Life Scieacae, Vol . 21, pp . 1545-1558 Printed is the U .S .A .

Pergamon Press

MINIREVIEW ENDOCRINE PROFILE OF ERGOT AIRAIAIDS Eugenio E. Mûller* Alberto E . Paaerai~; Daniela Cocchi and Paolo Mantegazza *Institute of Pharmacology and Pharmacognosy, University of Cagliari, 09100 Cagliari, and Department of Pharmacology (I Chair), University of Milan, Via Vanvitelli 32, 20129 Milano, Italy.

List of Abbreviations ACTH AP CB 154 CNS DA DMBA E Ec GH hGH L-DOPA LH-RH

adrenocorticotropic hormone anterior pituitary (Sandoz) 2-Br- d -ergocryptine central nervous system dopamine 7,12-dimathylbenz(a)anthracene epinephrine ergôcornine growth hormone human growth hormone 3,4 dihydroayphenylalanine luteinizing hormone-releasing hormone

MCE ME MSA MTWS NE PIF PRL 3TW5 TRH TSH 5-HT 7315a

metergoline median eminence melanocyte stimulating hormone pituitary tumor secreting PRL and GH norepineghrine prolactin inhibiting factor prolactin pituitary tumor secreting GH thyrotropia releasing hormone thyroid stimulating hormone serotonin pituitary tumor secreting ACTH and PRL

During the past decade extensive physiologic investigations have been performed aimed at defining the complex hypothalamic hormone-pituitary hormone interrelationships . As a result of painstaking efforts directed toward isola tion and purification of active hypothalamic fractions, it has been possible to chemically characterize and synthesize four hormones controlling anterior pituitary function (1) . Along with the studies on the identification of specific neurohormonal influences, extensive investigation has focused on neurotransmitter control of secretion of the hypothalamic regulatory hormones (2, 3) . IInequivocal proof has been given that brain neurotransmitters plaq a significant role in the neurcendocrine control of AP hormones and it has been recognized that abnormal neurotransmission regulation can be responsible for the development of endocrine disorders (3, 4) . This has made the search for drugs capable of interfering with endocrine regulation a logical necessity. Amongst these drugs, ergot alkaloids have undoubtedly a considerable import . This paper will attempt to review the effects of ergot drugs and simpler ergoline derivatives on pituitary hormone secretion, particularly in the light of our own results . History, Source and Chemiatrq A brief introduction is needed on the history, source and chemistry of ergot drugs before tracing their endocrine profile. The history of ergot drugs gees parallel to the history of epidemics of ergotism in the Middle Ages (as *Present address : Dept . of Physiology, üniversity of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3, Canada . 1545

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in France, 994 and 1129) from eating bread from contaminated flour. The clinical picture was characterized by (a) gangrenous ergotiam (Holy Fire) e.g .,hot extremities, becoming numb, then veaciculation and black coloration, finally mummification and lose of extremities at joints without bleeding ; (b) convulsive ergotiam e . g., twitching, numbness in fingers and toes progressing to terrible pain with shrieking and vomiting . The first description of the ability of ergot to stimulate uterine contractions was by an American physicians, John Steams (1808), who described it as "a Remedy for quickening Child-birth". The ergot alkaloids originate in a fungus "Claviceps purpurea", which grows on rye and contains also a number of other pharmacologically active agents : ergoaterol, tyramine, histamine, acetylcholine. The growth of the fun gus is now carried out in fermentation vats in factories rather than in the field . Three groups of alkaloids have been separated: the ergotoxine group, the ergotoxine group and the ergotoxine group . Chemically the structure common .to all ergot drugs is lysergic acid and most of them are amines of this compound (Fig . 1) . Each alkaloid occurs as an isomeric pair, of which the levo form, derived from lysergic acid, ie pharmacologically active, the dextro form, from isolyaergic acid, is inactive . The ergotoxine and the ergotoxine groups are referred to as amino acid alkaloids, because the amide nitrogen bears the condensation product of 3 amino acids (Fig . 1) . Ergonovine and the other alkaloids

13

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CHpH3 ~ 2

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CH3

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ER6000RNINE

ER60CRISTINE

ER60CRYPTINE

ER60TAMINE

FIG. 1 Generalized structure for the peptide-containing ergot molecules . The differences among the four compounds listed reside in R and R' . have simple aubstituents . Aside from these naturally occurring alkaloids,whâse main peripheral pharmacologic actions consist of smooth muscle stimulation (oaytocic effect, vasoconstriction) and o(-adrenergic blockade (reversal of catecholamine effect on blood pressure), there are aemisynthetic hydrogenated

