Dynamics of basal and gonadotropin-releasing hormone-releasable serum follicle-stimulating hormone charge isoform distribution throughout the human menstrual cycle

In the present study we analyzed physiological changes in the relative distribution of FSH isoforms circulating under baseline conditions throughout the ovarian cycle as well as the forms discharged by GnRH stimulation from putative acutely releasable and reserve pituitary pools. Eight normally menstruating women underwent blood sampling on three occasions, once each during the presumptive early or midfollicular phase (FP), late follicular phase to midcycle (preovulatory phase; PO), and mid- to late luteal phase (LP) of the menstrual cycle. Blood samples were withdrawn at 10-min intervals for a total of 10 h before and after the iv administration of 10 and 90 μg GnRH. GnRH-stimulated FSH pulses were analyzed for secretory burst mass, secretory burst amplitude, integrated FSH concentrations, and endogenous FSH half-life by deconvolution. Serum FSH isoforms were separated by preparative chromatofocusing in 30 x 1-cm columns and identified by RIA of eluent fractions. The changes observed in serum FSH isoform distribution were then correlated with the corresponding secretory and clearance estimates of the released FSH molecules. In each phase of the menstrual cycle, a significant rise in serum FSH concentrations was observed after administration of the consecutive low and high dose GnRH pulses. The magnitude of the response in terms of secretory burst mass, secretory amplitude, and area of GnRH-induced FSH peaks was significantly higher during the PO. In all cycle phases, but particularly during the FP and PO, administration of the 90-μg GnRH dose elicited higher (1.4- to 1.7-fold) FSH secretory responses than the lower dose. Multiple parameter deconvolution of the GnRH-induced FSH pulses revealed that FSH molecules released in response to 10 μg GnRH at PO exhibited significantly (P < 0.01) shorter plasma half-lives (108 ± 11 min) than those released during the follicular and luteal phases of the same menstrual cycles (apparent plasma half-life of FSH released at FP, 222 ± 37 and 271 ± 47 min for 10 and 90 μg GnRH-induced FSH pulses, respectively; LP, 244 ± 41 and 198 ± 40 min; P = NS, FP vs. LP) and in response to the high dose GnRH challenge at PO (276 ± 40 min). Under all conditions studied, serum FSH charge isoforms were distributed along a pH range of 7.0 to less than 4.0. The relative abundance of more acidic isoforms, particularly those with pH values below 4.5, present under baseline conditions and released in response to exogenous GnRH decreased dramatically during PO compared to that in the follicular and luteal phases (ratio of serum FSH isoforms with elation pH values <4.5 relative to those with values >4.5 at PO, 3.2 ± 0.4, 2.9 ± 0.3 and 2.6 ± 0.3 for baseline and 10 and 90 GnRH-stimulated release, respectively; FP, 7.3 ± 0.8, 7.5 ± 1.0, and 5.3 ± 0.7; LP, 5.1 ± 0.8, 4.9 ± 0.6, and 4.7 ± 0.2; P < 0.05, PO vs. FP and LP in all study conditions; P < 0.05, base line follicular vs. baseline luteal), such that the release of more basic isoforms predominated. No significant differences between the pH distribution profiles of FSH in samples from basal vs. GnRH-stimulated conditions were detected within each individual phase of the cycle. Significant inverse relationships among key secretory parameters (FSH secretory burst mass and amplitude), serum FSH peak area of the exogenous GnRH-induced FSH pulses, and the changes in serum FSH isoform distribution were identified by regression analysis (r = -0.516, -0.650, and -0.583 for burst mass, amplitude and area of the FSH pulses, and the change in FSH isoform distribution; P < 0.001). Thus, with larger FSH responses to exogenous GnRH, the shift to less acidic serum isoforms was more pronounced. These results collectively indicate that under conditions characterized by both a high estrogenic milieu and increased GnRH-stimulated pituitary FSH release, a selective increase in the release of less acidic FSH forms occurs, thus modifying the intensity and duration of the blood FSH signal delivered to the gonad.