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PubMed1975

Effects of pinealectomy, anosmia and blinding on serum and pituitary prolactin in intact and castrated male rats.

Serum prolactin was measured in lightly etherized rats between 4 and 5 a.m. and between 11 a.m. and 12 noon at various times after operation in intact rats and rats that had been operated on. Serum prolactin was elevated in the late nocturnal samples from intact rats and this elevation was prevented by pinealectomy. With time following the operation, daytime serum prolactin was also lowered in pinealectomized animals. In animals rendered anosmic by olfactory bulb removal, serum prolactin was also lowered. Superimposed pinealectomy only lowered late nocturnal serum prolactin in anosmic rats. Blinding the rats by ocular enucleation lowered nocturnal serum prolactin initially and dampened the daily rhythm in prolactin, but superimposed pinealectomy had no effect on the blinded animals. The combined sensory deprivation produced by both blinding and olfactory bulb removal resulted in low prolactin titers regardless of whether blood samples were taken during the day or late at night and, as in the case of blinded animals, there was no effect of pinealectomy. Superior cervical ganglionectomy also lowered serum prolactin. Serum prolactin declined following castration in intact animals and this decline was accentuated by pinealectomy. Either blinding or anosmia also lowered serum prolactin in the castrated animals but, as in intact animals, pinealectomy had little effect on the sensory-deprived rats. A further lowering of prolactin occurred in castrated animals which were both blinded and anosmic; in these animals, pinealectomy again had no additional effect. Measurement of the pituitary prolactin content in the castrated animals at sacrifice revealed a significant lowering of values in blinded animals, with restoration of the values to control levels by pinealectomy. Anosmia also lowered the pituitary prolactin content but this was not reversed by pinealectomy. The lowest pituitary prolactin was found in blinded, anosmic animals and these changes were not reversed by pinealectomy. The weight of the pineal gland increased significantly in anosmic, blinded, or blinded and anosmic rats. It is concluded that pineal secretions in the male rat elevate serum prolactin, particularly late at night, and that loss of input from olfactory and to a lesser extent from visual pathways results in a decrease in the titer of the hormone. This decrease is especially apparent in blinded, anosmic rats.

Animals↗
PubMed1995

Investigation of intracellular signals mediating the anti-apoptotic action of prolactin in Nb2 lymphoma cells.

Studies were undertaken to identify intracellular mediators of prolactin inhibition of glucocorticoid-induced apoptosis in Nb2 lymphoma cells. A short-term assay was implemented that quantitates fragmented DNA released from the genome by reaction with diphenylamine. Induction and inhibition of internucleosomal DNA cleavage (indicative of apoptosis) was verified by agarose gel electrophoresis of extracted cellular DNA. Synchronized Nb2 cells (G0/G1) exhibited increased DNA fragmentation after 4-hr incubation with dexamethasone (DEX) (25-100 nM) which was inhibited by ovine prolactin (oPRL) (0.1-1 ng/ml), the glucocorticoid receptor antagonist, RU486 (500 nM), and the nuclease inhibitor, aurintricarboxylic acid (100 microM). Signals previously implicated in prolactin induction of mitogenesis in Nb2 cells were investigated for their role in prolactin inhibition of apoptosis including: protein kinase C activation, arachidonic acid metabolism, polyamine production, tyrosine phosphorylation, and extracellular calcium. Protein kinase C agonists, phorbol-12-myristate-13-acetate, and 1,2-dioctanoyl-sn-glycerol, +/- the calcium ionophore, A23187 (200 nM), did not mimic oPRL inhibition of DEX-induced DNA fragmentation. Protein kinase C inhibitors, gossypol and quercetin, did not block prolactin action. Arachidonic acid did not mimic prolactin protection against DEX-induced DNA fragmentation. Inhibitors of arachidonic acid metabolism, 5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid, and indomethacin did not block prolactin action. The polyamine, spermine, inhibited DEX-induced DNA fragmentation at 1.5 to 2.5 mM. However, inhibition of polyamine synthesis with alpha-difluoromethyl ornithine or methylglyoxal bis(guanylhydrazone) did not inhibit prolactin action. Prolactin action was not blocked by inhibitors of tyrosine kinase activation, genistein and tyrphostin-47. On the other hand, pervanadate, a potent tyrosine phosphatase inhibitor, consistently inhibited DEX-induced DNA fragmentation. Prolactin action and DEX-induced apoptosis both occurred in calcium-free PBS. In summary, protein kinase C activation and eicosanoid production do not appear to mediate this prolactin action. Although spermine could block DNA fragmentation, blockade of the polyamine cascade did not inhibit prolactin action, suggesting that polyamines do not mediate this prolactin effect. While inhibitors of tyrosine kinase activation did not block prolactin action, tyrosine phosphatase inhibition in the presence of basal tyrosine kinase activity mimicked prolactin action, suggesting tyrosine phosphorylation participation in the anti-apoptotic effect. Extra-cellular calcium was not required for prolactin or DEX action.

