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

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 Follicle-Stimulating Hormone (FSH) Threshold/Window Concept Examined by Different Interventions with Exogenous FSH during the Follicular Phase of the Normal Menstrual Cycle: Duration, Rather Than Magnitude, of FSH Increase Affects Follicle Development

“…The significance of a timely decrease in FSH levels to ensure single dominant follicle development may be relevant for gonadotropin induction of ovulation protocols (4). As shown recently, ovulation induction applying a decremental dose regimen (step down protocol) may result more frequently in monoovulatory cycles and reduced chances for complications (19). Findings from the present study may also provide a basis for further investigation regarding follicle maturation arrest in polycystic ovary syndrome patients.…”

“…On the basis of these findings, the FSH window concept has been proposed, stressing the significance of the (limited) duration of FSH elevation above the threshold level rather than the height of the elevation of FSH for single dominant follicle selection (4,16). In line with the FSH window concept, application of a decremental dose regimen for safe and effective gonadotropin induction of ovulation, mimicking the dynamics of normal follicular phase FSH levels, has proven successful (18,19).…”

“…Indeed, as has been demonstrated in primates, interference with the decrease in FSH levels in the midfollicular phase overrides selection of a single dominant follicle (17). Moreover, administration of gonadotropins for induction of ovulation in the human, applying a decremental dose regimen, has proven successful in reducing the incidence of multiple follicle development (18,19).…”

Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment

“…Surpassing the follicle-stimulating hormone (FSH) threshold for inducing follicular growth for too long may result in multifollicular development (3,4). In order to reduce the abovementioned complications and improve the effectiveness of treatment, new approaches have been suggested, such as patient selection on the basis of initial screening characteristics (5,6) or alternative dose regimens for FSH ovulation induction (7). Also new compounds such as aromatase inhibitors (8) or insulin sensitisers (9) are clinically applied in an attempt to improve treatment outcome.…”

FSH response-dose can be predicted in ovulation induction for normogonadotropic anovulatory infertility

“…This results in a serum FSH profile that mimics more closely physiological conditions in normo-ovulatory women (11,12). The major disadvantage of this regimen, however, is that the initial fixed FSH dose may be too high for some women resulting in enhanced chances of complications and cycle cancellations (13). We recently described a prediction model using initial patient characteristics for the individual FSH starting dose in low-dose regimens for ovulation induction (14).…”