Minimal Stimulation and Natural Cycle In Vitro Fertilization, 1st ed. 2015

4. The Use of Clomiphene Citrate in Natural Cycle IVF

Sonny J. Stetson 

(1)

Department of Surgery, Texas Medical Center, 3524 Omeara Drive, Houston, TX 77025, USA

Sonny J. Stetson

Email: drsjstetson@hotmail.com

Abstract

Natural cycle IVF (ncIVF) is a fertility treatment based on the natural menstrual cycle of patients. Compared with conventional IVF (cIVF), it is inexpensive and more convenient for patients, but in reality, it is more difficult to learn and to apply in an established cIVF clinic environment. The challenge for everyone, who is interested in learning ncIVF, is to master the techniques to control the luteinizing hormone (LH) surge. This chapter aims to give an overview over LH control through Clomiphene citrate.

Keywords

Natural cycle IVFLH surgeClomiphene citratePremature ovulationGonadotropinsGnRH antagonists

Rationale

With the imbalance of the growing population, there is a growing need for alternative treatment approaches in the field of Reproductive Medicine. In times like these of public health budget restrictions and global financial crisis, the current high-cost infertility treatment approach is not sustainable any more in many parts of the world. Natural cycle IVF could be part of the solution to more patient-friendly and cost-effective fertility treatments. As intelligent, educated professionals, we tend to overanalyze and complicate things that are relatively simple. Patients are becoming more aware of this alternative treatment option and are demanding it. This chapter tries to give an overview about this exploding new approach, in order to help interested reproductive endocrinologists to better understand the basics of this treatment and its difficulties.

Introduction

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.

In order to obtain the desired pharmacological effects, Clomiphene citrate can be administered in only very low doses. Suitable doses are 10–35 mg/day, preferably 25 mg/day, or 40–60 mg, preferably 50 mg every 2nd day until the oocyte within the follicle is mature. The exact dosage should be determined by the responsible physician on the basis of the desired inhibitory effect on the pathological premature LH rise and potential side effects of Clomiphene citrate.

Clinical Discussion

The key to a successful ncIVF treatment is the art to understand the patient’s individual hormonal cycle pattern and the techniques to control LH surge and ovulation. Several methods have been presented and published in the literature and all of them work but have their advantages and disadvantages.

Two great advantages of ncIVF in general should be mentioned here. The first one is that no ultrasound has to be performed for follicle controls within the treatment cycle. With only one or two blood tests per cycle, the exact time point of ovulation induction or egg retrieval can be determined. This is very convenient for the patient and allows the IVF clinic to work much more efficiently. The second big advantage is that there is no need for anesthesia during egg retrieval. Using thin single lumen needles between 19G and 21G, without follicle flushing, the egg retrieval takes only about 30 s and is not painful for the patient. This is also very convenient for the patients and allows a much faster patient flow, less work load, and less personnel for the IVF clinic.

Recent Advances

Natural cycle IVF is still very far away from being a mainstream treatment. Only very few groups around the world have established ncIVF programs. But, the success and the growth of these groups are ground-breaking. Patients travel from continent to continent to these clinics in order to receive treatment. It is inexpensive, it is natural, and it is very convenient. Everyone, who is practicing and experiencing ncIVF in his or her daily routine, believes that this is the method of the future.

Conclusion

Over the years, the efficiency of IVF treatments increased thanks to the introduction of gonadotropins, such that, ncIVF treatments were no longer regarded as being meaningful. However, a new trend has emerged over the last 10 years or less. IVF treatments with a low stimulation dose are being increasingly used; these avoid complications on the part of the reproductive endocrinology and infertility specialists and concerns about hormonal treatment on the part of the patient. Even IVF treatments without hormonal treatments are a realistic option because the age of the patients at the time of IVF treatment is growing rapidly and in low/poor responders, gonadotropin stimulation is rarely indicated or not indicated at all. The stimulation protocols in cIVF also appear to have a negative effect on the physiology of the follicle states (von Wolff et al. (2013b) and Vaucher et al. (2013). However, the number of ncIVF treatments is still very low, for instance, less than 1 % in the USA from 2006 to 2007 (Gordon et al. 2013). According to a survey in the USA, the cause appears to be the low success rates and the lack of patient interest (Gordon et al. 2010); however, this contrasts with a patient survey in which many patients would even prefer a ncIVF treatment if the pregnancy rates were only 10–15 % per initiated cycle (Pistorius et al. 2006).

