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Control of prolactin secretion in the vertebrates—A comparative survey
Gen Pharmac Vol 15, No 3, pp 189-195, 1984 Printed m Great Britain All rights reserved
0306-3623/84 $300+000 Copyright © 1984Pergamon Press Ltd
MINIREVIEW CONTROL OF PROLACTIN SECRETION IN THE VERTEBRATES--A COMPARATIVE SURVEY T R HALL* Department of Pure & Apphed Zoology, The Umversity of Leeds, Leeds LS2 9JT, U K (Tel 0532-431751) 13 July 1983)
(Recewed
INTRODUCTION
l AUTONOMOUS RELEASE
The science of neuroendocrinology has been growing at a seemingly exponential rate since the discovery by Harris (1955) that the hypothalamus appears to elaborate specific chemical factors that stimulate or inhibit secretion of pituitary gland hormones This hypothesis was convincingly vahdated when the research groups of Schally and Gulllemin isolated several of these factors, beginning with the trIpeptlde thyrotrophln releasing hormone (TRH) (Tixler-Vadal and Gourdj1, 1981) Similar hormones have been detected in the central nervous systems of nonmammalian vertebrates (Jackson, 1979) More recently, neuroendocrmologIsts have concentrated on the mechamsms governing the control of secretion of the hypothalamlc hormones In mammals, recent reviews (see Fuxe e t a l , 1979) imphcate a varxety of neurotransmltters and neuromodulators in this process and suggest that physiological changes in hormone secretion may be a consequence of altered neurotransmltter metabohsm However, only a handful of the many putative transmitters have been examined in detail, mainly in mammals The little ewdence available shows that s~milar mechanisms operate in non-mammahan species A number of reviews have been published during the past dozen years that cover certain aspects of the control of pituitary function in vertebrates (Dodd e t a l , 1971, Holmes and Ball, 1974, Ensor, 1978, Mazzl, 1980, Ball, 1981) The purpose of this review is to integrate recently-published information on central mechanlslms governing the secretion of prolactln from the vertebrate pltmtary gland These mechanisms appear to involve interactions at various levels, the pituitary gland ltsself may possess some degree of autonomy, hormone release from the pituitary gland is modulated by hypothalamxc releasing and inhibiting hormones, secretion of the hypothalamic hormones is modified by neurotransmitters/neuromodulators, and activity of this system alters in response to various interoceptwe and exteroceptwe influences (Chadwick and Hall, 1983)
When the mammalian pituitary gland is removed from hypothalamic influence by autotransplantatlon, destruction of the mediobasal hypothalamus, pituitary stalk section or by m v i t r o culture, there is a prompt and sustained increase m prolactm secretion that involves d e n o v o synthesis in addition to elevated release of the hormone The magnitude of the response IS dependent upon age, sex, physiological condition and species employed (Mextes, 1978, Weiner and Ganong, 1978) The avian pituitary gland also shows some autonomy of function which is species-dependent Whereas duck pituitary shows many signs of secretory activity a considerable time after autotransplantation or tn v i t r o culture, pigeon prolactin cells are much less active, and chicken and quail lactotrophs rapidly degenerate when removed from hypothalamlc influence (Tixler-Vldal and Gourdji, 1972, Chadwick and Hall, 1983) Reptile pituitaries are also capable of releasing prolactln m w t r o for up to 24 h (Hall and Chadwick, 1979, Fxorlndo, 1980) and m one species at least for up to l0 days (Ensor, 1978) The amphibian pituitary gland may also show some autonomous function Prolactm cell activity remains high followmg autotransplantatIon Ectopic transplants induce precocious second metamorphosis in urodeles and sustain level growth and inhibit metamorphosis in anurans, Indicating high prolactm secretion Relatively large amounts of prolactln are secreted by pituitaries of some anuran and urodele species tn v i t r o (Ensor, 1978, Hall and Chadwick, 1979) Prolactln secretion from teleost pituitaries shows perhaps the highest degree of autonomy, and in some species considerable quantities of the hormone may be secreted m v i t r o (Hall and Chadwick, 1978, 1979, Ball, 1981)
*Present address Wolfson Institute, Umverslty of Hull, Hull HU6 7RX (Tel 0482-497067)
2 HYPOTHALAMICPEPTIDES Crude extracts of mammalian hypothalami usually possess prolactin inhibiting activity zn v i t r o and m v w o However it is suspected that these hypothalami also contain a prolactm releasing hormone The prolactin inhibiting hormone may be dopamine (see below), but the identity of the releasing hormone is not known TRH stimulates release of prolactin tn v t t r o and also m v w o under certain con&tions (e g
189
190
T
R
HALL
Table 1 Effects of hypothalamlc neurotransmltters and pepndes on prolactln secrenon Mammals Transmitters Dopamme Noradrenahne Serotonln Acetylchohne Histamine GABA Peptldes TRH Endorphms VIP Substance P Tetragastrm Neurotensln Bombesm Alatensm
B~rds
P~tmtary
Hypothalamus
Pttmtary
Hypothalamus
,~
(,,)
,~
,L
-({)
T ,t ~(Ht) ,L(H2) T(low E2){(high E2)
(D --(,L)
T t ~(Ht) ,~
T (D
-(?) (?)
7
(T} T (T) (T)
~
NT NT NT NT
NT NT NT NT
T
(D t --
{ T
$ --
Key
PItmtary~dlrect effect on pituitary, Hypothalamus--effect on releaslng/mhlbmng hormone, " increases PRL, ,L decreases PRL, - - no change, NT not tested, ( ) conjectural or unconfirmed response Data derived from McCann et al (1979),Tlxlcr-V1daland Gourdjl (1981), Harvey e~ al (1982),Chadwlck and Hall (1983) and unpubhshed ,nformatmn from our laboratory
following oestrogen priming) However it is hkely that other prolactIn releasing influences are also present in the mammalian hypothalamus, since there are many physiological states where prolactln secretlon is divorced from TSH secretion (e g heat and cold stress, suckhng stimulus) (Meates, 1977) Several other peptldes, found in high concentrations in the hypothalamus and median eminence, have direct or indirect effects on prolactln secretion, though their physiological functions are not known These include the endorphins, which interact with the dopamlnerglc and serotoninerglc systems (see below) to stimulate prolactln (Meltes e t a l , 1979) and a variety of gastrointestinal (vasoactlve intestinal polypeptide (VIP), tetragastrln, substance P, neurotensln) and amphibian skin-derived (bombesln, alatensin) peptides, whose affects are summarized in Table 1 Avian hypothalamt show pronounced prolactln stimulating activity m v i t r o and tn v w o i n short-term and long-term experiments (Hall and Chadwick, 1979, 1983a, Harvey e t a l , 1982, Chadwick and Hall, 1983) Interestingly, as in mammals TRH stimulates release of prolactin tn w t r o , but only sporadically m v w o (Hall e t a l , 1975, Harvey e t a l , 1978, Chadwick and Hall, 1983) It is unlikely that T R H is the only prolactln-stlmulatlng agent in the avian hypothalamus (Hall and Chadwick, 1983a) We have been testing other peptldes known to affect prolactln in mammals (Hall and Chadwick, manuscript in preparation) Endorphms stimulate prolactln vla a hypothalamIc mechanism, whereas VIP and substance P both stimulate prolactm release directly from the pituitary, though only from oestrogen-prlmed pituitaries in the case of substance P These peptldes may also stimulate release of prolactln releasing hormone from the hypothalamus There is some evidence for the existence of a prolactln inhibiting hormone (Chadwick and Hall, 1983), which may be dopamine (see below) Table 1 summarizes these responses Reptile and amphibian hypothalamlc extracts also stimulate release of prolactln from pituitaries m v i t r o , though only few species have been investigated (Hall and Chadwick, 1978, 1979, Florlndo, 1980) There is some evidence for an amphibian prolactln inhibiting