Animals↗
PubMed1990

[The effect of epidermal growth factor (EGF) with estradiol and progesterone on prolactin secretion from cultured human decidual tissues of early pregnancy].

Prolactin is now accepted as a normal product of the decidual cells of the human endometrium. We investigated the effect of epidermal growth factor (EGF) with estradiol and progesterone on prolactin secretion by the decidual tissues from the early pregnant endometrium. The decidual tissues were separated from villi, minced and cultured in collagen gel matrix with serum-free medium. Immunological staining of the cultured decidual tissues showed prolactin localization and EGF receptors on the stromal cells. Cultured media were collected every 2 days. The culture for the first 2 days was incubated with the serum-free medium alone (= preculture), and the following test culture was supplemented with/without additives. The prolactin content in cultured media was quantified by EIA. The results of the effect of steroid(s) and EGF were represented as a comparison of prolactin contents in the preculture and the test culture. An increase in prolactin secretion was found after the tissues were treated with a combination of 10(-8)M estradiol and 10(-6)M progesterone or 10(-6)M progesterone alone. After 8 days, the prolactin secretion rate increased about 3-fold over the precultured value. Estradiol alone kept the prolactin secretion at the precultured value. Prolactin secretion gradually decreased in the non-additive culture. These results indicate that progesterone was essential in the secretion of prolactin. Simultaneously, similar decidual tissues were incubated with a combination of EGF and steroid(s). The secretion of prolactin in the group treated with progesterone alone decreased dose-dependently responding to added EGF on the 8th day of culture. In the presence of estradiol and progesterone, the secretion rate decreased to the values similar to the progesterone alone group with the addition of 0.1, 1 ng/ml EGF, and the decrease in prolactin secretion was less with the addition of 10 ng/ml EGF. Mixed cultures of the decidual tissues and villi showed that the prolactin secretion rate increased in all groups treated with/without estradiol and/or progesterone. These results imply that progesterone derived from villi might control decidual prolactin secretion. The effect of high concentration EGF (50 ng/ml) on the prolactin secretion appeared similar to the isolated decidual tissues. These results suggest that decidual prolactin secretion is regulated by the combined effects of steroids and EGF.

Decidua↗
PubMed1980

Processing of prolactin by human breast cancer cells in long term tissue culture.

Two human breast cancer cell lines (T-47D and MCF-7) and one cell line derived from normal human milk (HBL-100) not only specifically bound but also degraded prolactin. Quantitative differences in the ability to bind and degrade prolactin among the cell lines exist, although there was a good correlation between the number of prolactin receptor sites and prolactin degradative activity. Iodo-prolactin as well as native prolactin were degraded. The prolactin molecule was processed to yield at least three small molecular weight peptides which were released into the incubation medium. These peptides neither bound to fresh receptors nor to anti-prolactin antibodies. The protease inhibitor N-alpha-p-tosyl-L-lysine chloromethyl ketone, lysosomotropic agents such as chloroquine and ammonium chloride, and metabolic inhibitors 2,4-dinitrophenol and sodium azide, all abolished prolactin degradation by the breast cancer cells. When prolactin degradation was inhibited, specific binding and the subsequent release of intact 125I-prolactin was still observable, suggesting that hormonal degradation was not a prerequisite to dissociation of prolactin. However, prolactin degradation did account for the accelerated rate of dissociation of prolactin. Studies utilizing inhibitors suggest that the receptor-bound 125I-prolactin was degraded by an energy-dependent internalization process such as pinocytosis; lysosomal enzymes are probably involved in the degradation of prolactin by human breast cancer cells.

Breast Neoplasms↗
PubMed1976

Incorporation of rat prolactin into rat milk in vivo and in vitro.

