Prolactin in the circulation of chronically catheterised piglet foetuses and pregnant sows, and the effect of thyrotrophin-releasing hormone

We chronically catheterised 12 piglet foetuses and 11 sows to determine the changes in circulating concentrations of prolactin during the last 2 weeks of gestation. Prolactin levels were measured by homologous radioimmunoassay and were found to average 2.12 +/- 0.23 ng . ml-1 in the foetuses and 4.19 +/- 0.84 ng . ml-1 in the sows. Foetal concentrations of prolactin increased significantly during the time period of the study. There was no change in maternal concentrations over the corresponding time. Injection of 5 micrograms TRH into 7 foetuses increased the plasma concentrations of prolactin in 6 animals, produced no apparent change in the seventh foetus and did not affect maternal concentrations of prolactin. The magnitude of the maximum response of TRH of the younger foetuses (less than 107 days delta = 0.7, 1.3, 4.2 ng . ml-1) was substantially less than that of the foetuses prior to term (greater than 107 days delta = 6.4, 21.7, 27.5 ng . ml-1). Injection of saline and the haemorrhage of blood sampling produced no significant change in the initial concentration of prolactin. We conclude that prolactin is present in the circulation of the pig foetus, that it is produced endogenously in lower concentrations than in the pregnant sow and that the foetal responsiveness to TRH stimulation increases towards the end of gestation.     

Physiological roles of thyrotrophin-releasing hormone and vasoactive intestinal peptide on the pulsatile secretory patterns of prolactin in pituitary-grafted female rats

Much is known about the fact that thyrotrophin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP) stimulate prolactin secretion but areas of uncertainty remain. This work was undertaken to describe the effects of TRH and VIP on the pulsatile secretion pattern of prolactin, in adult sham-operated and pituitary-grafted hyperprolactinaemic female rats. Two pulses of TRH (1 microgram/rat) or one pulse of VIP (20 micrograms/rat) were given 60 or 120 min after the period of blood sampling. Pituitary grafting increased the mean values of prolactin, absolute amplitude and duration of the peaks and decreased their frequency, compared with control animals. In sham-operated rats, TRH elevated prolactin levels by increasing the absolute and relative amplitudes and duration of the pulses, along with a decrease in their frequency. No priming effects of TRH were observed in this study. Hyperprolactinaemia blunted TRH effects on the pulsatile secretion pattern of prolactin. In sham-operated rats, VIP administration increased the absolute and relative amplitudes of the prolactin peaks. None of the other parameters studied were changed. In pituitary-grafted animals, VIP administration increased the absolute and relative amplitudes of the prolactin peaks but to a lesser extent compared with controls. These data suggest that TRH and VIP affect prolactin pulsatility differentially. The effects of TRH and VIP were blunted to some extent by exposure to previously elevated circulating prolactin levels.     

Effect of thyrotropin-releasing hormone on secretion of thyrotropin, prolactin, thyroxine, and triiodothyronine in pregnant and fetal rhesus monkeys

The effect of thyrotropin-releasing hormone (TRH) on the pituitary-thyroid axis and on prolactin secretion was studied in pregnant Rhesus monkeys during the latter period of gestation and in non-pregnant female controls. The baseline plasma concentrations of TSH, T3, T4, and prolactin (PRL) of pregnant monkeys did not differ from those of non-pregnant monkeys. After administration of TRH, plasma prolactin rose to higher levels in pregnant monkeys than in non-pregnant monkeys whereas there was a similar response of plasma TSH, T4 and T3 in both groups. The baseline plasma TSH was elevated and plasma T3 was decreased in the fetus compared with the mother. Administration of TRH iv to the maternal monkey caused a larger response in the fetal plasma TSH than in that of the mother and was followed by larger increments in plasma T4 and T3 concentrations in the fetuses than in the mothers. The larger increments of plasma TSH and thyroid hormones in the fetus compared with the mother also occurred when TRH was given iv to the fetus. There was a significant rise of plasma prolactin in both mother and fetus after administration of TRH to mother or fetus; the increase of plasma PRL was much higher in the mother than in the fetus. The data show that TRH can cross the primate placenta in either the maternal to fetal or fetal to maternal direction. The fetal thyroid of the Rhesus monkey during the latter period of gestation can release both T4 and T3 in response to TSH.     

