1538 FREEMAN,KANYICSKA,LERANT,AND NAGY Volume 80 There is VIAIA)tha ed is related to that the t tory effect over prolactin secretion (140)also changes ing (1182).These parameters appear to be similar in all throughout the day (420,1027).It has been shown that mals with only subtle exceptions For example,in daily in the ail min the 575e 1019 nine levels in the lons the odents 78.887.th anterior lobe of the pituitary gland (1101.1606.1903). nursing is superimposed by the endogenous circadian According to this daily rhythm,the dopaminergic tone of rhythm of prolactin secretion;that is,the same intensity TIDA ne stimulus can ele Of TIDA in pres ale rats ces the suckling stim with various ovarian steroid backgrounds (1606 1607 1903).It has been demonstrated that a similar pattern in The control of su ckling-induced prolactin secre 10I early gene express t lts certa s1022 va. 1020m T ents conducted in constant envir ent and ma anterior pituitary gland(1281).Thus the uekling stimulus nipulations of suprachiasmatic input(1101, 1100,1606) essentially relieves the lactotroph from tonic inhibition st that the daily rnythm ed by neu Ho ver e amount an tha do Hypothalamic oxytocin,which has been identified as pituitary gland.This argues for a prolactin-rele sing input a potential PRF,plays an important role in maintaining superim the diminution of the inhibitory inpu prolacti ula tory rhythm (71,7 provide suppres or of dau cretion (71),administration of an oxytocin antag onist TRH inhibits ckling-induced rolactin releas 405 abolishes the rhythm (74).Since these initial findings, 1603).However,the supremacy of TRH in regulating suck numerous other candidates of centra origin hav ed prolactin release not universally ac as po 813.18581912.1919 lian release of (isi).T po pitui has led to the sug stion that the no sterior lobe transfer B.Patterns of Prolactin Secretion in Different a PRF to the anterior lobe through the short portal vessels ctive State 1256).The identity of the postenor pituitary lates for 1 Lactation ntide va sin nr ecursor (1276.1277 The best-known physiological stimulus affecting pro 78)and even dopamine of posterior pitu lactin secretion is the suckling stimulus applied by the itary origin (1281).However,there is not universal agree nursing y has been char nzed as a c ind by an electrochemical stimulus is des PRE may he a heretofore unidentified osterior nituitary contraction reflex,one can describe the release of r (27,766,1059)or intermediate lobe(27peptide.It is safe lactin in response to the nursing young as a stimulus to say at this time that,although we have several plausible 1 within 10 min are sustained at a constant level as nd nursing continues,and fall when nurs is terminated 2.Estrous and menstrual cycles (684).The expression of prolactin mF RNA in the pituitary san epattern (1016) or th The on of prolactir has cretion and the rate of decre ase in hlood nrolactin lovels uhout most of the strous ovele a is proportional to the metabolic clearance rate of the low and unchanging from the evening of estrus through hormone(683,1274).Moreover,the amount of prolactin the moming of the next proestrus (254.608.1296.1647)
There is ample evidence (see sect. VIIA1A) that dopaminergic tone of hypothalamic origin that exerts inhibitory effect over prolactin secretion (140) also changes throughout the day (420, 1027). It has been shown that dopaminergic activity in the median eminence shows daily changes, strongly suggesting a daily rhythm of dopamine levels in the long portal vessels reaching the anterior lobe of the pituitary gland (1101, 1606, 1903). According to this daily rhythm, the dopaminergic tone of TIDA neurons decreases before the daily elevation in prolactin levels (1101). The presence of this daily rhythm of TIDA neuronal activity in female rats has been verified with various ovarian steroid backgrounds (1606, 1607, 1903). It has been demonstrated that a similar pattern in immediate early gene expression exists in neuroendocrine dopaminergic neurons of female rats in various reproductive states (1027, 1029). These data, as well as experiments conducted in constant environment and manipulations of suprachiasmatic input (1101, 1100, 1606), strongly suggest that the daily rhythm exhibited by neuroendocrine dopaminergic neurons is endogenous in nature and entrained by light. Hypothalamic oxytocin, which has been identified as a potential PRF, plays an important role in maintaining the endogenous prolactin-stimulatory rhythm (71, 73, 75– 77). Indeed, in rats treated with a dopamine antagonist at various times of day to unmask a rhythm of prolactin secretion (71), administration of an oxytocin antagonist abolishes the rhythm (74). Since these initial findings, numerous other candidates of central origin have emerged as possible regulators of circadian release of pituitary prolactin (813, 1858, 1912, 1919). B. Patterns of Prolactin Secretion in Different Reproductive States 1. Lactation The best-known physiological stimulus affecting prolactin secretion is the suckling stimulus applied by the nursing young. This has been characterized as a classical neuroendocrine reflex. Just as muscle contraction evoked by an electrochemical stimulus is described as a stimuluscontraction reflex, one can describe the release of prolactin in response to the nursing young as a stimulussecretion reflex. In rats, blood prolactin concentrations begin to rise within 1–3 min of initiation of nursing, peak within 10 min, are sustained at a constant level as long as nursing continues, and fall when nursing is terminated (684). The expression of prolactin mRNA in the pituitary gland follows the same pattern (1016). Cessation of the suckling stimulus results in termination of prolactin secretion, and the rate of decrease in blood prolactin levels is proportional to the metabolic clearance rate of the hormone (683, 1274). Moreover, the amount of prolactin released is related to the intensity of the stimulus as it is somewhat commensurate with the number of pups nursing (1182). These parameters appear to be similar in all mammals with only subtle exceptions. For example, in the rhesus monkey, nursing induces a biphasic release of prolactin (575). In humans (443, 1683), cattle (1019), and rodents (78, 887), the prolactin-secretory response to nursing is superimposed by the endogenous circadian rhythm of prolactin secretion; that is, the same intensity of suckling stimulus can elevate prolactin levels more effectively at certain times of day when the circadian input enhances the suckling stimulus-evoked secretory response. The control of suckling-induced prolactin secretion is somewhat enigmatic. It is certain that the suckling stimulus results in a diminution of the amount of dopamine released into portal blood (404) and arriving at the anterior pituitary gland (1281). Thus the suckling stimulus essentially relieves the lactotroph from tonic inhibition. However, the amount of prolactin released in response to suckling is far greater than that resulting from pharmacological or surgical interference with dopamine input to the pituitary gland. This argues for a prolactin-releasing input superimposed on the diminution of the inhibitory input provided by suckling-induced suppression of dopamine. Indeed, there are many candidates for a PRF stimulated by suckling. For example, passive immunization against TRH inhibits suckling-induced prolactin release (405, 1603). However, the supremacy of TRH in regulating suckling-induced prolactin release is not universally accepted (1481). The intriguing observation that posterior pituitary lobectomy abolishes suckling-induced prolactin secretion has led to the suggestion that the posterior lobe transfers a PRF to the anterior lobe through the short portal vessels (827, 827, 1256). The identity of the posterior pituitary PRF has eluded many investigators. Among the obvious candidates for PRF are vasopressin (1283) and its glycopeptide vasopressin-neurophysin precursor (1276, 1277), oxytocin (76, 78) and even dopamine of posterior pituitary origin (1281). However, there is not universal agreement on the candidacy of the vasopressin-neurophysin glycopeptide (829), and there is some indication that the PRF may be a heretofore unidentified posterior pituitary (27, 766, 1059) or intermediate lobe (27) peptide. It is safe to say at this time that, although we have several plausible candidates, none has emerged as the undisputed sucklinginduced PRF. 2. Estrous and menstrual cycles The secretion of prolactin has been most extensively studied during the estrous cycle of the rat. The secretion of prolactin throughout most of the estrous cycle appears low and unchanging from the evening of estrus through the morning of the next proestrus (254, 608, 1296, 1647). 1538 FREEMAN, KANYICSKA, LERANT, AND NAGY Volume 80
PROLACTIN 1539 During the afternoon of proestrus.a preovulatory surge of moval of the tonic dopaminergic inhibition results in en prolactin secretion occurs,which is similar in timing to hanced prolactin secretion.the role of dopamine as a that of LH(1647).Although the LH surge on proestrus is regulator of the proestrous surge of prolac oI prolactin dictory. Hypothal mo-nypopnysial portal aL fo tended termination phase (60.1259)Althoush most lab- oratories have rep ted a single surge of prolactin on emine nce (411).and the subs ntration of do proe strus (608 1296.1647).others have reported a sec pamine in the anterior lobe of the pituitary gland (420 ary on metay ele have bee n reported to decline on proe strus before the Because these latter results may have been caused by the secretion.On the othe r hand,others ove method and frequency of blood collection,it is generally accepted that the afteroon of proestrus is the only time ary have been orted to both in tha e (748)during the afternoon of proestrus.The source of dopa those of the primate mer mine controlling prolactin d to be TIDA neurons with cell bodies controls it would not be illogical to ex pect a midcycle surge of prolactin during the menstrual cycle that coin the r,only on ne of th e do ne ar es at the neak that is onl s anterior lobe of the nituitary uland from the nosterior lobe greater than prolactin levels of the early follicular phase that contains axon terminals of tuberohypophysial dopa minergic (THDA)neurons les are foun small changes can easily be over whose cell bo ges,thu ing to a f the ral part u idual h sig cear that the ising blood ev dopaminergic (PHDA)neurons that r side in the hypotha signal the hypothalamo-pituitary axis to release this surge 656)The short porta of prolactin on proestrus.Administration of an antiserum lamic periventricular nucleus (655, obes of the pitu gland may to estradiol s th pr ugh whic amine to in th surges of prolactin that are similar in timing to the of the proestrous surge of prolactin (1297 These data suggest that po results in a chronic elevation of actin secretion (1255)suggests a functional role for tence c dian hypoth mctiming mecha THDA ne urons.Ho ver,data are unavailable to suggest which in of e uron ing th the tha the hypothalamus since caudal transection of pre sion of the