Complete Natural Cycle IVF Treatment

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This is the fundamental treatment protocol of our clinic. Every woman’s oocyte has a different way of arriving at ovulation. Every woman has a distinct idiosyncrasy in the speed of follicular growth, the manner in which the female hormone (estradiol: E2) increases, and the timing at which the oocyte reaches ovulation. The oocytes of those who have had hormone drugs administered in the past might have deviated from natural conditions, and thereby not be able to go through the process of normal ovulation. Natural cycle IVF is important for grasping such “idiosyncrasies” and “the level of deviation”. Ovarian reserve (the capacity of the ovary to provide oocytes capable of fertilization) diminishes as women grow older. This is an unavoidable fact.

However, we believe we must refrain from administering potent drugs, contraceptive pills, and large amounts of ovarian stimulating drugs when the condition of the ovary is poor because they may deteriorate its condition further, endangering its ability to recover naturally. Natural cycle IVF is important for accurately assessing ovarian reserve.

What is more important than anything is the fact that natural cycle IVF is the cycle in which a good-quality oocyte is selected by nature. The dominant follicle selected in natural cycle IVF harbors, regardless of the woman’s age, the best oocyte in the given cycle, and this is what will be waiting for you. However much the ovarian reserve diminishes, the oocyte which will grow into a healthy baby always remains in the ovary.

The third day of the menstrual cycle (day 3) is the basic examination day. The basic information, such as the number of follicles (the sac which contains the oocyte; roughly 5mm in diameter on day 3 of the cycle), and the levels of FSH and AMH (the anti-Mullerian hormone which is an index for assessing the number of follicles) are measured. With natural cycle IVF, no drugs are used and the growth of the follicles is closely monitored.

The second visit to the clinic is normally on day 10 of the cycle (those who have had treatment in our clinic and have a record of ovulation occurring before day 10 may be designated to visit either on day 8 or day 9 of the cycle). For some patients, the date for the oocyte retrieval (taking out the eggs) may be decided as early as on the second visit. However, most patients are given the date for the third visit based on the data taken during the second visit.

After a couple of visits, the date for retrieving the oocyte is decided, when the level of female hormone (E2) and the size of the dominant follicle become optimal. Normally, when the E2 level reaches 250 pg/ml, the preparation for oocyte retrieval is set. In the case where the level of brain hormone (luteinizing hormone: LH) has not risen to the optimal level, a nasal spray of GnRH agonist (such as Sprecur® and Buserecur®) is administered to raise the level artificially, and then oocytes are retrieved two days later in the morning (scheduled oocyte retrieval). When the level of LH has risen earlier than expected, secretion of LH may be temporarily suppressed or the action of LH may be offset through the administration of a drug, and then the oocytes are retrieved two days later as planned (suppressed oocyte retrieval). However, if that is not feasible, oocytes are retrieved immediately before the ovulation on the day of the visit or the following day, following the course of nature (emergency retrieval).

When the oocytes have been successfully retrieved and the fertilized embryos have grown into blastocysts that meet the criteria on the fifth day of retrieval, one of these fresh embryos is transferred to the womb without being frozen, as long as there are no problems with the endometrium and the luteal function. However, if the development of the embryos is slow and/or there are problems with the endometrium and/or the luteal function, embryos are frozen, and one of them is thawed and transferred in the subsequent cycle.
* N.B: In our clinic, all patients are provided with oocyte retrieval based on natural cycle IVF protocol which is eligible for the contingency pricing scheme for their initial IVF treatment (on the condition that you can visit the clinic within the designated time frame on the designated days), except for those with amenorrhea and severe cases of menstrual disorder.