Dose-dependent effects of 17-beta-estradiol on pituitary thyrotropin content and secretion in vitro

We studied the basal and thyrotropin-releasing hormone (TRH) (50 nM) induced thyrotropin (TSH) release in isolated hemipituitaries of ovariectomized rats treated with near-physiological or high doses of 17-beta-estradiol benzoate (EB; sc, daily for 10 days) or with vehicle (untreated control rats, OVX). One group was sham-operated (normal control). The anterior pituitary glands were incubated in Krebs-Ringer bicarbonate medium, pH 7.4, at 37 degrees C in an atmosphere of 95% O2/5% CO2. Medium and pituitary TSH was measured by specific RIA (NIDDK-RP-3). Ovariectomy induced a decrease (P < 0.05) in basal TSH release (normal control = 44.1 +/- 7.2; OVX = 14.7 +/- 3.0 ng/ml) and tended to reduce TRH-stimulated TSH release (normal control = 33.0 +/- 8.1; OVX = 16.6 +/- 2.4 ng/ml). The lowest dose of EB (0.7 microgram/100 g body weight) did not reverse this alteration, but markedly increased the pituitary TSH content (0.6 +/- 0.06 microgram/hemipituitary; P < 0.05) above that of OVX (0.4 +/- 0.03 microgram/hemipituitary) and normal rats (0.46 +/- 0.03 microgram/hemipituitary). The intermediate EB dose (1.4 micrograms/100 g body weight) induced a nonsignificant tendency to a higher TSH response to TRH compared to OVX and a lower response compared to normal rats. Conversely, in the rats treated with the highest dose (14 micrograms/100 g body weight), serum 17-beta-estradiol was 17 times higher than normal, and the basal and TRH-stimulated TSH release, as well as the pituitary TSH content, was significantly (P < 0.05) reduced compared to normal rats and tended to be even lower than the values observed for the vehicle-treated OVX group, suggesting an inhibitory effect of hyperestrogenism. In conclusion, while reinforcing the concept of a positive physiological regulatory role of estradiol on the TSH response to TRH and on the pituitary stores of the hormone, the present results suggest an inhibitory effect of high levels of estrogen on these responses.     

Influence of infused prolactin on hormone binding to tissue slices

The influence of circulating prolactin on the binding of labeled hormone to tissue slices in vitro was investigated in rats bearing dimethylbenzanthracene-induced mammary tumors. Prolactin was infused into four animals over four 30-min periods to give serum levels ranging from 20 to 2000 ng/ml. Serial biopsies of liver and tumor were taken during infusion, and binding of labeled prolactin and insulin measured in tissue slices. Whereas insulin binding remained constant, prolactin binding was significantly depressed in both tissues when samples were obtained at serum prolactin levels greater than 300 ng/ml. This decrease was due to diminished numbers of available binding sites rather than a change in binding-site affinity for prolactin. The data indicate that under the conditions of this experiment, endogenous circulating prolactin may interfere with in vitro measurements of hormone uptake when serum levels excee 300 ng/ml.     

Changes in circulating levels of LH, FSH, LHbeta- and alpha-subunit after gonadotropin-releasing hormone, and of TSH, LHbeta- and alpha-subunit after thyrotropin-releasing hormone

The effect of the gonadotropin-releasing hormone (LRH) and thyrotropin-releasing hormone (TRH) on the blood levels of LH, FSH and TSH, and LHbeta- and alpha-subunit have been studied in 4 normal subjects during the first 20 min after administration of these releasing hormones. Increases in serum immunoreactive LH, LHbeta and alpha-subunit were seen in all subjects after LRH (100 mug iv) but in all subjects the rise in LH was preceded by a rise in alpha-subunit. All subjects showed an increase in TSH and 3 of the 4 subjects a rise in alpha-subunit after TRH (200 mug) but the alpha-subunit responses were smaller and less consistent than after LRH. Levels of LHbeta remained unchanged after TRH. The results demonstrate that the immunoreactive alpha-subunit of the pituitary glycoprotein hormones can be released independently of the intact hormones and that release occurs in response to the same releasing hormones, LRH and TRH, that release the intact hormones.     

The serum and pituitary prolactin variations under the influence of a pesticide substance in the male rat

Prolactin was measured in the serum and hypophysis of the male rat after five days of oral administration of malathion in suspension (200 mg/kg body), alone or associated with pimozide (a psychotropic drug). The release of prolactin observed in the group treated with malathion was lower (19.97 +/- 7.27 ng/ml) than in the groups treated with malathion and pimozide or pimozide alone (26.65 +/- 3.17 and 26.49 +/- 2.57 ng/ml, respectively) but significantly higher than in the control group (10.08 +/- 5.82 ng/ml). The administration of two dose levels of pure malathion solubilized in alcohol/water (v/v) failed to reproduce the same results. The discussions are focussed upon: 1) the mechanisms involved in the release of prolactin under the influence of malathion (vagomimetic action) and 2) the lack of cumulative effects of malathion and pimozide (presumably different levels of their influence).     