pre a role in the surg of tion fferents (939)or les proestrus.Numerous candidates abound.TrH is one of the earliest proposed candidates.Passive immunoneutral ulates s surge (1370).Indeed,ample evidence sugg of endog ous RH has been rep that both forms (a and B)of the estrogen recepto are 788) e pro the preoptic area(161,19, TRH d by the tal blood is slightly elevated during the aftemo roestrus (553).However,there is no distinct concomi cvcle will advance the proestrous surg tant elevation in TSH secretion during the afteroon of day (1305).Moreover.progesterone enhances the magni- proestrus (178)which,intuitively,should be expected t tud of an estrogen-induced proestru urge of pro to TRH rat 19 d the on r rus ha s vet to be described. estrus (1551).Hourly iniections of an oxvtocin antag Hypothalamic control of the preov ulatory proestrous surge of prolactin is far from clear.Although it is clear uates the that dopamine inhibits prolactin secretion and that re- estrogen-induced proestrus-like surge of prolactin (1537
During the afternoon of proestrus, a preovulatory surge of prolactin secretion occurs, which is similar in timing to that of LH (1647). Although the LH surge on proestrus is symmetrical, the surge of prolactin consists of a rapid, sharp peak followed by a prolonged plateau and an extended termination phase (60, 1259). Although most laboratories have reported a single surge of prolactin on proestrus (608, 1296, 1647), others have reported a secondary surge on estrus (254) or continuously elevated prolactin levels on proestrus, estrus, and metestrus (34). Because these latter results may have been caused by the method and frequency of blood collection, it is generally accepted that the afternoon of proestrus is the only time that a major surge of prolactin secretion occurs. Because the events of the rodent estrous cycle and those of the primate menstrual cycle share some common controls, it would not be illogical to expect a midcycle surge of prolactin during the menstrual cycle that coincides with that of luteinizing hormone. However, only one study finds a small, late follicular phase rise of prolactin secretion culminating in a midcycle peak that is only 50% greater than prolactin levels of the early follicular phase (1812). Such small changes can easily be overshadowed by pulsatile changes, thus leading to a failure to detect significant variations at midcycle in individual samples. It is clear that the rising blood levels of estradiol signal the hypothalamo-pituitary axis to release this surge of prolactin on proestrus. Administration of an antiserum to estradiol on the morning of diestrus-2 blocks the proestrous surge of prolactin (1302). A single injection of estradiol given to ovariectomized rats results in daily surges of prolactin that are similar in timing to the proestrous surge of prolactin (1297). These data suggest the existence of a circadian hypothalamic timing mechanism that is enhanced by estradiol. This mechanism by which estradiol induces a proestrous surge of prolactin secretion probably involves actions at the preoptic area of the hypothalamus, since caudal transection of preoptic efferents (939) or lesion of the preoptic area (1369) block the estradiol-stimulated surge of prolactin secretion, while implantation of estradiol in the preoptic area stimulates a surge (1370). Indeed, ample evidence suggests that both forms (a and b) of the estrogen receptor are expressed by the neurons of the preoptic area (161, 195, 358, 995, 1039, 1388, 1869, 1925). Progesterone administered on diestrus-3 of a 5-day cycle will advance the proestrous surge of prolactin by 1 day (1305). Moreover, progesterone enhances the magnitude of an estrogen-induced proestrus-like surge of prolactin in ovariectomized rats (259, 1911). However, the precise role of progesterone in the secretion of prolactin on proestrus has yet to be described. Hypothalamic control of the preovulatory proestrous surge of prolactin is far from clear. Although it is clear that dopamine inhibits prolactin secretion and that removal of the tonic dopaminergic inhibition results in enhanced prolactin secretion, the role of dopamine as a regulator of the proestrous surge of prolactin is contradictory. Hypothalamo-hypophysial portal blood concentrations of dopamine (140), the activity of tyrosine hydroxylase (287), the turnover of dopamine in the median eminence (411), and the subsequent concentration of dopamine in the anterior lobe of the pituitary gland (420) have been reported to decline on proestrus before the increase in prolactin secretion. On the other hand, others have reported no change in dopamine turnover at the same time (786, 1448). Similarly, dopamine receptors in the anterior pituitary have been reported to both increase (1384) and decrease (748) during the afternoon of proestrus. The source of dopamine controlling prolactin secretion is believed to be TIDA neurons with cell bodies in the arcuate nucleus of the hypothalamus and axons terminating in the median eminence. However, there is ample evidence that some of the dopamine arrives at the anterior lobe of the pituitary gland from the posterior lobe that contains axon terminals of tuberohypophysial dopaminergic (THDA) neurons whose cell bodies are found in the rostral part of the arcuate nucleus (63). In addition, dopamine may arrive from the intermediate lobe that contains axon terminals of periventricular-hypophysial dopaminergic (PHDA) neurons that reside in the hypothalamic periventricular nucleus (655, 656). The short portal vessels connecting the lobes of