Unexplained Infertility

Infertility is generally defined as the inability to conceive following one year of unprotected intercourse. This definition is often modified in couples where the female partner is 35 years of age or older, and many fertility specialists encourage the performance of an infertility evaluation following only six months of unsuccessful attempted conception in such cases. 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 six months, 76% within two years, and 87% within five years.³ In a review of previously published prospective, randomized trials, Guzick et al determined the cycle fecundity rate with expectant management in couples with unexplained infertility to be 1.3–4.1%, compared to the generally accepted cycle fecundity of 20% in proven fertile couples.⁴

This chapter will provide a critical, evidence based review of both the diagnosis and 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 and timely ovulation, adequate sperm production, fallopian tube patency, normal integrity of the endometrial cavity, adequate cervical mucous 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 post-coital test (PCT), an endometrial biopsy (EMB), and a diagnostic laparoscopy. Though evaluation of ovulation, a semen analysis, and hysterosalpingography are still commonly employed basic tests, the routine use of the PCT, EMB, and diagnostic laparoscopy has been called into question.                   

Over the past several years, the PCT has fallen into disfavor and it is no longer recommended as part of the routine infertility workup. Multiple studies have helped to diminish the importance of the PCT. In the early 1980s, a group of investigators performed mid-cycle 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 non-motile 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 et al followed a large group of patients who had discontinued their infertility treatment.⁶ Pregnancy rates observed over a subsequent two year period of time were correlated with results obtained from PCTs performed during the initial evaluations. No statistically significant differences in pregnancy rates were observed in these couples, despite a wide range of PCT results varying from more than 11 motile sperm per high power microscope field to the complete absence of sperm on the microscope slide. A subsequent randomized, controlled trial which compared couples receiving infertility evaluations with and without a PCT showed a higher rate of testing and treatment in couples receiving the PCT, but no significant difference was noted in pregnancy rates between the two groups at 24 months.⁷ Based on these and other similar studies, the PCT is no longer an integral part of the contemporary evaluation of infertility. While some physicians may still use it for other purposes, such as assessing cervical mucus production in women treated with clomiphene citrate in order to determine whether or not to recommend intrauterine insemination (IUI), many others have eliminated it from their evaluation algorithm altogether.

The routine endometrial biopsy is also no longer a universally accepted part of the contemporary infertility evaluation. Though the EMB was initially proposed as the optimal way to assess the synchrony between the development of the endometrium and the embryo, there was often substantial variability in interpretation by different examiners. In addition, up to 30% of normal ovulatory women can have an occasional out of phase biopsy.⁸ It may, therefore, be both reasonable and cost-effective to perform a biopsy only after a luteal phase length of fewer than 11 days has been detected in a preceding cycle. This approach will minimize patient discomfort and cost, while possibly reducing the incidence of a false positive diagnosis as well. Recent efforts to refine the histological definition of normal secretory phase endometrium in fertile patients have been unsuccessful.⁹ A prospective study of fertile and infertile patients revealed that histological dating of the endometrium did not discriminate between the two groups and should not be used in the routine evaluation of infertility.¹⁰ Although still thought to be a cause of recurrent miscarriage, more recent data suggest that luteal phase defect does not appear to be a prevalent cause of infertility.¹¹ 

