Klinische Wochenschrift

Klin Wochenschr (1990) 68 : 11521167

9 Springer-Verlag 1990

Review

Control of Prolactin Secretion* G. Benker ~, C. Jaspers 1, G. H/iusler 2, and D. Reinwein 1 a Abteilung fiir Endokrinologie, Medizinische Klinik und Poliklinik, Universit/it Essen 2 Abteilung ffir Pharmakologie, E. Merck, Darmstadt

Summary. 1. Prolactin is a 21,500 Dalton singlechain polypeptide hormone but may occur in 50 k D a and 150 k D a molecular variants. 2. These large P R L variants may be secreted predominantly; this condition is termed "macroprolactinemia". It is characterized by high immunological and normal biological serum levels of prolactin, and lack of clinical symptoms of hyperprolactinemia. 3. The information on P R L is encoded on chromosome 6. Transcription can be enhanced and suppressed by a variety of hormonal factors. 4. P R L is secreted in a pulsatile fashion; it displays a circadian rhythm (with a maximum during sleep) and is stimulated by some amino acids. P R L also responds to mechanical stimulation of the breast. 5. P R L rises during pregnancy, and maintainance of hyperprolactinemia (and, thereby, physiological infertility) is dependent on the frequency and duration of breast feedings. 6. Hypothalamic regulation of prolactin mainly involves tonic inhibition via portal dopamine. The physiological importance of various stimulating factors present in the hypothalamus is still incompletely understood. In particular, there is still no place for T R H in P R L physiology. 7. P R L is released in response to stress; this response may be mediated by opioids. The low-estrogen, low-gonadotropin amenorrhea of endurancetraining women is not mediated by prolactin, however. * Presented in part to the European Society for Clinical Investigation, Maastricht, April 27, 1990 Abbreviations: PRL = prolactin; rPRL = rat prolactin; mRNA=messenger ribonucleic acid; DNA=desoxyribonucleic acid; MEA=multiple endocrine adenomatosis; T R H = thyreotropin releasing hormone; VIP=vasoactive intestinal peptide; kDa = kilodalton; EGF = epidermal growth factor

8. Estrogens stimulate P R L gene transcription via at least two independent mechanisms. There are many clinical examples of this estrogen effect on prolactin serum levels, and also on the growth of prolactinomas. 9. Mild hyperprolactinemia remains an enigma which cannot satisfactorily be resolved by biochemical or radiological testing. The border between " n o r m a l " and "elevated" prolactin is illdefined. The possibility of macroprolactinemia complicates this matter even further. 10. The number of drugs which suppress prolactin by acting on pituitary D2 receptors, and which are useful in the treatment of hyperprolactinemia, continues to increase. In the field of ergot alkaloids, parenteral application appears to be a logical solution to the problem of the high first-pass effect; in addition, this form of treatment is frequently better tolerated than the oral route. 11. Prolactinoma development is presently being studied employing molecular biological techniques; the question of whether tumorigenesis can be attributed to specific defects of gene regulation remains to be answered. Key words: Prolactin - Prolactin gene - Estrogen - Pregnancy - Prolactin-producing tumors - T R H / Dopamine agonist drugs - Dopamine receptor

Since the detection ofprolactin as a hormone independent of growth hormone and the introduction of the radioimmunoassay, interest in this field has remained fairly constant for the last 10-15 years, attracting both basic scientists and clinicians. Cell and tissue culture studies, animal experiments, and studies in normal subjects and in patients with various disorders have contributed to our present

