The Use of Clomiphene Citrate in Natural Cycle IVF

Minimal Simulation and Natural Cycle In Vitro Fertilization, Allahbadia, G and Nitzschke, M, 2015

The Use of Clomiphene Citrate in Natural Cycle IVF (Stetson, S)

Dr Daiter’s summary of this chapter
The author points to SART data demonstrating a non-statistically significant 4% increase in embryo implantation rates for women under 35 years of age in natural cycle IVF compared to conventional IVF, and a statistically significant 16% increase in embryo implantation rates for women over 35 years of age in natural cycle IVF compared to conventional IVF.  However, there was an embryo transfer rate of only 37% per cycle start in natural cycle IVF.  This low embryo transfer rate per cycle start is thought to be primarily related to premature ovulation.  Treatments that attempt to limit premature ovulation include (1) a single dose of GnRH antagonist, (2) administration of non-steroidal anti inflammatory drugs, and (3) administration of Clomiphene citrate.

Clomiphene citrate is sometimes used for ovulation induction, in which case it should be started prior to cycle day 6 (which may impact the endometrium in a negative manner and reduce embryo implantation rates), or for inhibition of the LH surge, in which case it is started after cycle day 6 (which the author believes will not reduce embryo implantation rates since “the growth of the endometrium is already completed”).  For inhibition of the natural LH surge, Clomiphene 25 mg/day is usually started on cycle day 7 and continued to include the day of ovulation trigger with a GnRH agonist.  HCG trigger is not recommended when Clomiphene is used to block the LH surge since there seems to be a greater risk of ovarian cyst formation.  The author also contends that Clomiphene citrate does not hamper implantation when less than 4 follicles develop since it does not create a luteal phase defect in these circumstances.  The author also states that once a natural LH surge has begun, it is not possible to reliably trigger another LH surge using GnRH agonists, and retrieval should be planned for 36 hours following the natural LH surge.

The two biggest advantages of natural cycle IVF using the protocol herein is that there is no need for ultrasound monitoring of follicle growth during the cycle (the author uses 1-2 timed serum estradiol, LH, and FSH concentrations to determine when the follicle is mature and ovulation induction will occur) and there is no need for anesthesia for oocyte (egg) retrieval using thin (19 to 21 Gauge) single lumen catheters without flushing.  The author does compare his rate of collecting at least one mature egg at retrieval per IVF start (58%) with IVF centers using 2-4 consultations during the follicular phase (57-59%) as support for his decision to limit consultations.

The pregnancy rates for natural cycle IVF without Clomiphene citrate lie predominantly between 20-30% per embryo transfer in women up to 39 years of age, demonstrating the high reproductive potential of eggs retrieved from natural cycles.  The pregnancy rates with Clomiphene are often reported as somewhat higher per embryo transfer, but also there are less incidences of premature ovulation when Clomiphene is used so the pregnancy rates per IVF start are even greater.

Dr. Eric Daiter’s review of this chapter
Dr. Stetson of the LIV Fertility Center has associations with the Texas Medical Center and the Hospital San Javier Riviera Nayarit

The embryo transfer rate of only 37% per IVF start in natural cycle IVF is the focus of this chapter, and the author believes that the use of Clomiphene citrate at 25 mg/day (or 50 mg every other day) starting on cycle day 7 (for a woman with regular monthly menstrual cycle intervals) will limit cycle loss due to premature ovulation, improve egg and embryo quality, not effect the development of the endometrium or cause a luteal phase defect, and reduce cost of treatment by reducing the need for office visits during follicle development and by eliminating the need for anesthesia at egg retrieval.  These points seem to be well taken in this chapter.

The author claims that the endometrium is fully developed by cycle day 7, which is in contrast to my own experience that the endometrial stripe changes significantly in size and changes its appearance on ultrasound to become trilaminar most often after day 7.  I do not know if these differences are clinically relevant in the decision to use Clomiphene after cycle day 7.

The author also suggests aspiration of the follicle without flushing, which is in contrast to the suggestion of Dr. von Wolff in another chapter of this book.  Dr. von Wolff presents compelling data to support follicle flushing, such as the retrieval of  nearly twice as many mature eggs with 3 flushes per follicle.  Dr. Stetson does not present data to support the decision to not flush the follicles.

Other than the exceptions above, it appears that Dr. Stetson’s protocol for Clomiphene citrate to prevent the LH surge and limit the need for frequent office visits is very helpful.


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