hormone that appears during part of the annual cycle (Kuhn and Engelen, 1976) In anuran tadpoles hypothalamlc connections are undeveloped and prolactm secretion may be autonomous, but during prometamorphosls the hypothalamus presumably takes mcreasing control of pituitary function (Ensor, 1978) TRH stimulates release of prolactln from pituitaries of several chelonian and anuran species m v i t r o , but not apparently from urodele pituitaries (Hall e t a l , 1978, Clemons e t a l , 1979, Ball, 1981, Hall and Chadwick, 1984b) It is generally considered that teleost prolactln secretion is relatively independent, but may be influenced by a hypothalamxc inhibitory hormone m most species (Ball, 1981) In a few species hypothalamlc extracts stimulate release of prolactln (Hall and Chadwick, 1978, 1979) Whether inhibitory or stimulatory mfluences are found may depend upon the physiological state of the animal, the time of the year and even the method of assay employed (Hall and Chadwick, 1979) The effects of TRH on secretion of prolactln are contradictory, with inhibition In S a r o t h e r o d o n and stimulation in P o e c l h a (Ball, 1981) Hall and Chadwick (1983b) found stimulation of eel prolactin by T R H m v i t r o Urotensm II inhibits prolactln release in v i t r o (see Ball, 1981) Apparently other peptldes have not been tested for their effects on prolactin secretion in teleosts 3 H Y P O T H A L A M I C NEUROTRANSMITTERS (l) Dopamme
It is generally agreed that dopamxne is the major prolactln mhibitory agent of the mammalian hypothalamus Dopamlne and its agonists dopa, apomorphine, ergot drugs (bromocryptine, lergotrlle, etc ), plrlbedll and hsurlde inhibit prolacttn release from pituitaries m v i t r o and reduce basal levels as well as stress, TRH, pro-oestrus, suckhng and drugmduced secretion of prolactin in VlVO Dopamlne antagonists (plmozlde, haloperidol, chlorpromazlne, perphenazine, sulplrtde, etc ) reverse the effects of dopamine agonlsts, and also stimulate prolactln In v w o when given alone, indicating a tonic dopamlnerglc inhibition of secretion of prolactln Depletion of
Control of prolactln secretion dopamlne, either by tyroslne hydroxylase inhibition (~-methyl-para-tyroslne, AMPT), by storage granule disruption (reserpine) or by inhibition of aromaticL-amino acid decarboxylase (benserazide) also increase prolactm DopamIne levels in pituitary stalk plasma have been found to vary in a manner consistent with patterns of prolactln secretion, suggesting a physiological role for dopamIne in prolactin regulatmn (Welner and Ganong, 1978, Fuxe et al 1979) The effects of dopamlne on prolactin secretion in birds have been investigated recently In vtvo administration of dopamlne antagonists to pigeons activates prolactln cells and produces crop sac stimulation (Nlstico et a l , 1979, 1980a) and AMPT, plmozide, phenoxybenzamlne and reserpine all stimulate prolactln in vwo in the fowl (Scanes et a l , 1982), indicating a tonic dopamlnerglc prolactln inhibitory mechanism In vitro administration of dopamine and agomsts inhibits release of prolactln (Harvey et a l , 1982), though responses are more pronounced when prolactln release IS stimulated with TRH or hypothalamus (Hall, 1982, Hall and Chadwick, 1983a, Hall et a l , 1984a) or with oestrogen pretreatment (Hall et a l , 1984d) In recent experiments (manuscript in preparation) we have found that dopamlne also inhibits release of prolactln releasing activity from fowl hypothalaml, whereas plmozlde enhances the release of the hypothalamlc factor m vitro These results contrast with those of Nakajo and Sato (1981), who found little or no effect of dopamlne on prolactln release from fowl pituitaries, though they used the less-sensitive polyacrylamlde gel electrophoretlc assay procedure Dopamlne may also be a prolactln inhibiting hormone in amphibia and reptiles Catecholamlne fibres are present In the hypothalamus of anurans and urodeles, with high activity in winter and low activity during the breeding season (Ensor, 1981) Bromocryptlne blocks prolactln secretion m vwo in the newt Dopamxne inhibits the release of growthpromoting hormone (prolactln) from pituitaries of Bufo species (Mazzl, 1980, Ball, 1981) Sekl and Klkuyama (1982) showed that dopamlne and bromocryptlne inhibit release of newly synthesized prolactln from bullfrog pituitaries in vitro, an effect reversed by halopendol and plmozlde We have found that dopamlne inhibits TRH and hypothalamus-stlmulated release of prolactln from various amphibian and reptile pituitaries m vitro (Hall and Chadwick, 1984b) Dopamine is also a prolactin-inhlbitlng agent in teleosts Destruction of the type B amlnergic fibres with 6-hydroxydopamme activates prolactln cells in Tdapta L-dopa and ergocryptlne inhibit prolactln secretion in the eel, and bromocryptme reduces prolactln functmn in Poectha m vwo Incubatmn of pituitaries of several species with dopamlnergic drugs showed that dopamine acts directly on the pituitary gland to inhibit prolactln, and this mechanism is separate from the osmotic control mechanism (see below) (Ensor, 1978, Ball, 1981) (n ) Noradrenahne
Noradrenahne in vitro lnh~b~ts release of prolactm directly from the mammalian pituitary gland, though this may be due to an interaction with dopamxnergic
191
receptors The amine may have also a central stimulating role, since dehydroxyphenylserine (DOPS), which may be converted to noradrenallne in the brain, stimulates prolactin, as does the ~-adrenerglc agonlst clonldine in some circumstances In addition, the or-antagonist phentolamlne blocks diurnal oestrogen-lnduced prolactln surges (Weiner and Ganong, 1978, McCann et a l , 1979) In birds noradrenaline appears to be a potent stimulator of prolactln release m vitro It may have direct stlmulatory activity at the pituitary, but its major effect is to stimulate secretion of prolactln releasing hormone (Harvey et a l , 1982, Chadwick and Hall, 1983, Hall et a l , 1984a) Apparently the effects of noradrenallne on prolactin secretion have not been examined in other vertebrates (ut ) Serotomn
Prolactln secretion in mammals is stimulated by serotonin and Its agonlst qulpazlne, and there is some evidence that the amine stimulates prolactln releasing hormone rather than, or in addition to, inhibiting prolactln inhibiting hormone The precursor of serotonln, tryptophan and 5-hydroxytryptophan, stimulate prolactin, especially If their effects are potentiated by presynaptlc reuptake blockers such as tncycllc antidepressants (e g lmlpramlne) or fluoxetine The tryptophan hydroxylase inhibitor p a r a - c h l o r a p h e n y l a l a n m e (pCPA) and the receptor antagonists methyserglde and cyproheptidlne reverse these effects and reduce basal prolactln Prevention of serotonin metabohsm by Inactivation of monoamine oxldase (e g with pargyhne) increases prolactln, as does stimulation of serotonln turnover by electrical stimulation of the mldbraln raphe region (Clemens et a l , 1977, Weiner and Ganong, 1978, Advis et a l , 1979) In birds also, serotonln is a potent prolactln stimulating agent whose major effects are probably mediated at the hypothalamic level In vitro serotonin and qulpazlne stimulate prolactln release in pituitaryhypothalamus co-incubations, effects reversed by methyserglde (Hall, 1982, Hall et a l , 1984b) In vwo serotonlnerglc drugs (tryptophan, together with imlpramlne, 5-hydroxytryptophan, qulpazlne) stimulate prolactln cell activity and induce crop sac responses in pigeons, and elevate plasma prolactln In fowl Methysergade may reduce plasma prolactln, and methyserglde and cyproheptidlne block responses to serotonin agonlsts (NlStlCO et a l , 1980b, Rabli et a l , 1981, Scanes et a l , 1982, Hall et a l , 1983a,b) Pargyhne and other MAO inhlbltors (tranylcypromine, nialamlde, clorgyhne) also increase prolactln as consequence of elevated serotomn availability (Hall et a l , 1984f) Some aspects of the serotonlnerglc regulation of prolactln secretion in amphibia and teleosts have been reported Uruefia and Hall (1983) showed that pargyhne and L-tryptophan administration, both of which increased serotonin content of the hypothalamus, also increased pituitary concentration of prolactm whereas p C P A reduced serotonm and prolactm, In the grassfrog Rana plptens Similarly Olcese et al (1979) found increased pituitary content of prolactln m the goldfish following pargylxne 011vereau (1978) and Ohvereau and Ohvereau (1979)