1158 knowledge of this hormone. There are several key points of interest in this field: 1. Pituitary tumors in general, and prolactinomas in particular, continue to be an area of exciting diagnostic and therapeutic efforts for neurosurgeons, radiologists, and endocrinologists. 2. Adverse effects on reproductive function caused by hyperprolactinemia still represent an important diagnostic and therapeutic challenge to endocrinologists and gynecologists. 3. Hyperprolactinemia is related to psychotropic drugs and, hence, of interest to psychiatrists. 4. The relationship of prolactin to stress and exercise concerns neuroendocrinologists, behavioral scientists, gynecologists, and physicians involved in sports medicine. 5. Studies of the prolactin gene, and the control of m R N A transcription, connect prolactin research to molecular biology. 6. Lastly, development of drugs affecting prolactin secretion provides an expanding field for clinical pharmacologists and physicians involved in treatment of patients with hyperprolactinemia. I. Prolactin and the Prolactin Gene Progress in recent years has been made particularly in elucidating the molecular basis of prolactin physiology. Prolactin is composed of 199 amino acids and has a molecular weight of 21,500 Dalton; the prolactin gene is located on chromosome 6 and contains 914 base pairs [81]. The cDNA clone complementary to prolactin messenger R N A has been synthesized in vitro [77]. Demethylation seems to be an important control element, since non-prolactin-producing cell lines can be induced to express prolactin by treatment with 5-azacytidine, which inhibits D N A methylation [74]. Table 1 gives an overview of the hormones which regulate prolactin gene expression. Hormone-response elements have been identified in the Y-flanking region of the r P R L gene [26]. The distal enhancer region seems to contain elements which are responsive to several hormones, including cAMP, TRH, EGF, and estrogen [29]. Apart from the pituitary, prolactin is secreted by other tissues, in particular by the decidua, where it is thought to regulate volume transfer, and where regulation is different, involving progesterone, calcium, and arachidonic acid. 2. Normal Plasma Levels In the adult human, prolactin plasma levels average 10 gg/L (the existence of other prolactin stan-

G. Benker et al. : Control of Prolactin Secretion Table 1. Hormones which regulate expression of the prolactin gene (note that much of the experimentalwork has been carried out with rPRL). Various hormones act through differentintracellular mechanisms,e.g., TRH via protein kinase C, EGF by activation of a transmembraneprotein kinase, and VIP by activation of adenylatecyclase. Modified from Melmed et al. [73] and Davis et al. [28] Hormone

Gene SynthesisAcute transcriprelease tion

Longterm secretion

Intracellular

cAMP Calcium Phorbol ester

+ + +

+ + +

+

+

+ ?

+ + + +

Hypothalamic

Dopamine TRH [58] GABA [64] VIP [17, 96] GnRH-related peptide [80]

m

+

+

+ -

+ -

+ ?

+

no effect +

-

no effect -

+

no effect +

Peripheral

Estrogen [112] Glucocorticoid [1] Insulin [90] T3 [30] Vitamin D [125] EGF [113]

dards measuring gU/ml is a matter of frequent confusion), and the normal limit is about 20 gg/L. The upper limit of normal is difficult to define, but obviously bears on the reported incidence of hyperprolactinemia. Values in males and prepubertal children are lower than in females. Direct stimulation of the nipples and areolae is a powerful stimulus to prolactin secretion which does not act via dopamine or T R H [94]. Prolactin is also stimulated by amino acids, phenylalanine and tyrosine being the most important stimuli [19]. 3. Circadian Rhythm and Pulsatility of Prolactin Secretion Within the circadian rhythm, the existence of which has long been recognized, prolactin rises during the late hours of sleep to 160-180% of baseline levels [25]. Pulses of 12-13 gg/L are superimposed on basal prolactin secretion at a rate of about 14 per 24 hours, and at a duration of about 1 hour per pulse [121]. Since pulse frequency is unchanged by hypothalamopituitary disconnection, it appears that only pulse amplitude, and not frequency, is under direct hypothalamic influence [201.

G. Benker et al. : C o n t r o l o f Prolactin Secretion

1159

4. State in Plasma, Pituitary Secretion

the frequency and duration of feeding [46]. Suckling increases PRL m R N A levels in the pituitary, and thereby PRL synthesis and secretion; the cessation of suckling leads to a prompt decrease in synthesis and secretion within 24 hours [62]. Once pregnancy and breast-feeding are accomplished, there seems to be a lasting and irreversible decrease in prolactin levels. A study of 5000 women of Guernsey showed that increasing parity was associated with a step-wise reduction in mean prolactin levels; this effect was noted up to 35 years after childbirth; the protective effect on breast cancer risk of multiparity and early first pregnancy could be mediated by such a life-long reduction in blood prolactin levels [124].

