between infertility and stage III and IV endometriosis, no such consensus exists for stages I and II disease. A prospective, randomized, multicenter Canadian trial (“EndoCAN”) was the first well-designed study to demonstrate an association between lesser degrees of endometriosis and subfertility.9 Women in whom stage I or II endometriosis was observed at laparoscopy were randomized to resection or ablation of their disease or expectant management and observed for a minimum of 36 weeks after surgery. Ultimately, 31% of the patients in the treated group conceived, compared with 18% of those who were not treated (p < .05). However, in a subsequent Italian trial of similar design, birth rates in groups of treated and untreated women with minimal or mild endometriosis over the year following laparoscopic diagnosis or resection/ablation did not differ significantly.10
In patients with a normal HSG and pelvic examination and no history of prior intrauterine device (IUD) use, pelvic inflammatory disease, or abdominal or pelvic surgery, the likelihood of pelvic disease that may explain otherwise unexplained infertility is small. A mid-follicular phase transvaginal sonogram serves as an effective screening test for ovarian endometriomas, and in the absence of such findings, advanced stages of endometriosis (stage III or IV) can be excluded with a high degree of certainty. Some data suggest that a thorough medical history, an HSG, and a single transvaginal ultrasound examination may therefore eliminate unnecessary laparoscopy in up to 40% of patients with unexplained infertility, even more if one regards minimal or mild endometriosis as having no significant impact on treatment strategy or outcome.11
Just as some traditional tests are losing popularity and relevance in the diagnostic algorithm for infertility, others are emerging to take their place. Many specialists now recommend an early or midcycle transvaginal pelvic sonogram as a component of the basic infertility evaluation because it facilitates detection of uterine leiomyomata, endometrial polyps, müllerian anomalies, and ovarian pathology and provides the opportunity to observe the characteristics of endometrial growth and development (maximal endometrial thickness and pattern).
Because no single diagnostic algorithm for the evaluation of infertility exists, it should not be surprising that even among physicians certified by the American Board of Obstetrics and Gynecology as specialists in Reproductive Endocrinology and Infertility, practice patterns vary widely.12 Results from a nationwide survey (Table 1) indicate that at least 89% of specialists perform a basic evaluation that includes a semen analysis, at least one method of ovulation assessment, an HSG, and laparoscopy.13 Seventy-nine percent still perform a PCT and 62.5% still routinely perform EMB.
Taken together, available evidence suggests that approximately 60% of couples with unexplained infertility of less than 3 years’ duration will achieve pregnancy within 3 years without treatment.14,15 Although these data are generally encouraging, it is difficult to suggest that such couples “keep trying for a few more years,” even when they are young. Moreover, after 3 years of infertility, the prospect of future fertility decreases by approximately 24% in each subsequent year.16 The average normal monthly fecundity for fertile couples in which the female partner is 35 years of age or younger is 0.20 to 0.25, but only 0.013 to 0.041 in couples with unexplained infertility.4 Therefore, it is reasonable to offer treatment to couples concerned enough about their fertility to have made the decision to consult a physician. The goal of treatment is to increase monthly fecundity to a level that more closely approximates that observed in normally fertile couples.
In the absence of a single correctable abnormality, treatment for unexplained infertility is necessarily empiric. Several different treatment regimens have been recommended, including IUI, with or without superovulation using oral (CC) or injectable medications (recombinant or urinary follicle-stimulating hormone (FSH), or human menopausal gonadotropins) and ART. Because couples with unexplained infertility may truly be only subfertile rather than infertile, the need for appropriately designed controlled trials designed to evaluate and compare treatments is clear. Unfortunately, few such studies have been performed.