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alkaloids (e .g ., dihydroergotamine), in which saturation of the double bond at C 9-10 reduces the smooth muscle constricting activity, but intensifies their vasodilating action . PROLACTIN Ergot drugs have been used since 1954 as pharmacologic tools in the field of reproductive physiology . In that year, Shelesnyak (5) reported that ergotoxine, a natural miature of ergocornine, ergocryptine and ergocryatiae,was capable of inhibiting the formation of deciduomata in paeudopregnant rats and of interfering with geetariion in the rat during early gestation by inducing a new estrus cycle (6) . The analysis of these effects, which are mainly obtained by Ec, showed that the antiprogeatational action of the drug was counteracted by progesterone (7), by PRL (8) or by placental extracts (9) . It was then found that Ec decreases the proestrus surge is serum PRL (10), reduces PRL Tee ela in D1D3A-treated rata (11) and in the pituitary or tumor bearing mice (12) . Collectively, these findings led to the assumption that in the rat Ec inter fered with PRL secretion . However, the drug, at pharmacological doses, was not devoid of the uterotonic and vascular properties of the traditional ergot alkaloids . It was therefore mandatory to have available an alkaloid capable of more selectively influencing the endocrine system with no important side effects . The development of 2-Br-o(-ergocryptiae (CB 154, Sandoz) (13, 14) represented major progress in the field and allwed a valid comparison of ezperimentally-induced or clinical conditions characterized by an abnormal secretion of AP hormones (see below) . Ergot drugs, regardless of their route of administration, inhibit PRL secretion is all vertebrate species tested ao far (10, 12, 15, 16), including man (17, 18 and see below) . The inhibitory effect of ergot alkaloids, and CB 154 particularly, on PRL secretion does not require the presence of an intact hyrpothalamo-pituitary connection, even though, reportedly, Ec acts also on the CNS to increase the activity of PIF is the hypothalamus (10) . Proof of a direct action of CB 154 on the lactotrophe include its ability to inhibit directly PRL release from an AP incubated "in vitro" (19, 20) or to reduce strikingly the elevated plasma PRL levels in hypophysectomized rata bearing a heterotopic pituitary (21) . The inhibitory effect of CB 154 on PRL secretion is long-lasting . In rate a single subcutaneous injection inhibits PRL secretion for at least 12 hrs (22) ; in cows several days of treatment with the drug produced a depresèion of PRL aecretiaa which was still present for several days after discontinuation of therapy (23) . As specific inhibitors of PRL secretion ergot drugs are a valuable tool for clarifying the .phyeiologic and/or pathophyeiologic role of PRL in the intact animal . The key role PRL ezerts to promote lactation (24) explains the marked anti-galactopoietic effect of ergot drugs in most mammalian species e . g ., .in rats (13), rabbits (25), pigs (14), cattle (23) and man (see below) . In rodenta, .there exist PRL-dependent mammary tumors (see 26) and ergot drugs are effective to induce regression of tumor growth in various forms of spontaneous or experimentally-induced mammary tumorigenesie (12, 27, 30) . In man, the dependency of some breast cançers on PRL (31) has fostered a chemotherapy approach to breast carcinoma with ergot drugs. Application of CB 154 therapy to the treatment of huoman metastasizing breast cancer was accompanied by partial and temporary remission of the symptomatology in one .study (32) ; however, objective tumor regressions with ergot drugs were rarely seen is other investigations (33, 34), probably because other hormones besides PRL e .g ., estrogen and progesterone, are involved in breast tumor growth . Ergot drugs can reduce the weight of the pituitary in the normal rat and prevent estrogen from increasing the size of the gland (35) ; this led to an investigation of their action on the growth of spontaneous pituitary tumors . The growth of M7.W5 tumor transplants, which secrete large amounts of PRL and GH

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(26) was considerably reduced by chronic treatment with Ec, ergonovine as well as ergotamine : ergocryptine was less effective (36) . From this study it appears that the effectiveness of ergot drugs to inhibit the growth of the pituitary tumor dcea not parallel their ability to suppress PRL secretion. Thus, ergotamine only slightly affects synthesis and release of PRL from a normal pituitary gland (37) ; yet, it was more active to inhibit tumor growth than ergocryptine, a more potent suppreasor of PRL release. PRL-lowerin effect in man. The availability of ergot derivatives, some , are free of uterotonic or vascular effects, prompted of which, such as CB 1 their use as PRL suppression in states of physiologic or pathologic hyperpro lactinemia (3) . Clinical trials in women demonstrated the effectiveness of CB 154 in suppressing the onset of puerperal lactation (38-41), a state in which the elevated resting serum PRL levels gradually decline reaching the normal range in the second to third postpartum week . Serial measurements of serum PRL concentrations in the puerperium during a single daily administration of CB 154 (2 .5 mg po) showed that concomitant to a striking reduction in serum hormone titers there was inhibition of milk secretion (18) . It was then shown that the inhibitory effect on lactation was also present after milk secretion had already started, and also at a time when serum PRL had fallen to the normal range (39) . A controlled trial of estrogena versus CB 154 in suppression of puerperal lactation, showed the latter to be more effective, as judged by milk flow and the relief of breast pain and congestion, even though interruption of treatment after 14 days, resulted in a small rebound rise in PRL levels on day 21 corresponding with the clinical observation of slight increase in milk lealr age, congestion and discomfort (42) . Hyperprolactinemic amenorrhea with or without galactorrhea is a common disorder, occurring in 20x of women with amenorrhea (43) . Pituitary tumors secreting prolactin are common in this instance and the pituitary foana is often enlarged . Patients who have normal pituitary R-ray often have PRL-secreting microadenomatas . In all these patients, CB 154 treatment reduces PRL levels, and ie highly successful in repairing the reproductive defect, provided patients are not gonadotropin deficient (17, 41, 44) . Similar results can be obtained in male subjects with galactorrhea and secondary hypogonadism due to a PRL-secreting tumor (45, 46) . Cessation of galactorrhea and suppression of PRL levels is accompanied by regular menstruation in women and return of potency and libido in man . It is worth noting that ergot drugs and CB 154 which are so effective in restoring fertility in man showed their first endocrine effects as antifertility agents in the rat (6, 7), a apec es .which,. differently from man, requires PRL for implantation of the fertilized ovum . With regard to the mechanisms) whereby ergot derivatives are capable of re-establishing normal gonadal function in pathologic hyperprolactinemia of man, it is postulated that the reduction in elevated PRL levels would remove try inhibition of the hypothalamic centers çontrolling cyclic gonadotropin release (47, 48) . It ie know that high PRL levels increase DA turnover in the external layer of the ME (49) and indications exist that activation of dopaminergic neurotransmission at this level is associated with inhibition of neurone secreting the releasing hormone for gonadotropins (LH-RH) (50 and see below) . The return of a cyclic release appears to trigger then the pulsatile release of gonadotropins which would be also lost during hyperprolactinemia (4648) . In addition, reduction of plasma PRL titers by ergot drugs may cancel the inhibitory effect of PRL on the pituitary release of gonadotropins (48, 51) and on gonadal ateroidogeneais (52) . Finally, a direct action of ergot drugs on the ovary cannot be excluded as suggested by the increased estrogen levels found during CB 154 treatment in normoprolactinemic subjects with secondary amenorrhea (53) . PRL-lowerin effect : mechanism of action . . It was only in 197, i .e .,when the suppressive effect of ergot rugs on PRL secretion had been unequivocally