By gel filtration, most of the circulating prolactin (normally more than 90%) is monomeric; it is a 22 kD single polypeptide chain, while the remainder consists of 50 kD ("big prolactin") and 150 kD ("big big prolactin") components [111]. There is no evidence that the high molecular weight forms are due to protein binding. 150 kD prolactin may be predominantly released in some persons, a condition which has been termed "macroprolactinemia" [5, 49, 56, 127]. The large molecular weight forms have diminished receptor binding [33, 40] and decreased mitogenic activity in the Nb2 rat lymphoma assay (a cell line for which prolactin acts as a mitogen). Macroprolactinemia may, therefore, coexist with normal reproductive function; in pregnant women with macroprolactinemia, monomeric prolactin increases proportionally more than big big prolactin; monomeric prolactin also responds more readily to provocative stimuli, such as T R H and suckling, or to inhibition, such as by bromocriptine [39]. There has even been a report of macroprolactinemia being transmitted not via placental transfer - to an infant [50]. Little is known about the natural course of this abnormality, but the phenomenon may disappear spontaneously [65]. Posttranslational glycosylation of prolactin may take place; several glycosylated forms have been detected in human plasma, with molecular weights of 23, 25, and 27 K [68]; information about their physiological significance is still lacking. In the media of cultured murine pituitaries and in pituitary extracts, 2 proteins of 13,000-18,000 Da are detected which are termed prolactin-related proteins [107]. Their physiological role is as yet unclear.

5. Pregnancy and the Fetus During pregnancy, prolactin starts to rise in the first trimester, reaching 100-300 ~tg/L in the last trimester, and returning to normal within 23 months post partum unless breast-feeding is started. Normal 24-hour patterns of prolactin secretion are maintained during pregnancy [11]. In hyperprolactinemia, big big prolactin remains increased during pregnancy, with a shift towards little prolactin near delivery [57]. In the fetus, prolactin production of the pituitary starts at the l l t h week of gestation, and levels also rise until delivery. High prolactin levels are maintained in the mother during breast-feeding [129], depending on

6. Hypothalamic Control Hypothalamic influence is exerted via the portal blood system, the main (and probably exclusive) effect on the lactotrophs being inhibitory via dopamine. Dopamine receptors are expressed on pituitary lactotrophs. Other neurotransmitters have been implicated in prolactin regulation; however, dopamine is far more important than the serotoninergic or the GABAergic system [38]. Dopamine receptors are discussed below in paragraph 12. By acting on its receptor on the lactotrophe, dopamine finally inhibits prolactin m R N A levels at the level of prolactin gene transcription [72]. Opiates seem to exert a stimulatory effect, but are not essential for basal secretion; prolactin secretion is not altered by the antagonist naloxone. In cocaine users, the height of prolactin pulses is increased, pointing to a derangement of dopaminergic inhibition [76]. The hypothalamus contains several stimulating factors, for example, TRH, cholecystokinin, VIP, PHI-27, and neurotensin, but while their number increases, their role in the physiological regulation of prolactin is still uncertain [94]. Other hypothalamic peptides such as peptide histidine methionine can stimulate prolactin [98] and are candidates for the endogenous prolactin stimulating factor. Prolactin itself exerts a short-loop negative feedback on the hypothalamus; binding sites have been identified in the median eminence [7]. Hence, an increased central dopaminergic tone is seen in hyperprolactinemia and presumably accounts for the loss of LH pulsatility [38] and for altered dopaminergic regulation of TSH [100] in this condition. Also, an increased peripheral dopaminergic tone may account for aldosterone inhibition in hyperprolactinemia [52].

1160

7. Stress

Prolactin is considered a stress hormone; hypoglycemia and surgery both lead to acute elevations in prolactin levels [78]. The prolactin rise in response to surgical stress is suppressed by naloxone, which points to an opiate-mediated mechanism of this particular stress response [89]. Prolactin also rises acutely in response to exercise [105]; this seems to be induced partly by the change in body temperature [14]. However, the amenorrhea frequently seen in female runners, associated with low estrogen and LH, is not mediated by prolactin [37]. 8. Estrogens