Phencyclidine sedation as a technique for handling rhesus monkeys: effects on LH, GH, and prolactin secretion

Rhesus monkeys, sedated with phencyclidine hydrochloride (Sernylan), were quieted for prolonged periods of time, while maintaining somatic reflexes, muscle tone, and respiration. Brief daily periods of sedation did not interfere with the menstrual cycle. Prolonged sedation, however, interfered with the experimentally estrogen-induced LH surge, but not with the inhibitory action of estrogen on LH tonic secretion. Pulsatile release of LH, GH, and prolactin persisted even under prolonged sedation. The secretion of prolactin in response to the administration of TRH was increased in animals sedated with phencyclidine.     

Proestrous gonadotropin levels in thyroparathyroidectomized female rats

Intact and TPTx animals showed the expected afternoon increase in serum LH,FSH and prolactin levels. But the afternoon increase in serum LH levels in TPTx rats was less than that observed for intact animals (p less than 0.001). Neither serum prolactin nor FSH levels were altered by TPTx.     

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The effects of endothelin (ET) 1 on the release of somatostatin (SS) and thyrotropin-releasing hormone (TRH) from the rat stomach were studied in vitro. The rat stomach was incubated in medium 199 with 1.0 mg/ml of bacitracin (pH 7.4) for 20 min. The amounts of SS and TRH released into the medium were measured by individual radioimmunoassays. With the addition of ET-1, the release of SS from the rat stomach was inhibited significantly in a dose-related manner, whereas TRH released from the stomach was enhanced significantly. These effects of ET-1 on SS or TRH release were blocked by BQ-485, a blocker of ETA receptor. These findings suggest that ET-1 inhibits SS and stimulates TRH release from the rat stomach in vitro, and that these effects are mediate via ETA receptor.     

Dose-dependent prolactin releasing activity of arginine vasotocin in intact and pinealectomized estrogen-progesterone treated adult male rats

Estrogen-progesterone (EP) treated adult male rats were injected intravenously (iv) with 0.1, 1 or 10 mug arginine vasotocin (AVT) or Ringers lactate solution. A significant dose-related rise in plasma prolactin was evident 10 min after injection with AVT. In a second experiment, sham-operated or pinealectomized EP-treated male rats were injected iv with 0.1 or 1 mug AVT or diluent. Plasma prolactin was significantly elevated in both sham-operated and pinealectomized groups at both 10 and 20 min post-injection of 1 mug AVT. These results indicate that AVT has prolactin-releasing activity and that this activity is not dependent upon the presence of an intact pineal gland.     

Plasma prolactin responses to thyrotropin-releasing hormone in patients with breast cancer

Plasma human prolactin levels were measured by homologous radioimmunoassay in patients with primary breast cancer and in normal women of similar age. In normal controls mean (+/- SEM) basal plasma prolactin levels were 11.9 +/- 1.5 ng/ml and intravenous injection of synthetic thyrotropin-releasing hormone (TRH), 500 mug, caused a significant rise in plasma prolactin in all subjects examined with a maximum response of 52.6 +/- 3.3 ng/ml (mean +/- SEM). Markedly high plasma prolactin levels and exaggerated plasma prolactin responses to TRH were demonstrated in some patients with breast cancer. However, mean basal plasma prolactin levels and mean plasma prolactin increments following TRH in patients with breast cancer did not differ significantly from those in normal subjects. Plasma prolactin responses to TRH were slightly blunted during the administration of androgen in patients with breast cancer. These results suggest that some of the patients with primary breast cancer have abnormal prolactin secretion.     

Failure of LH and/or prolactin to prevent PGF 2alpha-induced luteolysis of ovine corpora lutea

Infusions of phosphate buffered saline, LH (4 microgram/min or 14 microgram/min), prolactin (42 microgram/min) or LH (4 microgram/min) plus prolactin (42 microgram/min) for 12 hr did not prevent luteolysis following intramuscular injections of prostaglandin F2alpha-tham salt two and six hr after beginning the infusion. Likewise, these treatments did not delay luteolysis since a similar rate of decline in peripheral plasma progesterone occurred in all groups. It was concluded that elevation of serum concentrations of LH and prolactin to high levels had no effect on PGF2alpha-induced luteolysis on day 8 following induced ovulation.     