Rat prolactin (11 i.u./mg) was continuously infused into the circulation of urethane-anaesthetized lactating rats for 35 min at doses of either 200 or 472 ng/min. The immunoreactive prolactin in both milk and plasma rose quickly during the first 20-25 min of infusion, then stabilized at similar levels over baseline (68 and 98 ng/ml for milk and plasma, respectively, with the 200 ng/min dose and 250 and 230 ng/ml, respectively, with the 472 ng/min dose). The concentration of prolactin in plasma fell after the infusion was stopped, whereas that in the milk either did not fall at all or fell slightly to a new stabilized level. There was a rapid and extensive loss in the immunoreactivity of prolactin added to milk when rat milk was incubated in vitro (37 degrees C for 1-120 min) with 600 ng/ml of extracted pituitary prolactin (NIAMDD RP-1) or unit equivalent amounts of prolactin obtained from pituitary culture media (secreted prolactin, supplied by C.S. Nicoll). Significantly greater amounts of added RP-1 prolactin were lost when it was incubated with milk obtained after 4 h than after 18 h of non-suckling. There was, however, no drop in endogenous immunoreactive milk prolactin levels (350-400 ng/ml) when rat milk was incubated with saline for 30 min. This suggests that milk prolactin obtained as a result of plasma transfer is different chemically from the milk prolactin resulting from the addition of either RP-1 or secreted prolactin to milk in vitro. Approximately 90% of 131I-labelled rat prolactin appeared in the trichloroacetic acid precipitable fraction after incubation (37 degrees C for 120 min) with milk obtained after 4 h of non-suckling in either the presence or absence of thiouracil (added to prevent binding of 131I or 131I-labelled fragments to milk protein). The recovery was slightly less when 131I-labelled prolactin was incubated with milk obtained after 18 h of non-suckling. These data suggest that prolactin is quickly transferred from plasma into milk in direct relation to the plasma concentration. Once there, much of it appears to be retained by the milk perhaps chemically or physically bound; there is little, if any, degradation of the hormone. We conclude that the lactating the mammary gland may function normally as an excretory organ for prolactin.

Animals↗
PubMed1994

Prolactin: its role in advanced tongue cancer.

Serum prolactin was measured pretherapeutically and sequentially thereafter using immunoradiometric assay method in 37 male patients with advanced tongue cancer and compared with 23 healthy, age-matched controls. Prolactin levels were correlated with age, various clinicopathologic parameters, overall survival, and patients with response and those with progressive disease. Patients with advanced tongue cancer had higher prolactin levels than controls (P < 0.02), but intergroup variation in prolactin was not observed when considering the age, site of the lesion, disease stage, histologic grade, and keratin. Of the patients, 30% had hyperprolactinemia (prolactin > 15.0 ng/ml). To assess the prognostic significance of pretherapeutic prolactin level, the patients were divided according to the cutoff level of prolactin (15.0 ng/ml). Hyperprolactinemic patients had more unfavourable prognosis than patients with prolactin < 15.0 ng/ml (X2 = 2.91, df = 1, P < 0.0037). In monitoring disease course, patients who responded to treatments had decreased prolactin levels at the end of 18 months as compared to their pretherapeutic levels (P < 0.01). In patients who subsequently developed progressive disease within 18 months, prolactin levels reduced initially at response, whereas with disease progression, prolactin levels increased significantly (P < 0.05). The positive and negative predictive value of prolactin was 100%. Immunohistochemical localization confirmed the ectopic production of prolactin by tongue tumors. In conclusion, our data indicate that hyperprolactinemia may be an independent predictor of short-term prognosis; circulating prolactin may be used as a marker for monitoring disease course in patients with advanced tongue cancer, and prolactin is produced ectopically by tongue tumors.

Adult↗
PubMed1997

Prolactin inhibits EGF-induced DNA synthesis in mammary epithelium via early signaling mechanisms: possible involvement of protein kinase C.

Prolactin and prolactin agonists inhibited EGF-induced DNA synthesis in mammary epithelium, whereas other pituitary hormones had no effect on EGF-induced DNA synthesis. The inhibitory effect of prolactin was seen for EGF and TGF-alpha, but not for IGF-I or cholera toxin. Autoradiography indicated that prolactin decreased the ability of EGF to induce cells to progress to S phase of the cell cycle, and time course studies indicated that the effects of prolactin were not due to an altered timing of DNA synthesis induction. Prolactin addition within 30 min of adding EGF was necessary to inhibit EGF-induced DNA synthesis. Conditioned media from prolactin-treated cells from which prolactin had been neutralized with the extracellular domain of the prolactin receptor had no effect on EGF-induced DNA synthesis, suggesting that the effect was due to prolactin, not an autocrine factor induced by prolactin. Prolactin induced a rapid association of protein kinase C with the membrane fraction of NMuMG cells, as well as increased threonine phosphorylation of the EGF receptor. Protein kinase C inhibitors eliminated most of the inhibitory effect of prolactin on EGF-induced DNA synthesis. The protein kinase C inhibitor Calphostin C restored high-affinity EGF binding in prolactin-treated cells and reversed the inhibitory effect of prolactin on EGF-induced EGF receptor tyrosine phosphorylation.