Quarter Clomiphene (qC) Cycle IVF Treatment

Touch to open The oocytes retrieved just before ovulation has the highest rates of oocyte maturation and retrieval. In fact, the best part of natural cycle IVF protocol and its real significance lies in the fact that we are able to retrieve the naturally selected oocyte just before nature itself releases it. Therefore, in natural cycle IVF treatment, it is crucial to grasp the onset of the LH surge (the time when the LH level begins to rise) appropriately, predict the timing of the ovulation accurately, and then retrieve the oocyte just before the ovulation. However, even daily examination leaves a 24-hour gap which may lead to missing the onset of the LH surge, the level of which changes every hour, sometimes every minute. There is always the situation where “Today is too early, but tomorrow will be too late.” Although this situation requires emergency oocyte retrieval, it might not be the best timing because of the restrictions imposed by office hours. In that case, the rate of retrieval of the oocyte and of its maturation would be lower than those of the scheduled and repressed oocyte retrievals.

Therefore, in ordinary IVF treatment, the onset of the LH surge is suppressed by drugs in order to avoid such a situation (in other words, unscheduled ovulation). There are two kinds of drugs used for that purpose, namely, gonadotropic hormone (FSH and LH)-releasing hormone agonist and antagonist. The representative trade names for such drugs are Sprecur® and Buserecur® for the agonist, and Cetrotide® and Ganirest® for the antagonist. The IVF cycles which use these drugs are called short, long, or antagonist protocols, and they all share the common characteristic that they stop ovulation by potently suppressing the secretion of brain hormone from the pituitary (i.e. FSH and LH) and at the same time stopping the growth of follicles. As a result, in any of these protocols, it becomes necessary to complement a large dose of drugs, namely FSH or hMG (human menopausal gonadotropin), by injection. In addition, hCG (human chorionic gonadotropin) must be administered by injection in order to induce ovulation.

Compared to these protocols (called controlled ovarian stimulation cycles), our clinic has a different method of suppressing the onset of the LH surge ? “the clomiphene cycle IVF”. Clomiphene is an estradiol (E2) antagonist and it counteracts E2 in the hypothalamus, which is situated in the level above the pituitary in the hypothalamic?pituitary?adrenal axis, preventing the promotion of gonadotropic hormone-releasing hormone secretion. As a result, the increase in the LH level which causes ovulation is stopped. The use of clomiphene is different from the conventional protocol in that the action of clomiphene only makes the brain temporarily forget about the commencement of the LH surge and then, with the use of drugs, such as Sprecur®, the brain is easily reminded of the necessity of the LH surge again. In addition, as it does not suppress the secretion of FSH, the follicular growth is maintained, making it unnecessary to administer drugs for enhancing follicular growth (FSH or hMG drugs).

Clomiphene cycle IVF has thus many advantages. However, the maintenance of follicular growth means the generation of small and middle-sized follicles, sometimes causing the problem of “retained follicles”. This is an abnormality where the follicle has already grown large and the E2 level also has already risen at the beginning of the subsequent menstrual cycle. Once this condition develops, it is difficult to put it back to normal.

Therefore we have pursued the possibility of drawing only the advantages from clomiphene and devised the method of using a minimal amount of clomiphene for a short period of time ? the protocol called qC cycle IVF. In this protocol, you will take a quarter tablet of clomiphene (12.5mg) daily from day 6 of your menstruation cycle. This low dose (one eighth of the normal dose of 100mg, which you start taking 3 days later than the normal regimen) can effectively suppress the onset of the LH surge and there are hardly any side-effects, and it is as close as one can get to the conditions of the natural cycle.

The schedule for visiting the clinic for examination for qC cycle IVF is the same for natural cycle IVF, but all the oocytes retrieved will be cryopreserved and then thawed/transferred. That is because we take into consideration the effect of clomiphene, even though only a minimal amount is used. With the qC cycle, there will be only one dominant follicle and many small follicles developed, in the same manner as in natural cycle IVF. As there are no middle-sized follicles, all the follicles complete their life-span and normally no remnant follicle remains. Therefore, even if an oocyte fails to be retrieved in the given cycle, it can be retrieved consecutively in the subsequent cycle and the quality of the oocyte will not be degraded.
* Note: The second qC cycle IVF treatment is also eligible for the contingency pricing scheme (on condition that you can visit the clinic within the designated time frame on the designated days, as well as you strictly observe the instructions for taking the drug.)