192
T R HALL
found decreased secretory actlwty in eel prolactln cells after pCPA and Increases after serotonln and 5-hydroxytryptophan administration (w) Acetylehohne
An inhibitory role in the control of prolactln secretion in mammals has been assigned to acetylchohne Systemic administration of the agonlst pdocarplne, or lntraventrlcular admlmstratlon of acetylchohne, reduce plasma prolactm This effect is blocked by the muscarlnlC antagonist atropine, and also by prior admlmstratlon of plmozxde, haloperldol or AMPT, suggesting that acetylchohne inhibits prolactm by enhancing dopamlnerglc transmission (Grandlson and Mextes, 1976, McCann et al, 1979) In birds m vitro, acetylchohne and pllocarpme stimulate prolactln release when the hypothalamus is present, and the stimulation is prevented by atropine (Hall et al, 1984b) In wro the chohnerglc agonist carbachol elevates plasma in the domestic fowl (Harvey et al, 1982) The effects of acetylchohne on prolactm in other vertebrates are not known (v) Htstamme Intraventrlcular administration of histamine to male and to ovariectomlzed steroid-primed rats stimulates prolactln secretion and this is blocked by the H1 antagonist dlphenhydramlne In addition dlphenhydramlne prevents stress-induced and attenuates suckhng-lnduced prolactin rises, whereas the H2 agonlst 4-methylhlstamlne blocks suckhng-lnduced prolactln secretion, and the H2 antagonist metlamlde increases basal prolactln levels There thus appears to be an antagonism between the two classes of histamine receptors in the physiological regulation of prolactln (Welner and Ganong, 1978, McCann et al, 1979) In birds histamine stimulates prolactin secretion m vwo (Harvey et al, 1982) In vitro histamine acts on prolactln via the hypothalamus and is blocked by the H1 antagonist, dlphenhydramme The response may involve inhibition of the dopammerglc mechanism (Hall et al, 1984c) (iv) Gamma-ammobutyrtc acid ( G A B A )
Schally et al (1979) Isolated a prolactln inhibiting hormone from porcine hypothalami, effective tn wtro and m wvo, that was identified as GABA It was subsequently demonstrated that the effects of GABA at the hypothalamlc level may be stlmulatory with low oestrogen (males, ovarlectomlzed females) or inhibitory with high oestrogen levels, these responses being mediated by dopamlne The direct inhibition of prolactln release from the pituitary may have no physiological significance (McCann et al, 1979) In birds GABA may be inhibitory to prolactm secretion by a direct action on the pituitary, but more importantly by inhibition of secretion of hypothalamlc prolactln releasing activity The hypothalamlc effects are blocked by bacuculhne and plcrotoxm (Harvey et al, 1982, Hall et al, 1984c) (vu ) Prostaglandms
The role of prostaglandms (PGs) an the regulation of anterior pituitary function is obscure It is beheved that they act at the final step in hormone release, at both hypothalamlc and pituitary sites Both PGE and
F series stimulate prolactln release in mammals (see Hall et al, 1984e for references) They found in the fowl m vttro that PGs have only little effect on prolactln release directly, but PGE2 increased and PGF2 decreases pituitary responsiveness to TRH, HE and to neurotransmltter-evoked prolactm releasing hormone (Hall et al, 1984e)
4 O T H E R FACTORS
(l ) Short-loop feedback In mammals prolactm injections cause a reduction in endogenous prolactln secretion and blunt the response to stress This may be mediated at least partly through the dopamlnergic system Administration of prolactln increases hypothalamlc dopamme turnover, which would act to reduce prolactm secretion (Advls et al, 1977, Wemer and Ganong, 1978) In the pigeon long term administration of hypothalamlc extracts or ovme prolactln reduces endogenous hypothalamic prolactm releasing activity (Hall and Chadwick, 1984a) Serotonln may partly mediate this response (unpublished results) Injections of ovme prolactm into eels results in prolactln cell degranulatxon and atrophy Prolactm released by transplanted teleost pituitaries suppresses prolactin release from the m sltu gland (Ensor, 1978) The role of the hypothalamus in this response has not been investigated (u) "Stress" A variety of stressful stimuli affect mammalian prolactln secretion, including handling naive animals, involuntary restraint, heat exposure, ether vapours and strenuous exercise, all of which elevate prolactin, apparently by increasing serotonln and histamine turnover in the hypothalamus (Welner and Ganong, 1978) In birds, few of these stresses affect prolactln However, water deprivation, salt-loading and resahnatlon markedly elevate prolactin secretion (Chadwick, 1977, Skadhauge et al, 1983) and at least part of this response is due to enhanced hypothalamlc serotonin availability (Hall et al, 19841) Osmotic stress is the major regulator of prolactln secretion in many teleosts There is a rapid adjustment of prolactm secretion in euryhahne teleosts when transferred between seawater and freshwater Prolactln cells are more active in many fish in freshwater Direct evidence for the action of osmotic factors on prolactm comes from m wtro incubations, where there is an inverse relationship between medium osmolahty (rather than just Na + concentration) and prolactm secretion (Ensor, 1978, Ball, 1981) However, there is also a long-term adaptation of hypothalamlc activity to altered salinity of the external medium (Hall and Chadwick, 1978) (m) SteroMs In mammals oestrogens stimulate prolactln secretion, with actions directly on the pituitary gland, and also at the hypothalamlc level Oestrogens reduce prolactm Inhibiting activity, both by reduction of dopamlne and also possibly by increasing noradrenaline Progesterone also induces surges of prolactm in rats An extra effect of oestrogens is to
Control of prolactm secreuon increase the number of binding sites for stlmulatory substances such as T R H m wvo and m pituitary cells in culture [see Chadwick and Hall (1983) and Hall et al (1984d) for literature review] In the fowl m wtro oestradiol 17fl stimulates release of prolactin and prolactin releasing hormone, but in additton mcreases pituitary sensitivity to T R H , hypothalamlc extracts and d o p a m m e (Hall et a l , 1984d) Conversely, both progesterone and testosterone reduce secretion of prolactln tn vttro and desensttlse the pxtultary to stlmulatory influences (Hall et a l , 1984g,h) Undoubtedly there are many other factors that regulate the secretton of prolactin in the vertebrates, but their mechanisms have not been studied m any detail It is known, for instance, that daylength is important in the regulation of reproductive phenomena, and increasing daylength stimulates noradrenaline turnover in the fowl (El Halawam and Burke, 1975) and serotonln turnover m the goldfish (Olcese et a l , 1980) The presence of eggs stimulates a massive secretaon of prolactin m pigeons and chickens but the mechanism is unknown (Lea et al, 1982)