Animals↗
PubMed2002

Production of recombinant goldfish prolactin and its applications in radioreceptor binding assay and radioimmunoassay.

Goldfish prolactin cDNA was subcloned into a pRSET A vector and expressed in Escherichia coli. Recombinant goldfish prolactin was expressed mainly as insoluble inclusion bodies in the form of N-terminal 6x His-tagged fusion protein. This fusion protein was purified, refolded, and (125)I-labeled to generate a radioligand for receptor binding and validation of a radioimmunoassay for goldfish prolactin. Using goldfish gill membrane as the substrate for prolactin receptor binding, both recombinant and native forms of goldfish prolactin were effective in displacing the specific binding of the radioligand in a similar dose range, suggesting that the fusion protein was refolded properly and could be recognized by goldfish prolactin receptors. To quantify prolactin contents in biological samples from the goldfish, a radioimmunoassay using the (125)I-labeled recombinant prolactin as a tracer was established. This assay was shown to be selective for goldfish prolactin without cross-reactivity with mammalian prolactin and pituitary hormones from other fish species (e.g., growth hormone and gonadotropin II). This newly validated assay system was used to investigate neuroendocrine and signal transduction mechanisms regulating prolactin release in the goldfish. In this case, the Ca(2+) ionophore A23187 and protein kinase C activator TPA were effective in elevating basal levels of prolactin secretion in perifused goldfish pituitary cells. In parallel studies using a static incubation approach, somatostatin and dopamine, but not vasoactive intestinal polypeptide, were inhibitory to basal prolactin release in goldfish pituitary cells. These results suggest that somatostatin and dopamine may serve as negative regulators of basal prolactin secretion and that extracellular Ca(2+) influx and protein kinase C activation may be important signaling events mediating prolactin release in the goldfish.

Animals↗
PubMed1987

Sequential prolactin evaluation of a "cured" patient with recurrence of prolactinoma.

Several investigators have suggested that prolactin secretion in some subjects with hyperprolactinemia associated with pituitary macroadenomas may have a resistance to the prolactin inhibitory hormone, dopamine. This report describes a male subject with a prolactinoma whose preoperative evaluation demonstrated a resistance of prolactin release to inhibition by dopamine. Evaluation of prolactin secretion from monolayer culture of his tumor also revealed a resistance to inhibition by dopamine. Four months postoperatively, normal serum prolactin levels and a normal maximal inhibition of prolactin to a dopamine infusion of 0.04 microgram/kg/minute suggested surgical cure. However, a 24-hour prolactin sampling revealed blunted nocturnal augmentation of prolactin release, an early escape of inhibition of prolactin release at 150 minutes from a 0.04 microgram/kg/minute dopamine infusion, and abnormal prolactin response to a low-dose (0.004 microgram/kg/minute) dopamine infusion. Hence, persistent abnormalities in prolactin secretory dynamics were noted with more extensive testing in this patient when he was thought to have been cured. One year postoperatively, the hyperprolactinemia recurred, prolactin release was markedly resistant to dopamine, and an abnormal 24-hour prolactin profile of release was present. Thus, resistance of prolactin secretion to inhibition by dopamine was present in this patient with a prolactinoma. Additionally, an abnormal prolactin response to dopamine was noted to precede the development of hyperprolactinemia with tumor recurrence.

Adenoma↗
PubMed1986

Evidence of short-loop inhibition of decidual prolactin synthesis by decidual proteins. Part II.