The stimulatory effect on prolactin secretion of estrogen is well known. The estrogen receptor binds directly to rDNA, which contains an estrogen-responsive element, resulting in rapid stimulation of gene transcription and accumulation of rPRL m R N A [126]. Estrogens act at the pituitary as well as at the hypothalamic level; they can modify directly the neuronal activity of several brain regions which regulate reproduction. Also, since immunoreactive prolactin and immunoreactive beta-endorphin exist in the same hypothalamic cell population, opioid peptides may mediate some effects of estrogen on the neural circuitry regulating reproduction [10@ The following are examples of estrogen-mediated effects: 1. Prolactin levels increase during pregnancy. 2. A mid-cycle peak of prolactin has been a controversial issue for years. This peak is difficult to detect, since it may be obscured by the episodic secretion of prolactin [6]. It is now generally accepted that estrogens increase the amplitude of episodic prolactin secretion [122]. 3. The prolactin response to T R H is much higher in females than in males. 4. Estrogen-containing oral contraceptives are usually listed as causes of hyperprolactinemia; however, usually little or no effect is seen [27, 48, 110]. It must nonetheless be remembered, that an increase in prolactin may go unnoticed unless pulsatile secretion is carefully monitored. In normally cycling women, estradiol supplementation increases prolactin pulses and thus may lead to a marked elevation of this hormone [69]. 5. Prolactinoma has developed after estrogen treatment of tall stature in girls (anecdotal) [82]. 6. Both development and exacerbation of prolactinoma have been reported (anecdotally) after testosterone treatment in males, and were explained by dihydrotestosterone-estradiol conversion [44,

G. Benker et al.: Control of Prolactin Secretion

91]. However, an autopsy study of 318 men, of whom 67 had been treated for prostatic carcinoma with stilbestrol, did not reveal a statistically increased risk of lactotroph hyperplasia or pituitary adenoma; therefore, neither testosterone nor estrogen treatment can be considered to be an important risk factor for the development of prolactinoma [102]. Does estrogen act by inhibiting dopamine at the pituitary level? In cell culture, no estrogendopamine interaction was detected with normal human pituitary cells, but with prolactinoma cells, estrogen inhibited dopamine action, and this was reversed by treatment with tamoxifen [55]. In humans, estradiol treatment increases, and ovarectomy decreases PRL sensitivity to dopamine [51]. D-Trp-LHRH treatment in patients with microprolactinoma decreases PRL, there is no parallel change in serum estradiol levels, but the decrease in gonadotrophins brought about by this treatment may act directly on the lactotrophe to reduce prolactin secretion [97]. 9. TRH

TRH, while not the natural endogenous prolactinreleasing hormone, has a pronounced sex-specific effect on prolactin secretion. It stimulates both prolactin gene expression (within minutes) and invitro and in-vivo secretion of prolactin [73], and it prolongs the half-life of cytoplasmic m R N A [26]. T R H stimulates the hydrolysis of membrane phospholipids, resulting in protein kinase C activation, calcium mobilization, and phosphorylation of cytoplasmic and nuclear proteins [26]. The response to T R H has been used for the diagnosis of prolactinoma; however, while most patients with prolactinoma will exhibit a " f l a t " response, this finding lacks specificity and cannot replace other means of differentiation between tumorous and non-tumorous hyperprolactinemia. For example, diminished responses may also be seen in stalk compression [99]. The lack of T R H response in prolactinomas is surprising, since the presence of T R H receptors has been demonstrated [60]; these receptors have even been detected in 11 of 12 non-secreting pituitary adenomas [59]. There are different types of interactions between T R H and dopamine: dopamine at a rate of 0.1 gg/kg/min reduces the prolactin response to T R H in normal women while increasing the blunted response in hyperprolactinemic patients [79]. T R H is not responsible for the prolactin release with suckling, since there is no concomitant increase of TSH secretion [41].