These developments are in contrast to the low number of scientific reports about the increasing effectiveness of ncIVF treatments. Natural cycle IVF can only be an alternative to cIVF when the effectiveness of the treatment is high, the costs are low, and the time and effort required for the patients and the assisted reproduction centers are low. An increase in effectiveness can nevertheless only be achieved by modifications and use of adjuvants, which must be systematically tested and optimized in research.

The number of consultations has not been analyzed in any studies up to now. Alongside a basic scan at the start of the cycle, Polyzos et al. (2012) carried out monitoring every 2 days from cycle day 7 or 8 and Schimberni et al. (2009) daily. Aanesen et al. (2010) and Ingerslev et al. (2001) have also had at least 2–3 consultations prior to follicular puncture; however an exact analysis of the number of consultations was not carried out in any of the studies. As many consultations increase the costs and offset the simplicity of a natural cycle IVF treatment; a low number of consultations are essential.

The lowest number of consultations possible was the aim from the start of our study. A baseline scan at the start of menstruation was not carried out at all; the first consultation took place around 2–4 days before expected ovulation, and the number of consultations could thereby be kept very low. Even for IVF treatment without Clomiphene citrate, at 58.3 % the number of cycles with at least one collected oocyte was the same as for Aanesen et al. (2010) (58.9 %) and for Ingerslev et al. (2001) (57.0 %) despite our low number of consultations. Schimberni et al. (2009) and Polyzos et al. (2012) did not carry out a detailed analysis regarding the number of follicular punctures without a collected oocyte. The number of transfers per initiated cycle in the study by von Wolff et al. was 39.8 % without Clomiphene citrate, for Aanesen et al. (2010) was 46.5 %, and for Ingerslev et al. (2001) was 25.4 %. The pregnancy rate per transfer and per initiated cycle for Clomiphene citrate were 27.9 % and 10.7 %, respectively, in the study by von Wolff et al. (2014ab); for Aanesen et al. (2010), they were 26.7 and 12.4 %; and for Ingerslev et al. (2001), they were 13.8 and 3.5 %. The low pregnancy rates in the study by Ingerslev et al. (2001) are not comprehensible, especially as only women younger than 35 years were included. However, a very low fertilization rate of 47.1 % attracts attention, which could indicate poor egg quality. The pregnancy rate for ncIVF without Clomiphene citrate lies predominantly between 20 and 30 % per transfer. Schimberni et al. (2009) also demonstrated corresponding rates (≤35 years, 29.2 %; 36–39 years, 20.6 %) and the SART and CORS register demonstrated similar rates of 26.2 % (Gordon et al. 2013). All these data show the high implantation potential of naturally matured oocytes. Many authors have proven that similar success rates can also be achieved with a very low number of consultations. The data also make clear that the low embryo transfer rate is a greater limiting factor than the implantation rate of the embryos.

Other study groups had already used Clomiphene citrate as an adjuvant to improve the success rate of ncIVF treatment; however, the doses used were considerably higher. Aanesen et al. (2010) and Ingerslev et al. (2001) carried out a direct comparison of ncIVF with cIVF and administered Clomiphene citrate in a dose of 100 mg/day from cycle days 3–7. The number of consultations with this treatment was neither described exactly nor compared with ncIVF without Clomiphene citrate. The premature ovulation rate was also not stated.

