Role of GnRH in the ontogeny and regulation of the fetal hypothalamo-pituitary-gonadal axis in sheep.

Adult reproductive ability is to a large extent determined by the appropriate development of the reproductive axis during fetal life. Studies have investigated the role of the fetal hypothalamus in the ontogeny and regulation of pituitary gonadal function during fetal development in sheep. Using immunocytochemistry, we examined the ontogeny of gonadotroph development in the pituitary of female sheep fetuses. At day 70 of gestation (term = 145 days), only immunopositive LH beta cells were present. The number and intensity of staining of these LH beta cells had increased by day 100 but had declined again by day 130. Immunopositive alpha-subunit and FSH beta cells appeared at day 100 of gestation and had further increased in number and staining intensity by day 130 of gestation. Treatment of fetuses with the GnRH agonist buserelin resulted in desensitization of the fetal pituitary gonadotrophs, inhibition of pituitary LH beta and FSH beta mRNA expression and a reduction in the number of immunopositive gonadotrophin-containing cells. Pulsatile GnRH treatment resulted in pituitary-gonadal activation and an increase in LH, FSH and testosterone secretion in males. Thus, the synthesis and secretion of the gonadotrophins during fetal development is critically dependent on the secretion of GnRH from the fetal hypothalamus. Inhibition of fetal gonadotrophins by buserelin treatment from day 70 of gestation resulted in a 40% reduction in the size of the fetal testis at birth, and there were no effects on the fetal ovaries. This reduction in testis size was due to a 45% reduction in the number of Sertoli cells. However, when buserelin was given between day 70 and day 110 of gestation, there were no effects on testis size or morphological development of the testis, suggesting that gonadotrophins regulate testicular development during a 'critical window' late in gestation. Taken together, these studies provide convincing evidence that GnRH plays a central role in the ontogeny and regulation of pituitary-gonadal function during fetal life.