|Year : 2014 | Volume
| Issue : 3 | Page : 158-162
NSAIDs in natural cycle IVF
M Nitzschke, F Rodríguez
The Canary Islands Institute of Infertility, Grand Canary Islands, Spain
|Date of Web Publication||7-Oct-2014|
Dr. M Nitzschke
S. L. Canario Infertility Institute, Calle Leóny Castillo, 284, 35005 Las Palmas de Gran Canaria
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Nitzschke M, Rodríguez F. NSAIDs in natural cycle IVF. IVF Lite 2014;1:158-62
| Introduction|| |
Natural cycle in vitro fertilization (NCIVF) is the oldest IVF treatment approach in science. The first few IVF babies were born with this technique >30 years ago.  The main problem back in those pioneer times of IVF was the control of luteinizing hormone (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 anti-estrogenic effect to control the LH surge. Then, many reproductive endocrinologists started to use controlled ovarian hyperstimulation with clomiphene citrate and human menopausal gonadotropin, in order to get more than only one egg per treatment cycle. More eggs allowed to compensate for the loss of eggs and embryos during the IVF process. We should not forget that back in those times, IVF laboratories were also quite inefficient, as modern embryo culture techniques did not exist. The breakthrough came in the early 1980's with the application of GnRH analogs in IVF treatments.  In order to control 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 injecting the missing FSH for follicle growth exogenously. This allows multiple follicle growths 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. IVF soon became a mainstream treatment, and more and more IVF clinics opened around the world.
| Why Natural Cycle in vitro Fertilization?|| |
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 has not been much change over many years. Only recently the introduction of GnRH antagonists has 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 presently, especially the newer 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 anymore, and regulations were established, forcing IVF specialists to transfer fewer embryos. Simultaneously, 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 of 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 Scandinavian countries have recently started to regulate 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. The second issue is the oocyte and embryo quality after ovarian stimulation. A group from the Netherlands  could demonstrate that a healthy woman is able to produce around two 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 potential life-threatening condition, which is the result of an overreaction 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 endometrial 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, instead of ovarian stimulation. 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 the 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 anymore. 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 NCIVF 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 NCIVF. There are many reasons for this. The most important reason is the widespread belief that NCIVF 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, NCIVF is the most efficient IVF treatment that exists. Taking into account the oocyte to live birth rate per oocyte, for example, comparing stimulated IVF with NCIVF, there is a huge difference between both treatment approaches. In a recent study, a group from the United States  has looked at the oocyte to live birth rate in their clinic. In their best group consisting of young and healthy egg donors, the oocyte to live birth rate was only 7% per oocyte. We compared this result with different publications about NCIVF in the literature and our own results.  Depending on the study, the oocyte to live birth rate was between 20% and 30% per oocyte in NCIVF. 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 NCIVF is the fact that it is not easy to learn. In contrast to stimulated treatments, success and failure depend on the correct interpretation of the patient's hormonal patterns. The key to a successful NCIVF 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, NCIVF may become more popular in the near future.
Non-steroidal anti-inflammatory drugs in natural cycle in vitro fertilization
The key to a successful NCIVF program is an 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 inconveniences. For more than a decade non-steroidal anti-inflammatory drugs (NSAID) have been studied as effective drugs preventing follicular rupture during the ovulatory process.
Ovulation is a complex process with multiple steps. It initiates with the hormonal LH pre-ovulatory surge, triggering the expression of a series of genes that determine the biochemical events leading to the release of a mature oocyte from the cycling ovary. Genes encoding the progesterone receptor and cyclooxygenase-2 (COX-2) enzyme seem to be essential for ovulation. After the LH surge, starts a multiple step process, such as the resumption of the meiotic process, cumulus expansion, rupture of the follicle wall mediated by a series of proteolytic enzymes, and finally, the release of the cumulus oocyte complex from the ovarian tissue. 
The effect of NSAID is to inhibit COX-2, one of the main enzymes that facilitates the ovulation process, limits prostaglandin production and prevents follicular rupture with oocyte release. 
Different NSAIDs have been studied for preventing ovulation, Indomethacin,  Ibuprofen, Diclofenac or Meloxicam, , for emergency contraception. Other trials have explored NSAID to control spontaneous ovulation during NCIVF. ,
Kadoch et al.  evaluated spontaneous ovulation occurring before oocyte retrieval in NCIVF with and without the use of indomethacin. The authors obtained a statistically significant association between the premature ovulation prevention and indomethacin, with and odds ratio of 3, 8 (P = 0.02-95% confidence interval [CI], 1.2-12.3), the odds of ovulation with no indomethacin were 4 times higher than the odds of ovulation with indomethacin.
Kawachiya et al.,  in a retrospective cohort study of 1865 NCIVF cycles evaluated the effect of low-dose post-trigger NSAID treatment for a premature ovulation prevention (diclofenac). In this study, NSAID was significantly associated with a lower risk of premature ovulation (odds ratio [OR]: 0.24, 95% CI: 0.15-0.39), P < 0.0001), and higher embryo transfer per scheduled egg retrieval (OR: 1.38, 95% CI: 1.06-1.61, P = 0.012).
