Pharmacology of Reproduction. Proceedings of The Third International Pharmacological Meeting July 24–30, 1966 PDF
Preview Pharmacology of Reproduction. Proceedings of The Third International Pharmacological Meeting July 24–30, 1966
Proceedings of the First International Pharmacological Meeting, Stockholm, 22-25 August, 1961 Vol. 1 Part 1: Plenary Session Part 2: Pharmacological Control of Release of Hormones Including Antidiabetic Drugs Vol. 2 Effects of Drugs on Synthesis and Mobilization of Lipids Vol. 3 New Aspects of Cardiac Glycosides Vol. 4 Drugs and Membranes Vol. 5 Methods for the Study of Pharmacological Effects at Cellular and Subcellular Levels Vol. 6 Metabolic Factors Controlling Duration of Drug Action Vol. 7 Modern Concepts in the Relationship between Structure and Pharmacological Activity Vol. 8 Pharmacological Analysis of Central Nervous Action Vol. 9 Part 1: Bradykinin and Vaso-dilating Polypeptides Part 2: Pharmacology of the Lung Vol. 10 Proceedings of the Second International Pharmacological Meeting Prague, 20-23 August, 1963 Vol. 1 Pharmacology of Conditioning, Learning and Retention Vol. 2 Biochemical and Neurophysiological Correlation of Centrally Acting Drugs Vol. 3 Pharmacology of Cholinergic and Adrenergic Transmission Vol. 4 Drugs and Enzymes Vol. 5 Pharmacology of Cardiac Function Vol. 6 Pharmacology of Smooth Muscle Vol. 7 Pharmacology of Oriental Plants Vol. 8 Evaluation of New Drugs in Man Vol. 9 Recent Advances in the Pharmacology of Toxines Vol. 10 Oxytocin, Vasopressin and their Structural Analogues Vol. 11 Drugs and Respiration Proceedings of the Third International Pharmacological Meeting, Sao Paulo, 24-30 July, 1966 Vol 1 Modes of Action of Anti-parasitic Drugs Vol 2 Pharmacology of Reproduction Vol 3 Clinical Pharmacology Vol 4 Mechanisms of Drug Toxicity Vol 5 The Control of Growth Processes by Chemical Agents Vol 6 Drugs in Relation to Blood Coagulation, Haemostasis and Thrombosis Vol 7 Physico-chemical Aspects of Drug Action Vol 8 Salt and Water Balance Vol 9 Pharmacology of Pain Vol 10 Rapports entre les Actions Pharmacologiques des LM.AO. et Leurs Effets chez Γ Homme Vol 11 Immunopharmacology Pharmacology of Reproduction Edited by E. DICZFALUSY Karolinska Sjukhuset^ Stockholm Assistant Editor A. KOVARIKOVA Research Institute for Natural Drugs, Prague ,000 ©@[J^@l^[l@@0il9 © ; puillll 1 PERGAMON PRESS OXFORD · LONDON · EDINBURGH · NEW YORK TORONTO · SYDNEY · PARIS · BRAUNSCHWEIG Pergamon Press Ltd., Headington Hill Hall, Oxford 4 & 5 Fitzroy Square, London W.l Pergamon Press (Scotland) Ltd., 2 & 3 Teviot Place, Edinburgh 1 Pergamon Press Inc., 44-01 21st Street, Long Island City, New York 11101 Pergamon of Canada, Ltd., 6 Adelaide Street East, Toronto, Ontario Pergamon Press (Aust.) Pty. Ltd., Rushcutters Bay, Sydney, New South Wales Pergamon Press S.A.R.L., 24 rue des Ecoles, Paris 5® Vteweg & Sohn GmbH, Burgplatz 1, Braunschweig Copyright © 1968 Pergamon Press Ltd. First edition 1968 Library of Congress Catalog Card No. 67-19416 08 003260 5 LIST OF AUTHORS ARIMURA, A. Endocrine and Polypeptide Laboratories, Veterans Admi- nistration Hospital, New Orleans, La., U.S.A. ARRAU, J. Laboratorio de Fisiología, Universidad Católica de Chile, Santiago, Chile BOWERS, C. Y. Endocrine and Polypeptide Laboratories, Veterans Admi- nistration Hospital, New Orleans, La., U.S.A. CROXATTO, H. R. Laboratorio de Fisiología, Universidad Católica de Chile, Santiago, Chile DE LA LASTRA, M. Laboratorio de Fisiología, Universidad Católica de Chile, Santiago, Chile DÍAZ, S. Laboratorio de Fisiología, Universidad Católica de Chile, Santiago, Chile DiCZFALUSY, E. Hormonlaboratoriet, Karolinska Sjukhuset, Stockholm, Sweden HELLER, C. G. Pacific Northwest Research Foundation, Seattle, Wash., U.S.A. LALLI, M. F. Pacific Northwest Research Foundation, Seattle, Wash., U.S.A. LAMB, E. Hormonlaboratoriet, Karolinska Sjukhuset, Stockholm, Sweden MANCINI, R. E. Departamento de Histología, Facultad de Medicina, Uni- versidad de Buenos Aires, Buenos Aires, Argentina MARTINI, L. Istituto di Farmacología e di Terapia, Universitá degli Studi, Milano, Italy MCCANN, S. M. Department of Physiology, University of Texas, Dallas, Tex., U.S.A. MÜLLER, Ε. Ε. Endocrine and Polypeptide Laboratories, Veterans Admi- nistration Hospital, New