Gonadotropin-releasing hormone agonists (GnRHa) were demonstrated to result in pituitary desensitization and successfully dealt with these problems, becoming the next major breakthrough in IVF treatment. In the late 1980s, gonadotropin-releasing hormone agonists (GnRH agonists) were introduced as a means of downregulating the pituitary to prevent premature ovulation, which in the past had necessitated canceling approximately 15 % of IVF cycles prior to egg retrieval. Since their introduction, pregnancy rates have increased because of the opportunity to retrieve cycles that would have been lost to early ovulation and because of the increase in the number of oocytes obtained in GnRH-agonist cycles [13].

The long protocol is the oldest and still the most commonly used regimen for ovarian stimulation. Most commonly, the GnRH agonist is started in the midluteal phase, and gonadotropin treatment is started following menstruation. The downregulating effects of GnRH agonists, as opposed to the stimulatory effects of GnRH, are related to the frequency of administration and the prolonged occupation of GnRH receptors by the agonists. GnRH agonist is being administered daily subcutaneously or by depot preparation. Criteria for downregulation to complete and start stimulation after getting menstruation are estradiol (E2) levels below 180 pmol/L, luteinizing hormone (LH) below 2 IU/L, and P4 below 2 nmol/L. Ultrasonography is used prior to initiation of gonadotropin treatment to rule out the presence of an ovarian cyst larger than 15 mm. Ovarian cysts form in approximately 10 % of women when the GnRH agonist is started in the midluteal phase, but these cysts almost always regress spontaneously in 1–3 weeks. Gonadotropin treatment is postponed until the cysts disappear or decrease to less than 15 mm in size. GnRH-agonist administration is continued for the duration of gonadotropin treatment (Fig. 7.5) [14].

Once downregulation is achieved, gonadotropins are administered to stimulate follicular growth with the GnRH agonist being continued at a lower dose. The initial dose of gonadotropin is usually 150–300 IU/daily, except in young women or those with polycystic ovarian disease where a lower dose (75–150 IU/daily) is appropriate. Intramuscular injections of urinary menopausal gonadotropins containing both FSH and LH were the mainstays of treatment until the development of a urinary gonadotropin that contained primarily FSH. Still newer, highly purified urinary FSH products introduced the advantage of being effective with subcutaneous administration. Recombinant FSH also allows subcutaneous administration. The hMG/FSH dose is subsequently adjusted according to follicular growth, as monitored by serum E2 levels and/or transvaginal ultrasonography. Human chorionic gonadotropin (hCG), either urinary or recombinant, is given once the follicular cohort consists of at least two follicles more than 18 mm in diameter. Oocyte retrieval follows 35–36 h later.

This protocol provides excellent cycle control making it the protocol of choice for first-time patients as well as for those with previous normal response. The main disadvantages of the long protocol are uncertainty of pregnancy at the start of GnRH-agonist treatment, longer duration of treatment, greater consumption of gonadotropins, and higher cost. In GnRH-agonist step-down regimen study by Olivennes et al. using leuprolide 0.1 mg/day, s.c., from day 21 and reducing it to 0.05 mg/day on stimulation, the cancelation rate remained high, and the pregnancy rate was relatively low [15].

Another study of the same step-down fashion of leuprolide (from 0.1 to 0.05 mg/day) showed higher number of oocytes and improved pregnancy rates [16]. In a Cochrane review, a single-dose depot of GnRH-agonist preparation (leuprolide 3.75 mg) was administered on day 21 of a previous cycle. It was observed that there was no evidence for differences between the long protocols using depot or daily GnRH agonist for IVF cycles. The use of depot GnRH agonist was associated with increased requirements for gonadotropins and a longer time for ovarian stimulation [17].

The administration of a GnRH agonist to a woman who has menstrual function will initially produce a stimulatory response, known as the “flare.” The magnitude of the flare response depends upon when in the cycle the agonist is administered. In the short protocol, the administration of GnRH agonist is started in the early follicular phase (day 2 of menses), and gonadotropins are started on the same day or on the following day (day 2/3). The monitoring, timing of hCG injection, and oocyte retrieval are for the long protocol. This protocol tries to derive benefit from an initial “flare-up” response due to endogenous FSH release from the pituitary gland that usually occurs in the first few days of GnRH-agonist administration. As there is no preceding pituitary suppression, this protocol results in a better response than the long protocol. However, the most important disadvantage is the high progesterone level during the early follicular phase, likely caused by the rescue of the preceding corpus luteum. Studies have confirmed a lower pregnancy rate using this protocol compared to the long protocol. Hence, in practice it is used only in patients with poor ovarian reserve or those with a previous poor response in the long protocol cycle (Fig. 7.6) [18, 19].