Couples who have not used any contraception for one year and have normal sexual intercourse without a successful pregnancy are said to be infertile. This diagnosis consists in turn of basic tests to assess ovarian function, sperm quality and anatomy. In about 1 in 4 cases, infertility has no apparent cause; these cases can be better described as low fertility. So what is the best treatment for unexplained infertility? In a recent paper published in the journal Fertil Steril (IF: 4.426), researchers from the Center for Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, conducted a randomized controlled study comparing the following treatments for unexplained infertility: 1. expectant therapy 2. regular intercourse 3. intrauterine insemination (IUI) 4. intracytoplasmic mono sperm injection 5, IVF 6, and clomiphene (CC), aromatase inhibitors (AI), or gonadotropins (hMG) Primary endpoints: clinical pregnancy rate, sustained pregnancy rate, and live birth rate. A search of the literature resulted in 13 studies involving 3081 women with unexplained infertility eligible for enrollment, which showed that clomiphene was more effective and gonadotropins more effective than letrozole, but was associated with an increased risk of multiple pregnancies. Based on the current evidence, IVF with or without intracytoplasmic but sperm injection is not more effective than hMG+IUI. The specific results were as follows: 1. There was no significant difference in pregnancy rates with ovarian stimulation using CC with regular intercourse compared with expectant therapy. 2. There was no significant difference in pregnancy rates between expectant treatment and natural cycles with IUI or controlled ovarian stimulation with CC, AI, or hMG. 3, A higher pregnancy rate was found in one study using AI stimulation + IUI compared to CC + IUI, but no difference was found in another, larger study. 4, Pregnancy rates were increased using hMG+IUI compared to CC+IUI or AI+IUI. However, no clinical benefit was found for hMG in the other two randomized controlled trials RCTs. hMG use was also associated with higher rates of multiple pregnancies. The limited evidence did not show a superior effect of IVF over IUI on pregnancy rates. The authors concluded that in unexplained infertility, expectant therapy is as effective as regular intercourse or oral medication + IUI. Gonadotropins appear to improve clinical prognosis, but are associated with higher multiple pregnancies. Finally, based on the limited evidence, IVF is not more effective than hMG+IUI. The authors note that the evidence for feasibility is very limited and therefore further RCTs are needed to evaluate treatment options. Expert opinion: The common approach for couples with unexplained infertility is to first clarify the absence of significant reproductive tract abnormalities in the couple, rather than providing further evaluation. Expectant treatment is an option, but couples need to be selected carefully. Younger couples, with a short history of infertility and no significant infertility stress may be ideal candidates. Older couples, who have been trying for many years and have infertility stress would benefit from treatment options. The process of intervening in couples’ decision making is very important. It should be explained that if one treatment fails, this treatment can reach another level even if it continues (e.g. IVF after failure of IUIs ). The risks of the intervention should be taken into account, such as the higher risk of IVF compared to IUI. On the other hand, IUI is also associated with a higher risk of multiple pregnancies, which is also undesirable. This requires a joint effort by the couple and the timing of the pregnancy is also very important, as the right timing of switching from one treatment to another can reduce the rate of treatment abandonment. All of these factors need to be considered when making decisions. Hopefully, further RCTs in the future will compare these treatments to provide clinicians with better options.