Modifications of platelet phospholipid fatty acid composition in streptozocin-induced diabetic rats

Mesulergine (N,N-dimethylsulphamide-N'-1,6-dimethyl-ergoline-8 alpha-yl) is an active semisynthetic ergot derivative with lower antiprolactin potency compared with bromocriptine or pergolide. Since no data are yet available on the effects of mesulergine on pituitary dopamine receptors, the present study has been designated to elucidate the influence of this drug on prolactin secretion in vivo and in vitro and 3H-spiperone binding by the anterior pituitary gland in female Wistar rats with experimentally induced hyperprolactinemia. Three weeks after bilateral ovariectomy and subcutaneous implantation of silastic tubes, containing 10 mg of diethylstilbestrol, a dramatic rise in serum prolactin levels was observed (1.67 +/- 0.23 vs. 80.82 +/- 3.80 ng/ml; P less than 0.001). Mesulergine attenuated the stimulatory effect of diethylstilbestrol on serum prolactin level in a time- and dose-dependent fashion. At concentration range between 10(-5) and 10(-7) M it also inhibited prolactin secretion from cultured rat pituitary cells to the medium during 180 min incubation in a dose-dependent manner. Scatchard analyses performed on the in vitro 3H-spiperone binding kinetics in a dispersed anterior pituitary cell culture, prepared from the pituitaries from rats treated for four weeks with diethylstilbestrol, showed that chronic mesulergine treatment (in dose of 3.0 mg/kg injected s.c. for 10 days) induced a significant decrease in the number of dopamine D2-binding sites (Bmax 28.00 +/- 4.20 vs. 42.80 +/- 4.76 fmol/10(6) cells; P less than 0.01) without any changes in D2-receptor affinity. Our results suggested that antiprolactin activity of mesulergine in vivo and in vitro is probably associated with agonistic effect of this drug on D2-dopamine receptors.     

Effect of endothelin-1 in man--impact on basal and stimulated concentrations of luteinizing hormone, follicle-stimulating hormone, thyrotropin, growth hormone, corticotropin, and prolactin

The effect of endothelin-1 on basal and stimulated serum (plasma) concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH), prolactin (PRL), growth hormone (GH), and corticotropin was investigated in healthy male volunteers (n = 5). Intravenous (IV) administration of endothelin-1 (5 ng/kg/min for 15 minutes, followed by 2.5 ng/kg/min for 105 minutes) induced an increase in basal plasma concentrations of corticotropin. Serum concentrations of PRL, TSH, LH, FSH, and GH remained unchanged. The increase in serum concentrations of these pituitary hormones induced by IV administration of LH-releasing hormone ([LH-RH] 100 micrograms), thyrotropin RH ([TRH] 400 micrograms), GH-RH (100 micrograms), and corticotropin-releasing factor ([CRF] 100 micrograms) was suppressed in regard to PRL (P < .01) and GH (P < .01) and enhanced in regard to corticotropin (P < .01). Stimulated serum concentrations of LH and FSH also tended to be higher following administration of endothelin-1 (P < .05), whereas the increase in serum concentrations of TSH remained unchanged. Thus, when administered in pharmacological doses, endothelin-1 influences pituitary hormone secretion in man.     

Facilitation of Chemoreceptor-induced reflex vasoconstriction by intravertebral arterial administration of clonidine

The influence of clonidine on the reflex vascular responses to stimulation of carotid body chemoreceptors and bilateral carotid occlusion was studied in morphine, chloralose-urethane anesthetized dogs. Bilateral carotid occlusion and intracarotid injection of nicotine (30 and 100 microgram) or sodium cyanide (200 and 500 microgram) elicited reflex vasoconstriction in the perfused gracilis muscle vascular bed. Infusion of clonidine (2-4 microgram/kg) into the vertebral artery significantly lowered blood pressure. Reflex vasoconstrictor responses to chemoreceptor stimulation were significantly enhanced after clonidine administration whereas reflex vasoconstrictor responses to carotid occlusion were markedly reduced. The facilitation of chemoreceptor reflex responses by clonidine was observed in dogs with intact or sectioned vagi and in animals in which the carotid arteries were perfused at constant blood flow. Inhibition of carotid occlusion responses by clonidine was observed in dogs with intact or sectioned vagi. Infusion of clonidine directly into the carotid arteries did not significantly alter responses to chemoreceptor stimulation. These experiments demonstrate that clonidine antagonizes the reflex vasoconstriction caused by carotid occlusion while potentiating the vasoconstriction elicited by chemoreceptor stimulation. The data suggest that clonidine exerts central actions which result in a facilitation of the chemoreceptor reflex and a simultaneously occuring hypotension which is probably due to an action on baroreceptor pathways.     

