Homerton Fertility Centre, Homerton University Hospital, London, UK
When intra-uterine insemination (IUI) is chosen for the treatment of mild male factor infertility or idiopathic (unexplained) infertility, there are a number of options for ovarian stimulation for these women who are usually ovulating spontaneously. There is now general agreement that for pure mild male factor infertility (sperm concentration 5–15 million/ml and/or progressive motility 20–32 %), whether the ovaries are stimulated or not before IUI makes very little difference to the results. For unexplained infertility, stimulated cycles in combination with IUI are more effective than unstimulated cycles as regards pregnancy rates. The combination of IUI with stimulated cycles, although improving pregnancy rates, is often accompanied by unacceptable multiple pregnancy rates. With ovarian stimulation with gonadotrophins, I aim to achieve a maximum of two ovulatory follicles and this with strict criteria for administering hCG seems to give optimal results with minimal twinning rates.
Ovarian StimulationIntra-uterine InseminationOvulationDominant ovulatory follicleFSHOvulation inductionMultifollicularOvarian responseMultiple pregnanciesOvarian hyperstimulation syndromeIVFOocytesFertilizationEmbryo replacementOestradiolGnRH agonistAntagonistICSIIntra-uterine insemination IUILetrozoleGonadotrophinIdiopathic infertilityhMGMonofollicularMultiple pregnancy rateOvulatory folliclesPremature luteinizationUnexplained infertility
The previous chapters have primarily dealt with induction of ovulation for women with anovulatory infertility in which the aim was to stimulate the ovary just enough to produce, preferably, one dominant ovulatory follicle. When using an FSH preparation for ovulation induction, the principle is to estimate and administer the threshold dose for an ovarian response but not to exceed it. This, theoretically, avoids a multifollicular response and the associated complications of multiple pregnancies and ovarian hyperstimulation syndrome.
The object of controlled ovarian (hyper)stimulation used for IVF is very different to that of ovulation induction. For IVF, it is the deliberate intention to produce multifollicular development in order to harvest a significant number of oocytes for fertilization and eventual embryo replacement. This can only be done by a much stronger stimulation with FSH, well over the threshold dose. In order to avoid premature luteinization induced by high oestradiol levels, a GnRH agonist or antagonist is almost invariably incorporated into the stimulation regimen. The starting dose of the FSH containing preparation and the size of the incremental dose rise, if necessary, can all be adjusted and tailored individually. There are then, a variety of ovarian stimulation protocols that can be applied for purposes of egg collection for IVF/ICSI.
When intra-uterine insemination (IUI) is chosen for the treatment of mild male factor infertility or idiopathic (unexplained) infertility, there are a number of options for ovarian stimulation for these women who are usually ovulating spontaneously. Some prefer not to use any ovarian stimulation at all, some clomiphene citrate or letrozole and some, stimulation with FSH. Here, the pros and cons and results of these various options will be discussed.
15.2 Treatment Regimes for IUI
Since its inception, the indications for the use of IUI have gradually broadened. The aims of its original use for the treatment of mild male factor infertility are quite clear – increasing the density of motile sperm available and placing them close to the available egg(s). In this respect, IUI has proved more successful than timed intercourse  whether in stimulated (pregnancy rate 13.7 % per cycle) or unstimulated cycles (8.4 % per cycle). There is now general agreement that for pure mild male factor infertility (sperm concentration 5–15 million/ml and/or progressive motility 20–32 %), whether the ovaries are stimulated or not before IUI makes very little difference to the results. This is not the case for unexplained infertility.
For the treatment of unexplained infertility, IUI has also made a contribution. Stimulated cycles in combination with IUI are more effective than unstimulated cycles as regards pregnancy rates [1, 2]. The combination of IUI with stimulated cycles, although improving pregnancy rates, is often accompanied by unacceptable multiple pregnancy rates. This suggests that the additional efficacy of stimulating the ovaries before IUI is due to multiple follicular development although correction of an undetected subtle defect in ovulatory function is also a possible contributory factor.
Firstly, it has been firmly established that IUI with gonadotrophin stimulation has proved to be more effective than gonadotrophins alone .
The main question to be settled regarding treatment with IUI for idiopathic infertility is if and when ovarian stimulation is justified. In an analysis of 45 reports , IUI + hMG (pregnancy rate 18 % per cycle) was found to be more effective than IUI + CC (6.7 % per cycle) and IUI in a natural cycle (4 %). It is also our experience that when combined with IUI, FSH yields much superior results compared with CC. Personally, I have abandoned the use of CC for unexplained infertility as it is little better than expectant treatment.
In a large American RCT , 231 couples treated with superovulation and IUI had a higher pregnancy rate (33 %) than in the 234 couples receiving IUI in a natural cycle (18 %). But, and it is a big ‘but’, whereas there were no multiple pregnancies in the 42 pregnancies resulting from IUI in natural cycles, of the 77 pregnancies following stimulation + UI, there were 2 sets of quadruplets, 3 sets of triplets and 17 sets of twins. This is too big a price to pay for an increased pregnancy rate. However, in my opinion, the solution is not to resort to completely unstimulated cycles but to find the golden mean, i.e. mild stimulation and strict criteria for the withholding of hCG. In the study just referred to, stimulation was started with 150 IU of FSH from day 3–7 of the cycle and could be adjusted on day 8 according to ultrasound and oestradiol examinations.
The importance of the type of stimulation protocol in the generation of multiple pregnancies can be further illustrated from published results. Goverde et al.  employed a low dose protocol with a constant dose of 75 IU FSH in the first cycle, withholding hCG when there were more than three follicles of >17 mm or six follicles >13 mm. However, if monofollicular development was seen in the first cycle, the dose for the second cycle was increased by 37.5 IU. Live birth rates per monofollicular cycle were 7 % and in cycles in which more than one follicle >13 mm developed the live birth rate was 10 %.
An unpublished study from the UK, reported by the National Institute of Clinical Excellence in 2004, involved the outcome of 1,580 stimulated IUI cycles. There were 11 twins, 2 triplets and 1 quadruplet pregnancy from 126 pregnancies, a multiple pregnancy rate of 11 %. While maintaining a pregnancy rate of 8 % per cycle, the milder stimulation regimen in the UK, compared with the more aggressive regimes in the USA, yielded a much more acceptable multiple pregnancy rate.
Clearly, multiple pregnancy rates increase with multiple follicular development. This was emphasized in an evaluation of prognostic factors  in which it was seen that more than four mature follicles at the time of hCG administration was associated with a very high rate of multiple pregnancies. With ovarian stimulation with gonadotrophins, I aim to achieve a maximum of two ovulatory follicles. This seems to give optimal results with minimal twinning rates.
Another innovation is the introduction of a GnRH antagonist into a mild FSH stimulation protocol in preparation for IUI in order to prevent premature luteinization and increase treatment efficiency. However, a large randomised trial did not show any advantage of introducing a GnRH antagonist into the protocol .
Recent calls to completely abandon gonadotrophin/IUI treatment for unexplained infertility [8, 9] are being eagerly adopted by IVF orientated practitioners but they are based on flimsy evidence (See Chap. 14). Trials directly comparing these two modes of treatment are still needed to settle the argument.
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