G. Benker et al. : C o n t r o l o f Prolactin Secretion

10. Hyperprolaetinemia There is unsatisfactory discrimination between normal prolactin levels and hyperprolactinemia; a hospital survey [32] on the upper limits of normal prolactin has given opinions between 290 and 1,000 mU/1 (appr. 10 30 ~tg/L). This could result in misclassification of patients either as hyperprolactinemic or as falsely normoprolactinemic. In patients with macroadenomas, prolactin levels of more than 8,000 mU/1 are consistent with a prolactinoma, while levels below 3,000 mU/1 point to stalk compression by an inactive tumor (levels between 3,000 and 8,000 are compatible with either diagnosis) [9]. The problem is worse with microprolactinoma, where radiological evidence may be misleading. About 44% of patients with mild hyperprolactinemia will have pituitary abnormalities on CT examination [12], but similar lesions are found in 36-42% of patients with normal prolactin levels [15]. Differentiation between tumorous and non-tumorous hyperprolactinemia may be difficult or even impossible. A variety of tests has been proposed; e.g., the prolactin response to perphenazine was said to be decreased in tumors but not in functional hyperprolactinemia [71]. Normal prolactin response to domperidone virtually excludes prolactinoma, while a negative response is not specific and may also occur in idiopathic hyperprolactinemia. A nomifensine suppression test has also been proposed [16]. Sleep-related prolactin peaks are reduced or absent in tumors but not in the hyperprolactinemia of the empty sella syndrome [66]. The prolactin response to T R H may be decreased in prolactinoma and in pituitary stalk compression; however, the response to domperidone is usually pronounced in prolactinoma and absent in stalk compression. In stalk compression, TSH response to T R H is delayed. Generally, though, stimulation or suppression tests are not cost-effective in hyperprolactinemia [118]. Borderline and moderate hyperprolactinemia remain an enigma in many cases, allowing for such confliction opinions as "hyperprolactinemia as a transitional stage to prolactino m a " [85] and "hyperprolactinemia as a distinct disease entity" [23]. In clinical practice, this problem appears less important. After a thorough initial checkup, a repeated battery of tests and imaging procedures should be avoided in most cases, and whether a lesion is visible or not, only pharmacologic treatment of symptoms should be advised, with the rare exception of invasive tumors or tumors with involvement of the optic chiasm. Some important differential diagnoses should

1161

be mentioned. Prolactin may be increased in the primary empty sella syndrome, with levels up to 500 ~tg/L [42]. On the other hand, it is important to remember that infarction of a pituitary tumor can lead to an apparently empty sella. Prolactin may be elevated in primary hypothyroidism, and there may also be a large sella or a "thyrotropino m a " [36, 47, 88, 114] due to hyperplasia of thyrotropic and lactotropic cells (resulting probably from T R H stimulation). The tumor may become so large as to cause chiasmatic compression [61]. Erroneous diagnosis of prolactinoma is possible. Hyperprolactinemia with impaired response to stimuli is frequently seen in renal failure, even in its early stages, and in dialysis patients [63, 83, 92]. It has been attributed to neurotransmitter imbalance [10]. Although hyperprolactinemia is correlated with low serum zinc levels in uremia, oral zinc supplementation does not normalize prolactin [115]. 11. Prolactinoma Prolactinomas account for at least 30% of all pituitary adenomas [54]. Why a functional adenoma should develop from the pluripotent pituitary stem cell is still far from clear. Factors which may be involved are age (increase of spontaneous tumorigenesis), irradiation, and retroviruses, since experimental tumors also express the m R N A for the myc andfos cellular oncogenes [73]. Escape from hypothalamic inhibition could result from the development of tumor arteries which dilute portal dopamine [101]. In most cases, tumor growth and secretory capacity appear to be functionally linked, but striking exceptions have been reported [109]. Plasma prolactin is heterogeneous in prolactinomas and contains more large molecular weight prolactin than in normals [95]. More "big prolactin" is present in microprolactinomas than in macroprolactinomas [3]. Prolactin secretion in tumor patients is characterized by the following: 1. loss of PRL pulsatility and diurnal rhythm 2. altered dopamine responsiveness of plasma catecholamines [117] 3. reduced PRL response to suckling [4] 4. reduced or absent PRL responses to hypothalamic stimuli, neuroactive drugs and food ingestion, altered GH response to drugs, altered LH and TSH responses to dopamine receptor antagonists, disappearance of LH pulsatility and the midcycle gonadotropin surge, and re-establishment of pulsatile LH secretion with naloxone treatment [16]. Whether these findings constitute an "intrin-