5. CONCLUSIONS The regulation of secretion of prolactin shows striking similarities throughout the vertebrates, as well as some important differences N o r m a l secretion is dependent, m most species, upon intact hypothalamic connections The hypothalamus apparently contains prolactin-releaslng principle(s) and prolactin-lnhlbiting principle(s) However, the relative proportion of releasing inhibiting activity may be species specific, influenced by physiological con&tlon and be seasonally-dependent In teleosts osmotic influences may play a major role in the control of prolactin secretion from the pituitary, but in tetrapods most controlling influences act by way of the hypothalamus T h r o u g h o u t the vertebrates dopamine is a prolactin inhibiting agent, but its effects depend strongly upon the intrinsic activity of the prolactm cells Serotonm stimulates secretion of prolactin releasing hormone m all vertebrate species tested M a n y other neurotransmitters are undoubtably involved in control of prolactin, though they have not been tested in most vertebrates T R H and other peptldes may act as prolactin releasing hormones, though evtdence for this conjecture is very sparse as yet The table summarizes the effects of peptldes and transmitters on prolactin secretion in mammals and birds Activity of the hypothalamus-hypophyseal system is enhanced or dinunished by a large number of external mfluences Daylength, temperature, presence of mate/offspnng, tactile, olfactory and psychic stimuli, amongst many others, are responsible for changmg patterns of hormone secretion The relative importance of each of these factors is presumably related to the ecological niche mhabitated by the ammal Internal factors include a variety of hormones, mineral balance, nutritional status and shortloop feedback, all of which are of importance m the maintenance of pituitary homeostasis
193
Acknowledgements--I would hke to thank Dr A Chadwick
for rewewmg this manuscript The unpubhshed work reported here was supported m part by a grant from Leeds Philosophical and Literary Sooety REFERENCES
AdvtsJ P , H a l l T R , H o d s o n C A , M u e l l e r G P and Meltes J (1977) Temporal relationship and role of dopamxne in "short loop" feedback of prolactln Proc Soc exp Biol Med 155, 567-570 Advis J P, Slmpklns J N , Bennett J and Meltes J (1979) Serotonerglc control of prolactm release in male rats Life Sct 24, 359-366 Ball J N (1981) Hypothalamlc control of the pars distahs in fishes, amphibians, and reptiles Gen Comp Endocr 44, 135-170 Chadwick A (1977) Comparison of mdk-hke secretions found m non-mammals Syrup Zoo! Soc Lond 41, 341-358 Chadwick A and Hall T R (1983) Mechanisms regulating the secretion of prolactln m birds In Progress m NonMammahan Brain Research, Vol III (Edited by Nlstico G and Bohs L) CRC Press In press Clemens J A, Smalstlg E B and Shaar C J (1977) Further evidence that serotonln Is a neurotransmltter involved m the control of prolactin secretion Endocrinology 100, 692-698 Clemons G K , Russell S M and Nlcoll C S (1979) Effect of mammahan thyrotrophin releasing hormone on prolactm secretion by bullfrog adenohypophyses Gen Comp Endocr 58, 62-67 Dodd J M , Follett B K and Sharp P J (1971) Hypothalamlc control of pituitary function m submammahan vertebrates Adv Comp Physwl Btochem 4, 113-223 E1 Halawanl M E and Burke W H (1975) Role of catecholamlnes in photoperlodlcally-lndlced gonadal development in Coturnlx quail Btol Reprod 13, 603 609 Ensor D M (1978) Comparative Endocrmology of Prolactm Chapman & Hall, London Fiorlndo R P (1980) Further evidence for a prolactm stimulating neurohormone in reptdes Gen Comp Endocr 40, 52-58 Fuxe K , Andersson K , Lofstrom A , Hokfelt T Ferland L, Agnatl L F , Perez D E, La Mora M, Schwarcz R, Eneroth P, Gustafsson J-/~ and Skett P (1979) Neurotransmltter mechanisms m the control of the secretion of hormones from the anterior pltmtary In Central Regulation of the Endocrme System (Edited by Fuxe K , Hokfelt T and Luft R ) pp 349-380 Plenum Press, New York Grandlson L and Mextes J (1976) Evidence for adrenerglc medmUon of chohnerglc inhibition of prolactm release Endocrinology 99, 775-779 Hall T R (1982) Neurotransmitter effects on release of prolactm and growth hormone tn vitro from pltmtary glands of the pigeon Columba hvta J Endocr 92, 303-308 Hall T R and Chadwick A (1978) Control ofprolactln and growth hormone secretion in the eel Angudla angutlla Gen Comp Endocr 36, 388-395 Hall T R and Chadwick A (1979) Hypothalamic control of prolactm and growth hormone secretion in &fferent vertebrate species Gen Comp Endocr 37, 333-342 Hall T R and Chadwick A (1983a) Hypothalamic control of prolactin and growth hormone secretion m the pituItary gland of the pigeon and the chicken m wtro stu&es Gen Comp Endocr 49, 135-143 Hall T R and Chadwick (1983b) The effect of thyrotrophm releasing hormone on secretion of prolactln and growth hormone from eel pituitaries incubated m vitro IRCS Med Sct 11, 1009-1010 Hall T R and Chadwack A (1984a) Ewdence for "short
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T R HALL
loop" feedback regulation of prolactln and growth hormone secretion in the pigeon Gen Comp Endocr In press Hall T R and Chadwick A (1984b) Effects of synthetic mammahan thyrotrophm releasing hormone, somatostatln and dopamlne on the secretion of prolactIn and growth hormone from amphIbmn and reptile pituitary glands incubate in wtro J Endocr In press Hall T R , Chadwick A and Harvey S (1983a) Serotonlnerglc drugs affect prolactm and growth hormone secretion m the domestic fowl Comp Btochem Phystol 76C, 151 155 Hall T R , Harvey S and Chadwick A (1983b) Mechanism of serotonln effects on prolactin and growth hormone secretion m domestic fowl Acta Endocr 104, 266-271 Hall T R , Harvey S and Chadwick A (1984a) Neurotransmitter effects on m vitro prolactln and growth hormone release from fowl pltmtary glands Dopamme and noradrenahne Gen Pharmac In press Hall T R , Harvey S and Chadwick A (1984b) Serotonln and acetylchohne affect the release of prolactln and growth hormone from pituitary glands of domestic fowl in vitro in the presence of hypothalamic tissue Acta Endo~r In press Hall T R , Harvey S and Chadwick A (1984c) Prolactln and growth hormone secretion in chickens stlmulatmn by histamine and inhibition by gamma-amlnobutync aod Acta Endocr In press Hall T R , Harvey S and Chadwick A (1984d) Oestradiol 17fl modifies fowl pituitary responsiveness tn vitro Gen Comp Endocr In press Hall T R , Harvey S, Chadwick A and Scanes C G (1984e) Stimulatory and inhibitory effects of prostaglandln E 2 on prolactin release m the domestic fowl Gen Comp Endocr In press Hall T R , Harvey S and Chadwick A (1984f) Relationship between hypothalamic serotoninergic activity and prolactln and growth hormone secretmn in the domestic cockerel Neuroendocrmology In press Hall T R , Harvey S and Chadwick A (1984g) Progesterone inhibits prolactln and growth hormone release from fowl pltmtary glands tn vitro Br Poult Set In press Hall T R , Harvey S and Chadwick A (1984h) Inhlbmon by testosterone of prolactm and growth hormone release from chicken anterior pitmtary glands m vitro J Endocr In press Hall T R , Chadwick A , Woodhouse J and Harvey S (19841) Brain serotonln turnover and plasma prolactln and growth hormone concentrations dunng changes in osmotic balance in the domestic fowl J eomp Phystol Submitted Hall T R , Chadwick A , Bolton N J and Scanes C G (1975) Prolactln release m vitro and m vwo in the pigeon and the domestic fowl following administration of synthetic thyrotrophm-releasing factor (TRF) Gen Comp Endocr 25, 298-306 Hall T R , Chadwick A , Scanes C G and Callard I P (1978) Effects of hypothalamlc extracts and steroids on the secretmn of prolactln, growth hormone and lutelnlzlng hormone by the pituitary gland of the terrapin (Chrysemys ptcta) m vitro J Endocr 76, 169-170 Harris G (1955) Neural Control o f Pituitary Gland Arnold, London Harvey S, Scanes C G , Chadwick A and Bolton N J (1978) The effect of thyrotrophm-releasing hormone (TRH) and somatostatln (GHRIH) on growth hormone and prolactln secretion tn vitro and m vtvo in the domestic fowl (Gallus domesttcus) Neuroendocrmology 26, 249-260 Harvey S, Chadwick A , Border G , Scanes C G and Phillips J G (1982) Neuroendocrme control of prolactln secretion In Aspects o f Avian Endocrmology (Edited by Scanes C G , Ottinger M A , Kenny A D , Balthazart