Orleans, La., U.S.A. ROWLEY, Μ. J. Pacific Northwest Research Foundation, Seattle, Wash., U.S.A. SAITO, T. Endocrine and Polypeptide Laboratories, Veterans Admi- nistration Hospital, New Orleans, La., U.S.A. SCHALLY, A. V. Endocrine and Polypeptide Laboratories, Veterans Admi- nistration Hospital, New Orleans, La., U.S.A. SEGAL, S. J. The Population Council, The Rockefeller University, New York, N. Y., U.S.A. TAUSK, M. N.V. Organon, Oss, Netherlands VI PHARMACOLOGICAL IMPLICATIONS OF THE HYPOTHALAMIC CONTROL OF GONADOTROPHIN AND PROLACTIN SECRETION S. M. MCCANN* Department of Physiology, University of Texas, Southwestern Medical School, Dallas, Texas THIS communication is designed to serve a twofold purpose. First, to outline the present status of our knowledge of hypothalamic control of gonadotrophin and prolactin secretion, and second, to indicate how drugs can influence the secretion of these hormones by interactions with the controlling mechanism. HYPOTHALAMIC CONTROL OF GONADOTROPHIN AND PROLACTIN SECRETION It has become abundantly clear in recent years that the secretion of these hormones is controlled by the hypothalamus. Electrical stimulation of this part of the brain in rats or rabbits can evoke ovulation.^^^^ Con- versely, lesions in the median eminence of the tuber cinereum block the estrous cycle in the rat.^*^^ There is a failure of ovulation, and a decrease in pituitary and plasma levels of both FSH^^^^ and LH^*®^ has been demon- strated under appropriate conditions by bioassay. Since both plasma^^^' and pituitary levels of these hormones are reduced by these lesions, it would appear that the hypothalamic influence aff"ects both synthesis and release of these gonadotrophins. By contrast with the effects on secretion of FSH and LH, hypothalamic lesions can induce prolactin release in both male^'^ and female rats^^^^ and in female rabbits^^^^ as indicated by the occurrence of mammary secretion. Sufficient prolactin is secreted in such animals to maintain milk secretion at high levels/^^^ Consequently, the hypothalamic influence on prolactin •Research conducted in the author's laboratory was supported by NIH grant AM 10073-2 and by the Ford Foundation. VI 2 S. Μ. MCCANN secretion is an inhibitory one, and in the absence of hypothalamic control secretion of prolactin is enhanced. Even when the pituitary is maintained outside the body in tissue culture, the secretion of prolactin continues at a high rate whereas that of gonadotrophin declines.^^^^ Thus, the hypothala- mus has a stimulatory effect on the secretion of FSH and LH and an inhi- bitory effect on the secretion of prolactin (Fig. 1). 1 FSH LH LTH MAX. BASAL FIG. 1. Effect of hypothalamic lesions on the secretion of the three gonado- trophins. Max., maximum (McCann, S. M., Physiology for Physicians, 1, No. 12 (1963)). In addition to the basal tuberal mechanism described above, the hypo- thalamus also appears to regulate the cyclic fluctuation in gonadotrophin secretion which is responsible for the estrous cycle in lower forms and for the menstrual cycle in primates. This so-called "cyclic timing mechanism" appears to lie in the suprachiasmatic region since lesions in this area can block ovulation and lead to the development of persistent vaginal corni- fication.^^^^ In this situation the ovary is filled with large follicles which appear to be on the brink of ovulation. Apparently, constant amounts of FSH and LH are released, and the burst of LH secretion which normally triggers ovulation at mid-cycle is absent. Neonatal treatment with androgen can produce a similar syndrome,^^^ and the current view is that androgen from the infantile testes exerts an inductive influence on this suprachias- matic region to convert the female cyclic pattern of gonadotrophin release into the male acyclic pattern. MECHANISM OF HYPOTHALAMIC CONTROL OF GONADOTROPHIN AND PROLACTIN RELEASE Although the anterior pituitary gland is devoid of a secretomotor inner- vation, a portal system of veins drains capillary blood from the median eminence and pituitary stalk to the sinusoids of the anterior lobe. This provides an alternate route by which the nervous system may influence CONTROL OF GONADOTROPHIN AND PROLACTIN SECRETION 3 anterior pituitary function, and the concept has developed that specific neurohumoral agents may