Kisspeptin: Past, Present, and Prologue - Kisspeptin Signaling in Reproductive Biology - page 3

he had either removed one testis and “relocated” it to within the abdomen or removed
both testes and transplanted a spanking new testis into the animal's abdominal cavity.
To his astonishment—despite the testicular swapping, the cockerels retained their
lusty ways and avian pulchritude. The transplanted testes had become vascularized
and produced sperm, but notably lacked nervous innervation. Berthold wrote (in a
translation by D.P. Quiring): . . . So far as voice , sexual urge , belligerence , and growth
of combs and wattles are concerned , such birds remain true cockerels . Since , how-
ever , transplanted testes are no longer connected with their original site and severed
from their innervations . . . it follows that the results in question are determined by the
productive function of the testes . . . their action on the blood stream . . . and then the
entire organism , of which it is true , the nervous system represents a considerable part
[ 1 ]. Such was the beginning of experimental endocrinology and the fi rst whiff that
hormones act upon the brain to regulate reproduction .
At the turn of the twentieth century, two neurologists, Joseph Babinski and
Alfred Frölich, described patients with a condition called dystrophia adiposogeni-
talis (later called Frölich's or Babinski-Fröhlich syndrome), whose clinical features
include sexual immaturity and which were known to be caused by tumors of the
basal forebrain and pituitary. A debate raged for some 20 years thereafter about
whether this syndrome was attributable to lesions of the brain or pituitary. In 1912
Bernhard Aschner exhorted: Not only hypophysectomy — but even a mere wound in
the base of the thalamencephalon leads to atrophy of the gonads in male and female
dogs [ 2 ]. However, 30 years would pass until seminal studies in rats by Walter
Hohlweg and Karl Junkmann demonstrated that . . . internal secretion of the
anterior pituitary and the gonads is controlled by a nervous system [ 3 ]. They
accomplished this remarkable feat by showing that the capacity of the pituitary to
respond to castration required its close proximity to the brain—and the so-called
“nervous sex center” (now recognized to include the hypothalamus), which regu-
lates gonadotropin secretion as a feedback control system. Over the next 20 years,
scientists, including F.L. Dey [ 4 ], C.H. Sawyer, and G.W. Harris, placed lesions and
evoked electrical activity within discrete regions of the forebrain and observed their
effects on reproduction, and by the early 1950s it became widely accepted that the
hypothalamus constitutes the central processor of reproduction—governing the
onset of puberty, gonadotropin secretion in both sexes, and timing of ovulation in
females. In the 1930s, the anatomy of the hypothalamo-hypophyseal portal system
was argued and settled, and the concept of “neurosecretion” gained traction. Belief
in the existence of GnRH became widespread by the 1950s, but the fi nal character-
ization of GnRH would come only after 20 more years of protein chemistry and
physiology—in the late 1960s and early 1970s. Thus, the cornerstone of the brain-
pituitary-gonadal axis was laid—and acknowledged by the Nobel Committee in
1977. But mysteries remained.
The 20 years that followed awarding the Nobel Prize in Physiology or Medicine
to Roger Guilleman and Andrew Schally produced highly reductionist studies of
hypothalamic circuitry, which characterized many afferent inputs to GnRH neurons,
with the use of pharmacological, neurosurgical, biophysical and, eventually, molec-
ular techniques. This research imparted appreciation to the complexity of the mech-