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established for several years (10-12), that the aeurochemical event underlying this effect was recognized . It was discovered, in fact, that ergot drugs are capable of stimulating DA receptor sites in the striatum and limbic system, CB 154 and ergocornine being amongst the more active agenté in thie . seasé (54-56), ergotamine and dihydrogenated ergotoxine alkaloids (55) having less activity . More recent studies showed that, similarly to DA, ergotamine and its derivatea stimulate also specific DA receptor sites on the lactotropa and CB 154, at low concentrations, partially inhibits the binding of 3H-DA at this level (20, 37) . Thus, it appears that the PRL suppressive effect of ergot drugs rests on their intrinsic dopaminergic activity . A further possibility is that, by analogy with the effect of L-DOPA (57), ergot drugs may also transiently increase the clearance of PRL from plasma, by stimulating PRL uptake into peripheral receptor

sites . With regard to the main site (s) of the DA agoniat action of ergot drugs in relation to PRL release, e .g . stimulation of DA receptors in the hypothalamic tubero-infundibular system (58) and then release of PIF (10) or direct stimula tion of DA receptors located on the lactotropha (20, 37), our present incomplete knowledge is related to the uncertainty on the mechanism(e) whereby DA suppresses PRL release and to the possibility that DA itself may be the physiologic PIF (2, 3) . A direct stimulation of DA receptors located on the AP is more likely and would account for the effectiveness of ergot drugs to inhibit PRL secretion in patients with PRL-secreting tumors (43, 44) . In these cases, is fact, indirect DA agoniat drugs appear to be ineffective (E .E . M"uller, A. Genazzani and S . Murru, unpublished results) . GONADOTROPINS Chronic administration of CB 154 to mature male rats does not affect baseline pituitary and plasma LH levels (21), a finding compatible with the ineffectiveness of DA agoniat drugs to alter gonadotropin secretion in man (59, 60). Instead, ergocornine and CB 154 aan block ovulation in immature rats treated with pregnant mare serum ganadotropin, an effect which is shared also by other DA agoniste e .g ., apomorphine and piribedil and is partially antagonized by DA receptor Mockers (61) . It has been suggested that the blockade of ovulation found after ergot drugs could be due to activation of DA receptors in the ME (58) which then inhibits the secretion of hypothalamic LH-RH (50) . The ability of ergot drugs to re-establish a cyclic LH-RH release in hyperprolactinemic states (see above) is not necessarily irreconciliable with their blockade of ovulation is immature rate . Conceivably, in the hyperprolactinemic states the suppressive action of ergot drugs on PRL secretion can override their intrinsic ability to block the LH-RH releasing mechanism. TSH Acute studies oa euthyroid subjects have disclosed neither an effect of CB 154 on basal TSH levels (62, 63) nor blockade of the TRH-TSH response,(63) . However, in 6 subjects with primary hypothyroidism acute administration of the drug waa followed by a significant decrease of serum TSH, with no consistent change in serum thyrozine and trüodothyronine (64) . The aforementioned observations, when viewed together with the inability of IrDOPA to alter TSH secretion in normal subjects (65) but its effectiveness to lower plasma TSH levels in hypothyroid subjects (66), suggest that the mechanism of action of CB 154 in suppressing the increased TSH secretion ie dopaminergic in nature . Whether a CNS or a pituitary site of action are involved is presently unknown . GROWTH HORMONE The clear-cut suppressive effect of CB 154 . and ergot drugs on PRL secretion in rodents is not accompanied by similar changes in the secretion of GH . Earlier studies (12) had shown that prolonged treatment of mice with CB 154 does not