1162

G. Benker et al. : Control of Prolactin Secretion

Table 2. Studies of the "natural course" of untreated hyperprolactinemia Author

Year

Number of patients

Tumor growth (cases)

Koppelman et al. [53] March et al. [67] Martin et al. [70] Sisam et al. [108] Schlechte et al. [103]

1984 1981 1985 1987 1989

25 43 41 38 30

1 2 .1 none 6

sic" defect, or develop as a consequence of prolactin excess (which may, via shortloop feedback, increase dopaminergic tone in the hypothalamus) is still a matter of debate. About a quarter of acromegalic patients present with hyperprolactinemia, and the adenomas show prolactin content. Low-level hyperprolactinemia (less than 80 ng/ml) has been shown to be independent of hGH secretion, while in patients with higher prolactin levels, secretion of both hormones is correlated [104]. Prolactinomas may occur together with other endocrine tumors in the context of M E A type I [18], and in single cases together with aldosteronoma [43]. Since prolactinomas contain estrogen receptors [87], they may grow in pregnancy, leading to neurosurgical emergencies. However, the oppositeshrinkage of a prolactinoma during pregnancy has also been observed [13, 31]; it is most probably related to initial growth, subsequent lack of nutrient supply, and eventually necrosis. 12. Pharmacological Control of Prolactin Secretion

Treatment of hyperprolactinemia has been reviewed extensively [118]. As experience with dopamine agonists grows, the place for surgery and radiotherapy has been declining constantly, and drug treatment has become the first choice in the vast

majority of patients. However, if either hyperprolactinemia or a prolactinoma is left untreated, what will happen to a patient after several years? Table 2 lists some studies of the "natural course". In a retrospective follow-up of 25 patients over 11 years, amenorrhea and galactorrhea resolved without treatment in one third [53], and only one patient had tumor growth. Other studies [67, 70, 103, 108] have also shown little progress of the disease, and sometimes regression, with time. However, hyperprolactinemia was only mild in some cases (starting at 25-30 gg/L), and many patients might have had "idiopathic" non-tumorous hyperprolactinemia; some studies included treated patients and patients with empty sella syndrome; also, mean follow-up time was in the range of only 3 to 6 years; and lastly, resolution of CT will differ over a period of many years. Prolactin release is inhibited mainly by stimulation of dopamine receptors at the lactotrophs of the anterior pituitary. The so-called prolactin re-, lease-inhibiting hormone that is involved in the hypothalamic control of prolactin release is in all probalility identical with dopamine. Thus, dopamine receptor agonists appear to mimic a hypothalamic inhibitory control mechanism. Currently dopamine receptors of the brain are divided into two subtypes, designated D1 and D2 receptors. They differ in a variety of aspects, including molecular weight, coupling to adenylate cyclase, location, and affinity for agonists and antagonists (see Table 3). For the creation of behavioral patterns D 1 and D2 receptors interact in a complex manner; apart from a few exceptions, it is difficult to assign a particular behavior to sole activation of either DI or D2 receptor subtypes. However, there is no doubt that inhibition of prolactin release is mediated only by Dz receptors which are labelled by butyrophenones and coupled to calcium channels [75]. The same holds true for the inhibition of the release of 0~-melanocyte-stimu-

Table 3. Classification of dopamine receptor subtypes

Property

D1 receptor

Dz receptor

Apparent molecular weight Adenylate cyclase coupling Prototype receptor location

72,00~79,000 stimulatory parathyroid gland

Location Electrophysiological effect (extracellular recording) Behavioral effects of selective receptor stimulation

postsynaptic inhibitory

93,000-136,700 inhibitory or unlinked anterior and intermediate pituitary lobe pre- and postsynaptic inhibitory

grooming, abnormal oral movements

locomotion, low-intensity stereotype

G. Benker et al. : Control of Prolactin Secretion Table 4. Ligands for dopamine receptors

1163 Table 5. Some directly acting dopamine agonists

Ligand

Agonists

Antagonists

A Ergot alkaloids

Nonselective

dopamine apomorphine d-amphetamine (indirect)

cis (Z)-flupentixol cis (Z)-pitflutixol cis (Z)-clopentixol

Selective for D1 receptors

SKF 38 393 fenoldopam Lu 24-040

SCH 23 390 R-SKF 83 566 bulbocapnine?

