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

1. ART Stimulation in the Next Decade: An Overview

Luis Arturo Ruvalcaba Castellón 


Department of Ginaecology and Obstetrics, Centro Medico Puerta de Hierro, IMI – Instituto Mexicano de Infertilidad, Boulevard Puerta de Hierro No. 5150, Torre C, 5to Piso, Interior 503-C, Zapopan, Jalsico, CP 45116, Mexico

Luis Arturo Ruvalcaba Castellón



The majority of the world’s population has no access to infertility treatments because of their high costs. Time has come to develop simplified and cost-effective treatment solutions for developing countries. Those groups, who are able to reduce treatment costs and stay profitable at the same time, will find a whole new virgin market without any competition. On the other hand, in affluent countries, the sector will become more mature and will eventually solidify, which will leave only a few big players, who will share the market. Infertility specialists in these countries will have to deal with more and more complicated patients, due to the aging population. On the laboratory aspects, more and more expensive technology and knowledge will be necessary to improve pregnancy rates in older patients. On the clinical side, well-informed and independent patients will ask for more patient-friendly and less burdensome treatment approaches. For historical reasons, there is a lack of infertility specialists in many countries, which will make it more and more difficult to find qualified professionals in the future.


Low-cost IVFDeveloping countriesPatient-friendly IVFNatural cycle IVFMinimal stimulation IVFAging population


After a fascinating period of almost 30 years of IVF and 15 years of intracytoplasmic sperm injection (ICSI), it must be admitted that only a small part of the world population benefits from these new reproductive technologies.

Worldwide, more than 80 million couples suffer from infertility; the majority of this population are residents of developing countries (Fathalla 1992). New reproductive technologies are unavailable, scarcely available, or very costly in so far that the large majority of the population cannot afford infertility treatment at all (Van Balen and Gerrits 2001; Nachtigall 2006). Developing countries have a large reservoir of infertility problems, of which bilateral tubal occlusion is the most important one (World Health Organization 1987; Nachtigall 2006), a condition that is potentially treatable by assisted reproductive technologies. Tubal factor infertility, the most common etiological factor in developing countries, is mainly caused by sexually transmitted diseases (STD), postpartum or post-abortal infections, pelvic tuberculosis, and other infectious and parasitic diseases. In most developing countries, reproductive health care is synonymous with family planning and contraception. In developing countries however, infertility and fetal and neonatal death constitute an important public health problem resulting in a high prevalence of childlessness (Bergstrom 1992).

During recent decades, politicians have always shown great interest in reducing the number of births in developing countries, the so-called political “top-down” perspective (Hamberger and Janson 1997), but infertility care received little or no attention. Especially in developing countries, where poverty and infections are commonplace, fertility and fetal care are affected by many different cultural, environmental, and socioeconomic factors. The most cost-effective approach to tackle infertility problems in developing countries is prevention and education (Leke et al. 1993). However, in those cases where prevention has failed, simplified assisted reproduction must be thought of as a valuable option (Malpani and Malpani 1992).

In Egypt, it was previously stated that only 50–60 % of couples could afford to pay for IVF and embryo transfer, induction/monitoring of ovulation, or artificial insemination with husband’s spermatozoa, all of which only the private sector provided. These results demonstrate that prevention of infertility is still the most efficient option in developing countries (Serour et al. 1991ab).

In recent years, there has been increasing interest in milder approaches to IVF treatment such as minimal ovarian stimulation or natural cycle IVF (NC-IVF). These approaches decrease the physical burden and psychological distress for patients, increase patient convenience, and reduce treatment costs (Devroey et al. 2009; Fauser et al. 2010). NC-IVF is especially attractive because it is completely safe, requires minimal medication, and can be easily repeated over successive cycles. The main drawback of NC-IVF is its low efficiency per cycle, which is partly related to high cancelation rates due to premature LH surge and premature ovulation, detected at the time of oocyte retrieval (Pelinck et al. 2005).

The time has come to incorporate those new insights in a specially designed infertility care program, leading to a cost-effective simplified assisted reproduction program with special attention to avoid ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy, as a valid treatment protocol in developing countries when prevention or alternative methods have failed.

In affluent countries, the situation looks a lot different. Instead of simplifying procedures to reduce costs, complexity is about to increase. The reason is that patients in affluent countries have a completely different profile compared to patients in developing countries. Here the main indication for IVF treatments is advanced age and low ovarian reserve. To treat these highly complex conditions successfully, it is necessary to improve stimulation protocols and IVF laboratory technologies. On the medical site, mild stimulation protocols or modified natural cycle IVF become more and more important. The reason is that older patients will not respond adequately to traditional stimulation protocols using high doses of gonadotropins. Instead of oocyte quantity, the treatment will focus more on oocyte quality.

