Urinary Follicle-Stimulating Hormone for Normogonadotropic Clomiphene-Resistant Anovulatory Infertility: Prospective, Randomized Comparison between Low Dose Step-Up and Step-Down Dose Regimens1

Abstract

A low dose step-up and step-down regimen for induction of ovulation using urinary FSH was compared in a prospective randomized fashion in 37 normogonadotropic clomiphene-resistant oligo- or amenorrheic infertile women. The objectives was to assess potential differences in duration of treatment, ovarian stimulation (serum FSH levels), and response [serum estradiol (E2) levels and number and size of follicles]. Monitoring (blood sampling and transvaginal sonography) took place on the day of initiation of treatment, the first day of ovarian response as assessed by ultrasound (i.e. the first day a follicle > or = 10 mm could be recognized), the day of hCG administration to induce ovulation, and 3 days thereafter. The median duration of treatment in the low dose step-up group was 18 (range, 7-41) days compared to 9 (range, 4-16) days in the step-down group (P = 0.003), and the total numbers of ampules administered were 20 (range, 7-69) and 14 (range, 7-33), respectively (P = NS). Serum FSH levels from the first day of sonographic ovarian response until the administration of hCG were constant (median increase, 2%/day) in patients receiving the low dose step-up protocol, but showed a decrease (median, 5%/day) in step-down cycles (P < 0.001). Monofollicular growth, defined as not more than one follicle 16 mm or larger on the day of hCG administration, was observed in 56% of low dose step-up and 88% of step-down cycles (P = 0.04). The percentage of patients with normal range periovulatory E2 serum levels (500-1500 pmol/L) was 33% in the low dose step-up group vs. 71% in the step-down group (P = 0.03). We conclude that a step-down protocol for gonadotropin induction of ovulation exhibits a more physiological, late follicular phase FSH serum profile than a low dose step-up protocol. This results in a shorter duration of treatment, a greater number of monofollicular cycles, and more cycles with periovulatory E2 levels within the normal range in the step-down protocol.

The step-up protocol increases clinical pregnancy rates compared with the step-down in patients with unexplained infertility. A randomized controlled trial

“…The higher multifollicular developments in the stepdown group causing a 25% of cancellations are consistent with some reports from studies on PCOS patients (Andoh et al, 1998), differing from others (van Santbrink & Fauser, 1997;Andoh et al, 1998;Balasch et al, 2001). Van Santbrink & Fauser (1997) observed a higher monofollicular development in PCOS clomiphene-resistant patients following the step-down protocol compared with the ones following the step-up (88% vs. 56%; p=0.04).…”

“…The higher multifollicular developments in the stepdown group causing a 25% of cancellations are consistent with some reports from studies on PCOS patients (Andoh et al, 1998), differing from others (van Santbrink & Fauser, 1997;Andoh et al, 1998;Balasch et al, 2001). Van Santbrink & Fauser (1997) observed a higher monofollicular development in PCOS clomiphene-resistant patients following the step-down protocol compared with the ones following the step-up (88% vs. 56%; p=0.04). This could be attributed to their basal anovulatory condition, better responding to higher initial doses followed by a more physiological decrease of rFSH than to a stepping up approach possibly leading them to a higher number of cancellations (Koundouros, 2008).…”

“…However, our study included normoovulatory women only, with better chances of initial monofollicular response to rFSH lower doses than some PCOS (Sagle et al, 1991;Homburg et al, 1995). Also, our stepup regimen resulted in a longer-lasting induction with comparable rFSH units required versus the step-down, similarly to what other authors reported (van Santbrink & Fauser, 1997;Christin-Maitre & Hugues, 2003).…”

“…These regimens have been widely but heterogeneously evaluated in polycystic ovary syndrome (PCOS) patients, with major risk of multifollicular growth because of their elevated ovarian reserve and particularly extreme sensitivity to exogenous gonadotropins (Sagle et al, 1991;Homburg et al, 1995;Kamrava et al, 1982;Seibel et al, 1984;Polson et al, 1987;Buvat et al, 1989;Shoham et al, 1991;Dale et al, 1993;van Santbrink et al, 1995;White et al, 1996). Although both protocols have shown to be successful in reducing the number of growing follicles versus other strategies, the authors found conflicting results when comparing their efficacy on time to follicular recruitment, hormone concentrations, and resulting pregnancy rates (Mizunuma et al, 1991;van Santbrink & Fauser, 1997;Andoh et al, 1998;Balasch et al, 2001;Christin-Maitre & Hugues, 2003). Moreover, their potential benefits have not been evaluated in non-PCOS patients, who represent the leading cause of IUI performance.…”

Aspects of Ovarian Follicle Development throughout Life

“…Initial experience with the step-down protocol in a series of 82 women suggested that the duration of treatment and total gonadotropin dosage were reduced compared with the low-dose step-up protocol and that monofollicular growth was more frequently achieved [50]. These findings have recently been confirmed by a prospective randomized comparison of low-dose step-up and step-down regimens in 37 clomiphene-resistant women [51]. In comparison to the step-up regimen, women treated with step-down regimen were shown to have pre-ovulatory estradiol in the normal range in 71% as opposed to 33%.…”