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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 Development¹

Division of Reproductive Medicine, Department of Obstetrics and Gynecology (I.S., B.C.J.M.F.), and the Department of Epidemiology and Biostatistics (W.C.J.H.), Dijkzigt Academic Hospital and Erasmus University Medical School, Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Prof. B. C. J. M. Fauser, Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Dijkzigt Academic Hospital, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.

Abstract

According to the threshold concept, FSH concentrations need to surpass a distinct level to stimulate ovarian follicle growth. The window concept stresses the significance of a limited duration of elevated FSH levels above the threshold for single dominant follicle selection. The aim of this study was to investigate effects on follicle growth of increased FSH levels, differing in duration and magnitude of elevation, during the follicular phase. Twenty-three normo-ovulatory (cycle length, 26–31 days), young (age, 20–31 yr) women volunteered for this study. In all subjects a series of daily transvaginal sonography scans of the ovaries and blood sampling [for FSH and estradiol (E₂) determinations] were performed during two consecutive cycles. The first study cycle (control cycle) started 10 days after urinary assessment of the LH surge in the preceding cycle (Day_LH) and was concluded on the day of ovulation assessed by transvaginal sonography scans. The second series of daily monitoring (intervention cycle) started 10 days after Day_LH in the control cycle. After randomization, subjects received either 375 IU urinary FSH, sc, as a single injection on Day_LH+14 (group A; n = 11) or 75 IU daily from Day_LH+19 until Day_LH+23 (group B; n = 12).

In group A, FSH levels increased on the day after injection to a median concentration of 10.1 IU/L, which was 1.9 times higher (P < 0.01) than levels on matching days during the control cycle. Concentrations returned to basal levels 3 days after injection. In group B, a moderate elevation of FSH concentrations (15% increase; P < 0.05) was observed compared to levels during the control cycle. In group A, E₂ concentrations increased (P = 0.03) 1 day after FSH injection and returned to baseline levels within 2 days. In group B, E₂ levels started to increase after the first injection of FSH and remained significantly higher (P < 0.01) during the following 5 days compared to those on matching days in the control cycle. Compared to matching days in the control cycle an increased number of follicles 8–10 mm in size was found in group A (P < 0.01) during the period from Day_LH+14 until Day_LH+19, without an increase in follicles 10 mm or larger thereafter. In contrast, in group B, the numbers of both 8- to 10-mm and 10-mm or larger follicles were higher during the period from Day_LH+19 until Day_LH+24 in group B (P = 0.02 and P < 0.01, respectively).

Results from the present study suggest that a brief, but distinct, elevation of FSH levels above the threshold in the early follicular phase does not affect dominant follicle development, although the number of small antral follicles did increase. In contrast, a moderate, but continued, elevation of FSH levels during the mid to late follicular phase (effectively preventing decremental FSH concentrations) does interfere with single dominant follicle selection and induces ongoing growth of multiple follicles. These findings substantiate the FSH window concept and support the idea of enhanced sensitivity of more mature follicles for stimulation by FSH. These results may provide the basis for further investigation regarding ovulation induction treatment regimens with reduced complication rates due to overstimulation.

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