the pituitary gland may serve as the vascular pathway through which dopamine is transported to the anterior lobe from the neural and intermediate lobes of the pituitary gland. Indeed, the fact that posterior lobectomy results in a chronic elevation of prolactin secretion (1255) suggests a functional role for THDA neurons. However, data are unavailable to suggest a similar role for PHDA neurons. Further muddying these waters is the fact that a prolactin-releasing hormone of hypothalamic origin must play a role in the surge of prolactin secretion on proestrus. Numerous candidates abound. TRH is one of the earliest proposed candidates. Passive immunoneutralization of endogenous TRH has been reported to partially inhibit (963) or delay the onset (788) of the proestrous surge of prolactin. Indeed, the concentration of TRH in portal blood is slightly elevated during the afternoon of proestrus (553). However, there is no distinct concomitant elevation in TSH secretion during the afternoon of proestrus (178) which, intuitively, should be expected to accompany the increase in prolactin secretion on proestrus. Similar to TRH, the concentration of oxytocin increases in portal blood during the afternoon of proestrus (1551). Hourly injections of an oxytocin antagonist block the proestrous surge of prolactin (867), and administration of an antiserum to oxytocin attenuates the estrogen-induced proestrus-like surge of prolactin (1537). October 2000 PROLACTIN 1539
1540 FREEMAN,KANYICSKA,LERANT,AND NAGY Volume 80 3.Mating and pregnancy which lactin se in th is a lute otrophic hormo】 stimulation or manipulation of the preoptic area requires an intac luteal phase due to the lack of sufficient prolactin to dorsomedial/ventromedial hypothalamic nu 710 maintain the corpus luteum.However,if mating occurs or (70% a copulomimetic stimulus is applied to the uterine cervix. nuclei of the hypothalan s ar sible for the faithful tin a of the g-ind corpus lut eum is res was ssumed tha surges of prolactin (168).which are under the control of With the an endogenous cir adian rhythm (167).After cervica iol of the firs for prolactin (1304)it was shown that mating did not ation,w aily reases mn t roe induce constantly elevated prolactin secretion but rather 1029.tha sted that s of prolact the rats are produces a se speciflc stimulatory rhythm regulating prolactin secretion which is unmasked by the dopamine noon (1300 ng I the maning he ute 1500 b)reaches neak values during the early evening (1700-1800 h),and retumns to basal levels by 2400h. othe surge, called noctura begins blood feeding the sinusoid capillaries of the anterior pi by03 approf the tuitary gland (73,76).The timing of these events,the 10 tile and ults in nregnaney (255 1648) for crease in dopaminergic ton ed by 12 days in pseudo regnancy when mating is sterile or ds to the copulomimetic (584.1647. There are animals (76)The key neurotransmitters regulating each of thes oxvtocin-dependent events are different The oxytocin-m tal laot 1amic1 evels(64,649,1755,1756,1760-1763.1832-1834 e to ion73,74 1838),the details of which re described in section vic. 77 stimulate It has been argued that a luteotrophic mechanisn can ids()n inde activa d by a manng stimulus,is one of e more etnc I00 cretion of ns udopremancy end after day due to the diminishing secretion of progesterone from the waning shorten the lutea ase during cucles when an corpora lute with the rising titers of estradio ovulation is not associated with a fertile mating and con- from the wly cepto whereas an active luteal phase,preparing the embryo,is only associatec ed fo which inhibi timuln of an by acting directly on the lactotroph (647.648.650) The reas of the hypothalamus upon which the mat ing stimu C.Prolactin Release in Re to E sponse 710020m tra ath nelvie nerve (275 1509 1874)Presumably the mating stimulus is carried over spinal afferent pathways and A)CIRCADIAN PATTERNS.In photoperiodic mammals such enters the brain. hough the exact pathy as rats.light is an importan regulator of prolactin secre ing of the light ph 179.h mothalan on the hasis of classical lesion and stim induced nroestrus-like and the mating-induced ulation studies,it appears that the preoptic area of the surges of prolactin in rats (1418)When placed in constan hypothalamus contains two lunctional neuronal popula light,rats become acyclic (772).Complete removal of a by placing 1 s-lik of (581,706).It appears that the uterine cervical stimulation estrogen-treated ovariectomized rats (1418)and free-run of mating inactivates the former and activates the latter. ning mating-induced surges of prolactin secretion (167
3. Mating and pregnancy As noted earlier, prolactin is a luteotrophic hormone in the rat. Indeed, the unmated rat has an extremely short luteal phase due to the lack of sufficient prolactin to maintain the corpus luteum. However, if mating occurs or a copulomimetic stimulus is applied to the uterine cervix, the corpus luteum is rescued. It was assumed that the mating stimulus eventuated in elevated prolactin secretion. With the availability of the first radioimmunoassay for prolactin (1304), it was shown that mating did not induce constantly elevated prolactin secretion but rather twice daily surges of prolactin. If the rats are kept under 12:12-h dark-light cycles, with lights on at 0600 h, the diurnal surge of prolactin secretion begins in the afternoon (1300–1500 h), reaches peak values during the early evening (1700–1800 h), and returns to basal levels by 2400 h. The other surge, called nocturnal, begins by 0100 h, peaks by 0300–0700 