Neuroendocrine Control of Follicle-Stimulating Hormone (FSH) Secretion: II. Is Follistatin-Induced Suppression of FSH Secretion Mediated via Changes in Activin Availability and Does It Involve Changes in Gonadotropin-Releasing Hormone Secretion?1

Abstract

The objective of the present study was to determine to what extent activin participates in setting the level of FSH secretion and if this regulation includes mediation via changes in GnRH secretion. We administered follistatin, the high-affinity binding protein for activin, to five ovariectomized sheep; we reasoned that the resultant binding of follistatin to activin should lower activin bioavailability and FSH secretion. Hypophyseal portal and peripheral blood samples were collected simultaneously at 10-min intervals for 18 h to measure GnRH, LH, FSH, and both activin-free and total follistatin. Six hours into collection, each ewe received 150 microg/kg i.v. of recombinant human follistatin-288. A week later, the same ewes were subjected to a second series of blood collections of similar length (time control). The FSH levels in pituitary portal blood were approximately 8-fold higher than those in the peripheral circulation. The FSH secretory patterns changed minimally during the time-control period. In contrast, follistatin had profound suppressive effects on FSH secretion. Maximal FSH suppression after FS-288 administration occurred at 5-6 h in the pituitary portal (65% suppression) and 9-10 h in the peripheral (48% suppression) circulation. Follistatin had no effect on GnRH or LH secretory patterns. Disappearance of total follistatin (i.e., free follistatin plus activin-bound follistatin) from the circulation was slower (P < 0.05) than that of free follistatin alone, suggesting that some of the follistatin was complexed with circulating activin, thus reducing the bioavailability of activin. The slower clearance of total follistatin and the lack of follistatin effects on GnRH secretion suggest that changes in activin bioavailability dictate the level of pituitary FSH secretion and that this is a pituitary-specific effect.

Fetal Programming: Excess Prenatal Testosterone Reduces Postnatal Luteinizing Hormone, But Not Follicle-Stimulating Hormone Responsiveness, to Estradiol Negative Feedback in the Female

“…It should be noted, however, that FSH secretory dynamics could not be assessed reliably from peripheral measurements because of its long circulatory half-life (48). This would require measurements closer to the site of release (51,52).…”

Relationships among body composition, circulating concentrations of leptin and follistatin, and the onset of puberty and fertility in young female sheep

“…Follistatin is secreted by the sheep ovary (Tisdall et al, 1992) but circulating concentrations vary little during the oestrous cycle (McFarlane et al, 2002), probably because it is produced in a variety of tissues, particularly muscle, where its importance for muscle growth and development has been demonstrated (Matzuk et al, 1995;Lee and McPherron, 2001;Gilson et al, 2009). With respect to reproduction, follistatin seems to have no effect on hypothalamic GnRH secretion in sheep (Padmanabhan et al, 2002), but it does act at pituitary level to inhibit FSH secretion in rodents (Ueno et al, 1987). The ultimate trigger for the first ovulation at puberty might be GnRH and LH pulses, but FSH is essential for the months-long process of ovarian development leading to that point -without it, there would be no follicular development, no oestradiol production and therefore, no ovulation (Schwartz, 1974).…”

Intra-pituitary administration revisited: Development of a novel in vivo approach to investigate the ovine hypophysis

“…Not only is this expensive, but injecting a large dose of a peptide into the general circulation may have undesirable pharmacological effects on homeostasis. For example, significant amounts of follistatin, which is hypothesized to work through an intra-pituitary paracrine pathway (Denef, 2008), are required for in vivo effects, especially in large animal models (Padmanabhan et al, 2002). High doses of factors administered intravenously may also cross the blood-brain barrier, with possible cerebral effects (Caraty and Skinner, 2008).…”