J , Cronshaw J and Chester Jones I ) pp 41 64 Grad Studies Texas Tech Unlv Holmes R D and Ball J N (1974) The Pituitary Gland A Comparative Account Cambridge University Press, England Jackson I M D (1979) The releasing factors of the '.vpothalamus In Hormones" and Evoluuon (Edited by Barrlngton E J W ) Vol 2. pp 723-790 Academic Press, London Kuhn E R and Engelen H (1976) Seasonal variation in prolactln and TSH releasing activity in the hypothalamus of Rana temporarta Gen Comp Endocr 28, 277-282 Lea R W , Sharp P J and Chadwick A (1982) Dally variations in the concentrations of plasma prolactm in broody bantams Gen Comp Endotr 48, 275-284 Mazzl V (1980) Prolactln regulation, a comparative survey M e m Acad Set Tormo 4, 3 39 McCann S M , Kruhch L , Ojeda S R , Negro-Vllar A and Vljayan E (1979) Neurotransmltters in the control of anterior pituitary function In Central Regulation o f the Endocrine System (Edited by Fuxe K , Kokfelt T and Luft R ) pp 329-347 Plenum Press, New York Meltes J (1977) Evaluation of research on control of prolactln secretion In Comparatlre Endocrinology of Prolacttn (Edited by Dellmann H D , Johnson J A and Lachko D L) pp 135-152 Plenum Press. New York Meltes J , Brunl J F , Van Vugt D A and Smith A F (1979) Relation of endogenous oplold peptldes and morphine to neuroendocrlne function Ll/e SCl 24, 1325-1336 NakaJo S and Sato K (1981) Effects of monoamines on prolactln secretion of chicken anterior pituitary In vitro Europ W r d Poultry Conf 4, 279 285 NlStlCO G , Germana G , Clrlaco E and Bronzettl B (1980a) Morphological changes of pigeon crop sac mucosa and pituitary lactotrophs after systemic and lntraventrlcular administration of neuroleptlc drugs Gen Comp Endocr 41, 180~189 NIstlco G , Germana G , Clriaco E , Bronzettl B, Rotlrotl D and Scapagnlnl U (1979) Crop-sac response after systemic and lntraventrlcular administration of neuroleptxc drugs Neuroendocrtnology 29, 418-425 NlStlCO G , Germana G , Clrlaco E , Rotlrotl D , Faraone F and Scapagnml U (1980b) Ultrastructural changes of pltmtary lactotrophs and crop sac after lntraventricular rejections of drugs enhancing serotonlnerglc transmission in pigeons, In Central and Perzpheral Regulauon o f Prolactm Funcuon (Edited by Macleod R M and Scapagnlnl U ) pp 339-346 Raven Press, New York Olcese J M , Darr C , De Murl B, Hall T R and De Vlamlng V (1980) Photopenod effects of hypothalamlc serotonlnerglc activity in the goldfish, Carasstu~ auratus Comp Blochem Phy~tol (~iA, 363-365 Olcese J M , Hall T R , Flgueroa H R and De Vlamlng V L (1979) Hypothalamlc monoamlne oxldase, a component in the serotonlnerglc control of pituitary prolactln content in Carasstus auratu~ L Gen Comp Endo~r 38, 309-313 Ohvereau M (1978) Effects of parachlorophenylalanlne, a brain serotonin depictor, on the prolactln cells of the eel pituitary Cell Tzss Res 191, 93-99 Ohvereau M and Ohvereau J (1979) Effect of serotonln on prolactm and MSH-secretlng cells in the eel Comparison with the effect of 5-hydroxytryptophan Cell Tlss Res 196, 397-408 Rabu J , Buonomo F and Scanes C G (198l) Role of serotonln in the regulation of growth hormone and prolactin secretmn m the domestic fowl J Endocr 90, 355-358 Scanes C G , Rabn J and Buonomo F C (1982) Brain amines and the regulation of anterior pituitary secretion in the domestic fowl In Aspects o[ Avian Endocrinology
Control of prolactln secretion (Edited by Scanes C G , Ottmger M A , Kenny A D , Balthazart J , Cronshaw J and Chester Jones I ) pp 13-31 Grad Studies Texas Tech Unlv Schally A V , Reddlng T W , Snmura A , Dupont A and Lmthlcum G L (1977) Isolation of gamma-amlnobutync acid from pig hypothalaml and demonstration of Its prolactln release-inhibiting (PIF) activity in vtvo and in vitro Endocrmology 100, 681-691 Sekl T and Klkuyama S (1982) In vitro studies on the regulation of prolactln secretion in the bullfrog pituitary gland Gen Comp Endocr 46, 473~,79 Skadhauge E , Thomas D H Chadwick A and Jallageas M (1983) Time course of adaptation to low and high NaC1 diets in the domestic fowl Effects on electrolyte excretion and on plasma hormone levels Caldosterone,
GP
15/~B
195
Cortlcosterone and prolactln) Pflugers Arch 396, 301-307 Tixler-Vldal A and Gourdjl D (1972) Cellular aspects of the control of prolactln secretion in birds Gen Comp Endocr 3 (Suppl), 51-64 Tlxier-Vidal A and Gourdji D (1981) Mechanism of action of synthetic hypothalamlc peptldes on anterior pituitary cells Physlol Rev 61, 974-1011 Uruefia G and Hall T R (1983) Serotonln modulation of pituitary prolactln and growth hormone content m the grassfrog, Rana ptptens Gen Comp Endocr Submltted Weiner R I and Ganong W F (1978) Roles of brain monoamines and histamine in regulation of anterior pituitary secretion Physlol Rev 58, 905-976
0306-3623/84 $300+000 Copyright © 1984Pergamon Press Ltd
MINIREVIEW CONTROL OF PROLACTIN SECRETION IN THE VERTEBRATES--A COMPARATIVE SURVEY T R HALL* Department of Pure & Apphed Zoology, The Umversity of Leeds, Leeds LS2 9JT, U K (Tel 0532-431751) 13 July 1983)
(Recewed
INTRODUCTION
l AUTONOMOUS RELEASE
The science of neuroendocrinology has been growing at a seemingly exponential rate since the discovery by Harris (1955) that the hypothalamus appears to elaborate specific chemical factors that stimulate or inhibit secretion of pituitary gland hormones This hypothesis was convincingly vahdated when the research groups of Schally and Gulllemin isolated several of these factors, beginning with the trIpeptlde thyrotrophln releasing hormone (TRH) (Tixler-Vadal and Gourdj1, 1981) Similar hormones have been detected in the central nervous systems of nonmammalian vertebrates (Jackson, 1979) More recently, neuroendocrmologIsts have concentrated on the mechamsms governing the control of secretion of the hypothalamlc hormones In mammals, recent reviews (see Fuxe e t a l , 1979) imphcate a varxety of neurotransmltters and neuromodulators in this process and suggest that physiological changes in hormone secretion may be a consequence of altered neurotransmltter metabohsm However, only a handful of the many putative transmitters have been examined in detail, mainly in mammals The little ewdence available shows that s~milar mechanisms operate in non-mammahan species A number of reviews have been published during the past dozen years that cover certain aspects of the control of pituitary function in vertebrates (Dodd e t a l , 1971, Holmes and Ball, 1974, Ensor, 1978, Mazzl, 1980, Ball, 1981) The purpose of this review is to integrate recently-published information on central mechanlslms governing the secretion of prolactln from the vertebrate pltmtary gland These mechanisms appear to involve interactions at various levels, the pituitary gland ltsself may possess some degree of autonomy, hormone release from the pituitary gland is modulated by hypothalamxc releasing and inhibiting hormones, secretion of the hypothalamic hormones is modified by neurotransmitters/neuromodulators, and activity of this system alters in response to various interoceptwe and exteroceptwe influences (Chadwick and Hall, 1983)
