Unexplained Infertility: A Most Frustrating Diagnosis
!There are many critical steps in the process of getting pregnant which we can not directly assess; such as how efficiently the eggs are captured by the fallopian tubes, how efficiently the tubes push the eggs along to the uterus, how well the sperm are fertilizing the eggs, how well the fertilized eggs are developing to embryos, and how efficiently the embryos find their way to the uterus. All these steps are criticalyet we have no direct test. If one were to proceed to an IVF cycle, we can then make some assessment of these steps, but not prior.
So, if the evaluation shows normal egg quality (FSH, Estradiol, ultrasound), dye study (HSG) shows open tubes, sperm test shows normal count and motility, and there is no evidence of endometriosisthis typically defines unexplained infertility. One of the first studies addressing the efficacy of treatment for unexplained infertility was published in 1998 (1), and indicated that patients who underwent no treatment had a 1-4% pregnancy rate per month; insemination alone, 3.8% pregnancy rate/cycle; clomid alone, 5.6% pregnancy rate/cycle; Clomid plus insemination, 8.3% pregnancy rate/cycle; gonadotropins alone, 7.7% pregnancy rate/cycle; and gonadotropins plus insemination 17.1% pregnancy rate/cycle. This study was retrospective, and did include patients with mild endometriosis, so while providing good insight, more studies were needed to better define treatment efficiency for these patients. However, it was important to see that insemination alone did not provide an improvement, and best improvement was noted with combination therapy.
Next, Guzick and colleagues published a large randomized study addressing superovulation with gonadotropins and insemination, for patients with unexplained infertility (though again mild endometriosis was included) (2). The control group was patients who had intracervical inseminations (to assure sperm exposure). Pregnancy rates for this group were 10% per cycle. Those who underwent intrauterine insemination had an 18% pregnancy rate. Those who underwent gonadotropin stimulation plus intracervical insemination have a 19% pregnancy rate, verses 33% for those with gonadotropin plus intrauterine insemination. Therefore, couples who undergo superovulation and intrauterine insemination have a 3 times higher chance of achieving a pregnancy, than the control group. The question of which type of ovulation induction agent to use, oral verses injectable, has been addressed in a meta-analysis published in 2002 (3). This review of 5 randomized controlled trials shows that pregnancy rates were higher in injectable cycles (gonadotropins), though live-birth rates were not different between oral and injectable cycles. Their conclusion was that oral agents may therefore be more suitable for ovulation induction, since the multiple rates were lower, and cost of the cycle less. Last year, a prospective trial looking at using oral Clomid verses Letrozole with inseminations in patients with unexplained infertility was published (4). This study showed that the total number of follicles was greater for the Clomid users (3.1 vs 1.6), but the pregnancy rates were the same for each group (Letrozole 19%/cycle verses Clomid 18.3%/cycle). Therefore, both agents are equally effective, and the multiple rate may be less with Letrozole. Last year, another randomized control trial evaluated expectant management (no treatment), verses Clomid alone or intrauterine insemination alone in patients with unexplained infertility ( though included mild endometriosis patients) (5). This study again confirmed that Clomid alone (14% live-birth rate) or insemination alone (23% live-birth rate) was not statistically different than expectant management (17% live-birth rate). They evaluated patient satisfaction with the treatment process, and patients who were randomized to the expectant management arm were much less satisfied than those who were doing Clomid or insemination therapy, despite no improvement for those patients live-birth rates. So, some take home points are as follows:- Unexplained infertility does not mean no infertility
- Empirical clomiphene and/or unstimulated intrauterine inseminations are unlikely to offer an improvement over expectant management (no treatment)
- Best options are to consider Clomid or gonadotropins with intrauterine inseminations (depending on patient age, etc..)
- If this fails, then IVF is best option
- Depending on age and other evaluation, IVF may be best first optionFootnotes:
1. Guzick DS, et al. Efficacy of treatment for unexplained infertility. Fert Ster 1998; 70:2, 207-213.
2. Guzick DS, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med 1999;340;177-83.
3. Athaullah N, et al. Oral vs injectable ovulation induction agents for unexplained subfertility. Cochrane Database Syst Rev 2002;3:CD00352
4. Badawy A, et al. [Clomiphene citrate](http://www.pacificfertilitycenter.com/treatment-care/clomiphene) or aromatase inhibitors for superovulation in women with unexplained infertility undergoing intrauterine insemination: a prospective randomized trial. Fert Ster Aug 2008
5. Bhattacharya S, et al. Clomiphene Citrate or unstimulated intrauterine insemination compared with expectant management fro unexplained infertility: pragmatic randomized controlled trial. BMJ 2008;337:a716