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1~ 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. 12 ©1988by1Sl® CURRENT CONTENTS®