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influence pituitary GH content; the addition of CB 154 to the GR3 strain of the rat pituitary tumor cells synthesizing both GH and PRI while suppressing PRL secretion, left the secretion of GH unaltered (67) . More recent studies in uaaneathetized rats have é~how that acute administration of CB 154 reduces, although not significantly, the puleatile release of GH (68) . Prolonged treatment with CB 154 for up to 5 weeks did not affect pituitary and plasma GH levels in rats, and acute or chronic administration of the drug was also usable to modify basal GH levels in hypophysectomized rats bearing a heterotopic pituitary (21) . With regard to the effect of CB 154 on GH secretion from the neoplastic pituitary, discrepant results have been reported so far . Gautvik et al . (67) were usable to observe any effect of CB 154 on GH secretion when added to rat pituitary tumor cells, whereas Quadri and Meites (69) reported direct suppression of GH secretion during chronic treatment with CB 154 in rats carrying MtT.WlS pituitary tumor transplants producing PRL and GH . The relevance of these findings in relation to the GH-lowering effect of ergot drugs in acromegalic subjects (see below) is obvious . Effect of CB 154 on hGH secretion . a. _Normal sub~eçt . The ability of ergot drugs and CB 15 to stimulate DA receptor sites is the CNS (54, 56, 58) is consistent with the effectiveness of CB 154 to stimulate GH release in man (70, 71), a species in which dopaminergic stimulation is associated with increased GH release (68) . Unlike L-DOPA, which induces a clear-cut and prompt rise (peak GH levels at 90 min), a single oral administration of CB 154 elicits only a small and delayed GH rise (peak levels 240-300 min) (Fig . 2, upper part) . Interestingly, the delayed neurceadocrine response after CB 154 correlates well with the latency of onset of the behavioral stimulation induced by CB 154 in rata with unilateral degeneration of nigro-striatal and mesolimbic DA neurone (61) . Evidence presented for the existence of a nigral-hypothalamic medial emi= nence dopamisergic pathway (72) provides an additional dimenaian to these findings . CB 154 appears to be a valuable tool for investigating the hypothalamic function in some deteriorating diseases of the CNS . In subjects with Huntington's chorea, acute CB 154 administration induced a more prompt and consistent GH rise than in controls ; instead, it was less effective in suppressing the elevated basal PRL levels in choreic than PRL levels of control subjects (73) . These findings suggest the ezfsteace in Huntingtos'a chorea of an abnormal regulation of GH and PRL secretion probablq due to alterations in central dopaminergic neurotransmission . b . AcromeQal9 . The positive GH response elicited by CB 154 in the normal subjects contrasts with its strong inhibitory effect on GH secretion in about 60x of acromegalic subjects (70, 71, 74) . It is apparent that the time-course of the GH-lowering effect of CB 154 in the "responder" acromegalics i .e ., subjects in whom a decrease of at least 50x below the basal values ié achieved, is almost the mirror image (GH nadir at 240-300 min) of the time-course of its GH stimulatory effect in the normal subject (Fig . 2, lower part) . Again the delayed asd long-lasting effect of CB 154 contrasts with the more prompt but short-lived inhibition induced by L-DOPA . It is of note that another DA mimetic drug e .g ., apomorphine, elicits in acromegalic subjects an inhibitory effect on GH secretion even shorter thaw that induced by L-DOPA (75) ; this recalls the fact that apomorphine, amongst DA agoniste, is capable of ônly a transient activation of eatrapyramidal DA receptor sites (61) . That dopamiaergic activation is responsible for the GH-lowering effect of CB 154 was supported by the fact that pimozide, a DA receptor Mocker, administered before CB 154, reduced the hGH lowering effect of the latter (76) . Although the mechanism of action of ergot drugs and dopaminergic compounds is lowering plasma GH levels in acromegaly i .e ., CNS vs pituitary action, has yet to be definitely proved, evidence so far presented makes it likely a di rect action on DA receptors located on somatotrophe (68, 71) . In favor of a pituitary site of action are : 1) the almost complete dissociation observed in

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FIG . 2 Upper part . Plasma hGH values (mean + SE) in 13 male sad female healthy subjects after administration of CB 154 (2 .5 mg po) or L-DOPA (500 mg po) . Lower part . Plasma hGH values in "responder'I acrbmegalic patiente after administration of CB 154 (2 .5 mg po) or L-DOPA (500 mg po) . Values are azpressed ae ratio of suppressed (3) to baseline (B) + SE, Number of patients in parentheses (Redrawn from Liuzzi etal . (71), by courtesy of Ezcerpta Medics) . the same patients between GH responses elicited by argot drugs and responses evoked by CNS-acting stimuli (e .g ., insulin hypoglycemia, arginiae infusion etc.) and, conversely, t~6e finding that combined application of CB 154 testing and administration of TRS (77), a stimulus which releases G8 by acting at the pituitary level (78), revealed most of the patients to be either responsive to both etimuli,or to none ; 2) the observation that DA, which does not cross the blood brain barrier and does not stimulate GH secretiom in the normal subjects, lowers GH levels when infused into responsive acromegalics (79) ; 3) the fact that the competence of a given dopaminergic compound to suppraes the release

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of GH from the tumorous or hyperplaetic pituitary appears to be related to its ability to stimulate DA receptors directly (68) . Indirect DA-mimetic drugs, whose action occurs mainly through pre-synaptically released DA, while active in releasing GH in the normal subjects (68), are ineffective to lower GH levels in acromegaly (68, 80) . Whatever their mechaniem(s) of action, ergot drugs and particularly CB 154, represent a new valid aad safe pharmacologic approach to the treatment of acromegaly (71, 74, 81) . In fact, long term administration of CB 154, besides sup pressing circulating GH levels, induces also marked clinical and metabolic improvements . Collectively, it appears that the selective suppressive effect of bromocryptine on GH (and PRL) levels, the rapidity of its action, its low toxicity make it particularly suitable for early mild acromegaly or for the large number of patients who show only a partial response to other forma of therapy . ACTH and MSH The information on the action of CB 154 and ergot derivatives on ACTH secretion is rather scanty . Studies in rats demonstrated that both ergotamine and CB 154 are capable on chronic treatment of stimulating ACTH secretion (82) . A reverse picture was present when ergotamine was administered to rats bearing an ACTH (and PRL)-secreting tumor, 7315 a; in this instance, in contrast to its stimulatory effect on the pituitary glands' secretion of ACTH in control rate, ergotamine decreased the elevated serum ACTH levels, without affecting pituitary ACTH concentration (82) . In man, preliminary data in patients with pituitary-dependent Cuehing'e syndrome (83) or Nelson's syndrome (84) demonstrated inhibition of the elevated plasma ACTH and cortiaol levels after acute administration of CB 154. In normal volunteers no difference was found with aad without bromocryptine in the unstimulated plasma ACTA levels, studied during the day . Similarly, the drug did not change the mammal increase of plasma ACTH after lysine-vasopressin administration (83) . Suppression of MSH secretion from the salamander "Ambyostoma tigrinum" has been reported following "in vivo" administration of Ec (85) . A single injection of Ec caused lightening of salamanders that persisted for about 11 days . The experiments did not reveal whether inhibition of MSH secretion was effectéd at the level of the hypothalamus or directly at the pituitary level. This problem was investigated in more recent studies, from which it appears that ergonovine, in low concentrations, inhibits MSH secretion from incubated frog, rat and mouse pituitary glands . The inhibitory effect was irreversible during the incubation period of the experiment and was blocked by dibenamine, an a(-adrenergic antagonist, and chlorpromazine (86) . The bulk of these data suggest that ergot alkaloids' action in blocking MSH secretion is mediated through the stimulation of adrenergic and/or DA receptors present in pare intermedia cells . Supporting this view is the finding that inhibition of MSH secretion from the frog or rat pituitary by catecholaminea, such ae NE, E and DA, was mediated through a( adrenergic receptors and/or DA receptors (87) . Table 1 lists the inhibitory or stimulatory actions on AP hormone secretion of ergot drugs, as derived from the experimental evidence above mentioned . Endocrine Effects of Ergoline Derivatives Apart from classic ergot drugs, whose complex aide chain complicates a synthetic approach to their availability, a new class of compounds is represented by ergoline derivatives . Chemically they derive from the ergoline nucleus of the ergot alkaloids and many are 9,10-dihydro-compounds . From the 6-methylergoline nucleus (Pig . 3, upper part), 6-methyl-8- substituted derivatives (6-methy1-8-~ -carboxamide, 6-methyl-8-formamide and 6-methyl-8-methyl ergolines) have been obtained (87), some of which (Fig . .3, lower part) are currently undergoing experimental and clinical trials for treatment of PRL and GH-dependent disor ders (22, 40, 89, 90) .