Bromocriptine [119], 2-Brom-alpha-ergocriptine mesylate. Usual dose: 2.5-10 ( - 2 0 ) mg daily, or 50-100 mg i.m. every 4 weeks Cabergoline [34, 35] (ergoline derivative with extended duration of action). Usual dose: 0.2-3 mg/week, ~ 3 times per week Lisuride hydrogenmaleate. Usual dose: 0.~0.6 mg/day Pergolide. Usual dose: 0.025-0.1 mg/day Terguride [24, 45] (C9 10 dihydrogenated lisuride)

Selective for D2 receptors

quinpirole ( - ) sulpiride bromocriptine clebopride roxindole (EMD 49980) raclopride pergolide ? spiperone LY 141865 domperidone RU 24213 haloperidol metoclopramide zetidoline

lating hormone from the intermediate pituitary lobe. Functional measurements in tissues possessing prototypical D1 or D2 receptors, in combination with radioligand binding studies, have led to the identification of agonists and antagonists [123, 128] which appear to interact selectively with either of the two receptor subtypes (see Table 4). The development of selective agonists and antagonists has helped to demonstrate that the pharmacology of the D1 and D2 receptors in the brain is very similar to that of the DA1 and DA2 dopamine receptors in the cardiovascular system. Apart from these compounds that directly activate dopamine receptors (dopamine agonists), there is a number of drugs that stimulate dopamine receptors indirectly through the release of this neurotransmitter from dopamine-containing neurons (indirectly acting dopamine receptors agonists, IADA). The latter include amphetamine, methylphenidate, nomifensine, and amineptine. 1-DOPA as the precursor of dopamine could also be included in this list. As expected, these drugs require an intact hypothalamic-pituitary axis for their action and are therefore ineffective in tumor patients [16]. Table 5 lists some of the directly acting drugs and their doses used in the treatment of hyperprolactinemia. There are some drugs with a completely different site of action; e.g., cysteamine depletes pituitary and plasma prolactin in rats and suppresses the prolactin response to T R H in human subjects, together with a decrease in calcium levels and suppression of the anticipated rise in serum parathyroid hormone [22]. Dopamine agonists such as bromocriptine and

B Non-ergot drugs Dopamine CQP 201-403 CV 201-502 [93, 120] (octahydrobenzo (g) quinoline). Usual dose: 0.03-0.15 mg daily

CV 201-502 act at a pretranslational level; they inhibit accumulation of rPRL m R N A [72]. Treatment will in most cases reduce or even normalize hyperprolactinemia, although there is a large spectrum of suppressibility, and it is also well established that tumor size will be reduced in a substantial proportion of patients. The bioavailability of ergoline drugs is poor, and so is their tolerability; indeed, treatment is not acceptable for many patients. To improve this situation, long-acting parenteral forms of dopamine agonists have been developed which can suppress prolactin for 4-6 weeks after one injection is given, and which appear to be more acceptable to patients, including those who were unable to take these drugs orally. Another advantage of parenteral treatment is quick information on whether the patient's tumor will respond both biochemically and morphologically, and whether the size of larger tumors may be sufficiently reduced to allow transsphenoidal surgery. Experience with this parenteral treatment is accumulating [8, 86, 1161. Prolactinomas may be resistant to dopamine agonists from the start or may become resistant later; in some instances they may then respond to another drug [2], but generally all drugs will be ineffective in this situation. Several mechanisms have been proposed, mainly lack of dopamine receptors; in adenomas resistant to bromocriptine therapy, the density of [3H]spiro-peridol-binding sites was diminished, and in tumors which had grown during bromocriptine therapy, dopamine paradoxically stimulated adenylate cyclase activity [84]; in addition, a selective deficiency of Go proteins - which may mediate dopamine action [21]

1164

has been proposed; resistance of PRL m R N A accumulation to dopaminergic suppression suggests relative autonomy of gene expression [28].

-

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Received : July 12, 1990 Accepted: September 5, 1990

Prof. Dr. Georg Benker Department ZWD E. Merck Frankfurter Str. 250 W-6100 Darmstadt, FRG