Natural cycle IVF is the oldest IVF treatment approach we have. The first IVF babies were born with this technique more than 30 years ago. The main problem back in pioneer times of IVF was the control of the LH surge and ovulation. If the female menstrual cycle is left alone, LH surge and ovulation may occur at any time, and in the majority of the cases, it does not occur during the working hours of the IVF clinic. Often enough, the egg retrieval had to be done in the middle of the night. In these times, many researchers started to look for possibilities to control ovulation and the LH surge, in order to make IVF treatments more convenient for doctors and patients. The early reproductive endocrinologists had a deep understanding of the hormonal patterns of the female menstrual cycle. Some of them were experimenting with drugs like Clomiphene citrate, using its antiestrogenic effect to control the LH surge. Subsequently, many reproductive endocrinologists started using ovarian hyperstimulation with Clomiphene citrate and human menopausal gonadotropin (hMG), in order to get more than only one egg per treatment cycle. More eggs allowed compensating for the loss of eggs and embryos during the IVF process. We should not forget that back in these early days, IVF laboratories were also quite inefficient, as modern embryo culture techniques did not exist. The breakthrough came in the early 1980s with the application of GnRH analogs in IVF treatments. In order to control the LH surge and ovulation, GnRH agonists can be used to put the patient into a “temporary artificial menopause,” blocking her natural FSH and LH production while supplementing the missing FSH for follicle growth from outside. This allows multiple follicle growth without the risk of premature ovulation. With the possibility of hCG triggering, egg retrievals could be programmed within the opening hours of IVF clinics, which made IVF treatments much more convenient for medical staff and patients. Furthermore, transferring more than one embryo allowed raising the pregnancy rate per IVF treatment. Thus, IVF became a mainstream treatment and more and more IVF clinics opened around the world.
Over the following decades, research focused mainly on improving the IVF laboratory, developing better embryo culture systems and new fertilization techniques, such as ICSI. On the clinical side, there have not been a lot of changes over many years. Only recently has the introduction of GnRH antagonists brought some alternative stimulation protocols into the mainstream IVF treatment. Nevertheless, the long agonist protocol is still the most widely used stimulation protocol for IVF in the world. The main reason for its success story is that it is very easy to use. The patient is on “autopilot” stimulation and the responsible doctor only has to check, when the follicles are ripe for harvesting. The simplicity of this protocol is the reason that many reproductive endocrinologists in our days, especially the new generation, have lost the ability to understand and to interpret the hormonal changes during the menstrual cycle. In many Western countries, high multiple pregnancy rates after IVF treatments had become an issue of public debate. Society did not accept the high costs related to multiple pregnancies any more, and regulations were established forcing IVF specialists to transfer fewer embryos. At the same time, embryo culture systems in these countries have improved in a way that allowed the transfer of only one or two embryos, without a loss in pregnancy rate.
After 25 years of ovarian stimulation for IVF, the scientific community is well aware about the drawbacks of this method. One major issue is the high multiple pregnancy rate after stimulated IVF treatments. In most of the countries, it is very common to transfer more than two embryos in order to raise the pregnancy rate per cycle. Some Western European countries have recently started regulating IVF treatments in a way that elective single-embryo transfer became the method of choice, but in many other countries, multiple pregnancies after IVF treatment remain a serious problem. A second issue is the oocyte and embryo quality after ovarian stimulation. Recently, researchers could demonstrate that a healthy woman is able to produce around two to three genetically normal oocytes per cycle. All the other oocytes and embryos obtained after a stimulated IVF cycle are genetically abnormal and will not lead to a live birth. In the recent years, a lot of research has been conducted in order to find the best and healthiest embryos for transfer. Ironically, this has led to more and more sophisticated and expensive IVF laboratories. Hence, embryo selection is one of the main reasons for the high costs of IVF treatments. Another reason for the high costs of IVF treatments is the medication for ovarian stimulation itself. It is estimated that between 60 and 80 million couples around the world have no access to IVF treatments because of its high costs. A third drawback of stimulated IVF treatments is the risk of developing ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening condition, which is the result of an over-reaction of the patient to the stimulation medication. Severe OHSS with hospitalization occurs in about 2–4% of all stimulated IVF cycles. The last major drawback of stimulated IVF is reduced endometrium receptivity after ovarian stimulation. It is known that high serum levels of estrogen and progesterone during ovarian stimulation lead to an accelerated endometrium development. As embryo development and endometrium development synchronization is absolutely necessary for successful implantation, an advanced endometrium development is the main reason for implantation failures.