The role of routine laparoscopy in the infertility evaluation continues to be a source of much controversy. Although most investigators recognize a strong correlation between infertility and stages III and IV endometriosis, no such consensus is present for stages I and II disease. A prospective, randomized, multi-center Canadian trial ('EndoCAN') was the first well-designed study to demonstrate such an association.¹² In this trial, women diagnosed intraoperatively with Stage I or II disease were randomized to intraoperative resection or ablation of their disease, or to diagnosis alone. All patients were then followed expectantly for a minimum of 36 weeks. At the end of the study period, 31% of the patients in the laparoscopic surgery group had conceived, compared to 18% in the diagnostic group (p<0.05). Although interesting, these findings have not been universally accepted. A subsequent similarly designed prospective, randomized Italian trial showed no difference in the one-year postoperative birth rate in 96 women undergoing resection/ablation or diagnosis alone at the time of laparoscopy.¹³ In the patient with a normal HSG and pelvic examination, and no history of prior IUD usage, PID, or previous abdominal or pelvic surgery, the likelihood of finding significant pelvic adhesions is remote.¹⁴ In addition, an early or mid-follicular transvaginal sonogram appears to be a reasonable screening test for the presence of an ovarian endometrioma or other significant pelvic pathology. In the absence of such findings, one can rule out the presence of stages III or IV endometriosis with a high degree of certainty. Recent data suggest that a good history, an HSG, and a single transvaginal ultrasound may well eliminate a needless laparoscopy in up to 40% of patients. This number may even be higher if one includes patients who are found to have only stages I or II endometriosis at laparoscopy.¹¹

Just as some tests appear to be losing their place in the diagnostic algorithm for infertility, many specialists have recently added an early or mid-cycle pelvic sonogram to the basic infertility evaluation. This examination facilitates the detection of uterine leiomyomata, endometrial polyps, and ovarian pathology, while also affording a timely assessment of maximal endometrial thickness and pattern.

As no universal algorithm exists for the diagnosis of infertility, it should not be surprising that there appears to be a lack of consistency among even Board Certified Reproductive Endocrinologists (REs). Glatstein et al published a nationwide survey assessing the tests employed by such specialists as part of their routine infertility evaluation.¹⁴ Of the 473 Board Certified REs surveyed, 397 responded, representing a response rate of 83.9%. Of the respondents, 54.7% were university hospital affiliated, while 45.3% were in private practice. Results from the survey (Table 1) indicated that at least 89% of REs performed a basic evaluation that included a semen analysis, at least one method of ovulation assessment, an HSG, and a laparoscopy. Seventy-nine percent still performed post-coital testing, while 62.5% routinely performed an endometrial biopsy.

Some data suggest that approximately 60% of couples with unexplained infertility of less than three years’ duration will become pregnant with three years of expectant therapy.^{15, 16} Although these data may be somewhat promising, it is frequently difficult to ask a patient, even if she is young, to ‘keep trying for a few more years’. In addition, following three years of infertility, the prospect of future fertility decreases by approximately 24% each year.¹⁷ Therefore it is reasonable to initiate therapy once the couple is concerned enough to have made the decision to consult a physician.

The average normal monthly fecundity for fertile couples in which the female partner is 35 years of age or younger is 20–25%; however the monthly fecundity for couples with unexplained infertility is only 1.3–4.1%.⁴ A laudable goal for the physician is therefore to increase the pregnancy rate for these couples to the normal monthly fecundity for fertile couples.

Epidemiological studies have suggested that a variety of lifestyle issues, including cigarette smoking, abnormal body mass index, excessive caffeine intake, and alcohol consumption can reduce fertility in the female partner.¹⁸ Couples undergoing treatment for unexplained infertility should therefore be counseled about discontinuing tobacco products; also, the female partner should be encouraged to limit alcohol consumption to fewer than four drinks weekly, minimize caffeine intake to less than 250 mg daily, and to achieve and/or maintain a body mass index between 20 and 27 kg/m².

In the absence of a single correctable abnormality, the therapy for unexplained infertility has, by default, been empiric. Several different treatment regimens have been proposed, including the use of intrauterine insemination (IUI) with or without superovulation with either oral or injectable medications, and/or assisted reproductive technologies (ARTs). As these patients may truly be subfertile rather than infertile, the need for appropriately designed and controlled trials evaluating these empiric therapies is profound. Unfortunately, there has been a relative paucity of such studies.

Intrauterine Insemination

The use of IUI appears to improve cycle fecundity when combined with either clomiphene citrate (CC) or gonadotropins (see below); its use alone in couples with purely unexplained infertility has only been evaluated in one prospective, randomized trial.¹⁹ In this study, Kirby et al compared IUI to intercourse, each performed 40 hours following the detection of a serum LH rise, in 73 couples with unexplained infertility. Pregnancies resulted in three of 123 intercourse cycles (2.4%) compared to six of 145 IUI cycles (4.1%; p=NS). Guzick et al published a prospective, randomized, controlled trial in couples with unexplained infertility.²⁰ In this study, they reported significantly greater cycle fecundity with IUI (18%) than ICI (10%), which was chosen as their 'control' treatment.