We have recently demonstrated the suppression of decidual prolactin synthesis by decidual proteins accumulating in a dialysis membrane. In this report the reversibility of this suppression and the molecular weight range of the suppressor(s) are examined. Samples of 300 mg of decidua (n = 10) were cultured in three environments: in 30 ml of medium (control), in 3 ml of medium in a dialysis membrane suspended in 27 ml of medium, and in 2.7 ml of medium with 0.3 ml of concentrated decidual proteins of 10,000 to 35,000 molecular weight (giving a time 0 prolactin concentration of 220 ng/ml) in a dialysis membrane suspended in 27 ml of medium (n = 5) or in 2.7 ml of medium with 0.3 ml of concentrated decidual proteins greater than 35,000 molecular weight (giving a time 0 prolactin concentration of 5 ng/ml) in a dialysis membrane suspended in 27 ml of medium (n = 5). Dialysis membranes were discontinued at 48, 96, and 144 hours and the decidua within was subsequently cultured in 30 ml of medium until 240 hours. The suppression of prolactin synthesis identified previously was confirmed in this study. Further it was found that the suppression of decidual prolactin synthesis was reversed by the removal of decidua from the high decidual protein-prolactin environments of the dialysis membranes. Third, only the addition of decidual proteins between 10,000 and 35,000 molecular weight with a high prolactin concentration enhanced the suppression of new prolactin synthesis. We conclude that a decidual protein(s) between 10,000 and 35,000 molecular weight, possibly prolactin itself, is the primary control factor(s) in the modulation of prolactin synthesis in term decidua. Further the normal physiologic state of decidua is a high prolactin concentration in equilibrium with low prolactin synthesis. Therefore studies intended to assess the effects of modulators of prolactin synthesis in decidua should not be performed in low prolactin concentration-high prolactin synthesis conditions during short time periods (as has been the case in a majority of studies to date) since such conditions do not reflect normal physiologic conditions and may result in invalid conclusions.

Amniotic Fluid↗
PubMedDate not supplied

Regulation of the synthesis and release of decidual prolactin by placental and autocrine/paracrine factors.

Human decidual tissue synthesizes and secretes a protein that is identical to pituitary prolactin in its chemical, biological and immunological properties. Nevertheless, the factors that regulate the synthesis and release of prolactin from the decidual tissues appear to be different to those regulating the synthesis and release of pituitary prolactin. Studies from our laboratory over the past few years indicate that the synthesis and release of decidual prolactin are regulated, at least in part, by factors released by placenta, fetal membranes and decidua. The placenta releases a 23.5 KMr protein [decidual prolactin-releasing factor (PRL-RF)] that stimulates a rapid release of prolactin within the first few minutes of exposure and a sustained, prolonged, increase in the synthesis and release of prolactin beginning 6-8 h after exposure. The acute release of prolactin in response to PRL-RF is inhibited by decidual prolactin release-inhibitory factor (PRL-IF), a 35-45 K Mr protein that is released by the decidua. The secondary increase in the synthesis and release of prolactin in response to PRF-RF is blocked by lipocortin I, which is synthesized by both the placenta and decidua. IGF-I, insulin and relaxin also stimulate the synthesis and release of prolactin. However, the stimulation in response to these factors does not occur until 24-48 h after exposure. The cellular mechanisms involved in the release of decidual prolactin are as yet unknown. However, recent studies implicate activation of adenylate cyclase, phospholipase C-mediated phosphoinositide hydrolysis and phospholipase A2-mediated arachidonic acid release in the regulation of prolactin release. The finding that the synthesis and release of decidual prolactin are regulated, at least in part, by PRL-RF, IGF-I, insulin, relaxin and lipocortin I strongly suggests that there is novel feedback regulation between the placenta, fetal membranes, and decidua in the regulation of the synthesis and release of decidual prolactin.

Annexins↗
PubMed1987

Effect of exogenous prolactin administration on lactational performance of dairy cows.

Eight Holstein cows were utilized to examine the effect of prolactin on lactational performance prior to peak milk production (day 21-34 postpartum) and after peak milk production (day 60-73 postpartum). During each 14 day period, cows received daily intramuscular injections of pituitary-derived bovine prolactin (120 mg; 13.0 IU/mg protein) or excipient. Cows were housed in a controlled environment at 18.1C, 47.8% relative humidity and a 15 hr light: 9 hr dark cycle. In cows administered exogenous prolactin, circulating prolactin concentrations increased within one-half hr post injection, peaked within 2 to 6 hours and declined through the remainder of the day. Average prolactin concentration in the plasma was increased 2 to 5 fold over the 24 hr period in response to prolactin treatment. Yields of milk and milk components (fat, lactose and protein) were not affected by prolactin treatment in either period but the concentration of alpha-lactalbumin in milk was significantly increased (P less than .10) in both periods. Circulating concentrations of somatotropin, triiodothyronine, thyroxine, glucagon, nonesterified fatty acids and glucose were not altered. In prolactin-treated cows, the milking-stimulated prolactin release was decreased at both the PM milking, when circulating concentrations of prolactin were high, and the AM milking, when prolactin concentrations had returned to baseline. Concentration of prolactin in milk tended to increase but was not significantly altered by administration of exogenous prolactin. However, prolactin concentrations in plasma were correlated (r = .56) with milk concentrations. It is clear that postpartum administration of exogenous prolactin during the period of lactation prior to peak milk yield or after peak milk yield does not alter lactational performance in high producing dairy cows.