The transfer rates per initiated cycle in the study by von Wolff et al. (2014ab), Aanesen et al. (2010) and Ingerslev et al. (2001) were 54.4 %, 60.4 %, and 53.2 %, respectively, and were therefore 14.6, 13.9, and 25.4 % higher than without Clomiphene citrate. The pregnancy rates per transfer and per initiated cycle were 25.0 % and 13.6 %, respectively, in the study by von Wolff et al. (2014b), 27.2 and 16.4 % in the study by Aanesen et al. (2010), and 33.9 and 18.0 % in the study by Ingerslev et al. (2001). Using Clomiphene citrate in the studies done by von Wolff et al. (2014b) and those of Aanesen and Ingerslev, they are around 3 %, 4 %, and 15 %, respectively, and therefore increased the pregnancy rates per cycle. Why the pregnancy rate without Clomid in the study by Ingerslev et al. (2001) was disproportionally low and with Clomid disproportionally high is mystical.

Ingerslev et al. (2001) only carried out a direct comparison of a ncIVF treatment with and without Clomiphene citrate in their study and in the study albeit with different Clomiphene citrate doses and different study designs. The primary outcome measure of Ingerslev et al. (2001) was the pregnancy rate, which is why the patients were randomized. Primary outcome measures in the study by von Wolff et al. (2014b) were the premature ovulation rate and the transfer rate per initiated cycle, which is why both groups were as homogeneous as possible, which was achieved by the patients undergoing both treatments where possible. The randomization in the study by Ingerslev et al. (2001) resulted in somewhat heterogeneous study groups. Whether this is a reason for the clearly differing fertilization rates, which may also have contributed toward the considerable discrepancy in the pregnancy rate, is unclear.

Although von Wolff et al. (2014ab) did not intentionally carry out randomization, it can be interpreted as a weakness in their study. The study groups were however, largely homogeneous except for the dropout rates because of the pregnancies occurring in the first IVF treatment and thereby, allow a good comparison of the parameters tested. The question arises of whether the pregnancy rate per transfer was falsely low in the second IVF treatment (cIVF with Clomiphene citrate) as a result of the dropout rate of possibly very fertile women in the first IVF treatment. Even though this cannot be excluded, the continually high pregnancy rate per transfer with ncIVF during at least 5 consecutive treatment cycles (Schimberni et al. 2009) argues against this assumption. As a result, von Wolff et al. (2014ab) found a direct statistical comparison and also the pregnancy rates of both treatment groups to be justifiable.

A further important criterion in treatment using Clomiphene citrate is whether this also leads to side effects. Ingerslev et al. (2001) have also investigated side effects. Ingerslev et al. (2001) administered 100 mg Clomiphene citrate per day and therefore, a total dose of 500 mg Clomiphene citrate per treatment cycle. Ingerslev et al. (2001) described hot flushes in 32 % and nausea in 13 % of the patients. In our collective, hot flushes were reported by only 5 % and nausea by 0 % of patients, and these side effects were described as being mild.

von Wolff et al. (2014a) used 25 mg Clomiphene citrate per day, thereby offering a considerably more favorable side effect profile. The development of persistent cysts, which can occur with higher doses of Clomiphene citrate over long periods, can hinder monthly treatment cycles and was not observed in their study.

This data leads to the last question of whether a monthly treatment with the low number of consultations described here and the pregnancy rate determined under Clomiphene citrate use can be an alternative to cIVF with respect to costs and the duration of treatment. An extensive cost calculation has not been carried out in any of the studies described up to now. Assuming 1.2 consultations per cycle prior to follicular puncture and a pregnancy rate per cycle of 13 %, von Wolff et al. (2014ab) calculated the costs and treatment duration of ncIVF compared to cIVF with Clomiphene citrate. According to this calculation, the costs of ncIVF are less than those of cIVF treatment with the same probability of pregnancy, although the treatment duration is 30 % longer (von Wolff et al. 2014a).

In conclusion, the therapy treatment with 25 mg Clomiphene citrate per day allows few consultations before follicle aspiration, does not cause any relevant side effects, and results in a significant reduction in premature ovulation and increased transfer rate per cycle. Adjuvant treatment with Clomiphene citrate should therefore be considered in ncIVF therapies to increase its efficacy and effectiveness.