How to use it?
Different NSAID drugs, doses and routes of administration have been described in studies evaluating its ovulation effect. Only a few trials described the use of NSAIDs specifically during NCIVF, Modified NCIVF or Minimal Stimulation IVF protocols.
There are only few groups in the world that focus their protocols on the natural cycle and minimal stimulation IVF, and have good experience using NSAIDs. Among them, we could find a few different drugs that are actually used in practice for premature ovulation prevention. [Table 1] shows a resume of NSAIDs, route of administration and doses.
The NSAIDs first dose starts from the morning of LH rise, or at the time of trigger injection, until the night before egg retrieval.
Here is an example for a protocol using Ibuprofen 600 mg/8 h.
The patient does her very first hormonal assay on her day 10 or 11 of the cycle: E2 + LH. If LH surge is not seen on this first test, it should be repeated 1 or 2 days later, until LH surge is seen. Alternatively, it is also possible to induce ovulation with GnRH analogues 0.1 mg injection, if E2 >250 pg/mL without seeing an LH surge. In this case, we already have a mature follicle, but LH surge has not started yet. On the day of LH surge or ovulation induction, a treatment with Ibuprofen 600 mg/8 h should be started, until the morning of egg retrieval. The egg retrieval should be performed 48 h after LH surge is seen or 36 h after ovulation induction. If, on the day of hormonal assay, LH was already >30 UI/L, the egg retrieval should be done 36 h after LH surge is seen, instead of 48 h. A fresh embryo transfer should be performed 2-3 days after egg retrieval. Luteal support should be done with vaginal progesterone 200 mg/day till a positive pregnancy test.
This is a case of IVF in a complete natural cycle. The only medication we used in this protocol is NSAIDs to control ovulation. NSAIDs induce a temporary luteinized unruptured follicle syndrome, while LH surge and oocyte maturation occur normally. As the enzyme COX and its product prostaglandin play an important role in the process of follicle rupture, their inhibition by NSAIDs delays ovulation.  Using this protocol, transvaginal ultrasound controls for follicle monitoring are not necessary any more. The patient detects her LH peak using commercial urinary ovulation indicators at home. Only when urinary LH is positive, the patient needs one hormonal essay of LH and serum estradiol, in order to schedule the exact time point for egg retrieval. This protocol is very cheap and convenient for the patient. Only one blood test is necessary per cycle, which can be done in any medical laboratory at the patient's hometown. No vaginal ultrasound has to be done for follicle monitoring. For egg retrieval and embryo transfer, the patient travels to the clinic. The problem with this protocol is, that date and time of LH surge and egg retrieval cannot be influenced. Although it is possible to delay the egg retrieval for 1 day with the use of a GnRH antagonist, the patient has to be available for the procedure at a certain day. The second inconvenience is that statistically, only every second egg retrieval leads to an embryo transfer. As in nearly all of the cases single embryo transfer is performed, the patient can expect a pregnancy rate of about 30% per transfer.
A 35-year-old nulliparous woman with 3 years of infertility was referred to our center for IVF. She had undergone an infertility work-up after attempting to conceive naturally for 1 year. She had a normal hormonal profile, normal hysterosalpingogram, and mild endometriosis was found and treated at laparoscopy. Her husband's semen analysis was normal. They had failed six cycles of gonadotropins - Intrauterine insemination.
Before starting treatment, we normally observe the patient's cycle for at least 1 month in order to know on which day LH rise starts and when ovulation occur. This particular patient has a regular menstrual cycle of 26 days. As luteal phase in a healthy woman normally takes 14 days, we expected her to ovulate on day 12 of her cycle. In this case, we asked the patient to come at day 10 at 8 am for a vaginal ultrasound and hormonal essay. We found a follicle of 18 mm on the right ovary; antral follicles on the left side. The endometrium was 7.3 mm with a typical trilaminar structure. Serum estradiol was 234 pg/mL and LH 19 IU/L. We asked the patient to come the next day at the same time for the same exam. We found the follicle on the right side with 19 mm, serum estradiol of 253 pg/mL and LH 73 IU/L. We asked the patient to have intercourse during the night, but no pregnancy was achieved this month. Next day at 8 am, the follicle was gone, and serum estradiol was 183 pg/mL and LH 23 IU/L. Next cycle we prescribed 50 mg Indomethacin, twice a day from the morning of her 9 th day of the menstrual cycle and asked her to come to our center for hormonal essay the morning of the following day. Her serum estradiol was 237 pg/mL and LH 12 IU/L. We asked her to continue Indomethacin twice a day and to come back for egg retrieval 2 days later, the 12 th day of her cycle. At 9 am that day, we performed a vaginal ultrasound and found the follicle of 19 mm on the left ovary. We punctured the follicle and retrieved a mature egg. IVF was performed, and we could transfer a beautiful 4-cell embryo 2 days later. After 14 days, serum beta-HCG was 256 IU/L and the pregnancy developed normally.
| Conclusions|| |
Some groups are using NSAID to control ovulation. The ovulation process inside the follicle is an inflammatory process, which is primarily mediated by prostaglandins. High dosage of prostaglandin inhibitors at the time of LH rise can delay or even bock ovulation completely. This is the reason, why it was even considered as an emergency contraceptive by some groups.  This method is a very natural approach, because LH surge is not blocked, and the natural ovulation process can take place. Only the very last step, the rupture of the follicle is delayed. In the right dosage, NSAID is able to delay ovulation only for a few hours, in order to prevent ovulation during night and save the follicle until the next morning for egg retrieval.
