In today’s technological breakthroughs and medical advancements, it appears that every day there are increasing numbers of patients who wish to undergo in vitro fertilization (IVF) treatments with ncIVF (Payne et al. 2012). For years, many people believed that more hormonal treatment leads to greater number of eggs retrieved, meaning a greater chance of a successful fertilization. While this may seem the case, there is a better chance of fertilization, with better eggs; there is no need to collect as many eggs. Therefore, if it is possible to collect fewer higher quality eggs, using safer, more natural cycles, the risks start to decline. Therefore, studies are needed to compare the various treatment modifications such as the addition of Clomiphene citrate and low dosages of gonadotropins and GnRH antagonists, and treatment protocols must be further optimized to boost the effectiveness of ncIVF as needed.

In the meanwhile, von Wolff et al. (2013a) and several authors found that the implantation rate in ncIVF is higher than in unselected embryos in cIVF, even though a direct comparison has not yet been carried out. Reports by SART (Society for Assisted Reproductive Technology) and CORS (Clinical Outcome Reporting System) (Gordon et al. 2013) showed that ncIVF implantation rates in women aged less than 35 years were calculated to be 4 % higher; however, these rates were insignificant. In women aged greater than 35 years, the results were shown to be 16 % higher for implantation rates, which were higher in cIVF and more significant (Gordon et al. 2013). In these findings, the average pregnancy rate for ncIVF in all age groups was 26 % per transfer and the birth rate per transfer was 20 %. Reports of SART and CORS showed a transfer rate per initiated cycle of only 37 % (Gordon et al. 2013).

The low transfer rate in ncIVF has also been confirmed in other reports. Aanesen et al. (2010) described a transfer rate per initiated cycle of 47 % and Polyzos et al. (2012) reported a 42 %. The low transfer rates can be explained by the high rate of premature ovulation. Treatment options for the prevention of premature ovulation include a single dose of gonadotropin-releasing hormone (GnRH) antagonists, administration of non-steroidal anti-inflammatory drugs (Kawachiya et al. 2012), and administration of Clomiphene citrate.

Previous studies on the efficacy of Clomiphene citrate are only of limited use. First, there is no accurate comparison of study protocols with or without Clomiphene citrate. Second, the dosage of 50–100 mg per day of Clomiphene citrate is relatively high and can cause side effects, such as hot flushes, headache, and ovarian cyst formation, which make consecutive monthly treatments impossible. Third, there are no studies that have shown whether the number of consultations prior to follicle punctures indicates reduced amount of time and effort for the patients and the assisted reproduction centers. The latter is essential when ncIVF is to be the alternative to cIVF with regard to time, effort, cost, and efficacy.

Based upon reports by von Wolff et al. (2014b), it has been shown that a treatment using only 25 mg Clomiphene citrate per day has minimal or less side effects compared to treatment with 50–100 mg per day. Meanwhile, von Wolff et al. (2014a) described the effectiveness of their treatment with regard to having a minimum number of consultations, as well as the rate of premature ovulations and transfers per initiated cycle. To improve the comparison of both treatment protocols and to reduce individual variations, the same patients underwent ncIVF without Clomiphene citrate as well as with Clomiphene citrate when possible.

The easiest and cheapest way to control premature LH rise in ncIVF is to use the antiestrogenic effect of Clomiphene citrate around ovulation. As a competitive inhibitor of estrogen receptors at the hypothalamic level, the system is tricked to “think” that the follicle is still not mature enough to trigger the LH surge. Depending on the dosage, Clomiphene citrate is able to delay LH surge or to block it completely (Teramoto and Kato 2007). In this case, it is necessary to trigger the LH surge and ovulation artificially with GnRH analogs, once the follicle has reached maturity. Oocyte retrieval is done 35–36 h later. It is important to understand that Clomiphene citrate can be used in two different ways: either for ovarian stimulation, if given before day 6 of the menstrual cycle; but in this case, it may have a negative impact on the endometrium and implantation. If Clomiphene citrate is given after day 6 of the menstrual cycle, it only has an inhibitory effect on the LH surge and ovulation, but probably no negative impact on the endometrium. In ncIVF treatments, the use of Clomiphene citrate given around ovulation can improve follicle maturation and oocyte quality. The standard protocol in this case is 25 mg Clomiphene citrate per day from day seven of menstrual cycle including the evening of ovulation induction by GnRH analogs. The use of hCG to trigger ovulation is not recommended, if Clomiphene citrate was used after day 6 of menstrual cycle. Clomiphene citrate has a relatively long half-life and hCG somehow boosts its stimulating effect on the ovaries. If both drugs are used together, there is a higher risk for functional ovarian cysts than if GnRH analogs are used for triggering. Some people think that using GnRH analogs for triggering ovulation may cause a luteal phase defect and hamper implantation, but this is only the case after ovarian stimulation with more than four mature follicles, not in a natural cycle. It is also not beneficial to use vaginal progesterone or other methods to support the luteal phase. If the ovulation has been from a mature follicle, due to the use of Clomiphene citrate, the resulting corpus luteum should be supportive enough for a good luteal phase. Commercially available Clomiphene citrate is a mixture of two geometric isomers, enclomiphene (E-clomiphene, trans-isomer) and zuclomiphene (Z-clomiphene, cis-isomer). Enclomiphene has a shorter half-life time in the body than its more active isomer Zuclomiphene.

As Teramoto and Kato (2007) reported, the mechanism of Clomiphene citrate is still “shrouded in mystery,” even though its antiestrogenic action and its action to prevent the premature LH surge, which represents the biggest problem in IVF, were described and used in his protocol. The terminology “premature LH surge” as used by Teramoto and other authors means a LH surge naturally produced in the body during stimulation of the ovaries in preparation for an in vitro fertilization (IVF). If the LH rises, triggered by the own body functions, the ovulation cannot be induced in a controlled manner anymore and one is forced to retrieve the ovum 36 h after the start of the LH surge.

According to the present protocol of ncIVF and in contrast to the common use of Clomiphene citrate in prior assisted reproduction technology (ART) as described above, Clomiphene citrate is only administered from the 6th or 7th day of the menstruation cycle, when a dominant follicle has been selected, not before. At this stage, the growth of the endometrium is already completed. Hence, despite the intake of Clomiphene citrate, the embryos produced in this cycle can directly be transferred in the same cycle without freezing them in the meantime. The Clomiphene citrate treatment is continued until the follicle is mature and ovulation occurs or is triggered. In view of the half-life of Clomiphene citrate and its isomers, it is possible to give the last dose of the drug 1 day before the ovulation is triggered or occurs. If the dose is higher, e.g., 50 mg orally, it is even possible to give the last dose 2 days before ovulation induction. Each of these cases is included in the term “until the maturation of the oocyte.” At this point, the ovulation can be triggered. After ovulation a pregnancy can either be achieved in the natural way inside the body of the woman, or by IVF.