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Activin Modulates Differential Effects of Estradiol on Synthesis and Secretion: DISCUSSION(3)

DISCUSSION(3)

The question arises whether the effect of estradiol on FSHp gene expression, which was very dramatic (up to 70%), may be mediated by the relatively lesser decrease (<46%) in expression of activin. We hypothesize that a small reduction in free activin concentration may be sufficient to inactivate second messenger cascades and thereby greatly reduce synthesis and secretion of FSH as reported for GnRH receptor expression mediated by GnRH.

Ovine anterior pituitary cells locally synthesize follista-tin, and activin stimulates the production of follistatin, independently of inhibin. However, there appear to be important differences among species with respect to effects of activin on FSH secretion. The activin concentration necessary to stimulate FSH secretion in ovine gonadotropes is three times that required in rat gonadotropes (EC50 = 0.3 and 0.1 nM, respectively), and the corresponding increase in FSH secretion was 150% and 500% (respectively) of control values. Likewise, a more robust FSH response was obtained to lower concentrations of activin (EC50 = 0.18 nM) with cultured ovine pituitary cells from immature lambs. Thus, it appears that factors such as age, sex, and gonadal status of the donor animals may affect pituitary production of FSH via the activin/follistatin intrapituitary feedback loop.

The studies reported herein were performed with pituitary cells obtained from anestrous ewes. These pituitary cells appear to be particularly responsive to estradiol, and the endogenous concentrations of activin and fol-listatin may differ from those in the ovine pituitary gland at other times of the year An investigation into seasonal changes in pituitary concentrations of activin and follistatin in sheep is needed.

In summary, we report that estradiol inhibits synthesis and secretion of FSH and stimulates secretion of LH in ovine pituitary cells during anestrus. These effects were independent of GnRH. Estradiol appears to reduce the in-trapituitary production of activin (3B but does not affect production of follistatin. Furthermore, immunoneutraliza-tion of activin reduced FSH secretion but did not influence secretion of LH. We conclude that estradiol may directly influence gonadotropin secretion in the ewe through local mediators such as the activin-follistatin network. Further examination of molecular mechanisms is needed to better understand this intrapituitary system in sheep.