Embryos of older patients seem to develop slower in vitro due to the lack of mitochondria. This may cause synchronization problems between embryo development and the endometrial implantation window. In order to overcome this synchronization gap, more and more groups avoid fresh embryo transfers in older patients. Instead, they try to cultivate all embryos to the blastocyst stage and then vitrify the embryos, in order to transfer them in following cycles. This approach may lead to several stimulation cycles, where embryos are obtained and “banked.” If the patient is afraid of aneuploidies because of advanced maternal age, now there is the possibility of efficient preimplantation genetic screening (PGS) using trophectoderm biopsy from blastocysts and the comparative genomic hybridization technique (CGH). This approach allows a similar implantation rate like young patients, once an embryo is tested genetically normal (Harton et al. 2011).

Vitrification is a very important tool in this approach. This simple and only recently introduced embryo freezing technique will change the way IVF treatment is done. As embryos and unfertilized oocytes can be frozen now without quality loss, there is no more need for the relatively inefficient “fresh embryo transfer” approach after ovarian stimulation. Using a good embryo freezing program, it becomes possible to better synchronize the embryo and endometrium. Implantation rates for good frozen blastocysts can reach up to 46 % and more per transfer (Lathi et al. 2012).

Even in younger patients with low complexity infertility in affluent countries, natural cycle and minimal stimulation IVF will become more popular in the future. In many affluent countries, organic food can be found in regular supermarkets now, and people prefer a healthy lifestyle. Similarly, they also prefer a more natural approach to infertility treatments with less medicine. A few IVF clinics have already discovered the niche of patient-friendly “organic IVF.” This segment will further grow in the future and eventually replace conventional high stimulation IVF treatments, especially because well-designed prospective randomized studies have shown that there is no real benefit of heavy ovarian stimulation (Baart et al. 2007).

In our opinion, infertility treatments are heading into two different directions. On the one hand, infertility treatments in affluent countries, with their growing older populations, will become more and more complex, but only at the laboratory level. Educated and well-informed patients will demand patient-friendly treatment approaches with shorter treatment protocols, less controls, less medicine, and less injections. It will be a challenge for reproductive endocrinologists to design and develop new kinds of efficient and at the same time patient-friendly treatment protocols. Those pioneer groups, who are able to satisfy this growing demand of the population, will be among the most successful in the future.

On the other hand, there will be a tendency to more simplification of infertility treatments, which will allow cost reductions. Instead of focusing on the highest pregnancy rates, specialized groups will follow a “good-enough” strategy. A combination of natural cycle or minimal stimulation IVF together with special simplified IVF laboratories and a new organization of the clinics will allow the generation of high patient volumes and reduction in the costs of IVF to a fraction of the treatment costs we see today. Pregnancy rates per egg retrieval will only range between 15 and 20 %, but with prices per cycle of 600–800 USD, millions of new patients, who previously had no access to infertility treatments, will be able to pay for it.

Another tendency we see for the future is the concentration of fertility treatments offered. Only a few big clinics or chains of clinics will share the market. This tendency can be seen in any industry on the way of consolidation. Smaller clinics are bought by bigger clinics or groups, and eventually the markets are heading to an oligopoly. This is not necessarily bad for the patients in this context, as the health sector and especially infertility is very much government controlled. Big groups have the advantage of standardized treatments and protocols and a certain standard of quality control. And of course, only the groups who deliver the best results will survive.

Bad news for the sector is that in many countries, training of infertility specialists is not taken care of in an organized and systematic way. This has lead to a shortage of young doctors interested in this field, although the sector of infertility is financially very rewarding. The reason is that the first generation of infertility specialists 35 years ago has left the universities to open their own private IVF clinics. These pioneers immediately started making a lot of money and have lobbied the regulatory bodies to raise the hurdles for new young doctors in order to avoid competition. Because of these hurdles and because many gynecologists never get in touch with infertility during specialization, today, in some European countries, it becomes hard to find junior infertility specialists. Many of the first-generation doctors have come into the age of retirement and are having a hard time to sell their clinics, because of this phenomenon.


In conclusion, we see this sector of Reproductive Medicine in affluent counties mowing toward consolidation. There will be a few big players controlling the market. The complexity of patients will grow due to the aging population. Some specialized groups will find their way into developing counties and reduce price and complexity of infertility treatments. These groups will be rewarded with being pioneers in a huge virgin market.


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