Clomiphene Citrate Therapy

Although it has been suggested that the empiric use of clomiphene citrate (CC) in ovulatory women can cause alterations in the normal endocrinology of ovulation, its use has been championed by numerous investigators.²¹ Superovulation with CC (100mg, cycle days 5 –9) combined with intercourse was evaluated in a prospective, randomized, double blind, placebo-controlled trial in 564 cycles from 148 patients with unexplained infertility. Patients receiving CC exhibited significantly higher fecundity (5.1%) and cumulative pregnancy rates (19%) than did patients receiving placebo (0%, 0%).²² These results were confirmed in a subsequent prospective, randomized, crossover trial of 118 couples with unexplained infertility.²³ In this study, the patients treated with CC (100 mg) exhibited a significantly greater cumulative pregnancy rate over three cycles than did the placebo treated patients (22.3% vs. 14.6%; p<0.05). The empiric use of CC combined with IUI has been evaluated in a prospective, randomized study of 298 treatment cycles involving 67 couples.²¹ In this trial, 14 pregnancies resulted from 148 treatment cycles (fecundity 0.095) compared to five pregnancies from 150 cycles involving timed intercourse (fecundity 0.033). A retrospective literature review involving 932 cycles suggested that the addition of IUI increased cycle fecundity rates with CC from 5.6% to 8.3%.⁴ A subsequent prospective, randomized, crossover trial suggested superiority of CC/IUI when compared to IUI alone, as cycle fecundity rose from 5% to 26.1% when CC was added.²²

In contrast, another prospective, randomized trial suggests that CC may not be efficacious in the treatment of unexplained infertility.²⁴ Fujii et al compared 18 users of CC (50 mg) to 15 control patients over a total of 117 treatment cycles. Cycle fecundity was significantly greater in the control patients (11/51, 0.21) than in the treated patients (4/66, 0.06; p<0.005), leading the authors to conclude that not only was CC not beneficial, but rather that it was detrimental.

A recent meta-analysis of 11 prospective trials of CC for women with unexplained infertility revealed that CC modestly improved the pregnancy rate compared to placebo or no treatment.²⁵ The odds ratio (OR) for pregnancy per CC treatment cycle was 2.5 (95% CI, 1.35 to 4.62).

Clomiphene Citrate and IUI

The empiric use of CC combined with IUI has been evaluated in a prospective, randomized study of 298 treatment cycles involving 67 couples with unexplained infertility.²⁶ In this trial,14 pregnancies resulted from 148 treatment cycles (fecundity 9.5%) compared to five pregnancies from 150 cycles involving timed intercourse (fecundity 3.3%, p < 0.05). A retrospective literature review involving 932 cycles suggested that the addition of IUI increased cycle fecundity rates with CC from 5.6% to 8.3%.⁴ A subsequent prospective, randomized, crossover trial suggested superiority of CC/IUI when compared to IUI alone, as cycle fecundity rose from 5% to 26.1% when CC was added (p < 0.05).²⁷

Gonadotropin Therapy

Empiric gonadotropin therapy has been demonstrated to be an effective therapy for unexplained infertility, especially when combined with IUI.⁴ Welner et al treated 97 couples awaiting IVF with gonadotropins and IUI and noted improved fecundity when compared to 48 control couples (p < 0.05).²⁸ In a more recent study of 492 couples, both cycle fecundity and pregnancy rate per patient were superior when gonadotropin therapy plus IUI was compared to expectant management (p < 0.05).²⁹

A few trials comparing various stimulation regimens have been reported. In a prospective, randomized, comparative trial, gonadotropin/IUI was found to be superior to CC/IUI (cycle fecundity 0.19 vs. 0.04; p<0.05).³⁰ The addition of GnRH to gonadotropins, however, does not appear to improve fecundity rates.³¹