When the mammalian pituitary gland is removed from hypothalamic influence by autotransplantatlon, destruction of the mediobasal hypothalamus, pituitary stalk section or by m v i t r o culture, there is a prompt and sustained increase m prolactm secretion that involves d e n o v o synthesis in addition to elevated release of the hormone The magnitude of the response IS dependent upon age, sex, physiological condition and species employed (Mextes, 1978, Weiner and Ganong, 1978) The avian pituitary gland also shows some autonomy of function which is species-dependent Whereas duck pituitary shows many signs of secretory activity a considerable time after autotransplantation or tn v i t r o culture, pigeon prolactin cells are much less active, and chicken and quail lactotrophs rapidly degenerate when removed from hypothalamlc influence (Tixler-Vldal and Gourdji, 1972, Chadwick and Hall, 1983) Reptile pituitaries are also capable of releasing prolactln m w t r o for up to 24 h (Hall and Chadwick, 1979, Fxorlndo, 1980) and m one species at least for up to l0 days (Ensor, 1978) The amphibian pituitary gland may also show some autonomous function Prolactm cell activity remains high followmg autotransplantatIon Ectopic transplants induce precocious second metamorphosis in urodeles and sustain level growth and inhibit metamorphosis in anurans, Indicating high prolactm secretion Relatively large amounts of prolactln are secreted by pituitaries of some anuran and urodele species tn v i t r o (Ensor, 1978, Hall and Chadwick, 1979) Prolactln secretion from teleost pituitaries shows perhaps the highest degree of autonomy, and in some species considerable quantities of the hormone may be secreted m v i t r o (Hall and Chadwick, 1978, 1979, Ball, 1981)
*Present address Wolfson Institute, Umverslty of Hull, Hull HU6 7RX (Tel 0482-497067)
2 HYPOTHALAMICPEPTIDES Crude extracts of mammalian hypothalami usually possess prolactin inhibiting activity zn v i t r o and m v w o However it is suspected that these hypothalami also contain a prolactm releasing hormone The prolactin inhibiting hormone may be dopamine (see below), but the identity of the releasing hormone is not known TRH stimulates release of prolactin tn v t t r o and also m v w o under certain con&tions (e g
189
190
T
R
HALL
Table 1 Effects of hypothalamlc neurotransmltters and pepndes on prolactln secrenon Mammals Transmitters Dopamme Noradrenahne Serotonln Acetylchohne Histamine GABA Peptldes TRH Endorphms VIP Substance P Tetragastrm Neurotensln Bombesm Alatensm
B~rds
P~tmtary
Hypothalamus
Pttmtary
Hypothalamus
,~
(,,)
,~
,L
-({)
T ,t ~(Ht) ,L(H2) T(low E2){(high E2)
(D --(,L)
T t ~(Ht) ,~
T (D
-(?) (?)
7
(T} T (T) (T)
~
NT NT NT NT
NT NT NT NT
T
(D t --
{ T
$ --
Key
PItmtary~dlrect effect on pituitary, Hypothalamus--effect on releaslng/mhlbmng hormone, " increases PRL, ,L decreases PRL, - - no change, NT not tested, ( ) conjectural or unconfirmed response Data derived from McCann et al (1979),Tlxlcr-V1daland Gourdjl (1981), Harvey e~ al (1982),Chadwlck and Hall (1983) and unpubhshed ,nformatmn from our laboratory
following oestrogen priming) However it is hkely that other prolactIn releasing influences are also present in the mammalian hypothalamus, since there are many physiological states where prolactln secretlon is divorced from TSH secretion (e g heat and cold stress, suckhng stimulus) (Meates, 1977) Several other peptldes, found in high concentrations in the hypothalamus and median eminence, have direct or indirect effects on prolactln secretion, though their physiological functions are not known These include the endorphins, which interact with the dopamlnerglc and serotoninerglc systems (see below) to stimulate prolactln (Meltes e t a l , 1979) and a variety of gastrointestinal (vasoactlve intestinal polypeptide (VIP), tetragastrln, substance P, neurotensln) and amphibian skin-derived (bombesln, alatensin) peptides, whose affects are summarized in Table 1 Avian hypothalamt show pronounced prolactln stimulating activity m v i t r o and tn v w o i n short-term and long-term experiments (Hall and Chadwick, 1979, 1983a, Harvey e t a l , 1982, Chadwick and Hall, 1983) Interestingly, as in mammals TRH stimulates release of prolactin tn w t r o , but only sporadically m v w o (Hall e t a l , 1975, Harvey e t a l , 1978, Chadwick and Hall, 1983) It is unlikely that T R H is the only prolactln-stlmulatlng agent in the avian hypothalamus (Hall and Chadwick, 1983a) We have been testing other peptldes known to affect prolactln in mammals (Hall and Chadwick, manuscript in preparation) Endorphms stimulate prolactln vla a hypothalamIc mechanism, whereas VIP and substance P both stimulate prolactm release directly from the pituitary, though only from oestrogen-prlmed pituitaries in the case of substance P These peptldes may also stimulate release of prolactln releasing hormone from the hypothalamus There is some evidence for the existence of a prolactln inhibiting hormone (Chadwick and Hall, 1983), which may be dopamine (see below) Table 1 summarizes these responses Reptile and amphibian hypothalamlc extracts also stimulate release of prolactln from pituitaries m v i t r o , though only few species have been investigated (Hall and Chadwick, 1978, 1979, Florlndo, 1980) There is some evidence for an amphibian prolactln inhibiting
hormone that appears during part of the annual cycle (Kuhn and Engelen, 1976) In anuran tadpoles hypothalamlc connections are undeveloped and prolactm secretion may be autonomous, but during prometamorphosls the hypothalamus presumably takes mcreasing control of pituitary function (Ensor, 1978) TRH stimulates release of prolactln from pituitaries of several chelonian and anuran species m v i t r o , but not apparently from urodele pituitaries (Hall e t a l , 1978, Clemons e t a l , 1979, Ball, 1981, Hall and Chadwick, 1984b) It is generally considered that teleost prolactln secretion is relatively independent, but may be influenced by a hypothalamxc inhibitory hormone m most species (Ball, 1981) In a few species hypothalamlc extracts stimulate release of prolactln (Hall and Chadwick, 1978, 1979) Whether inhibitory or stimulatory mfluences are found may depend upon the physiological state of the animal, the time of the year and even the method of assay employed (Hall and Chadwick, 1979) The effects of TRH on secretion of prolactln are contradictory, with inhibition In S a r o t h e r o d o n and stimulation in P o e c l h a (Ball, 1981) Hall and Chadwick (1983b) found stimulation of eel prolactin by T R H m v i t r o Urotensm II inhibits prolactln release in v i t r o (see Ball, 1981) Apparently other peptldes have not been tested for their effects on prolactin secretion in teleosts 3 H Y P O T H A L A M I C NEUROTRANSMITTERS (l) Dopamme
It is generally agreed that dopamxne is the major prolactln mhibitory agent of the mammalian hypothalamus Dopamlne and its agonists dopa, apomorphine, ergot drugs (bromocryptine, lergotrlle, etc ), plrlbedll and hsurlde inhibit prolacttn release from pituitaries m v i t r o and reduce basal levels as well as stress, TRH, pro-oestrus, suckhng and drugmduced secretion of prolactin in VlVO Dopamlne antagonists (plmozlde, haloperidol, chlorpromazlne, perphenazine, sulplrtde, etc ) reverse the effects of dopamine agonlsts, and also stimulate prolactln In v w o when given alone, indicating a tonic dopamlnerglc inhibition of secretion of prolactln Depletion of