Evidence indicates that IUI can improve cycle fecundity when combined with either CC or exogenous gonadotropins, but only one prospective, randomized trial has examined the efficacy of IUI alone as treatment for couples with unexplained infertility.4,17,18 Kirby and associates studied 73 couples with unexplained infertility and compared the efficacy of IUI with that of intercourse, each performed 40 hours following the detection of a midcycle LH surge.18 Pregnancies were observed in 3 of 123 (2.4%) intercourse cycles compared with 6 of 145 IUI cycles (4.1%, NS). Guzick and coworkers conducted a prospective, randomized trial that compared the results of IUI and intracervical insemination (ICI) in couples with unexplained infertility and observed greater cycle fecundity with IUI (18%) than with ICI (10%).17
Clomiphene Citrate Therapy
Although empiric use of CC in already ovulatory women may have unintended consequences, its use as treatment for unexplained infertility has been championed by numerous investigators.19 Superovulation with CC combined with intercourse has been evaluated in a prospective, randomized, double-blind, placebo-controlled 4-month trial in 148 patients (564 cycles). Patients receiving CC (100 mg/day, cycle days 5 to 9) achieved significantly higher cycle fecundity (0.051) and cumulative pregnancy rates (19%) than did those receiving placebo (0.0; 0%).20 Comparable results were observed in a subsequent randomized crossover trial involving 118 couples with unexplained infertility; the cumulative pregnancy rate over 3 cycles in treated women (22.3%) was greater than in the women who received a placebo (14.6%).21 Empiric treatment with CC combined with IUI has been evaluated in a prospective, randomized study of 298 treatment cycles involving 67 couples with unexplained infertility.22 Cycle fecundity in treatment cycles (14 pregnancies in 148 treatment cycles; 0.095) was greater than in cycles involving only timed intercourse (5 pregnancies in 150 cycles; 0.033). An analysis of 932 cycles culled from previously published trials concluded that IUI increased cycle fecundity in CC-treated cycles from 0.056 to 0.083.4 In another prospective, randomized, crossover trial, the cycle fecundity achieved with combined CC/IUI treatment (0.26) was clearly superior to that observed in couples treated with IUI alone (0.05).23 In contrast, one small prospective randomized trial has questioned the efficacy of CC treatment for unexplained infertility. Fujii and colleagues compared the cycle fecundity of 18 patients who received empiric CC treatment (50 mg) to that in 15 untreated control women and observed lower cycle fecundity in those who received treatment (4 pregnancies in 66 cycles; 0.06) than in those who did not (11 pregnancies in 51 cycles; 0.21).24
Empiric treatment with exogenous gonadotropins has been demonstrated to be effective therapy for unexplained infertility, particularly when combined with IUI. 4 Welner and associates treated 97 couples awaiting IVF with gonadotropins and IUI and observed improved fecundity compared with that observed in 48 control couples.25 In a more recent study involving 492 couples, both cycle fecundity and the overall pregnancy rate observed in patients treated with exogenous gonadotropins and IUI were greater than in couples receiving expectant management.26
A few trials have compared varying stimulation regimens. In one prospective randomized trial, the cycle fecundity observed in couples treated with gonadotropins and IUI (0.19) was clearly superior (p < .05) to that in others treated with CC/IUI (0.04).27 However, the addition of a gonadotropin-releasing hormone agonist to the treatment regimen does not appear to further improve the efficacy of combined treatment with gonadotropins and IUI.28
The value of IUI as a component of the treatment regimen has been clearly demonstrated in studies involving sequential stimulation with CC and exogenous gonadotropins or gonadotropins alone.29,30 A review of 27 separate studies involving more than 2900 patients concluded that the addition of IUI to gonadotropin stimulation clearly improved cycle fecundity in couples with unexplained infertility.4 Similarly, the benchmark multicenter trial conducted by Guzick and coworkers demonstrated that couples who received combined treatment with gonadotropins (specifically FSH alone) and IUI achieved a higher cumulative pregnancy rate (33%) than those treated with gonadotropins alone (19%), IUI alone (18%), or ICI alone (10%).17
Assisted Reproductive Technology
Results of IVF frequently provide insight into the possible causes of a couple’s otherwise unexplained infertility because the procedure itself eliminates many “unknown” variables. The various elements of an IVF cycle ensure that sperm and the oocytes will meet and also document the presence or absence of fertilization. Direct transfer of embryos into the uterus bypasses the fallopian tubes and ensures that the embryos will reach the endometrial cavity. The most important remaining variables include the chromosomal composition of the embryos and the factors that determine whether implantation will occur. A host of other biochemical, anatomic, and functional issues that contribute to a successful pregnancy remain to be investigated.