be released into these vessels to trigger the secretion of pituitary hormones. LH-releasing factor,—Convincing evidence is now at hand for the existence of an LH-releasing factor (LH-RF) in extracts of stalk-median eminence (SME) tissue from several species. This factor was originally demonstrated with the use of the ovarian ascorbic acid depletion assay of Parlow. It has now been shown that hypothalamic extracts can elevate plasma LH levels in a variety of situations. They are active even in rats in which neural control of the pituitary has been eliminated by hypothala- mic lesions. This indicates that the extract acts directly on the gland to evoke LH release rather than via the nervous system/^'^ a contention which is strengthened by the finding that these extracts act when added directly to the pituitary either in v/W^'' or in vitroM^' Extracts from the basal tuberal region overlying the median eminence also have some LH-releasing activity, whereas extracts of other hypothala- mic areas and of cerebral cortex are inactive.^^7) The active factor in these extracts is heat stable, at least in crude extracts, and has been inactivated by digestion with pepsin or trypsin^^?. is) It has been purified by a combination of extraction, gel filtration through Sephadex G-25, and ion exchange chromatography.^^' Because of its inactivation by enzymatic digestion and its behavior in several chromato- graphic systems, it has been thought to be a small polypeptide. If the LH-RF is the physiologic mediator of LH release, one might expect to find changes in the content of stored releasing factor in situations associated with an altered secretion rate of LH. A decrease in LH-RF content of the hypothalamus has indeed been reported at proestrous,^^' at a time when LH release is augmented. Furthermore, plasma from long- term hypophysectomized rats and chickens can deplete ovarian ascorbic acid.^^*'^^^ Since this test measures LH or LH-RF and there is little hkehhood that LH would be present in the circulation of hypophysectomized ani- mals, it would appear that there is a circulating LH-RF in the biood of these chronically hypophysectomized animals. The work to date is consist- ent with the thesis that changes in secretion of the LH-RF are largely responsible for mediating alterations in LH release. FSH-releasing factor (FS^íT-i^F).—Hypothalamic extracts also elevate the level of plasma FSH even if the median eminence has been destroyed to ehminate neural control of the pituitary.^20) xhese extracts increase the release of FSH into the medium of pituitaries incubated in vitro}^^' Thus the FSH-RF also acts directly on the gland. The FSH-RF has been 4 S. Μ. MCCANN purified by the same procedures that were used to purify the LH-RF. Separation of LH-releasing from FSH-releasing activity can be achieved at either the gel filtration step^®^ or later after ion exchange chromato- graphy/ii^ Prolactin-inhibiting factor (PIF).—In view of the inhibitory nature of hypothalamic control of prolactin release one might postulate the exist- ence of an inhibitory neurohumor. Such a factor, termed PIF, was first discovered with the use of pituitaries in tissue culture. Addition of hypo- thalamic extracts inhibited release of prolactin into the medium.^^^^ To obtain in vivo evidence for the existence of PIF we have taken advan- tage of the fact that the suckling stimulus has been shown to deplete pitu- itary prolactin. Hypothalamic extracts can block this suckling-induced decline in prolactin, while extracts of cerebral cortex are ineffective.^^^^ The active agent has been purified as described above for the LH-RF however, so far we have not been able to separate prolactin-inhibiting activity consistently from the LH-RF. A highly purified sample of LH-RF has been reported to be devoid of PIF on estimation with pituitaries incubated in vitro however, these workers have not reported the presence of PIF in their purified fractions. The question of the separate identity of PIF has not yet been satisfactorily resolved. Alterations in the content of PIF in the hypothalamus in conditions associated with altered prolactin release have been reported.^^^^ CHEMICAL NATURE OF THE RELEASING AND INHIBITING FACTORS The FSH-RF, LH-RF and PIF can be separated from the other hypotha- lamic releasing factors, such as corticotrophin-releasing factor, and growth hormone-releasing factor.