Ovarian Responses in Macaques to Pulsatile Infusion of Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone: Increased Sensitivity of the Maturing Follicle to FSH*

Abstract

This study investigated the relationship between plasma gonadotropin concentrations and the initiation and maintenance of preovulatory follicular growth in macaques. Eight adult cynomolgus monkeys were treated with a GnRH antagonist [AcD2Nal1-4ClDPhe2, DTrp3, DArg6, DAla10]GnRH X HOAc to block endogenous gonadotropin secretion. In four animals, a pulsatile infusion of human FSH and human LH (hLH) (one 3-min pulse/h) was initiated, and the amount of hFSH delivered per pulse was increased every 3-4 days until serum estradiol concentrations rose. Thereafter, the amount of FSH delivered per pulse was reduced by 12.5%/day for 5 days, whereas the amount of LH delivered per pulse was not altered. Results indicated that plasma FSH concentrations in the range of 15-20 mIU/ml were associated with the initiation of estrogen production; in addition, a progressive reduction in plasma FSH concentration to 8-10 mI/ml over the subsequent 5 days was accompanied by continued rises in estradiol concentrations and preovulatory follicular growth. In contrast, in four control animals, maintenance of plasma FSH concentrations at 8-10 mIU/ml for 13 days did not result in elevation in serum estradiol concentrations or antral follicular growth. These observations demonstrate that after stimulation by elevated FSH concentration, follicles can continue to mature in the presence of FSH concentrations which are unable to support the growth of less mature follicles. Thus, this may account for the mechanisms by which the maturing follicle continues to develop during the mid-through late follicular phase of the menstrual cycle, whereas other less mature follicles undergo atresia.

Evidence to support a follicle-stimulating hormone threshold theory for follicle selection in ewes chronically treated with gonadotrophin-releasing hormone agonist

“…These data support the hypothesis proposed by Brown (1978) and agree with the evidence reported for monkeys (Zeleznik & Kubik, 1986) and humans (Poison et ai, 1987;Glasier et ai, 1989;Remorgida et ai, 1989) that a threshold exists above which FSH induces preovulatory follicular development. In this study, when the FSH concentration was maintained below the threshold requirement, there was no stimulation of the later stages of follicular development.…”

“…This increased oestrogen production throws the switch and sensitizes the granulosa cells of the selected follicle to FSH, so protecting it from the deleterious effects of the decline in FSH during the follicular phase of the cycle (Baird et ai, 1981;Wallace et ai, 1988;Picton, 1989 (Hillier et ai, 1988) or perhaps intrafollicular growth factors and peptides (reviews: Cahill, 1984;Hsueh et ai, 1984;Ying, 1988;Tonetta & diZerega, 1989) (1990a) show that this is not the case. Once the FSH concentration increases to the stimulatory range the subsequent duration of the FSH treatment influences the number of follicles which develop (Zeleznik & Kubik, 1986;Picton et ai, 1990a). This suggests that the physiological determinant of the number of follicles destined to ovulate in the ewe is the systemic concentration of FSH in the 48-72 h before the onset of spontaneous luteal regression.…”

“…On the basis of observations on the induction of ovulation using exogenous gonado¬ trophins in hypogonadotrophic women, Brown (1978) evolved the concept that there is a threshold concentration of follicle-stimulating hormone (FSH) above which the final stages of follicular development can be induced. Evidence from rhesus monkeys (Zeleznik & Kubik, 1986) and ewes (Picton et ai, 1990a) infused with FSH after treatment with gonadotrophin-releasing hormone (GnRH) antagonist or agonist, respectively, provides direct experimental proof in favour of this hypothesis. In agonist-treated ewes, infusion of a high concentration of FSH stimulates the development of an increased number of large preovulatory follicles, whereas infusion of a lower concentration of FSH does not (Picton et ai, 1990a).…”

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

“…Distinct differences in dominant follicle growth comparing both groups stress the significance of timing and duration of the FSH elevation as opposed to the FSH concentration per se. It may be proposed that recruited follicles increase their sensitivity to FSH during the course of their development (13,14), supposedly due to the induction of a variety of autocrine factors (15,(35)(36)(37).…”

“…Apparently, the maturing dominant follicle requires less FSH to continue its growth (13,14). This may be due to intraovarian changes in growth factors, which up-regulate the FSH sensitivity of follicles in more advanced developmental stages (15).…”