h, and approaches baseline by 1100 h. These surges recur for 10 days if the mating is fertile and results in pregnancy (255, 1648), or persist for 12 days in pseudopregnancy when mating is sterile or copulomimetic (584, 1647). There are abundant data which show that the surges of prolactin cease after day 10 of pregnancy due to the negative-feedback action of placental lactogen acting at both pituitary and hypothalamic levels (64, 649, 1755, 1756, 1760–1763, 1832–1834, 1838), the details of which are described in section VIIC3. Prolactin secretion stimulated by copulomimetic stimuli can be initiated and maintained independent of ovarian steroids (585). In contrast, the surges of prolactin secretion of pseudopregnancy end after day 13 due to the diminishing secretion of progesterone from the waning corpora lutea coupled with the rising titers of estradiol from the newly developing ovarian follicles (645). Moreover, the nonpregnant uterus itself secretes an, as yet, uncharacterized factor, which inhibits prolactin secretion by acting directly on the lactotroph (647, 648, 650). The areas of the hypothalamus upon which the mating stimulus acts to initiate this unique pattern of prolactin secretion have also been characterized (581, 705–707, 710, 920). The primary transduction pathway involves the pelvic nerve (275, 1509, 1874). Presumably, the mating stimulus is carried over spinal afferent pathways and enters the brain. Although the exact pathways in the entire brain have not been mapped, pharmacological and physiological studies have implicated various areas of the hypothalamus. On the basis of classical lesion and stimulation studies, it appears that the preoptic area of the hypothalamus contains two functional neuronal populations controlling prolactin secretion (581). In the unmated rat, one population is tonically active and inhibits the nocturnal surge of prolactin, whereas the other is inactive (581, 706). It appears that the uterine cervical stimulation of mating inactivates the former and activates the latter, which eventuates in nocturnal and diurnal surges of prolactin secretion. Induction of the surges either by cervical stimulation or manipulation of the preoptic area requires an intact dorsomedial/ventromedial hypothalamic nucleus (707, 710). The suprachiasmatic nuclei of the hypothalamus are responsible for the faithful timing of the mating-induced surges of prolactin (168), which are under the control of an endogenous circadian rhythm (167). After cervical stimulation, two daily decreases in the activity of neuroendocrine dopaminergic neurons of the hypothalamus occur (1029). It has been suggested that the hypothalamus produces a sex-specific stimulatory rhythm regulating prolactin secretion which is unmasked by the dopaminelowering actions of the mating stimulus at the uterine cervix (71). It has been proposed that prolactin-releasing quanta of oxytocin are released twice each day into portal blood feeding the sinusoid capillaries of the anterior pituitary gland (73, 76). The timing of these events, the decrease in dopaminergic tone followed by an increase in the concentration of oxytocin in portal blood, corresponds to the release of prolactin in cervically stimulated animals (76). The key neurotransmitters regulating each of these oxytocin-dependent events are different. The early morning (nocturnal) oxytocin-mediated prolactin release is regulated by VIP, whereas the diurnal event seems to be dependent on serotonergic activation (73, 74, 77). It has been argued that a luteotrophic mechanism, activated by a mating stimulus, is one of the more efficient systems governing reproduction (580). In rodents, it is advantageous for quick turnover of generations to shorten the luteal phase during estrous cycles when an ovulation is not associated with a fertile mating and conception, whereas an active luteal phase, preparing the uterus for implantation of an embryo, is only associated with a mating stimulus. C. Prolactin Release in Response to Exteroceptive Stimuli 1. Light A) CIRCADIAN PATTERNS. In photoperiodic mammals such as rats, light is an important regulator of prolactin secretion. Indeed, shifting of the light phase results in a coincidental shift of the proestrous surge (179), the estrogeninduced proestrus-like surge, and the mating-induced surges of prolactin in rats (1418). When placed in constant light, rats become acyclic (772). Complete removal of a photoperiod by placing the animals in constant light or through various means of light deprivation result in freerunning proestrus-like surges of prolactin secretion in estrogen-treated ovariectomized rats (1418) and free-running mating-induced surges of prolactin secretion (167, 1540 FREEMAN, KANYICSKA, LERANT, AND NAGY Volume 80