Vol . 21, No . 11, 197

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FIG. 3 Upper part . 6-methylergoliae nucl®us. Lower part . Chemical structura of some ergoline derivatives . From the data obtained so far, it appears that nrgoliaes are both a valuable tool for use in the study of PRL çontrol in animals and maa and promising agents in the treatment of hyperprolactinemic states . Metergoline has been used successfully to inhibit or suppress lactation in subjects with puerperal hyperprolactinemia (40) ; lnrgotrile was fouad as potent as Ec in reducing serum PRL levels "in vivo" is the rat (91) and active also to inhibit PRL secretion is men (89) . Lisuride hydrogen maleate, a derivative of isolyeergic acid, proved also to be highly effective ae PRL suppressor in various hyperprolactinemic states of the rat (22, 92) . A problem which has to be clarified for some of these compounds is that of the true mechanisms) and hence site s) of action of their endocrine effects . Even though ergot drugs and ergolines seem to affect predominantly DA receptors in the CNS and/or the pituitary (see above and 93, 94), they are also capable to influence NE and 5-HT receptors in the CNS or in the periphery (95-97) . For

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inataace, MCS has been originally proposed as a highly potent, long-lasting and selective antagonist of both central and peripheral 5-HT receptors (98100) . In keeping with a central anti-S-HT effect for MCS vas the finding that in the dog,simili~ly to p-chlorophenylalanine, a Mocker of 5-HT biosynthesis (101), MCE vas effective in potentiating hypoglycemia-induced GH release (71, 102) . Ia man, MCS vas capable of partially inhibiting the increased ACTH release iii~ich follows administration of metyrapone (103) or the insulin stimulus (104) . On recalling the stimulatory action of 5-HT on ACTH secretion (3),theae data also favored the idea of an anti-S-HT effect of NdCE . However, is subjects with active acromagaly, who were responsive to CB 154, administration of MCE lad to an inhibition of the elevated GH sad PRL levels almost superimposable to that elicited by CB 154 ; in addition, its suppressive effect an GH sad PRL, as that of CH 154,'vas counteracted by prntreating patients with pimoside (90) . Thus, added to an 5-HT receptor blockade (98-100), a dopaminergic mechanism of action was proposed for this drug, at least based on the findings obtained in the acromegalic subjects (90) . Conclusions

It appears from the fotegoing data that ergot drugs are both as useful tool for use in the study of neuromdocrine control of pituitary hormone aecretion sad a valid phatmscologic weapon for the suppression of puerperal lac tation, the treatment of pathologic hyperprolactinemia, of GH and, probably, of ACTH and .MSH hyperaecretion . They are capable of a long-lasting disruption of PRL secretion from a normal or tumoroua pituitary gland, are unable to affect directly aomatotropha of an intact AP but stimulate GH release in man through as action emerted as the CNS. They inhibit GH sad, probably, ACTH secretion from a hyperplastic or tumoroua AP gland. The mechanism whereby ergot drugs ' affect AP hormone secretion appears to be the stimulation of DA receptor sites in the .AP gland or in the CNS. Ergoli~s also exert marked PRL-lowering affects and are capable of .suppressiag GH secretion in acromegaly . Their intimate mechanisms) snd hence site (s) of action await clarification . References

1 . S. REICHLIN, R . SAPSRSTEIN, LM.D . JACKSON, A.S . BOYD III, and Y . PATSL, Ann. Rev . Physiol . 38 389-424 (1976) . 2 . S .M. McCANN, and R.L. M03S, Life Sci . 16 833-852 (1975) . 3 . S .E . MÔLLSR, G. NISTICO', and D. SCAPAGtiII~I, Neurotransmitters and Anterior Pituitary Function, Academic Press, Nav York, (1977) . 4 . L.A . FROH!lAN, and M.S . STACHURA, Mstaboliem 24 211-234 (1975) . 5 . M.C . SHSLESNYAR,Am. J . Physiol . 179 301-3041954) . 6 . M.C . SHSLESNYAtC, Acta Endocrinol~Kbh .) 23 151-157 (1956) . 7 . H.R . LINDNER, and M.C . SBBIESNYAR, Acta Sndocrinol . (Kbh .) _56 27-34 (1967) . 8. M.C . SHBLSSNYAK, Acta Sndocrinol . (Kbh .) 27 99-105 (1958) . 9 . S .S . KISCA, and M.C . 3HSLSSNYAH, J . Reprod. Fert . 15 401-407 (1968) . 10 . W. WUTT10;, S . CASSSL, and J. MBITSS, Sadocrinology SS 737-741 (1971) . 11 . H. NAGASAWA, and J . MBITES, Proc . . Soc . Ezp. Biol . Mew. 135 469-472 (1970) : 12 . R. YANAI, and H. NAGASAÜA, Szparientia 26 649-650 (197T 13 . E. FLi1CKIGSB, sad H.R . WAGNER, S:periant~a 24 1130-1131 (1968) . 14 . E . FLITCKIGSR, in "Prolactin and Carcinogena~s A.R . Boyns and K. Griffiths (eds .), pp " 162-171; Alpha Omega Alpha, Cardiff (1972) . 15 . G.D . NISWENDER, Biol . Reptoduct. 7 138-139 (1972) . 16 . H. KARG, D. SCRAMS, and V. RSIIQHARDT, Szperieatia 28 . 574-576 (1972) . 17 . P.M. LDTTSRBECK, J .S . PRYOR, L. VARGA, and R. WSRNBR, Brit . Med. J . 3 228229 (1971) . 18 . S. DEL POZO, R. BRDN DSL RS, L. VARGA, and H. FRISSSN, J. Clin . Sndocrinol . Matab. . 35 768-771 (1972) . 19 . H. NAGASAWA, R . YANAI, and E . FLDCKIGER, in "Human Prolactin" J .L . Pasteele

