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This Week’s Citation Classic®SEPTEMBER12,1988
esserG M, Parke L, Edwards C R W, Forsyth I A & McNeilly A S.
Galactorrhoea: successful treatment with reduction of plasma prolactin levels by bromI ergocryptine. Brit. Med. J. 3:669-72, 1972.
[Medical Professorial Unit. St. Bartholomew’s Hospital, London and National Institute for
Research in Dairying, Shinfield, Berkshire. England]
This paperwas the first to report that the ergot alkaloid say was being carried out
2 by A.G. Frantz at Columbia
derivative 2-bromo-a-ergokryptine (bromocriptine,
University, New York.
CB1 54, Sandoz, BaseD could be used to treat galacFollowing the publication of our paper, we were
torrhoea; and it showed, using prolactin bioassay and contacted by Sandoz of Basal, Switzerland. Edward
radloimmunoassay, that the drug reversibly lowered Fluckiger, a senior pharmacologist and endocrinolelevated circulating prolactin levels. These initial ob- ogist there, had long believed that it would be shown
servations were soon confirmed, and the drug has that prolactin existed in the human. Flückiger,an exbeen in regular use worldwide since that time. (The pert in the field of ergot alkaloids, showed that the
SC! indicates that this paper has been cited in over ergot mixture ergotoxin could lower rat prolactin,
335 publications.]
that the less toxic derivative 2.bromo-a-ergokryptine
(bromocriptine) was equally effective, and that the3
action was directly on the pituitary in the rat.
Fluckiger realised the therapeutic potential of this
compound. We gladly accepted the offer of Sandoz
—
to investigate this drug. The five patients reported
on in this paper were the first in whom it was shown
that, as the drug was given, galactorrhoea disapG.M. Besser
peared and hypogonadism reversed, accompanied by
Department of Endocrinology
St. Bartholomew’s Hospital
a rapid reduction of the elevated serum prolactin
levels to normal. The effectswere indeed dramatic.
London EC1A 7BE
England
We later realised that prolactinomas were very
common and that truly functionless tumours were
much less frequent than had been previously
thought. Even though female patients had been inNovember 4, 1987 fertile and amenorrhoeic or male patientsimpotent
for many years, administration of bromocriptine frequently resulted in the return of normal gonadal
function within a few weeks.These patients became
Prior to 1970 most authorities in the world be- highly fertile. Furthermore, the tumours could be
lieved that prolactin did not exist as a human pitu- made to shrink in over 80 percent of such cases, and
itary hormone separate from growth hormone, medical treatment now often replaces surgery.
which was thought to be responsible for all the piWhen first introduced, wedid not know how bratuitary lactogenic activity. However,towards the end mocriptine lowered prolactin, but it was later shown
of the 1960s, many researchers became dissatisfied that bromocriptine was a long-acting dopamine
with this view. We had seen patients with pituitary agonist and that activation of dopamine receptors
tumours who had inappropriate lactation and hype- on the pituitary
cells directly inhibits prolactin se4
gonadism withoutsigns ofgrowth hormone excess. cretion. In the mid-1970s it was also shown that
We were fortunate to make contact with Isabel bromocriptine lowers growth hormone levels in a
Forsyth of the National Institute for Research in proportion of acromegalic patients with resolution
Dairying, Shinfleld, England. She had a bioassay for ofthe acromegalic syndrome. This has been shown
animal prolactin using a rabbit breast preparation to be effective in long-term treatment.°
Introduction of this compound marked an interthat could be induced to lactate in nonproliferative
culture. Forsyth collaborated with us, and we estingcoincidence, since it is most unusual for a new
showed that lactogenic activity could be demon- hormone to be discovered at the same time as the
strated in the serum of 14 of 20 patients with inap- treatment for its disturbed secretion. This remarkable
propriate lactation and hypogonadism.’ Appropriate circumstance led to a dramatic advance in the uncontrol studies left us with the conclusion that the derstanding of the physiology ofthe pituitary.gonadactivity had to be due to prolactin. At exactly the al axis, and the story is a great tribute tothe original
sametime, similar work using a mouse breast bioas- developer of the compound, Flückiger.
L
I. Forsyth I A, Beaver G M, Edwarde CR W, Franets L & Myraa R P. Plasma prolactin activity in inappropriate lactation.
Bru. Mat. 1. 3:225-7, 1971. (Cited 70 times.)
2. Franlx A G & Kkinberg D L. Prolactin: evidence that it is separate from growth hormone in human blood.
Science 170:745-7, 1970. (Cited 140 times.)
3. Fhlckiger E & Wagner if R. 2-Br.a-Ergokiyplin: Becinflussung von Fertilitit sod Laktation bei des Ratte (2-Br-oergoktypdne: influence on fertility and lactation in the rat). Expthentza 24:1130-I, 1968. (Cited 11$ times.)
4. Groavenan A & Bnaer G M. Prolactinomas. Bm. Mcd. 1. 290:182-4. 1985. (Cited 25 times.)
5. Beaver G M & Wave 3 A H. The use of dopamine agoniata in the management of acromegaly. (Robbins R S & Melnied S.
edo.) Acromegaly: a cennuy of scientific and clinked progress. New York: Plenum Press, 1987. p. 261-6.
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