In contrast, however, the addition of IUI to empiric gonadotropin therapy does appear to significantly improve fertility rates. This has been reported in patients stimulated with CC combined with gonadotropins as well as in patients stimulated with gonadotropins alone.^{32, 33} A literature review of 27 studies involving over 2900 patients with unexplained infertility suggested a significant improvement in fecundity when IUI was added to gonadotropin stimulation.⁴ Similarly, Guzick’s recent prospective, randomized, multicenter trial demonstrated that patients treated with gonadotropins (specifically FSH alone) combined with IUI had higher cumulative pregnancy rates (33%) than those treated with gonadotropins alone (19%), IUI alone (18%), or ICI (10%).²⁰

Assisted Reproductive Technology

In vitro fertilization (IVF) frequently provides insight into the possible causes of the couple’s infertility, as the procedure itself eliminates many ‘unknown’ variables from consideration as possible etiologies for the infertility. For example, in the IVF procedure, both oocyte release and fertilization are clearly documented. In addition, uterine transfer lends relative comfort that the embryos have been placed into the correct anatomic location, bypassing potentially damaged fallopian tubes. While to the lay person, the only remaining variables are implantation and chromosomal normalcy, in fact a litany of other biochemical, anatomic, and functional issues contributing to a successful pregnancy remain unaddressed.

Although advocated by many clinicians and supported by retrospective and/or uncontrolled trials, there are no well-designed studies evaluating the use of ART for purely unexplained infertility. In 2005, the live birth rate among women with unexplained infertility using ART was 30.4%, based on the Centers for Disease Control and Prevention (CDC), the American Society for Reproductive Medicine (ASRM), and the Society for Assisted Reproductive Technology (SART) report.³⁴ The available literature, consisting of 18 studies involving IVF or gamete intrafallopian transfer (GIFT), suggests that pregnancy rates for these patients average approximately 20.7% (range 12.2–31.4%) for treatment with IVF and 27% (range 19–28.6%) with GIFT.⁴

In a randomized clinical trial of women with tubal patency and nonsevere male factor, the live birth rate was 20 of 68 (29%) in the IVF group compared with 1 of 71 (1%) in the expectant management group.³⁵

A few recent trials have suggested that there does not appear to be a benefit to the use of intracytoplasmic sperm injection (ICSI) over conventional insemination when ART is done for the treatment of unexplained infertility.^{36, 37}

Other Therapies

In addition to the treatment regimens discussed above, a variety of other therapies have been proposed in the infertility literature. Specifically, the use of either bromocriptine or danazol has been studied in limited detail. Neither preparation has been demonstrated to be effective in pooled analyses of published studies.^{38, 39} A small randomized, controlled study has also been published evaluating the use of tubal flushing in patients with unexplained infertility. This trial demonstrated a higher subsequent spontaneous pregnancy rate over six months in patients with unexplained infertility who underwent tubal flushing with lipiodol (5/17) compared to a control group of patients who received no tubal flushing (0/17).⁴⁰

Despite the fact that most published studies evaluating empiric therapy for unexplained infertility include a heterogeneous patient population, Level I evidence supporting the use of CC or gonadotropins combined with IUI does exist. Level II evidence supporting a recommendation for ART in the treatment of unexplained infertility also exists. When appropriately monitored, these therapies appear to be both safe and effective.

When counseling patients about therapeutic options, it is important to include a discussion of both cost and efficacy.  The literature suggests cycle fecundity rates of 4–18% for IUI alone, compared to 5–9% for CC without and 5–26% for CC with IUI.  Published fecundity rates observed with gonadotropin therapy combined with IUI vary from 13–33%, and rates achieved with ART may even be higher.

Fortunately, as a result of these available therapies, many patients will be able to conceive.  As there is more progress in scientific endeavors in this area, new diagnoses will be uncovered, new diagnostic tests will be developed, and new therapies will emerge.