References

Aanesen A, Nygren KG, Nylund L. Modified natural cycle IVF and mild IVF: a 10 year Swedish experience. Reprod Biomed Online. 2010;20:156–62.CrossRefPubMed

Gordon JD, Dimattina M, Botes A, Celia G. Opinions regarding unstimulated IVF: a survey of clinics reporting to SART. Fertil Steril. 2010;94:S158.CrossRef

Gordon JD, Dimattina M, Reh A, Botes A, Celia G, Payson M. Utilization and success rates of unstimulated in vitro fertilization in the United States: an analysis of the Society for Assisted Reproductive Technology database. Fertil Steril. 2013;100(2):392–5.CrossRefPubMed

Ingerslev HJ, Højgaard A, Hindkjaer J, Kesmodel U. A randomized study comparing IVF in the unstimulated cycle with IVF following clomiphene citrate. Hum Reprod. 2001;16:696–702.CrossRefPubMed

Kawachiya S, Matsumoto T, Bodri D, Kato K, Takehara Y, Kato O. Short-term, low-dose, non-steroidal anti-inflammatory drug application diminishes premature ovulation in natural-cycle IVF. Reprod Biomed Online. 2012;24:308–13.CrossRefPubMed

Payne D, Goedeke S, Balfour S, Gudex G. Perspectives of mild cycle IVF: a qualitative study. Hum Reprod. 2012;27:167–72.CrossRefPubMed

Pistorius EN, Adang EM, Stalmeier PF, Braat DD, Kremer JA. Prospective patient and physician preferences for stimulation or no stimulation in IVF. Hum Fertil (Camb). 2006;9:209–16.CrossRef

Polyzos NP, Blockeel C, Verpoest W, De Vos M, Stoop D, Vloeberghs V, Camus M, Devroey P, Tournaye H. Live birth rates following natural cycle IVF in women with poor ovarian response according to the Bologna criteria. Hum Reprod. 2012;27:3481–6.CrossRefPubMed

Schimberni M, Morgia F, Colabianchi J, Giallonardo A, Piscitelli C, Giannini P, Montigiani M, Sbracia M. Natural-cycle in vitro fertilization in poor responder patients: a survey of 500 consecutive cycles. Fertil Steril. 2009;92:1297–301.CrossRefPubMed

Teramoto S, Kato O. Minimal ovarian stimulation with clomiphene citrate: a large-scale retrospective study. Reprod Biomed Online. 2007;15(2):134–48.CrossRefPubMed

Vaucher A, Kollmann Z, Bersinger NA, Weiss B, Stute P, Marti U, von Wolff M. Gonadotropin stimulation in in vitro fertilization (IVF) significantly alters the hormone concentrations in follicular fluid – a comparative study between Natural Cycle and conventional IVF. Hum Reprod. 2013;28(S1): i321–323.

von Wolff M, Hua YZ, Santi A, Ocon E, Weiss B. Follicle flushing in monofollicular in vitro fertilization almost doubles the number of transferable embryos. Acta Obstet Gynecol Scand. 2013a;92:346–8.PubMedCentralCrossRef

von Wolff M, Kollmann Z, Vaucher B, Weiss B, Bersinger NA. AMH, a putative follicular marker of oocyte quality, is concentrated around 3-fold higher in follicular fluid of Natural Cycle-IVF than in gonadotropin stimulated IVF. Hum Reprod. 2013b;28(S1):i333–4.

von Wolff M, Rohner S, Santi A, Stute P, Popovici R, Weiss B. Modified natural cycle in-vitro fertilization – an alternative IVF treatment with lower costs per achieved pregnancy but longer treatment time. J Reprod Med. 2014a;59(11–12):553–9.

von Wolff M, Nitzschke M, Stute P, Bitterlich NS, Rohner S. Clomiphene citrate at low at dosages reduces the rate of premature ovulation and increases the transfer rate per cycle in natural cycle IVF. Reprod Biomed Online. 2014b;29(2):209–15.