PROLACTIN 1541 1418).The effects require an intact suprachiasmatic engendered these seemingly paradoxical sequences of nucleus (168).These data point to the fact that these events. events are 2.Audition fected by of day ler 1 In adult male hamster 2 mo of ev to a short nsive and robust but the least studied (682 photoperiod (5 h of light.19 h of darkness)causes testic se of 1733,1831).Recordings of ultrasounds of hungry pups (96 170 ough testicula regressi stimulat prolactin secretion in lactating and virgin ra 733).Thi ne nypo adult iated with short days is not c This may the basis for this response has not been studied,one can not be unexpected given that the effects of short photo period on testicular regression and blunting of prolactin sily imagine its utility.Indeed,ultrasound-induced ma prola may e respons or prepa sec may be under certain the ed n in is tr rted to the milk to act as otion can he re a stimulator of the pups'development. versed by infusion of Vip into the paraventricular nueleus 3.Olfaction of the hypothalamus (97) n ewe anothe seasonal mammal,shortene bust o the ch olf ctory stimuli play ar days the se prolac to the ant female will result in early loss of pregnancy in mice.This phenomenon is iod is mediated by melatonin secre ted from the pineal referred to as the Bruce effect,in recognition of its dis gland (385,1431,1432),transduced through the suprachi- r(229 o).The omor signal is co yed to asmatic nuc eus (1 on the glan 050 ratigdrewyonhepa glomeruli.The mitral cells.in turn.excite cells of the corticomedial amygdala(1038),which excite cells in the aminergic activity does not ear to have a direct medial preopti area of the hypothalamus effect on prolactin secretion (1817).In addition,dopa- and re that the mine does not mediate the suppressing ef cts of melato- to the lopamine-induced suppr on of prolactin secre d informatio tion (1503)and consequently its luteotrophic support Indeed, replaceme of prolactin reverse abortive from mother to fetus in both she (488)and har male (1600).Pregnant ewes exposed to short days give birth to th the mother's cage stimulates prolactin se lambs that have lower serum prolactin concentrations (1183.1184)but.interestingly.inhibits milk secretion in than those of dams exposed to long days.Pre atal expo late lactation (6 sure of pre days res 2).On the other hand,when placed nex to the LO tho om dams ex sed to long days :Female ha onates are unaffected by altered pr tory mechanism is more sensitive than the galacto natal nhotoneriod These prolactin-secretory responses prest mably involve poetic mechanism to pup odor in late lactating rats. nin as affe ted by the photoperiod (190 4.Stress eep,od 2 3831 It is cle cretion with i the tal mus appears to mask or suppress these effects (801)The to characterize such effects on retion.These basis for the return of fetal independence from matemal include,but are not limited to,the following:ether stre influence is not yet fully appreciated.It is possible that the 667.866 876.89 107 1105, varying paradigms of photoperiod exposure may have 1913),restraint stress(416,590,598,883,923,944,1446
1418). These effects require an intact suprachiasmatic nucleus (168). These data point to the fact that these events are under the control of an endogenous circadian rhythm and that lighting periodicity entrains that rhythm. B) SEASONAL PATTERNS. Prolactin secretion is also affected by variations of day length in seasonal mammals. In adult male hamsters, 2 mo of exposure to a short photoperiod (5 h of light, 19 h of darkness) causes testicular regression and a precipitous decline in release of prolactin (98, 170). Although testicular regression is blocked by transections dorsal or ventral to the hypothalamic paraventricular nucleus (845), the fall in prolactin secretion associated with short days is not (99). This may not be unexpected given that the effects of short photoperiod on testicular regression and blunting of prolactin secretion may be dissociated under certain regimens (455), thus suggesting two different levels of control for these two photoperiodic events. Indeed, the effect of shortened photoperiod on prolactin secretion can be reversed by infusion of VIP into the paraventricular nucleus of the hypothalamus (97). In the ewe, another seasonal mammal, shortened days lead to a diminution of prolactin secretion (927). In rams, the effect presents itself within a week of exposure to the shortened photoperiod (1052). The effect of photoperiod is mediated by melatonin secreted from the pineal gland (385, 1431, 1432), transduced through the suprachiasmatic nucleus (1582), or acting directly on the pituitary gland (1050). Short days also diminish the activity of tyrosine hydroxylase and the content of dopamine in the median eminence (1738, 1816). However, this reduction in dopaminergic activity does not appear to have a direct effect on prolactin secretion (1817). In addition, dopamine does not mediate the suppressing effects of melatonin on prolactin secretion (1051, 1053, 1817). It has been shown that photoperiodic information regulating postnatal prolactin secretion is transferred from mother to fetus in both sheep (488) and hamsters (1600). Pregnant ewes exposed to short days give birth to lambs that have lower serum prolactin concentrations than those of dams exposed to long days. Prenatal exposure of pregnant hamsters to short days results in male offspring producing higher prolactin concentrations than those from dams exposed to long days. Female hamster neonates are unaffected by altered prenatal photoperiod. These prolactin-secretory responses presumably involve maternal melatonin as affected by the photoperiod (1908, 1909). In fetal sheep, prolactin secretion is also affected by maternal photoperiod or melatonin (124, 1383). However, with increasing gestational age, the fetal hypothalamus appears to mask or suppress these effects (801). The basis for the return of fetal independence from maternal influence is not yet fully appreciated. It is possible that the varying paradigms of photoperiod exposure may have engendered these seemingly paradoxical sequences of events. 