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Ergot and Pituitary Hormoaea

Vol . 21, No . 11, 1977

and C . Robyn (ede .), pp . 313-315; Eacerpta Medics, Amsterdam (1973) . 1077-1085 (1974) . 20 . R.M . McLEOD, and J.E . LEHEMEYER, Endocrinology 94 21 . E.E . MÖLLER, D . COCCHI, A.E . PANERAI, I. GIL-AD, V. LOCATSLLI, and P. MANTEGAZZA, Pharmacology, in press . 22 . R.-J. GRÄF, F. NEiJ!lANN, and R. ROROWSRI, Endocrinology 98 598-605 (1976) . 23 . D. SCRAMS, V. REINHARDT, and H. RARG, Experientia 28 697-699 (1972) . 24 . C .S . NICOLL, in "The Pituitary Gland and its Neuroéadocrine Control" E . Rnobil and W.R . Sawyer (eda .), pp . 253-292; American Physiological Society, Washington (1974) . 25 . J.C . TAYLOR, and M. PEAKSR, J. Endocr . 67 .313-314 (1967) . 26 . J . FORTH, in "Human Prolactin" J .L . Pasteels and C. Robya (eda .), pp . 233248; Excerpts Medics, Amsterdam (1973) . 27 . R. YANAI, and H. NAGASAWA, J . nat. Cancer Inst . 48 715-719 (1972) . 28 . S .R . QUADRI, and J. MEITES, Proc . Soc . Exp. Biol.Med. 13 8 999-1001 (1971) . 29 . H. STAHLLIN, B . BURCRHARDT-VISCHSR, and E. FLÜCRIGER, Experientia _27 915916 (1971) . 30 . E .E . CASSELL, J. MEITES, and C.W . WELSCH, Cancer Res . 31 1051-1053 (1971) . 31 . J .R . HOBBS, H. SALIR, H . FLAB, and W. BRANDER, in "Human Prolactin" J.L . Pasteels and C . Robyn (eds .), pp . 249-258; Egcerpta Medics, Amsterdam (1973) . 32 . R.-D. SCHULZ, P.-J. CZYGAN, E. DEL POZO, sad H.G . FRIESEN, in "Human Prolactin" J.L . Pasteels sad C. Robyn (eds .), pp . 268-271 ; Excerpts Medics, Amsterdam (1973) . 33 . J .C . HEUBON, A. COULAS, and M. STAQUET, Europ. J. Cancer 8 155-156 (1972) . 34 . P .G . GUSRZON, and O .H . PEARSON, Clin . Res. 22 632A (1974j. 35 . R.-H. LU, Y. ROCK, and J. MEITES, Endocrinology 89 229-233 (1971) . 36 . S .R . QUADRI, R .-H . LU, and J . MEITES, Science 176 417-418 (1972) . 37 . R.M . McLEOD, H . RI!lIiRA, and I . IAGIN, in "GrowthHormone and Related Peptides" A. Pecile and E .E . lYiuller (ede .), pp . 443-453; Excerpts Medics, Amsterdam (1976) . 38 . L . VARGA, P . LUTTERBECR, J .S . PRYOR, R. WENNER, and H. ERB, Brit . Med. J . 2 743-744 (1972) . 39 . R. BRUN DEL RE, E . DEL POZO, P. DE GRANDI, H . PRIESEN, M. HINSELMANN, and A. WYSS, Obstet . Gynec. 41 884-890 (1973) . 40 . R. ROLLAND, F.R . DE JONG,L. A. SCHELLERENS, and R.M. LEQUIN, Clin . Endocrinol . 4 27-38 (1975) . 41 . P .G . CROSIGNANI, M. PERACCHI, A. D'ALBERTON, G. C. LOMBROSO, L . TROJSI, G. CAMMARERI, A. CACCAMO, A. ATTANASIO, and E. RESCHINI, in "Prolactin and Human Reproduction" P.G . Crosignani (ad.), Academic Press, New York, in press . 42 . S . WALKER, B. M. HIBBAUD, G. GROOM, R. GRIFFITHS, and R.H . DAVIES, Lancet II 842-845 (1975) . 43 . S . FRANKS, and H.S . JACOBS, .in "Prolactin and Human Reproduction" P .G . Crosignani (ed .), Academic Press, New York, in press . 44 . G.M . HESSER, L . PARKS, C.R .W . EDWARDS, I .A . FORSYTH, and A.S . McNEILLY, Brit . Med. J. 3 669-672 (1972) . 45 . G. COPINSCHI, M. L'HERMiTE, J.L . PASTEELS, AND C. ROBYN, in "Hormones sad Antagonists" P .O . Hubinot, S .M . Hendels, sad P . Preumoat (ede .), pp . 128129 ; S. Rarger, Basel (1972) . 46 . M.O . THORNSR, and G.M . BESSER, in "Prolactin sad Human Reproduction" P .G . Crosignani (ed .) ; Academic Press, New York, in press . 47 . R.M . BOYAR, S. RAPEN, J .W . FINRELSTEIN, M. PERLOW, J.F . BASSIN, D.R . PURUSHIMA, E .D . WIETZMAN, and L . HELLMAN, J . Clin . Invest . _53 . 9a . .( .1974) . 48 . A.G . BONNET, H.G . DAHLEN, W . WUTTRE, and H.P .G . SCHNEIDER, J. Clin . Endocrinol . Metab. 42 132-143 (1976) . 49 . T . ASKFELT, andK. FURS, Neurcendocrinology 9 100-122 (1972) . 50 . K . FIIRE, T, .HinCpELT, G . JONSSON, and A. LOFSTROwi, in "Neurosecretion - The Final Neuroendocrine Pathway" F . Knowles and L. Vollrath (eds .), pp . 269-

