Stimulation protocols used during In Vitro Fertilization vary. The most common protocols in the USA involve gonadotropins with the concomitant use of a GnRH agonist. Only a brief discussion of the available protocols is presented here since this collection of protocols is constantly being modified.
(1) Natural Cycle IVF
Natural cycle IVF is not commonly used (in the USA) despite advantages in terms of cost (of medication) and exposure to risks of controlled ovarian hyperstimulation (multiple pregnancy, ovarian hyperstimulation syndrome, ovarian torsion, and possibly ovarian epithelial carcinoma). The first successful IVF pregnancy (Louise Brown) followed single egg retrieval from a natural cycle. Since that time, the disappointing pregnancy rates following transfer of individual embryos (up to 12% per cycle in the best of reports), the high cancellation rate due to premature LH surge, and the need for cumbersome (blood for LH concentration) monitoring (every 2-3 hours) with around the clock availability of the IVF team for egg retrieval have made this protocol less popular.
(2) Clomiphene Citrate for IVF
Clomiphene citrate (alone) as an ovulation enhancing medication has been used (infrequently) during IVF. Usually, clomiphene (doses up to 150 mg a day for 5-8 days) is used starting between cycle days 2 and 5 with hCG trigger of ovulation when the lead follicle has a diameter of 17-18mm. Clomiphene citrate is not as effective as the gonadotropins at ovulation enhancement, so interest in its use as a single agent during controlled ovarian hyperstimulation and IVF has been low. Clomiphene IVF cycles have a high cancellation rate due to poor (rate of) follicular development, small numbers of developing follicles (usually 1 to 3 eggs per cycle) and premature LH surge.
(3) Clomiphene Citrate with Gonadotropins for IVF
Combined clomiphene citrate with gonadotropin cycles of controlled ovarian hyperstimulation and IVF have resulted in enhanced follicular development (compared to use of clomiphene citrate alone) but still have high cancellation rates compared to pure gonadotropin cycles. It appears that clomiphene citrate may be as (or more) effective than gonadotropins in (the smaller group of) older women undergoing IVF.
(4) Gonadotropin IVF
Gonadotropins can be combined with a GnRH agonist (that is initiated during different times of the menstrual cycle) to produce several different protocols that (try to) optimize follicular development.
Two GnRH agonists that are available in the USA are Lupron and Synarel, both result in an initial (“flare” or) several day period of endogenous (one’s own) gonadotropin (FSH and LH) release (from the pituitary gland), and then both effectively suppress gonadotropin release (for as long as the medication is adequately administered) to limit subsequent ovarian follicular development. Meta analysis of the available medical literature suggests a doubling in pregnancy rates when GnRH agonists are used during stimulation protocols for IVF. Also, use of GnRH agonists has allowed increased flexibility for timing of the egg retrieval.
Gonadotropins administered concomitantly with GnRH agonists during controlled ovarian hyperstimulation all contain FSH (Follicle Stimulating Hormone), which then promotes ovarian follicular development, and egg maturation (despite GnRH agonist suppression of endogenous FSH).
(a) The standard “long protocol”
This protocol involves pituitary and ovarian suppression prior to gonadotropin administration, most often using either lupron (1 mg subcutaneously a day) or synarel (400 microgram intranasally twice daily) starting in the midluteal phase (cycle day 21 of an idealized 28 day cycle = 7 days after ovulation). A few days after the onset of the next menstrual flow an ultrasound is performed (to rule out the presence of an ovarian cyst greater than 1.5 cm diameter, which may negatively affect pregnancy rates) and if gonadotropins are begun then the GnRH agonist dose is reduced in half and given each day with gonadotropins until the hCG injection (ovulation trigger).
If a large ovarian cyst is identified at the onset of the menstrual flow (following GnRH agonist) then the duration of administration of GnRH agonist alone is (usually) extended to allow the cyst to resolve spontaneously. Studies suggest greater numbers of mature eggs are produced and the eggs are of higher quality with the “long protocol.”
(b) A “short protocol” or “flare protocol”
This protocol was developed for poor (ovarian) responders. With this protocol, the GnRH agonist is started early in the menstrual cycle (cycle day 1 or 2) to take advantage of the initial release of stored gonadotropins from the pituitary gland (flare) and gonadotropins are often then initiated on cycle day 2 or 3 (for additional kick). This protocol reportedly results in fewer mature eggs at retrieval, but has an important role in women who do not recover from (make mature eggs following) ovarian suppression using the “long protocol.”
(c) A “microdose GnRH agonist flare” protocol
This protocol has been developed (with many modifications) for poor ovarian responders which uses an oral contraceptive pill during the month prior to stimulation, microdoses of GnRH agonist (lupron 40 microgram every 12 hours) during the first days of the (next cycle’s) follicular phase and gonadotropins starting a few days later.
Other strategies used with poor responders include increasing the dose of gonadotropins administered, reducing the amount of GnRH agonist given (after initiation in the midluteal phase the GnRH agonist may be stopped entirely at the onset of the cycle without known adverse effect), and co-treatment with growth hormone. The low or no dose GnRH agonist appears to be most useful for older women and those with unexplained poor response to gonadotropins.
(d) The high responder
These women represent another important difficult group of patients that are optimally treated using a customized protocol. Women with an exaggerated response to FSH (containing fertility medications) often have an elevated LH:FSH ratio (characteristic of polycystic ovarian syndrome) and produce very high estradiol concentrations (over 4000 pg/mL) in the presence of many (many) small to midsized follicles (with few mature follicles). These women are (1) at a tremendous increased risk for severe forms of ovarian hyperstimulation syndrome and (2) the (pregnancy) success of these cycles is actually reduced since there are fewer good quality eggs and the very high estradiol concentrations may interfere with embryo implantation.
High responders seem to do well with a low dose GnRH agonist long protocol (half the usual dose: .5mg a day initiated in the midluteal phase and .25 mg a day when gonadotropins are initiated through administration of hCG) and only 2 ampules (150 IU) of gonadotropin at the onset of the stimulation portion of the cycle. Reports are conflicting concerning the utility of using pure FSH versus LH containing gonadotropin medications with these patients. At Cornell University (a top quality IVF center in the USA), a protocol for high responders that reportedly is effective uses oral contraceptive pills for 25 days followed by suppression with Lupron (1mg/day overlapping the final 4 days of the contraceptive pills) with low dose (150 IU per day) gonadotropins initiated on the third day of withdrawal bleeding.