^^^^ It would appear that with the possible excep- tion of the PIF, there is a separate hypothalamic factor for each anterior lobe hormone. Even a melanocyte stimulating hormone-releasing factor^^^^ and a melanocyte stimulating hormone-inhibiting factor^^s) j^^yg ^^^j^ reported in hypothalamic extracts. Since several of these factors have shown a loss of activity following proteolytic digestion and since they have been found in the polypeptide- containing fractions in several chromatographic systems, they have been thought to be relatively small polypeptides dissimilar from the known neurohypophyseal polypeptides, vasopressin and oxytocin.^^^^ Recently, it has been suggested that the factors may be smaller molecules and not polypeptides at all.^*'^ Re-examination of this question is in order. CONTROL OF GONADOTROPHIN AND PROLACTIN SECRETION 5 Thus, the regulation of gonadotrophin and prolactin secretion is brought about by a hypothalamic mechanism which controls pituitary secretion by release of specific transmitter agents into the hypophyseal portal vessels. These transmitters then stimulate or inhibit release of a given pituitary hormone. A variety of inñuences are visualized as acting upon this hypothalamic- pituitary axis. Environmental stimuli have access to the hypothalamic regulator either via afferent pathways proceeding up from the brainstem or via impulses descending from the cerebral cortex. An example is the suckUng stimulus which augments prolactin secretion and inhibits that of FSH and LH. The gonadal steorids and other drugs are visualized as potentially acting on either the nervous system or the pituitary directly to alter gonadotrophin secretion. A diagrammatic view of the regulation of LH is shown (Fig. 2). Similar diagrams with some modifications could be constructed for FSH and prolactin. PROGESTERONE -C+) CEREBRAL CORTICAL INFLUENCES OVULAT/0/\f OVARY FIG. 2. Schematic diagram of the factors regulating the secretion of LH. For full explanation see text. O.C., optic chiasm; M.E., median eminence of tuber cinereum; M.B., mammillary bodies; P.L., posterior lobe of hypophysis; A.L., anterior lobe of hypophysis; LH-RF, luteinizing hormone releasing factor; <—), inhibition; (+), stimulation in the preovulatory phase of the menstrual cycle (McCann, S. M., Physiology for Physicians, 1, No. 12 (1963)). 6 S. Μ. MCCANN INFLUENCE OF DRUGS ON GONADOTROPHIN AND PROLACTIN SECRETION A variety of drugs can influence the output of these hormones from the pituitary/^2) general they can be divided into two categories: (1) those which are thought to act by aflecting the function of the nervous system and (2) various steroids which are thought to act either on the pituitary directly or on the nervous system to produce their effects. Drugs which Act on the Nervous System,—A variety of agents which influence the nervous system have been found capable of blocking ovula- tion in lower forms such as the rabbit and the rat^^^^ (Tables 1, 2). For TABLE 1 TYPES OF DRUGS WHICH AFFECT THE SECRETION OF GONADOTROPHINS AND THEIR SITES OF ACTION AAffffeecctt oonn Site of action TTyyppee ooff ddrruugg ggoonnaaddoottrroopphhiinn sseeccrreettiioonn Hypo- Pituitary thalamus 1. Central nervous system Blockade of ovulation J- depressants, ex., Nembutal, tranquilizers 2. Autonomic blocking agents Blockade of ovulation + 3. Gonadal steroids Inhibition (Stimulation) ( + ) + 4. Antifertility steroids Inhibition 7 ? + — = no effect. ^ = effect, (-f) = less important effect. ? = questionable. example, a single injection of Nembutal at the appropriate time of the rat estrous cycle will block ovulation.^^^' A variety of other central nervous system depressants are also effective. Tranquilizers, such as reserpine and chlorpromazine, will not only block ovulation but will induce a condition of pseudopregnancy in the rat.^^, 12) Pseudopregnancy is characterized by an augmented prolactin discharge accompanied by inhibition of release of the other gonadotrophins. It is as if a functional hypothalamic lesion were present. Even in humans, galactorrhea has been reported following the use of tranquilizers,^^^) ^nd this would appear to be analogous
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