2. Audition Of the many environmental inputs controlling prolactin secretion, the effect of specific sounds is one of the most responsive and robust but the least studied (682, 1733, 1831). Recordings of ultrasounds of hungry pups stimulate prolactin secretion in lactating and virgin female rats (1733). This response is specific to ultrasounds generated by pups as adult ultrasound or background tape noise does not affect prolactin secretion. Although the basis for this response has not been studied, one can easily imagine its utility. Indeed, ultrasound-induced maternal prolactin secretion may be responsible for preparing the mammary gland for a subsequent suckling bout or the released prolactin is transported to the milk to act as a stimulator of the pups’ development. 3. Olfaction Of the chemical senses, olfactory stimuli play a robust role in prolactin secretion. Pheromones secreted by a male unfamiliar to the pregnant female will result in early loss of pregnancy in mice. This phenomenon is referred to as the Bruce effect, in recognition of its discoverer (229–231). The pheromonal signal is conveyed to the accessory olfactory bulb by the vomeronasal nerves, which synapse on the primary dendrites of mitral cells in glomeruli. The mitral cells, in turn, excite cells of the corticomedial amygdala (1038), which excite cells in the medial preoptic area of the hypothalamus and result in excitation of TIDA neurons of the arcuate nucleus (1037). The implication is that the loss of pregnancy occurs due to the dopamine-induced suppression of prolactin secretion (1503) and consequently its luteotrophic support. Indeed, replacement of prolactin reverses the abortive effect of the unfamiliar male’s pheromones (453, 454). In lactating female rats, the odor of the pups placed beneath the mother’s cage stimulates prolactin secretion (1183, 1184) but, interestingly, inhibits milk secretion in late lactation (682). On the other hand, when placed next to the mother, pup odors are stimulatory to both prolactin secretion and milk secretion (682). Thus the prolactin secretory mechanism is more sensitive than the galactopoetic mechanism to pup odor in late lactating rats. 4. Stress It is clear that prolactin secretion is dramatically affected by “stress.” A myriad of stresses have been used to characterize such effects on prolactin secretion. These include, but are not limited to, the following: ether stress (116, 667, 866, 876, 893, 1077, 1105, 1200, 1257, 1296, 1913), restraint stress (416, 590, 598, 883, 923, 944, 1446), October 2000 PROLACTIN 1541
1542 FREEMAN,KANYICSKA,LERANT,AND NAGY Because in most cases ansa7ls VIL.REGULATION OF PITUITARY PROLACTIN SECRETION the prolactin-secretory re spo stin nulation or inhibition)differs deper Prolactin se cretion is affected by a large variety of anno a un stimuli provided by the environment and the interna with each sp e (Fig.3).The most important physiological stimul tha The prolactin-secretory response to ether stress has i2961208 been reported to differ during the reproductive state of ovarian steroids,primarily estrogen (1298,1301).Such the rat. stimuli are transduced by the hypothalamus which elab (1296)Ho er,ther ora a host of PRF and prolactin-inhibiting factors (PlF of the estrus.For example,ether stress ha (F1g 3). increase (855),decrease 1231.or effect on tor (40 on the other hand the is as (129 applied g the a evels c m00 I pro involved in the acute stimulatory control of prolactin re the secretion by removal of the inhibition (disinhibition) se the rge while application during the surge vor su p on nput.In a att es it (1649) Sin restraint stress the released by the lactotrophs the k or pro regulation)or by other cells s within the pituitary gland (paracrine regulation)(Fig.3). the surge of prolactin during (12921 pregnancy (1223).Bec ause dop pamine is the hypothalamic A.CNS harabtmgpoL The in the sly high view is that lac tion Indeed ni zide a dopamine antas onist n etion is under a toni restraint stress-induced decrease in the estroge nduced trus-like 8) tha This view is based on the following a m on in ary gla veling or lactating 9231r3ts Othe r pituitary stalk section)results in gradual inc ase ir substance implicated in the prolactin-secretory stres plasma prolactin that reaches a plateau within a week response includ serotonin( 76. (85 after thes 174,899,1004). is at s ra when d cin (956).and in (953) or neural connection to the hynothalamus (eg under the The physiological importance to the organism of the kidney cansule)(523 524)or when pituitary cells are cre ory response to stress is rather elusive.It cultured in vitro (1298,1299,1590).Thus it appears that is clear tha ely res vivo by the rat(1222)nor reduction of the mating-ac rated noc ma The n cise characteristics of the regulation of nre surge has any effect on the outcor of a pre nancy or lactin sec retion are fundamentally determined by the pseudopregnancy in the rat(1223 GI en the finding of cal status of the animal.Therefore,for the pur for pro nima od th ss has an imn odulatory function ng the of this specific atte tion will be ven to anima ganism from the cons cquences of stres (597 Although els with obvious physiological significance such as there are no experimental data to support the estrous cycle of female rats (proestrous prolactin t has b en sug that prolactin n,particularly surge oregnan that ced prolactin secretion) an other roles probably in maintaining homeostatic balance male rats (stress-related prolactin secretion).Different affected by other stress hormones.exist as well experimental models emphasizing particular stages of the