Control of prolactln secretion dopamlne, either by tyroslne hydroxylase inhibition (~-methyl-para-tyroslne, AMPT), by storage granule disruption (reserpine) or by inhibition of aromaticL-amino acid decarboxylase (benserazide) also increase prolactm DopamIne levels in pituitary stalk plasma have been found to vary in a manner consistent with patterns of prolactln secretion, suggesting a physiological role for dopamIne in prolactin regulatmn (Welner and Ganong, 1978, Fuxe et al 1979) The effects of dopamlne on prolactin secretion in birds have been investigated recently In vtvo administration of dopamlne antagonists to pigeons activates prolactln cells and produces crop sac stimulation (Nlstico et a l , 1979, 1980a) and AMPT, plmozide, phenoxybenzamlne and reserpine all stimulate prolactln in vwo in the fowl (Scanes et a l , 1982), indicating a tonic dopamlnerglc prolactln inhibitory mechanism In vitro administration of dopamine and agomsts inhibits release of prolactln (Harvey et a l , 1982), though responses are more pronounced when prolactln release IS stimulated with TRH or hypothalamus (Hall, 1982, Hall and Chadwick, 1983a, Hall et a l , 1984a) or with oestrogen pretreatment (Hall et a l , 1984d) In recent experiments (manuscript in preparation) we have found that dopamlne also inhibits release of prolactln releasing activity from fowl hypothalaml, whereas plmozlde enhances the release of the hypothalamlc factor m vitro These results contrast with those of Nakajo and Sato (1981), who found little or no effect of dopamlne on prolactln release from fowl pituitaries, though they used the less-sensitive polyacrylamlde gel electrophoretlc assay procedure Dopamlne may also be a prolactln inhibiting hormone in amphibia and reptiles Catecholamlne fibres are present In the hypothalamus of anurans and urodeles, with high activity in winter and low activity during the breeding season (Ensor, 1981) Bromocryptlne blocks prolactln secretion m vwo in the newt Dopamxne inhibits the release of growthpromoting hormone (prolactln) from pituitaries of Bufo species (Mazzl, 1980, Ball, 1981) Sekl and Klkuyama (1982) showed that dopamlne and bromocryptlne inhibit release of newly synthesized prolactln from bullfrog pituitaries in vitro, an effect reversed by halopendol and plmozlde We have found that dopamlne inhibits TRH and hypothalamus-stlmulated release of prolactln from various amphibian and reptile pituitaries m vitro (Hall and Chadwick, 1984b) Dopamine is also a prolactin-inhlbitlng agent in teleosts Destruction of the type B amlnergic fibres with 6-hydroxydopamme activates prolactln cells in Tdapta L-dopa and ergocryptlne inhibit prolactln secretion in the eel, and bromocryptme reduces prolactln functmn in Poectha m vwo Incubatmn of pituitaries of several species with dopamlnergic drugs showed that dopamine acts directly on the pituitary gland to inhibit prolactln, and this mechanism is separate from the osmotic control mechanism (see below) (Ensor, 1978, Ball, 1981) (n ) Noradrenahne
Noradrenahne in vitro lnh~b~ts release of prolactm directly from the mammalian pituitary gland, though this may be due to an interaction with dopamxnergic
191
receptors The amine may have also a central stimulating role, since dehydroxyphenylserine (DOPS), which may be converted to noradrenallne in the brain, stimulates prolactin, as does the ~-adrenerglc agonlst clonldine in some circumstances In addition, the or-antagonist phentolamlne blocks diurnal oestrogen-lnduced prolactln surges (Weiner and Ganong, 1978, McCann et a l , 1979) In birds noradrenaline appears to be a potent stimulator of prolactln release m vitro It may have direct stlmulatory activity at the pituitary, but its major effect is to stimulate secretion of prolactln releasing hormone (Harvey et a l , 1982, Chadwick and Hall, 1983, Hall et a l , 1984a) Apparently the effects of noradrenallne on prolactin secretion have not been examined in other vertebrates (ut ) Serotomn
Prolactln secretion in mammals is stimulated by serotonin and Its agonlst qulpazlne, and there is some evidence that the amine stimulates prolactln releasing hormone rather than, or in addition to, inhibiting prolactln inhibiting hormone The precursor of serotonln, tryptophan and 5-hydroxytryptophan, stimulate prolactin, especially If their effects are potentiated by presynaptlc reuptake blockers such as tncycllc antidepressants (e g lmlpramlne) or fluoxetine The tryptophan hydroxylase inhibitor p a r a - c h l o r a p h e n y l a l a n m e (pCPA) and the receptor antagonists methyserglde and cyproheptidlne reverse these effects and reduce basal prolactln Prevention of serotonin metabohsm by Inactivation of monoamine oxldase (e g with pargyhne) increases prolactln, as does stimulation of serotonln turnover by electrical stimulation of the mldbraln raphe region (Clemens et a l , 1977, Weiner and Ganong, 1978, Advis et a l , 1979) In birds also, serotonln is a potent prolactln stimulating agent whose major effects are probably mediated at the hypothalamic level In vitro serotonin and qulpazlne stimulate prolactln release in pituitaryhypothalamus co-incubations, effects reversed by methyserglde (Hall, 1982, Hall et a l , 1984b) In vwo serotonlnerglc drugs (tryptophan, together with imlpramlne, 5-hydroxytryptophan, qulpazlne) stimulate prolactln cell activity and induce crop sac responses in pigeons, and elevate plasma prolactln In fowl Methysergade may reduce plasma prolactln, and methyserglde and cyproheptidlne block responses to serotonin agonlsts (NlStlCO et a l , 1980b, Rabli et a l , 1981, Scanes et a l , 1982, Hall et a l , 1983a,b) Pargyhne and other MAO inhlbltors (tranylcypromine, nialamlde, clorgyhne) also increase prolactln as consequence of elevated serotomn availability (Hall et a l , 1984f) Some aspects of the serotonlnerglc regulation of prolactln secretion in amphibia and teleosts have been reported Uruefia and Hall (1983) showed that pargyhne and L-tryptophan administration, both of which increased serotonin content of the hypothalamus, also increased pituitary concentration of prolactm whereas p C P A reduced serotonm and prolactm, In the grassfrog Rana plptens Similarly Olcese et al (1979) found increased pituitary content of prolactln m the goldfish following pargylxne 011vereau (1978) and Ohvereau and Ohvereau (1979)
192
T R HALL
found decreased secretory actlwty in eel prolactln cells after pCPA and Increases after serotonln and 5-hydroxytryptophan administration (w) Acetylehohne
An inhibitory role in the control of prolactln secretion in mammals has been assigned to acetylchohne Systemic administration of the agonlst pdocarplne, or lntraventrlcular admlmstratlon of acetylchohne, reduce plasma prolactm This effect is blocked by the muscarlnlC antagonist atropine, and also by prior admlmstratlon of plmozxde, haloperldol or AMPT, suggesting that acetylchohne inhibits prolactm by enhancing dopamlnerglc transmission (Grandlson and Mextes, 1976, McCann et al, 1979) In birds m vitro, acetylchohne and pllocarpme stimulate prolactln release when the hypothalamus is present, and the stimulation is prevented by atropine (Hall et al, 1984b) In wro the chohnerglc agonist carbachol elevates plasma in the domestic fowl (Harvey et al, 1982) The effects of acetylchohne on prolactm in other vertebrates are not known (v) Htstamme Intraventrlcular administration of histamine to male and to ovariectomlzed steroid-primed rats stimulates prolactln secretion and this is blocked by the H1 antagonist dlphenhydramlne In addition dlphenhydramlne prevents stress-induced and attenuates suckhng-lnduced prolactin rises, whereas the H2 agonlst 4-methylhlstamlne blocks suckhng-lnduced prolactln secretion, and the H2 antagonist metlamlde increases basal prolactln levels There thus appears to be an antagonism between the two classes of histamine receptors in the physiological regulation of prolactln (Welner and Ganong, 1978, McCann et al, 1979) In birds histamine stimulates prolactin secretion m vwo (Harvey et al, 1982) In vitro histamine acts on prolactln via the hypothalamus and is blocked by the H1 antagonist, dlphenhydramme The response may involve inhibition of the dopammerglc mechanism (Hall et al, 1984c) (iv) Gamma-ammobutyrtc acid ( G A B A )