The Contingency Pricing Scheme

Both the first complete natural cycle IVF and the second qC cycle IVF treatment come under the contingency pricing scheme. With this scheme, the medical fee is restricted to less than 100,000 yen in the case where treatment did not succeed (please see the section on the pricing plan.) The contingency pricing comes into effect when the following conditions are met: consecutive pregnancy for more than 10 weeks has been achieved; the fetal height being more than 30mm, the fetal heart rate being more than 160 times per minute; no apparent abnormality being found with the fetus; and the patient having graduated from our clinic and having moved to a maternity facility for treatment.

letrozole®/Quarter Clomiphene (LqC) Cycle IVF

Touch to open If you could not graduate from our clinic successfully with the treatment by the second trial, letrozole® cycle IVF may be recommended for the third trial and onwards. letrozole® inhibits female hormone generation in follicles (i.e. it is a female hormone synthesis inhibitor). As a result, the hormonal sensitivity of follicles is increased and follicles become able to grow with even a little amount of FSH secretion. Even so, the number of follicles grown is not increased because letrozole® does not have an ovary stimulating effect. This characteristic of letrozole® protocol is almost the same as that for natural cycle IVF. The only difference is the fact that even women with a low FSH secretion level can develop follicles and have ovulation. In particular, the typical candidates for this treatment are women with polycystic ovarian disease (PCO: the only symptom is having a large number of follicles which do not meet the criteria for a pathological condition and the condition is commonly found in Japanese women) and polycystic ovarian syndrome (PCOS: this meets the criteria for a pathological condition and is commonly found in European and American women) whose hormone balance has been disrupted with high LH and low FSH secretion due to too many small follicles.

One shortcoming of using letrozole® alone is the difficulty of retrieving the oocyte at the best timing because it is hard to predict the shift in the level of the female hormone. In order to conquer this point, we combine the use of letrozole® with the aforesaid qC cycle protocol (thus LqC cycle IVF) in order to prevent the onset of the LH surge and to realize the best timing for oocyte retrieval.

Another disadvantage of letrozole® is the fact that using it for treating infertility is off-label use. letrozole® is marketed as a medicine for treating breast cancer. Because of that, the effects on the fetus have not been studied and therefore the utmost care needs to be taken with regard to its safety. As a precaution, we do not transfer embryos in the cycle letrozole® is administered. The embryo is cryopreserved and transferred in natural cycle IVF protocol in the subsequent cycle or later where there is no influence of letrozole®.

We also pay attention to the dose and the period for administration in order to secure safety: letrozole® is only administered for three days from day 3 of the menstrual cycle. This is because in this way we can make sure that letrozole® will not remain in the body after day 12 of the menstrual cycle because of the drug’s half-life. In other words, the oocytes existing at the time of ovulation will not be influenced by letrozole®. In this LqC cycle also, there are only one dominant follicle and many other small follicles. Therefore, oocyte retrieval can be carried out in the subsequent cycle consecutively, in the same manner as in natural cycle and qC cycle, which promises the harvesting of good-quality oocytes.

The schedule for visiting the clinic is the same as that for natural cycle IVF. Normally, the second visit to the clinic will be on day 10 of the menstrual cycle. When the E2 level has reached 250 pg/ml or more, the day for oocyte retrieval is decided based on your history with natural cycle IVF and qC cycle IVF treatment.
* N.B.: The third LqC cycle IVF treatment is not eligible for the contingency pricing scheme.