Vol . 21, No . 11, 1977

Ergot and Pituitary Hormones

155 7

284 ; Springer-Verlag, Berlin (1973) . 51 . R . MANECRJEE, B .R . SRINATH, and N . R. MOUDGAL, Nature 262 507-508 (1976) . 52 . R .P . McNATTY, R .S . SAWERS, and A. S . McNEILLY, Nature 250 653-655 (1974) . 53 . M. SEPPÄLA, H .-A. Uli~ERUS, E . HIRVONEN, and T . RANTA,J . Clin . Eadocrinol . Metab . 43 474-477 (1976) . 54 . H . CORRODI, R . FUSB, T . HÖRFELT, P . LIDBRINR, and U . IINGERSTEDT, J . Pharm . Pharmacol . 25 409-412 (1973) . 55 . A .M. JOHNSON, J . M. VIGOIIRET, and D .M. LOEW, Eaperientia _27 763 (1973) . 56 . A .J .J . PIJNENBURG, G .N . WOODRUFF, and J . M . VAN ROSSUM, Hrain Res . _59 289309 (1973) . 57 . A .A . VAN DER GUGTEN, P .C . SAHIILERA, G .H . VAN GALEN, and H .G . RWA, J . Endocr . 68 369-381 (1976) . 58 . T . HÖRFELT, and R . FIII~, in "Brain Endocrine Interaction . Median Eminence : Structure and Function" R .M . Rnigge, D .E . Scott, and A . Weindl (ede .), pp . 181-223 ; Rarger, Hasel (1972) . 59 . R .L . EDDY, A .L . JONES, Z .H . CHARMARJIAN, and M.C . SILVERTHORNE, J . Clin . Eadocrinol . Metab . 3 3 709-712 (1971) . 60 . A . RAYER, and J .D . CRAWFORD, J . Clin . Eadocrinol . Metab . 3 4 764-766 (1972) . 61 . R . FUGE, L .F . AGNATI, H . CORRODI, B .J . SVERITT, T . HÔRFSLT, A . LOFSTROM, and U . IINGERSTEDT, in "Advances in Neurology, Vol . 9" D . Calve, T .N . Chase and A . Barbeau (eds .), pp . 223-242 ; Raven Preas, New York (1975) . 62 . E . DEL POZO, H . FRIESEN, and P . BURMEISTER, Schwein . med . Wschr . _103 847848 (1973) . 63 . E . HIRVONEN, T . RANTA, and M . SEPPÄLX, J . Clin . Eadocrinol . Metab . _42 10241030 (1976) . 64 . R . MIYAI, T . ONISHI, M. HOSORAWA, R . ISHIBASHI, and Y . RUMAHARA, J . Clin . Eadocrinol . Metab . 3 9 391-394 (1974) . 65 . G .N . BDRROW, S .R . SPAULDING, R . DONABEDLAN, M . VAN VOSRT, and M .L . AMBANI, in "Advances in Neurology, Vol . 5" F . McDowell and A . Barbeau (eda .), pp . 489-493 ; Raven Preas, New York (1974) . 66 . M . MINOZZI, M . FAGGIANO, G . LOMBARDI, G . CARELLA, T . CRISCIIOLO, and II . SCAPAGNINI, Neuroendocriaology 17 147-153 (1975) . 67 . R . M . GAUTVIR, R .F . HOYT JR ., and A.H . TASHJIAN, J . Cell Physiol . _82 401410 (1973) . 68 . E .E . MÜLLER, A . LIUZZI, D . COCCHI, A .E . PANERAI, G . OPPIZZI, V . LOCATELLI, P . MANTSGAZZA, F . SILVESTRINI, and P .G . CHIODINI,ia "aldvancee in Biochemical Psychopharmacology, Vol . 16",E . Costa and G .L . Geasa (eds .), pp . 127138 ; Raven Press, New York (1977) . 69 . S .R . QIIADRI, and J . MSITES, Proc . Soc . Eap . Biol . Med . 14 2 837-841 (1973). 70 . F . CAMANNI, F . MASSARA, L . BELFORTE, and G .M . MOLINATTI,J. Clin . Eadocrinol . Metab . 40 363-366 (1975) . 71 . A . LIIIZZI, A.E . PANERAI, P .G . CHIODINI, C . SECCHI, D . COCCHI, L . BOTALLA, F . SILVESTRINI, and E .E . MÜLLER, in "Growth Hormone and Related Peptides", A . Pecile and S .E . Filler (eds .), pp . 236-251 ; Eacerpta Medics, Amsterdam (1976) . 72 . J .S . RIZER, M. PALROVITS, and M .J . BROWNSTEIN, Brain Rea . 108 363-370 (1976) . 73 . T . CARACENI, A .S . PANERAI, E .A . PARATI, D . COCCHI, and E .E . MÜLLER, J . Clin . Eadocrinol . Metab ., in press . 74 . M .O . THORNER, A . CHAIT, M . AITRSN, G . BENRER, S .M . BLOOM, C .H . MORTIMER, P . SANDERS, A . STIIART-MASON, and G . M . BESSER, Brit . Med . J . 1 299-303 (1975) . 75 . P .G . CHIODINI, A . LIIIZZI, L . BOTALLA, G . CRSMASCOLI, and F . SILVESTRINI, J . Clin . Eadocrinol . Metab . 38 200-206 (1974) . 76 . S .E . MÜLLER, I . GIL-AD, A .E . PANERAI, C . SSCCHI, A . LIUZZI, P .G. CHIODINI, and F . SILVESTRINI, in "Basic Applications and Clinical Uses of Hypothalamic Hormones" A .L . Charro-Salgado, R. Fernandez-Durango and G . Lopez del Campp (eda .), pp . 211-231 ; Eacerpta Medics, Amsterdam (1976) .