A possible solution to these problems might be the use of modified unstimulated cycle IVF, using the patient’s natural cycle. There is nearly no risk for multiple pregnancies due to single-embryo transfer. In most of the cases, there is only one oocyte and only one embryo for transfer per treatment cycle. Due to a natural selection process inside the body, the best oocyte is always selected for ovulation. The whole complicated embryo selection in the IVF laboratory after stimulated treatments is not necessary any more. Nature does it for free. Without the use of medication and using a simplified IVF laboratory procedure, the costs are also much lower in unstimulated cycles. Obviously, there is no risk of OHSS in an unstimulated IVF treatment. Endometrial receptivity is also much better because there is no accelerated development of the endometrium in the natural cycle.
So, if natural cycle IVF seems to be the solution for everything, why is this treatment so hard to find? Only very few IVF clinics around the world are actually offering natural cycle IVF. There are many reasons for this. The most important reason is the widespread belief that natural cycle IVF is not efficient, because the pregnancy rates per started cycle are lower than in stimulated cycles. This is partly true, but we have to look at the definition of efficiency here. In our opinion, natural cycle IVF is the most efficient IVF treatment that exists. Depending on the study, the oocyte to live birth rate is around 20 % per oocyte in natural cycle IVF. Of course, different studies are not comparable like this, but the difference in biological efficiency per oocyte looks impressive. Another reason for the unpopularity of natural cycle IVF is the fact that it is not easy to learn. In contrast to stimulated treatments, success and failure depend on correct interpretation of the patient’s hormonal pattern. The key to a successful natural cycle IVF program is the art of interpreting hormones to find the right moment to trigger ovulation and program the egg retrieval. We believe that in the right setting, natural cycle IVF may become more popular in the near future.
Minimal stimulation IVF is also quite an old approach. Before GnRH analogs had been introduced, everyone has used mild stimulation protocols based on Clomiphene citrate and hMG. After the introduction of GnRH analogs, nearly all the groups around the world switched to the long GnRH agonist protocol. Only a few groups, mostly in Japan, have continued working with the minimal ovarian stimulation approach based on Clomiphene and hMG over the last decades. Without a lot of contact outside Japan, the group that worked with Late Osamu Kato in Tokyo primarily had developed this protocol to near perfection. This approach has been so successful in Japan that Kato Ladies Clinic in Tokyo has become the largest IVF clinic in the world with nearly 25,000 egg retrievals per year.
Although we do not think that natural cycle IVF and minimal stimulation will replace conventional IVF completely in the near future, it is very likely that some specialized groups will focus on these approaches in certain patient groups.
The first patient group, which might benefit from natural cycle IVF or minimal stimulation IVF, is the so-called poor responders. These patients with a low ovarian reserve do not respond well to conventional stimulation protocols due to high FSH levels and reduced antral follicles. Whatever kind of stimulation is applied, minimal stimulation or conventional stimulation, these patients will not produce more than 4 to 5 mature follicles. As minimal stimulation protocols use much less medication, they are usually cheaper and less complicated compared with conventional stimulation protocols. If the same results can be expected regardless of which protocol will be applied, it is logical to use the simpler and cheaper protocol.
The second patient group for natural cycle IVF or minimal stimulation IVF is the patient group with advanced age over 40 years. This patient group is particularly sensitive to high FSH levels and FSH fluctuation during ovarian stimulation, which may be the cause for high aneuploidy rates in eggs and embryos obtained in these patients after conventional ovarian stimulation. Even if many of these patients may still have a normal ovarian reserve, egg quality could be improved and aneuploidy rates may be reduced using natural cycle IVF or minimal stimulation.
This monograph will take you through the entire process of these simpler technologies in a lucid manner.
Gautam N. Allahbadia
Markus Nitzschke
Mumbai, IndiaLas Palmas de Gran Canaria