Oocyte Retrieval from Small Follicles

Touch to open In natural cycle, only one follicle is selected out of the many that exist and this develops into the “dominant follicle.” With younger women with no treatment history, it can be said that the dominant follicle is the one that harbors the best oocyte. However, this natural order begins to be disrupted as the woman becomes older and under the influence of hormonal drugs her menstrual period begins to be disrupted. In fact, there is no rule that there is only one good-quality oocyte that can develop into a baby in a given cycle. For instance, when the dominant follicle exists in the right ovary, you cannot say with certainty that there is no follicle which harbors a good-quality oocyte in the left ovary. It may be that the oocyte in the left ovary is equally of good-quality but it has just not developed. And considering the fact that most of the women who receive IVF treatment are in their late 30s or early 40s and are experiencing the disruption of the menstrual cycle caused by hormonal drugs, it seems obvious that relying only on the dominant follicle in the natural cycle will not give you a good chance of encountering a good-quality oocyte.
Touch to open However, it is thought that, in the natural cycle, when the dominant follicle has fully developed, all the other non-developed follicles (called small follicles) will be closed and the oocytes inside them will die. Therefore, in common IVF treatment, follicles are potently stimulated with procedures called short, long, or antagonist cycles, in order to develop as many follicles as possible. These approaches seem to make sense on the surface but they require several conditions to be met. For example, there should be many follicles which can respond to the stimulation; these follicles should develop en bloc (in synchronization); and the oocytes in these follicles should be of good quality. In reality, however, one cannot expect women receiving IVF treatment to have these ideal conditions and the success rate per single treatment (live birth rate) is around 10% for a woman who is 38 years old. And, if the initial treatment should fail, what becomes a big problem is whether one can still have the same environment for the second trial when the unexpected drug use (stress) may have wreaked havoc on the body. Each time humans forget to respect nature, they suffer from reprisals, but we still seem unable to apply the lessons we should have learnt. Our clinic’s explanatory meeting session for would-be patients is geared to have you understand this mechanism in detail. Please come and listen to a further, more detailed explanation.
Touch to open Well, the crucial question is whether or not there is indeed no normal oocyte which can develop into a healthy baby in the follicles which have stayed small as they have not been stimulated by drugs. This question has unfortunately been totally disregarded until now. However, we have taken up this question and have found the evidence for the answer. Only our long experience of earnestly grappling with natural cycle IVF could have allowed us to carry out such an endeavor. As a result, we have found out that there are indeed many normal oocytes in the small follicles which have not been developed as the dominant follicle. And we have become the only IVF center in the world where such small follicles are utilized and which is achieving clinically significant results. There are mature and immature oocytes in the small follicles. Still, many of them infallibly harbor good-quality oocytes, the number of which exceeds that of oocytes derived from the dominant follicle (882 vs 1136).

The original aspiration needle that supports oocyte retrieval from small follicles

We started developing our clinic’s original aspiration needle in 1999 and now are using the extra-thin needle (23.5 gauge) which is less than half the thickness of the world standard (18-19 gauge.) However, as it is too thin from the point of view of flow velocity and ease of handling, we have developed an original technique called “the two-tier taper” in order to secure the same performance as that delivered by thicker needles.
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The blade at the tip of the needle is processed with a special technology in such a way that it can keep the damage to the tissues to a minimum. With this extra-thin needle, pain and bleeding is also kept to a minimum, making unnecessary the general anesthesia which is routinely given in other fertility centers. It only takes a few minutes normally to finish the oocyte retrieval in our clinic so that you only need to lie down briefly (20-40 minutes) after the procedure and then you can go home during the day. The biggest merit of our original needle is its ability to puncture very small follicles ? as small as 3 mm in diameter. As the size of small follicles is normally 3-6 mm, retrieving oocytes from small follicles is very easy with this needle as long as the physician is skilled at it. This two-tier tapered needle is extremely effective for puncturing small follicles in natural cycle and letrozole® cycle IVF. With our innovative technique to retrieve oocytes from all retrievable follicles regardless of their size, a high pregnancy rate that could not have been imagined in the past has been achieved across all ages from young to elderly.