Although IVF is advocated as treatment for unexplained infertility by many clinicians and is supported by the results of retrospective and uncontrolled trials, no well-designed studies to evaluate the efficacy of ART for purely unexplained infertility have been conducted. The available literature includes 18 studies involving IVF or gamete intrafallopian transfer (GIFT) and suggests that pregnancy rates approximating 20.7% (IVF) and 27% (GIFT) can be achieved in couples with unexplained infertility.4
Despite the fact that most published studies that have examined the efficacy of various forms of empiric treatment for unexplained infertility have include heterogeneous patient populations, level I evidence (derived from randomized, controlled trials) to support the use of CC or gonadotropins combined with IUI does exist. Level II evidence (derived from observational studies) and level III evidence (derived from case series) to support the use of ART also exists. When appropriately monitored, all such therapies appear to be both safe and effective.
When counseling couples with unexplained infertility on their therapeutic options, it is important to include a discussion of both cost and efficacy. Taken together, the available evidence suggests that the cycle fecundity rates that may be expected range from 0.04 to 0.18 for IUI alone, from 0.05 to 0.09 for CC alone, from 0.05 to 0.26 for combined treatment with CC and IUI, and from 0.13 to 0.33 to for combined treatment with exogenous gonadotropins and IUI—with comparable or even higher cycle fecundity possible with ART.
Fortunately, many patients with unexplained infertility will achieve a successful pregnancy with treatment. Continued research promises to provide greater insights into the causes of unexplained infertility, to yield new diagnostic methods, to refine and improve current therapies, and even to identify entirely new treatment strategies.
1. Dodson WC, Whitesides DB, Hughes CL, et al: Superovulation with intrauterine insemination in the treatment ofinfertility: A possible alternative to gamete intrafallopian transfer and in vitro fertilization. Fertil Steril 48:441, 1987
20. Fisch P, Casper RF, Brown SE, et al: Unexplained infertility: Evaluation of treatment with clomiphene citrate and human chorionic gonadotropin. Fertil Steril 51:828, 1989
21. Glazener CM, Coulson C, Lambert PA, et al: Clomiphene treatment for women with unexplained infertility: Placebo-controlled study of hormonal responses and conception rates. Gynecol Endocrinol 4:75, 1990
22. Deaton JL, Gibson M, Blackmer KM, et al: A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 54:1083, 1990
23. Arici A, Byrd W, Bradshaw K, et al: Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: A prospective, randomized, crossover study during intrauterine insemination cycles. Fertil Steril 61:314, 1994
24. Fujii S, Fukui A, Fukushi Y, et al: The effects of clomiphene citrate on normally ovulatory women. Fertil Steril 68:997, 1997
27. Karlstrom PO, Bergh T, Lundkvist O: A prospective, randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate. Fertil Steril 59:554, 1993
28. Sengoku K, Tamate K, Takaoka Y, et al: A randomized prospective study of gonadotropin with or without gonadotropin-releasing hormone agonist for treatment of unexplained infertility. Hum Reprod 9:1043, 1994
29. Arcaini L, Bianchi S, Baglioni A, et al: Superovulation and intrauterine insemination vs. superovulation alone in the treatment of unexplained infertility. A randomized study J Reprod Med 41:614, 1996
30. Chung CC, Fleming R, Jamieson ME, et al: Randomized comparison of ovulation induction with and without intrauterine insemination in the treatment of unexplained infertility. Hum Reprod 10:3139, 1995