Schally et al (1979) Isolated a prolactln inhibiting hormone from porcine hypothalami, effective tn wtro and m wvo, that was identified as GABA It was subsequently demonstrated that the effects of GABA at the hypothalamlc level may be stlmulatory with low oestrogen (males, ovarlectomlzed females) or inhibitory with high oestrogen levels, these responses being mediated by dopamlne The direct inhibition of prolactln release from the pituitary may have no physiological significance (McCann et al, 1979) In birds GABA may be inhibitory to prolactm secretion by a direct action on the pituitary, but more importantly by inhibition of secretion of hypothalamlc prolactln releasing activity The hypothalamlc effects are blocked by bacuculhne and plcrotoxm (Harvey et al, 1982, Hall et al, 1984c) (vu ) Prostaglandms
The role of prostaglandms (PGs) an the regulation of anterior pituitary function is obscure It is beheved that they act at the final step in hormone release, at both hypothalamlc and pituitary sites Both PGE and
F series stimulate prolactln release in mammals (see Hall et al, 1984e for references) They found in the fowl m vttro that PGs have only little effect on prolactln release directly, but PGE2 increased and PGF2 decreases pituitary responsiveness to TRH, HE and to neurotransmltter-evoked prolactm releasing hormone (Hall et al, 1984e)
4 O T H E R FACTORS
(l ) Short-loop feedback In mammals prolactm injections cause a reduction in endogenous prolactln secretion and blunt the response to stress This may be mediated at least partly through the dopamlnergic system Administration of prolactln increases hypothalamlc dopamme turnover, which would act to reduce prolactm secretion (Advls et al, 1977, Wemer and Ganong, 1978) In the pigeon long term administration of hypothalamlc extracts or ovme prolactln reduces endogenous hypothalamic prolactm releasing activity (Hall and Chadwick, 1984a) Serotonln may partly mediate this response (unpublished results) Injections of ovme prolactm into eels results in prolactln cell degranulatxon and atrophy Prolactm released by transplanted teleost pituitaries suppresses prolactin release from the m sltu gland (Ensor, 1978) The role of the hypothalamus in this response has not been investigated (u) "Stress" A variety of stressful stimuli affect mammalian prolactln secretion, including handling naive animals, involuntary restraint, heat exposure, ether vapours and strenuous exercise, all of which elevate prolactin, apparently by increasing serotonln and histamine turnover in the hypothalamus (Welner and Ganong, 1978) In birds, few of these stresses affect prolactln However, water deprivation, salt-loading and resahnatlon markedly elevate prolactin secretion (Chadwick, 1977, Skadhauge et al, 1983) and at least part of this response is due to enhanced hypothalamlc serotonin availability (Hall et al, 19841) Osmotic stress is the major regulator of prolactln secretion in many teleosts There is a rapid adjustment of prolactm secretion in euryhahne teleosts when transferred between seawater and freshwater Prolactln cells are more active in many fish in freshwater Direct evidence for the action of osmotic factors on prolactm comes from m wtro incubations, where there is an inverse relationship between medium osmolahty (rather than just Na + concentration) and prolactm secretion (Ensor, 1978, Ball, 1981) However, there is also a long-term adaptation of hypothalamlc activity to altered salinity of the external medium (Hall and Chadwick, 1978) (m) SteroMs In mammals oestrogens stimulate prolactln secretion, with actions directly on the pituitary gland, and also at the hypothalamlc level Oestrogens reduce prolactm Inhibiting activity, both by reduction of dopamlne and also possibly by increasing noradrenaline Progesterone also induces surges of prolactm in rats An extra effect of oestrogens is to
Control of prolactm secreuon increase the number of binding sites for stlmulatory substances such as T R H m wvo and m pituitary cells in culture [see Chadwick and Hall (1983) and Hall et al (1984d) for literature review] In the fowl m wtro oestradiol 17fl stimulates release of prolactin and prolactin releasing hormone, but in additton mcreases pituitary sensitivity to T R H , hypothalamlc extracts and d o p a m m e (Hall et a l , 1984d) Conversely, both progesterone and testosterone reduce secretion of prolactln tn vttro and desensttlse the pxtultary to stlmulatory influences (Hall et a l , 1984g,h) Undoubtedly there are many other factors that regulate the secretton of prolactin in the vertebrates, but their mechanisms have not been studied m any detail It is known, for instance, that daylength is important in the regulation of reproductive phenomena, and increasing daylength stimulates noradrenaline turnover in the fowl (El Halawam and Burke, 1975) and serotonln turnover m the goldfish (Olcese et a l , 1980) The presence of eggs stimulates a massive secretaon of prolactin m pigeons and chickens but the mechanism is unknown (Lea et al, 1982)
5. CONCLUSIONS The regulation of secretion of prolactin shows striking similarities throughout the vertebrates, as well as some important differences N o r m a l secretion is dependent, m most species, upon intact hypothalamic connections The hypothalamus apparently contains prolactin-releaslng principle(s) and prolactin-lnhlbiting principle(s) However, the relative proportion of releasing inhibiting activity may be species specific, influenced by physiological con&tlon and be seasonally-dependent In teleosts osmotic influences may play a major role in the control of prolactin secretion from the pituitary, but in tetrapods most controlling influences act by way of the hypothalamus T h r o u g h o u t the vertebrates dopamine is a prolactin inhibiting agent, but its effects depend strongly upon the intrinsic activity of the prolactm cells Serotonm stimulates secretion of prolactin releasing hormone m all vertebrate species tested M a n y other neurotransmitters are undoubtably involved in control of prolactin, though they have not been tested in most vertebrates T R H and other peptldes may act as prolactin releasing hormones, though evtdence for this conjecture is very sparse as yet The table summarizes the effects of peptldes and transmitters on prolactin secretion in mammals and birds Activity of the hypothalamus-hypophyseal system is enhanced or dinunished by a large number of external mfluences Daylength, temperature, presence of mate/offspnng, tactile, olfactory and psychic stimuli, amongst many others, are responsible for changmg patterns of hormone secretion The relative importance of each of these factors is presumably related to the ecological niche mhabitated by the ammal Internal factors include a variety of hormones, mineral balance, nutritional status and shortloop feedback, all of which are of importance m the maintenance of pituitary homeostasis
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Acknowledgements--I would hke to thank Dr A Chadwick
for rewewmg this manuscript The unpubhshed work reported here was supported m part by a grant from Leeds Philosophical and Literary Sooety REFERENCES
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GP
15/~B
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