Please see the scientific literature regarding this technique at the following site of Fertility and Sterility®. URL：http://www.fertstert.org/article/S0015-0282(16)30048-6/fulltext

Male Infertility

Detailed analysis of sperm indicates that many cases of infertility with unknown causes are in fact caused by male infertility. Repeated IVF failures, where it seems a woman cannot get pregnant however many times she has embryo transfer, are in fact often caused by severe cases of male infertility. However, the condition of male infertility is often misunderstood due to blind faith in the WHO criteria. The real problem with male infertility lies in the morphological abnormalities of sperm which cannot be diagnosed with an assessment method such as that adopted by WHO. In fact, many cases of infertility where the cause is thought to be unrelated to male infertility may in fact be caused by severe cases of male infertility.

Sperm abnormality is revealed by analyzing high precision video images and specially stained images using computer technology. Our original devices and internally developed analytical software application make possible an accurate diagnosis of sperm abnormality in a short period of time, thus allowing us to decide on the best insemination method. Furthermore, men with severe cases of male infertility are immediately given hormonal tests and testicle palpation in order to screen for the abnormalities without delay, such as a central defect in spermatogenesis and varicocele, so that treatment for male infertility can be performed simultaneously with ART (Assisted Reproductive Technology) treatment. Good-quality sperm is just as important as good-quality oocytes and it is our clinic’s treatment philosophy to pay equal attention to oocytes and sperm.

Sperm Collection from Epididymis and Testicles

These are procedures for men whose sperm cannot be found in the ejaculated semen. In the case of obstructive azoospermia, sperm are collected from the epididymis with an aspiration needle by piercing through the skin (PESA) and the whole procedure takes only a few minutes. When PESA does not seem to work, biopsy will be performed to retrieve tissues from the testicle and then sperm are extracted from them. This procedure (TESE) takes approximately 30 minutes and is more invasive than PESA. When it is predicted that it would be difficult to retrieve sperm with TESE, sperm must be retrieved under the microscope (MD-TESE). We perform all the above procedures and as long as you have one good-quality sperm, it can be fertilized with the procedure called intracytoplasmic sperm injection (ICSI).

Intracytoplasmic Sperm Injection (ICSI)

This is the technique for men who have a limited ability to inseminate oocytes due to problems with the number and the shape of sperm. A retrieved oocyte is pierced with the injection needle and directly inseminated with a sperm. In cases where a high rate of morphological abnormalities in the sperm is observed, we proactively perform intracytoplasmic morphologically selected sperm injection (IMSI) using a high-power microscope.

Blastocyst Culture

With this technique, the fertilized embryo is cultured for longer than normal, namely for 5-7 days, up to the blastocyst stage, the developmental stage of the embryo just before implantation in the womb. The implantation rate per embryo at the 4-cell embryo stage is far below 20%. On the contrary, the implantation rate of accurately evaluated blastocysts is more than 50%. In order to take advantage of blastocyst culture, highly sophisticated observational ability and control techniques are necessary. In our clinic, an extremely sophisticated information analysis is realized through our original successive image management application (ART diary) and the IC chip indicator. With those technologies combined, physicians and embryologists can share information in real time, and the three parties, including the patients, can mutually evaluate the condition of the embryo and the sperm simultaneously.

Assisted Hatching

This is a procedure to remove the shell surrounding the blastocyst (called the zona pellucida). The rate of embryo implantation depends on the number and the morphology of the trophectoderm (TE: cells that help an embryo attach to the uterus and help form the placenta) which composes the outermost layer of the the blastocyst. Therefore it is extremely important to evaluate the condition of the TE accurately. However, the zona pellucida creates great difficulty in observing the TE. In our clinic, therefore, we proactively perform the procedure of removing the zona pellucida in order to maximize the accuracy of TE evaluation.