Animals↗
PubMed1989

Plasma prolactin concentrations in mares and their neonates after oxytocin induction of parturition.

Studies were undertaken to investigate the effects of oxytocin induction on prolactin release in term (Group II) and preterm (Group III) mares and to compare these effects to spontaneously foaling mares (Group I). Since physiological concentrations of prolactin in blood have not been measured in the neonatal foal, experiments were designed to monitor prolactin in the cord artery and jugular blood of the foals from all groups of mares. Although prolactin levels varied in term mares (Group I and II) during the last 11 days of pregnancy, an increase was observed between Day -6 and Day 0 (2.7 and 11.9 ng/ml respectively; P less than 0.1). The average concentration of prolactin over the last 4 days (Days -3 to 0) had increased by 40% when compared to the average concentration on Days -6, -5, and -4. These findings indicate a rising trend which appears to occur concomitantly with changes in concentrations of 2 mammary components tested, sodium and potassium. Prolactin concentrations did not significantly increase in term mares after oxytocin treatment or in spontaneously foaling mares. However, the preterm induced mares had higher prolactin concentrations during the first stage of labor (19.3 +/- 7.2 ng/ml) than prior to treatment with oxytocin (4.7 +/- 2.0 ng/ml; P less than 0.01). Levels of prolactin in all groups significantly declined by 20-min post-placental expulsion. For the first 30 min after birth, prolactin concentrations in foals from oxytocin-induced mares appeared to be 2-fold higher than those from spontaneously foaling mares. Thereafter, prolactin values declined to baseline values by 48 hrs. When comparing cord arterial plasma with cord venous plasma in each group, prolactin concentrations were similar. However, the average prolactin levels in both the cord artery and vein appeared higher (ave: 1.1 ng/ml) in Group II and III than in Group I (less than 0.5 ng/ml). From these results, the authors suggest that 1) prolactin may have a role in regulating mammary secretory products in mares just prior to parturition; 2) oxytocin may increase prolactin secretion in preterm induced mares; 3) oxytocin induction may have a short term effect to increase circulatory prolactin concentrations in neonates in utero regardless whether their dams were treated preterm or term.

Animals↗
PubMed1997

In vivo investigation of luteal function in dogs: effects of cabergoline, a dopamine agonist, and prolactin on progesterone secretion during mid-pregnancy and -diestrus.

The role of prolactin on luteal function in dogs was investigated in vivo. The function of prolactin in mid-luteal phase was compared in pregnant and nonpregnant dogs. A dopamine agonist, cabergoline, known for its prolactin secretion inhibitory effects, was injected subcutaneously at a dose of 5 micrograms/kg body weight in five pregnant and five nonpregnant Beagle bitches. Mean plasma prolactin and progesterone were dramatically suppressed for 4 to 5 days after injection in both groups when compared with control pregnant and non-pregnant animals, whereas no effect on luteinizing hormone (LH) secretion was observed. The decline in plasma progesterone occurred after that in prolactin, suggesting plasma progesterone was impaired by inhibition of prolactin secretion. These results confirm the luteotropic importance of prolactin in pregnant bitches, and also demonstrate its importance in luteal phase of the nonpregnant dog. Second, to demonstrate that the effects of cabergoline were mediated by prolactin inhibition and not by a direct action on the corpus luteum, concomitant administration on Day 30 of cabergoline and prolactin (375 micrograms i.v. twice daily on Days 30 and 31) or cabergoline and LH (750 micrograms i.v. twice daily on Days 30 and 31) was affected in two groups of five pregnant animals each. Results showed that only prolactin was able to reverse the negative effects of cabergoline on circulating progesterone. This confirms the indirect mode of action of the dopamine agonist, cabergoline on corpus luteum function. Third, further investigation on the precise luteotropic role of prolactin was made by IV injection of 375 micrograms pure canine prolactin twice daily in five pregnant bitches on Days 30 and 31, and in five pregnant bitches on Days 40 and 41. No direct stimulatory effect of prolactin on plasma progesterone secretion occurred. Nor was there a noticeable effect on plasma LH secretion. These results suggest that prolactin is unable to directly stimulate progesterone secretion by the corpus luteum of pregnancy. The results of this study suggest that prolactin is an essential luteotropin in the dog from mid-luteal phase in both pregnant and nonpregnant animals. However, it appears to act by sustaining corpus luteum lifespan and function rather than by direct stimulatory effects on progesterone secretion.

