Gonadotropin Ovulation Induction

Exogenous gonadotropins have traditionally been used in PCOS patients who are resistant to ovulation induction with clomiphene and more recently those not responding to the addition of metformin or laparoscopic ovarian drilling. Gonadotropin preparations derived from hMG, a mixture that contains FSH, LH, and large quantities of urinary proteins, have been in use since the early 1960s (97). Other gonadotropin preparations in use today include purified urinary FSH (uFSH) and recombinant FSH (rFSH). Highly purified uFSH contains a reduced amount of LH and very small amounts of urinary proteins. The lack of urinary proteins in this preparation reduces adverse reactions such as local allergy or hypersensitivity (98). Preparations of rFSH were recently developed with a complete absence of LH and co-purified proteins, giving high specific bioactivity. These preparations share similar pharmacokinetic characteristics with purified uFSH (99). Whereas hMG is administered intramuscularly, uFSH and rFSH can be given by subcutaneous injection, which can be self-administered and appear to be better tolerated by the patient. There are no data suggesting a higher pregnancy rate in PCOS with the use of one product compared with another (100-102).

In general, ovulation induction with gonadotropins in clomiphene-resistant PCOS patients is less successful than in patients with hypogonadotrophic hypogonadism (103). However, women with PCOS are more sensitive to gonadotropin stimulation compared with spontaneously cycling women. This increased sensitivity appears to result from a larger pool of small antral follicles available for recruitment, rather than on differences in the FSH threshold level (104). Women with PCOS receiving gonadotropins for ovulation induction are particularly prone to a higher risk of overstimulation, multiple pregnancy, and OHSS rates (105).

Inappropriately elevated serum LH levels are found in up to 70% of women with PCOS (106). This persistent elevation in serum LH during the follicular phase has been correlated with decreased pregnancy and increased spontaneous abortion rates. These complications were also related to the higher LH levels commonly seen in women with PCOS (46). Consequently, it has been suggested that purified uFSH would be more effective than hMG for ovulation induction in PCOS. However, a recent meta-analysis including 14 randomized, controlled trials did not find any differences in pregnancy rates between women with PCOS receiving uFSH or hMG (107). The incidence of OHSS was lower, however, in women using uFSH compared with hMG (OR: 0.20; 95% CI 0.08-0.46). In this study no conclusions could be drawn regarding the relative effect of these preparations on miscarriage and multiple pregnancy rates because of insufficient reporting of these outcomes in the trials (107).

The conventional regimen of ovulation induction with gonadotropins begins with a starting dose of 75-150 IU/day, with an increase of 75-150 IU/day every 3-5 days in those women with an inadequate response (108). Regardless of the specific gonadotropin preparation used, this regimen gener ally induces multiple follicular development, resulting in high rates of multiple pregnancy and OHSS (109). Administration of lower doses of gonadotropins in a stepwise fashion (low-dose step-up or step-down, or sequential step-up, step-down) has generally replaced the conventional regimen and is reported to be effective in significantly reducing risks. The low-dose step-up protocol (110) generally involves starting with a dose of 75 IU/day or less, which is increased after 14 days by 37.5 IU/ day and every 7 days thereafter if no response is observed. The goal of the low-dose step-up protocol is to achieve the development of a single dominant follicle, rather than the development of multiple large follicles. This regimen is based on the concept of a follicular FSH threshold. The rationale is not to exceed the critical FSH concentration above which multiple follicles develop and result in increased risks of OHSS and multiple gestation (111).

The step-down protocol (112) usually begins with a dose of 150-225 IU/day for 2 days, which is decreased to 75 IU/day for 7 days and increased to 150 IU/day after the seventh day if there is inadequate follicular response. More recently, a "sequential step-up, step-down" protocol has been used, in which the FSH dose is reduced by half when the leading follicle has reached 14 mm (113). The purpose of the sequential step-up, step-down protocol is to mimic the normal menstrual cycle, in which the normal early follicular phase FSH elevation is followed by a decline until a small FSH peak accompanies the normal LH surge (112).

Low-dose regimens appear to be a promising approach when using gonadotropins for ovulation induction in clomiphene-resistant women with PCOS. The mono-ovulatory cycle rate is approximately 70%. The cumulative pregnancy rate is approximately 40%, and can be as high as 20% per cycle, comparable with conventional regimens. However, a multiple pregnancy rate of 6% and a low rate of OHSS (<1%) with low-dose regimens make these protocols more attractive than conventional gonadotropin regimens (114). A recent multicenter randomized study comparing the low-dose step-up and step-down protocols in clomiphene-resistant women with PCOS found that the low-dose step-up regimen of rFSH administration was as effective as, and safer than, the step-down regimen (115). In this study, the rate of monofollicular development was significantly higher (68.2 vs 32%, p < 0.0001) and the rate of multifollicular development significantly lower (4.7 vs 36%, p < 0.0001) with the step-up protocol compared to the step-down regimen (115).

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