In 1957, Béla Flerkó and János Szentágothai implanted ovarian and liver tissue autografts into two distinct hypothalamic regions or the adenohypophysis of female rats. The tiny pieces of liver were absorbed. By contrast, the ovary implants survived and continued to release oestrogens. Furthermore, when the ovarian tissue was implanted below the hypothalamic paraventricular nucleus, the weight of the uterus decreased and the oestrous cycle of most animals was arrested in dioestrus. Both of these consequences were attributed to reduced peripheral oestrogen signalling and were absent in rats that had the ovarian implants in either the mammillary region or the adenohypophysis. Flerkó and Szentágothai interpreted their results as evidence that the oestrogen released from the ovarian grafts, which could not inhibit gonadotrophic activity via direct effects on the adenohypophysis, acted on the nervous tissue of the hypothalamus to inhibit secretion of follicle-stimulating hormone.

The basic conclusion of the authors that oestrogens act predominantly in the hypothalamus to inhibit the secretion of gonadotrophs has remained valid since 1957. However, it should be recognized that the lesion and implantation techniques available at that time did not allow these investigators to precisely determine the hypothalamic site where negative feedback takes place. The results of these lesion experiments directed their attention to the anterior hypothalamus.