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77 . A . LIUZZI, P .G . CHIODIIiI, L . BOTALLA, F . SILVESTRINI, and E .B . MÜLLER, J . Clin . Endocrinol . Metab . 3 9 871-876 (1974) . 78 . G . UDESCHINI, D . COCCHI, l~ .E . PANERAI, I . GIL-AD, G .L . ROSSI, P :G . CHIODINI, A . LIUZZI, and E .E . MÜLLER, Endocrinology 98 807-814 (1976) . 79 . G . VERDE, G . OPPIZZI, G . COLUSSI, G . CREMA8COLI, L . BOTALhA, E .E . MÛId.ER, F . SILVESTRINI, P .G . CHIODINI, and A . LIUZZI, Clin . Endocrinol . _5 419-422 (1976) . 80 . F . CAMANNI, F . MASSARA, V . FASSIO, G .M. I~LINATTI, and E .E . MÜLLER, Neuroendocriaology 19 227-240 (1975) . 81 . Y . SACHDEV, W.M .G . TURNBRIDGE, R.D . WSIGHTMANN, A. GOMEZ-PAN, A . DUNS, and R . HALL, Lancet II 1164-1168 (1975) . 82 . R .M . McLEOD, andD.T. KRIEGER, 58th Ann . MOet . Endocr . Soc . S . Francisco, Abs . 317 (1976) . 83 . S .W .J . LAMBERTS, and J .C . BIRKENHXGER, J . Endocr . 70 315-316 (1976) . 84 . S .W .J . LAMBERTS, and J .C . BIRKENHI(GE$, Lancet II 811 (1976) . 85 . J .E . PLATT, and D .O . NORRIS, J . ezp . Zool . 1897-12 (1974) . 86 . C .M . AiORGAN, and M .S . HADLEY, Neuroendocrinology 21 10-19 (1976) . 87 . A . BOWER, M .B . HADLEY, end V .J . HRUBY, Science (N .Y .) 184 70-72 (1974) . 88 . M .J . SWSENEY, G .A . POORS, E .C . KORHFSLD, N .J . BACH, N .V .OWEN, and J .A . CLEè~NS, Cancer Res . 35 106-109 (1975) . 89 . L . LEMBERGER, R . CBABTREE, J . CLE?~NS, R .W . DYKE, and R . T . WOODBRUN, J . Clin . Endocrinol . Metab . 39 579-584 (1974) . 90 . P .G . CHIODINI, A . LIUZZI,É .E . MÜLLER, L . BOTALLA, G . CRSMASCOLI, G . OPPIZZI, G . VERDE, and F . SILVESTRINI, J . Clin . Endocrinol . Metab . _43 356363 (1976) . 91 . J .A . CLEMBNS, C .J . SHAAR, E .B . SMALSTIG, N .J . BACH, and E .C . KORNFELD, Endocrinology 94 1171-1176 (1974) . 92 . R . HOROWSKI, and K .-J . GRXF, Neuroendocrinology, in press . 93 . J .A . CLEMENS, E .B . SMALSTIG, and C .J . SHAAR, Acta Endocrinol . (Kbh .) _79 230-237 (1975) . 94 . R . HOROFTSRI, and H . WATCHSL, Europ . J . Pharmacol . 36 373-383 (1976) . 95 . H . CORRODI, L .-0 . PARNEBO, K . FU7~, and B . HAMBERGEâ, Europ . J . Pharmacol . 30 172-181 (1975) . 96 . 2. VOTAVA, and I . LAMPLOVA, in "Neuropharmacology", vol . II, E . Rothlin (ed .), pp . 68-73 ; Elsevier, Amsterdam (1961) . 97 . W . KSHR, Europ . J . Pharmacol ., in press . 98 . C . BERETTA, R . FERRINI, and A . GLX83ER, Nature (Load .) 207 421-422 (1965 99 . R . FSRRINI, and A . GLXSSER, Peychopharmacologia (Bert .)8 271-276 (1965) . 100 . K . FUSE, L . AGNATI, and B . EVERITT, Neurosci . Lett . 1 283-290 (1975) . 101 . B .R . KOE, and A . WSISSMAN, J . Pharmacol . Ezp . Therap. 15 4 499-516 (1966) . 102 . E .E . MÜhLSR, G . UDESCHINI, C . SECCHI, F . ZAMBOTTI, A .EPANERAI, . L . VICEN TINI, F . COCOLA, and P . MANTEGAZZA, Acta Endocrinol . (Rbh .) _82 71-91 (1976) . 103 . F . CAVAGNINI, A .E . PANERAI, F . VALENTI, P . BULGHERONI, M . PERACCHI, and M . PINTO, J . Clin . Endocrinol . Metab . 4 1 143-148 (1975) . 104 . F . CAVAGNINI, ..U . RAGGI, P . MICOSSI,Â. DI LANDRO, and C . INVITTI, J . Clin . Endocrinol . Metab . 4 3 306-312 (1976) .