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

5. The Role of Non-steroidal Anti-inflammatory Drugs in Natural Cycle IVF

Julio M. Voget  and Markus Nitzschke 


Departments of Obstetrics and Gynecology, Reproductive Endocrinology & Fertility, VOGET Reprodução Humana – ANDROFERT, Av. Dr. Heitor Penteado 1452, Campinas, São Paulo, 13075-460, Brazil


ICI – Instituto Canario de Infertilidad, Calle León y Castillo, 294, Las Palmas de Gran Canaria, C. P. 35005, Spain

Julio M. Voget (Corresponding author)


Markus Nitzschke



In the last years, there has been an increasing interest by the population for less aggressive approaches when reaching for in vitro fertilization (IVF) treatments. At the same time, the development of high-quality laboratories, with improved technology and high pregnancy rates, is encouraging infertility specialists to go back in time and practise the oldest IVF treatment approach, IVF using the natural unstimulated cycle (Steptoe and Edwards 1978).

The natural cycle IVF approach has many benefits. To name some of them, it is safe, drug-free, has close to zero multiple pregnancy rate, low time consumption, low cost, but is pretty unpopular, because of the relative high risk of premature ovulation, with low pregnancy rates per initiated cycle when compared to conventional protocols with pituitary desensitization.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) during the ovulation process is studied as an effective drug for delaying or even blocking the follicle rupture. With this objective, NSAIDs can be used before egg retrieval to lower premature ovulation rates and increase egg retrieval rates.

The aim of this chapter is to give the infertility specialist a useful tool that could help them to achieve better results, lowering the risk of premature ovulation and higher egg retrieval, resulting in higher pregnancy rates per initiated cycle.


Natural IVFNSAIDPremature ovulationTemporary LUF syndromeLH peakFollicle rupture

The Role of NSAIDs in Natural Cycle IVF

For more than a decade, non-steroidal anti-inflammatory drugs (NSAID) have been studied as effective drugs for preventing follicular rupture during the ovulatory process.

Ovulation is a complex process with multiple steps. It initiates with the hormonal luteinizing hormone (LH) preovulatory surge, triggering the expression of a series of genes that determine the biochemical events, leading to the release of the mature oocyte from the cycling ovary.

Genes encoding the progesterone receptor and cyclo-oxygenase 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 (Gaytán et al. 2006).

The effect of NSAID is that it inhibits cyclo-oxygenase-2, one of the main enzymes that facilitates the ovulation process, limits prostaglandin production and prevents follicular rupture with oocyte release (Duffy and Stouffer 2002).

Different NSAIDs have been studied for preventing ovulation: Indomethacin (Athanasiou et al. 1996), Ibuprofen, Diclofenac, or Meloxicam (Jesam et al. 2010; Massai et al. 2007), and for emergency contraception. Other trials have explored NSAID to control spontaneous ovulation during natural cycle IVF (Kadoch et al. 2008; Nargund and Wei 1996).

Kadoch et al. (2008) evaluated spontaneous ovulation occurring before oocyte retrieval in natural cycle IVF (nIVF) with and without the use of indomethacin. The authors obtained a statistically significant association between premature ovulation prevention and indomethacin, with an odds ratio of 3,8 (p = 0.02–95 % confidence interval, 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. (2012), in a retrospective cohort study of 1865 nIVF cycles, evaluated the effect of low-dose post-trigger NSAID (Diclofenac) treatment for premature ovulation prevention. In this study, NSAID was significantly associated with a lower risk of premature ovulation (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. Very few trials described the use of NSAIDs specifically during natural IVF, modified natural IVF, or minimal stimulation IVF protocols.

There are few groups in the world that focus their protocols on natural and minimally stimulated 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 5.1 shows a resume of NSAIDs, route of administration, and doses.

Table 5.1

Non-steroidal anti-inflammatory drugs for premature ovulation prevention


Route of administration




Rectal suppositories

50 mg 8/8 h

Kadoch et al. (2008)


Rectal suppositories

25 mg 6/6 h

Kawachiya et al. (2012)


Oral capsules

600–800 mg 8/8 h

Uhler et al. (2001)

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 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 gonadotropin-releasing hormone (GnRH) analogs 0.1 mg injection, if E2 > 250 pg/mL without an LH surge. In this case, we already have a mature follicle, but LH surge has not started yet. From 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 IU/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/d till a positive pregnancy test.

Case Study

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 LUF (luteinized unruptured follicle) syndrome, while LH surge and oocyte maturation occur normally. As the enzyme cyclo-oxygenase and its product prostaglandin play an important role in the process of follicle rupture, their inhibition by NSAIDs delays ovulation (Nargund et al. 2001). 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 the 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 and 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 (IUI).

Before starting treatment, we normally observe the patients cycle for at least 1 month in order to know on which day the LH rise starts and when ovulation occurs. This particular patient had 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 on day 10 at 8 am for a vaginal ultrasound and hormonal essay. We found a follicle of 18 mm on the right ovary and 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 in that 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 9th day of 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 12th 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.


The increasing interest for less invasive IVF treatments is leading the IVF practice to these more natural, less aggressive, and less complicated protocols.

These approaches are very well tolerated and accepted, especially by patients who have already experienced the burden of a conventional stimulation protocol for IVF. Recent trials show a very good cost/benefit ratio comparable to conventional IVF pregnancy rates in women >35 years; these data makes them even more attractive for couples.

As we emphasized during the introduction, the main reason for the unpopularity of these protocols in fertility clinics and among specialists is the relatively high risk of spontaneous ovulation when compared to conventional protocols with pituitary desensitization. To achieve success with the natural cycle and minimal stimulation IVF protocols, doctors need a thorough understanding of the LH peak, estradiol, and progesterone physiological curves to schedule a successful egg retrieval. Even with good training, there is still a risk of spontaneous ovulation.

The use of NSAID drugs during the ovulation process before egg retrieval is a useful tool to decrease premature ovulation rates, and increase egg retrieval rates, resulting in higher pregnancy rates per initiated cycle.


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