Animals↗
PubMed1990

Transcriptional and posttranscriptional regulation of the rat prolactin gene by calcium.

The rat prolactin gene is expressed at a high basal level in the pituitary tumor GH3 cell line. Culturing GH3 cells in a low-Ca2+, serum-free medium (SFM) depresses prolactin mRNA levels, and subsequent addition of Ca2+ to the SFM results in a specific, gradual, and sustained increase in prolactin mRNA levels. We have now examined whether the observed increase in prolactin mRNA levels can be attributed solely to an increase in the transcriptional rate of the prolactin gene. Treatment of GH3 cells in SFM with 0.4 mM CaCl2 for 24 to 48 h increased cytoplasmic prolactin mRNA levels by 5- to 10-fold, whereas the transcriptional rate of the prolactin gene was increased by less than twofold over values for SFM controls. Prolactin mRNA levels increased progressively during the 24-h period after Ca2+ addition, whereas prolactin gene transcription never exceeded a twofold increase over values for SFM controls. The activities of nuclear extracts from control and Ca2(+)-induced cells were examined in an in vitro transcription assay. The two extracts directed transcription from the prolactin promoter and the adenovirus major late promoter equally well. Cycloheximide had no effect on the ability of Ca2+ to increase or maintain prolactin mRNA levels. In dactinomycin mRNA clearance experiments, prolactin mRNA was cleared at the same rate in the absence and presence of Ca2+. These results demonstrate that although Ca2+ has a small effect on the transcriptional rate of the prolactin gene, Ca2+ produces a significant increase in prolactin mRNA levels by acting at a posttranscriptional site(s). Furthermore, Ca(2+) appears to increase prolactin mRNA levels by posttranslational modification of a stable protein, probably at a nuclear site.

Animals↗
PubMed1976

Localization of prolactin in chromophobe pituitary adenomas: study of human necropsy material by immunoperoxidase technique.

In order to identify prolactin-producing tumours in human pituitary glands, 45 chromophobe adenomas, obtained from unselected necropsies, have been studied by various staining procedures including the immunoperoxidase technique for the demonstration of prolactin. The presence of immunoreactive prolactin was revealed in the cytoplasm of the tumour cells in six cases (13%), indicating that the occurrence of prolactin-producing adenomas is not rare. No correlations were established between tumours and clinical history. Two adenomas were detected in female and four in male patients. The age of the patients at necropsy ranged from 28 to 75 years. Three adenomas were associated with disseminated carcinoma, two with fatal liver disease, and one with diabetes mellitus, atherosclerosis, and pyelonephritis. Manifest endocrine symptoms were not disclosed, and endocrine investigations, including measurements of blood prolactin levels, were not undertaken. Thus, direct evidence is lacking as to whether or not these tumours were actively secreting prolactin. In the non-tumorous parts of the anterior lobes the number of prolactin cells was decreased in two cases, suggesting that prolactin released from the adenoma cells suppressed prolactin production in the non-tumorous pituitary. However, the number of prolactin cells of the non-tumorous adenohypophysis seemed to be unchanged in two and increased in another two cases. The present findings conclusively proved the existence of the prolactin-producing adenomas as a distinct entity. These tumours do not stain with acid or basic dyes, they are PAS or thionin negative, and do not contain immunoreactive growth hormone. Thus, by conventional staining procedures they are indistinguishable from other chromophobe adenoma types. Herlant's erythrosin and Brookes' carmoisine methods, claimed spedifically to stain prolactin cells, failed to provide reliable results, hence their use cannot be recommended in tumour identification. Immunoperoxidase staining of prolactin is the only technique which conclusively reveals the presence of immunoreactive prolactin in the cytoplasm of the tumour cells and permits diagnosis. It is proposed that this technique be introduced in pituitary morphological studies. Its application may lead to a better understanding of problems related to prolactin-producing tumours and their secretory activity.

Adenoma, Chromophobe↗
PubMed1990

Age alters pulsatile prolactin release: influence of dopaminergic inhibition.