Using for example Ibuprofen, the starting dosage in this approach is 600 mg every 8 h from the morning of LH rise, until the morning of egg retrieval. Ovulation does not have to be triggered in this approach. Ideally, egg retrieval can be planned 48 h after the LH surge has been detected. Only in cases of very high LH over 30 IU, it can be discussed to plan egg retrieval earlier, after 36-40 h. This approach requires a lot of experiences and has a long learning curve. Only about half of the patients respond well to this dosage of Ibuprofen. About 25% of the patients need a higher dosage. They would ovulate normally already 36-40 h after the LH surge has started, despite Ibuprofen treatment. When they finally come for egg retrieval, they have already ovulated. Another 25% of the patients need a lower dosage in order to respond the right way. They still have their follicle 48 h after LH surge, but the eggs are immature, or they would not be released from the follicle, which means: Retrieval without egg. In these patients, the dosage or the retrieval time has to be adjusted. Nevertheless, this approach is working well for most of the patients and is particularly popular in Japan, where Diclofenac is used instead of Ibuprofen. 
| References|| |
|1.||Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet 1978;2:366. |
|2.||Römmler A. New model of the endocrine regulation of the female menstrual cycle. Fortschr Med 1983;101:2175-8. |
|3.||Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, et al. Milder ovarian stimulation for in vitro fertilization reduces aneuploidy in the human preimplantation embryo: A randomized controlled trial. Hum Reprod 2007;22:980-8. |
|4.||Patrizio P, Sakkas D. From oocyte to baby: A clinical evaluation of the biological efficiency of in vitro fertilization. Fertil Steril 2009;91:1061-6. |
|5.||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. |
|6.||Gaytán M, Morales C, Bellido C, Sánchez-Criado JE, Gaytán F. Non-steroidal anti-inflammatory drugs (NSAIDs) and ovulation: Lessons from morphology. Histol Histopathol 2006;21:541-56. |
|7.||Duffy DM, Stouffer RL. Follicular administration of a cyclooxygenase inhibitor can prevent oocyte release without alteration of normal luteal function in rhesus monkeys. Hum Reprod 2002;17:2825-31. |
|8.||Athanasiou S, Bourne TH, Khalid A, Okokon EV, Crayford TJ, Hagström HG, et al. Effects of indomethacin on follicular structure, vascularity, and function over the periovulatory period in women. Fertil Steril 1996;65:556-60. |
|9.||Jesam C, Salvatierra AM, Schwartz JL, Croxatto HB. Suppression of follicular rupture with meloxicam, a cyclooxygenase-2 inhibitor: Potential for emergency contraception. Hum Reprod 2010;25:368-73. |
|10.||Massai MR, Forcelledo ML, Brache V, Tejada AS, Salvatierra AM, Reyes MV, et al. Does meloxicam increase the incidence of anovulation induced by single administration of levonorgestrel in emergency contraception? A pilot study. Hum Reprod 2007;22:434-9. |
|11.||Kadoch IJ, Al-Khaduri M, Phillips SJ, Lapensée L, Couturier B, Hemmings R, et al. Spontaneous ovulation rate before oocyte retrieval in modified natural cycle IVF with and without indomethacin. Reprod Biomed Online 2008;16:245-9. |
|12.||Nargund G, Wei CC. Successful planned delay of ovulation for one week with indomethacin. J Assist Reprod Genet 1996;13:683-4. |
|13.||Uhler ML, Hsu JW, Fisher SG, Zinaman MJ. The effect of nonsteroidal anti-inflammatory drugs on ovulation: A prospective, randomized clinical trial. Fertil Steril 2001;76:957-61. |
|14.||Nargund G, Waterstone J, Bland J, Philips Z, Parsons J, Campbell S. Cumulative conception and live birth rates in natural (unstimulated) IVF cycles. Hum Reprod 2001;16:259-62. |
|15.||Hester KE, Harper MJ, Duffy DM. Oral administration of the cyclooxygenase-2 (COX-2) inhibitor meloxicam blocks ovulation in non-human isprimates when administered to simulate emergency contraception. Hum Reprod 2010;25:360-7. |
| Authors|| |
Markus Nitzschke is an infertility specialist from Germany. He was trained in France, Spain, Switzerland, Germany, USA and Japan. As one of Europe's most known pioneers in Natural Cycle IVF, Markus Nitzschke has started the first IVF program in Europe offering exclusively Natural Cycle IVF. He is regularly invited to give lectures at international conferences and workshops. In addition, he helps establishing Natural Cycle IVF programs at fertility clinics around the world. Together with other experts in this field, he also developed efficient alternative treatment options for patients with low ovarian reserve and premature ovarian failure based on Natural Cycle IVF. Markus Nitzschke is currently working in Spain.