thermal stress (1782a), hemorrhage (274, 883), social con- flict (817), and even academic stress in humans (1108). Because, in most cases, the prolactin-secretory response (i.e., stimulation or inhibition) differs depending on the nature of stress, one cannot describe a unitary mechanism but must define the mechanism associated with each specific stress modality. The prolactin-secretory response to ether stress has been reported to differ during the reproductive state of the rat. During diestrus of the estrous cycle, ether stress increases prolactin secretion (1296). However, there is no universal agreement as to the nature of the responses at proestrus. For example, ether stress has been reported to increase (855), decrease (1231), or have no effect on (1296) prolactin levels during the afternoon of proestrus. Restraint stress applied before the surge of prolactin secretion on the afternoon of proestrus enhances the surge while application during the surge attenuates it (1649). Similarly, restraint stress suppresses the proestrus-like estrogen-induced afternoon surge of prolactin in ovariectomized rats (598). It has also been reported that restraint stress suppresses the nocturnal surge of prolactin during pseudopregnancy (1221) or pregnancy (1223). Because dopamine is the hypothalamic neurohormone tonically inhibiting prolactin secretion, it is intuitively obvious that dopamine would also be implicated in the stress-mediated effects on prolactin secretion. Indeed, pimozide, a dopamine antagonist, prevents restraint stress-induced decrease in the estrogen-induced afternoon proestrus-like surge of prolactin (598). Moreover, a modest increase in TIDA neuronal activity accompanies restraint stress in estrogen-treated (1224) but not in cycling or lactating (923) rats. Other hypothalamic substances implicated in the prolactin-secretory stress response include serotonin (865, 876), histamine (953, 956), N-methyl-D,L-aspartic acid (214), atrial natriuretic peptide (571), b-endorphin and dynorphin (1407), oxytocin (956), and vasopressin (953). The physiological importance to the organism of the prolactin-secretory response to stress is rather elusive. It is clear that neither the stress-induced attenuation of the proestrous prolactin surge affects the estrous cycle of the rat (1222) nor reduction of the mating-activated nocturnal surge has any effect on the outcome of a pregnancy or pseudopregnancy in the rat (1223). Given the finding of a role for prolactin in humoral or cell-mediated immunity, it can be argued that the prolactin-secretory response to stress has an immunomodulatory function protecting the organism from the consequences of stress (597). Although there are no experimental data to support this hypothesis, it has been suggested that prolactin secretion, particularly during lactation, acts as a protective factor in stressinduced gastric ulcers (464). Teleology would advise that other roles, probably in maintaining homeostatic balance affected by other stress hormones, exist as well. VII. REGULATION OF PITUITARY PROLACTIN SECRETION Prolactin secretion is affected by a large variety of stimuli provided by the environment and the internal milieu (Fig. 3). The most important physiological stimuli that elevate pituitary prolactin secretion are suckling (1298, 1732), stress (1296, 1298), and increased levels of ovarian steroids, primarily estrogen (1298, 1301). Such stimuli are transduced by the hypothalamus which elaborates a host of PRF and prolactin-inhibiting factors (PIF) (Fig. 3). In mammals, the control exerted by the hypothalamus over pituitary prolactin secretion is largely inhibitory (140). On the other hand, the hypothalamus is also involved in the acute stimulatory control of prolactin secretion by removal of the inhibition (disinhibition) and/or superimposition of brief stimulatory input. In addition, prolactin secretion is also influenced by numerous factors released by the lactotrophs themselves (autocrine regulation) or by other cells within the pituitary gland (paracrine regulation) (Fig. 3). A. CNS The general and well-accepted view is that lactotrophs have spontaneously high secretory activity. Therefore, pituitary prolactin secretion is under a tonic and predominant inhibitory control exerted by the hypothalamus. This view is based on the following observations: 1) surgical disconnection of the pituitary gland and the medial basal hypothalamus (median eminence lesion or pituitary stalk section) results in gradual increase in plasma prolactin that reaches a plateau within a week after these surgeries (79, 174, 899, 1004), 2) prolactin secretion occurs at a high spontaneous rate when the anterior lobe is transplanted to a site that has no vascular or neural connection to the hypothalamus (e.g., under the kidney capsule) (523, 524), or 3) when pituitary cells are cultured in vitro (1298, 1299, 1590). Thus it appears that prolactin secretion is severely restrained in vivo by the action of hypothalamic PIF. The precise characteristics of the regulation of prolactin secretion are fundamentally determined by the physiological status of the animal. Therefore, for the purpose of this review, we will make reference to the animal model used in the studies involved. To narrow the scope of this review, specific attention will be given to animal models with obvious physiological significance, such as the estrous cycle of female rats (proestrous prolactinsecretory surge), pregnant/pseudopregnant female rats (daily nocturnal and diurnal prolactin surges), lactating female rats (suckling-induced prolactin secretion), and male rats (stress-related prolactin secretion). Different experimental models emphasizing particular stages of the 1542 FREEMAN, KANYICSKA, LERANT, AND NAGY Volume 80