To determine the effect of age on pulsatile prolactin secretion, we examined prolactin pulse characteristics by cluster analysis in healthy young and old male subjects during the day and night. Pulsatile prolactin secretion was identified in all subjects during the day and night, and prolactin pulse frequency remains stable with age. Younger subjects had a significantly higher prolactin pulse amplitude, area, and peak interval during the night compared with older subjects. In contrast, daytime prolactin pulse characteristics were similar in young and old subjects. Because the major neuroregulator of prolactin is dopamine and because normal aging has been reported to be associated with reductions in hypothalamic dopamine content and effect, we determined whether the mechanism of altered day-night prolactin pulsatile secretion was due to changes in dopaminergic tone. We examined endogenous prolactin secretion after administration of the dopamine antagonist metoclopramide. Metoclopramide significantly increased mean serum prolactin concentration and prolactin pulse height and amplitude in all subjects during the day and night. However, net prolactin pulse amplitude after metoclopramide stimulation at night was significantly higher in older subjects compared with younger subjects. We conclude that prolactin pulse amplitude is blunted in elderly men at night and that daytime pulsatile prolactin secretion is unaltered by age in normal men. The mechanism for this alteration of nighttime prolactin pulsatile secretion in elderly men may be due to age-associated changes in dopaminergic regulation.

Adult↗
PubMedDate not supplied

Pituitary prolactin-secreting tumor formation: recent developments.

Prolactinoma is the most common type of primary pituitary tumors. It occurs more frequently in women than in men. Dopaminergic agonists are effective in the shrinkage of prolactin-secreting pituitary tumor and are preferred in some patients. However, pituitary radiotherapy may enable the long-term removal of prolactin-secreting tumor cells. Recent evidence suggests that prolactinoma is a heterogeneous disorder with complicated and multifactorial etiology and pathogenesis. Apparently, a thorough understanding of prolactinoma tumorigenesis would be important. To facilitate investigations on tumorigenesis of prolactinoma, animal models for prolactinomas have been developed. These models have expedited our progress in the recent years. Many researchers consider the F(344) rat to be the most sensitive strain of rats to estrogen (E(2))-induced prolactinoma formation. Nonetheless, E(2) treatment for 60 days also induces the formation of pituitary prolactin-secreting adenoma in male Sprague-Dawley (SD) rats. Evidently, the SD rat is also a good animal for prolactinoma investigations. Following E(2) implantation, prolactinomas developed in the eutopic adenohypophysis in situ and/or ectopic pituitary grafted under the renal capsule in SD rats. These observations favor the hypothesis that prolactinoma growth is the result of pathological changes in the adenohypophysis and/or hypothalamus. In the latter case, abnormal release of hypothalamic dopamine, GABA, or brain-gut peptides (such as cholecystokinin, vasoactive intestinal polypeptide, galanin, angiotensin, opioid peptide, gastrin, gastrin-releasing peptide, pancreatic polypeptide, and adrenocorticotropic hormone) results in some of the pathological changes that may lead to hyperprolactinemia and/or prolactinoma development. Dysregulation of prolactin synthesis and secretion may be the result of prolactin gene modulation. In E(2)-induced rat prolactinomas, prolactin mRNA contents and the expression of some proto-oncogenes, e.g. c-myc and c-ras, TGFalpha and TGFbeta1 mRNA were significantly changed. The above findings are consistent with results in human prolactinoma development. In addition, in rats abnormal expression of the prolactin gene was correlated with hypomethylated status of CpG sites in exons 1, 2 and 4 of the prolactin gene, as well as the increase in hypersensitive sites to DNase 1 in the encoding region of the prolactin gene. In E(2)-treated rats, a point mutation with a base substitution from cytidine (C) to adenine (A) was found at the -36-bp site of the proximal promoter of the prolactin gene in eutopic pituitary prolactinomas, but no change was observed in the same sequence of the prolactin gene in ectopic prolactinoma. The association of a base substitution with the hyperexpression of the prolactin gene in eutopic prolactinomas suggests that different mechanisms may mediate the formation of eutopic and ectopic prolactin-secreting tumors. Melatonin decreases the expression of the prolactin gene in vitro suggesting that this pineal hormone may be a potential anticarcinogen in vivo. It has also been shown that MT(2) (Mel(1b)) melatonin receptors are expressed in anterior pituitary cells. The use of melatonin as a preventive or therapeutic drug for prolactinomas should be further investigated. In summary, improved knowledge on tumorigenesis of prolactinomas, especially in the rat model, was noted. These E(2)-induced rat prolactinoma models would facilitate future investigations, and expected results shall be fruitful and exciting for the development of future drug designs for the prevention and/or treatment of prolactin-secreting pituitary tumors.

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