Data on the optimum number of IUI treatment cycles are inconsistent. Most authors recommend not to continue IUI after three to four cycles [28] whereas some others advise to continue with IUI even after six or more cycles [29, 30]. In this group of patients is very difficult to quantify the appropriate number of IUI before proceeding to ART. In general, after four to six cycles of IUI in young patients it is appropriate to resort to ART [31]. Prognostic factors related to a higher cumulative pregnancy rate are duration of infertility less than 2 years, a previous pregnancy with the same partner and female age < 30 years. In these instances, couples could be encouraged to use less invasive treatments for up to 2–3 years because they have a similar chance of achieving pregnancy without treatment [32, 33]. ART (IVF or ICSI) is indicated as first treatment option when the duration of UI is at least 3 years. Some data suggest that each additional month of infertility reduces the chance of pregnancy by 2 %, or about 25 % year. Similarly, for each year of the female partner’s age > 30, the pregnancy rate is reduced by 9 % [2, 34].

Siam et al. [35] investigated the relationship between prevalence of antisperm antibodies and genital infection with Chlamydia trachomatis in women with UI. Infection with chlamydia is one of the most common sexually transmitted diseases and sperm-associated antibody could impair fertility through various mechanisms. The study, however, failed to find a positive correlation between current or past chlamydia infection and the level of antisperm antibodies in women suffering of UI. Antisperm antibodies were significantly higher in infertile women, but without a significant difference between infertile women with past or current C. trachomatis infection.

Another group of UI patients is those with “secondary UI” with the same or another partner. There are no clear data in the literature for these groups of patients. Good medical practice would suggest to do an extensive work-up to exclude conditions that could have altered the mechanisms of reproduction (e.g., a cesarean section with the prior delivery and the presence of pelvic adhesions) and then set up a therapeutic approach. Some authors have investigated the relationship between hyaluronan (HA)-binding assay and pregnancy rates in IUI cycles. The HA-binding evaluates the maturity and fertility potential of sperm and may be useful to discriminate between patients who would benefit from treatment with IUI if the binding is 80 % or higher [36]. Other authors have concluded that HA-binding test does not predict pregnancy rates in IUI cycle [37]. To our knowledge, there is no data about the effect of HA assay on IUI cycles in couples with UI.

IVF is a widely accepted treatment for UI, with estimated LBRs per cycle varying from 33.1 % in women younger than 35 years old and 12.5 % in women between 40 and 42 years [38]. Two randomized trials compared gonadotropin stimulated IUI with IVF in cases of UI. Crosignani et al. [39] showed birth rate of 24.5 and 22.9 %, respectively, when two cycles of each treatment were being offered. Goverde et al. [40] evaluated a treatment plan involving six cycles of unstimulated and stimulated IUI or IVF. This trial showed low pregnancy rate/cycles with IVF and multiple pregnancy rates of 21 %. Withdrawal rate was higher in IVF cycles (42 %) than FSH/IUI cycles (16 %). The Cochrane [41] analyzed six RTCs: LBR per patient was significantly higher with IVF (45.8 %) than EM (3.7 %) (OR 22.00). There was no evidence of a significant different in LBR between IVF and IUI alone (OR 1.96, 95 % CI 0.88 to 4.36), 40.7 % with IVF versus 25.9 % with IUI. The clinical effectiveness between FSH/IUI and IVF treatment of UI was small. Cost effectiveness of primary offer of IVF versus primary offer of IUI followed by IVF in couples with unexplained or mild male factor subfertility has been evaluated [42, 43]. The Cochrane concluded the review, assessing that IVF may result in more births than other techniques for couples with UI, but the research is not conclusive.

Treatment of UI is very much dependent on availability of resources and patients’ age and duration of infertility. The LBR for women > 40 years using COS with gonadotrophin/IUI is 2.6 % [44]. The standard protocol involves proceeding from low-tech to high-tech treatment options. A Cochrane review shows evidence that the addition of COS to IUI treatment improves LBRs in couples with UI. A smaller but statistical significant rise in pregnancy rate was found for IUI when compared with TI in stimulated cycles. The multiple pregnancy rates should be kept to a minimum by using mild stimulation protocols and strict cancellation criteria. Couples should be fully informed about the risks of IUI and COS and alternative treatment options should be offered. There is a definite need for multicenter randomized controlled trials to identify the best treatment option in UI. However, IVF may be more effective than the combination of IUI with ovarian stimulation, but results must be carefully interpreted. The perception of couples and their desire to achieve tangible results is also important. Adverse events and costs associated with the compared interventions have not been adequately assessed. Clinicians and couples should balance the invasive nature of IVF and related costs against chances of success with other treatment modalities. To best select an appropriate therapy, the patient’s characteristics (age, duration of infertility, parity, primary or secondary infertility, and previous therapy) should be fully explored and known.