Role of protein degradation in the growth of livers after a nutritional shift

Four patients with idiopathic pituitary dwarfism were shown to have growth hormone (GH), adrenocorticotropin (ACTH), and luteinizing hormone (LH) deficiencies. Basal levels of thyrotropin (TSH) were within normal range in three patients and slightly elevated in one. Exaggerated and delayed responses were obtained after TSH-releasing hormone (TRH) stimulation. Serum thyroxine (T4) values were low (2.3 +/- 0.4 mug/100 ml), while triiodothyronine (T3) levels were in the normal range (1.22 +/- 0.25 ng/ml), both rising substantially after exogenous TSH and consecutive TRH administration. Their hypothyroid state was, therefore, probably due to TRH deficiency. To examine the dose of L-T4 necessary to produce inhibition of the TSH response to TRH, 50 mug/m2/day of L-T4 was administered to these patients. At the end of 4 weeks of replacement, serum T4 rose to 5.2 +/- 0.5 mug/100 ml, whereas T3 was unchanged from the previous levels, after which TSH responses to TRH were completely suppressed in all patients. As a control group, six patients with primary hypothyroidism received gradually increasing doses of L-T4 for 4-week periods, and TSH response to TRH was tested at the end of each dosage of L-T4, until complete inhibition of TSH release was obtained. The primary hypothyroid patients required approximately 150 mug/m2/day of L-T4 for suppression of TSH response to TRH. At this dosage, serum T4 and T3 levels were 8.5 +/- 0.9 mug/100 ml and 2.34 +/- 0.5 ng/ml respectively, which were significantly higher than those levels in the pituitary dwarfs (P less than 0.001 for T4 and P less than 0.01 for T3). These observations indicate that the set point of TSH release in feedback inhibition by throxine is low in idiopathic hypopituitarism with TRH deficiency, and TRH seems to control the pituitary sensitivity to feedback regulation of thyroid hormones.     

Social subordination stress, behavior, and central monoaminergic function in female cynomolgus monkeys

BACKGROUND: Social subordination in female cynomolgus monkeys is stressful and activates the hypothalamic-pituitary-adrenal axis. In a previous experiment behavioral depression was observed in a subset of subordinates. METHODS: In the experiment reported here behavioral and physiological indicators of stress were evaluated in dominant and subordinate female cynomolgus monkeys, and brain dopaminergic activity was assessed, as reflected in the prolactin response to haloperidol, a dopamine2 (D2) receptor antagonist. RESULTS: Subordinates were aggressed more, spent more time in fearful scanning of the social environment, spent less time as the recipients of the active affiliative behavior of being groomed, had more variable heart rates in response to a novel environment, and were hypercortisolemic compared to dominants. Prolactin responses to haloperidol challenge were lower in subordinates than dominants, an observation consistent with the hypothesis that subordinate females have decreased D2 receptor function. CONCLUSIONS: These observations suggest that social subordination is stressful and may alter brain dopaminergic function in primates. The neurophysiological characteristics of social subordinates may contribute to their susceptibility to depression.     

Microinjection of thyrotropin-releasing hormone analogue into the central nucleus of the amygdala stimulates gastric contractility in rats

The effect on gastric contractility following bilateral microinjection of thyrotropin-releasing hormone (TRH) analog, RX 77368, into the central nucleus of the amygdala was examined in fasted, urethane-anesthetized rats. Extraluminal force transducers were used to measure gastric corpus contractility. Bilateral microinjection of RX 77368 (0.5 microgram, 1.0 microgram, n = 6 each) stimulated gastric contractility for up to 120 min post-injection, P < 0.05. Gastric contractility was not significantly stimulated by microinjection of 0.1 microgram RX 77368, 0.1% bovine serum albumin (BSA) into the central nucleus or RX 77368 (0.5 microgram, 1.0 microgram) into sites adjacent to the central nucleus. Peak responses (1.0 microgram) occurred 40 min post-injection and represented a 16-26-fold increase over basal values. The frequency of gastric contraction waves was attenuated for 0-90 min in rats receiving central amygdaloid microinjection of RX 77368 (0.1, 0.5 or 1.0 microgram) versus rats microinjected with the vehicle or RX 77368 into sites adjacent to the central nuclei. The stimulatory effect of RX 77368 (1.0 microgram) on gastric contractility was abolished by subdiaphragmatic vagotomy. These results indicate that the TRH analog, RX 77368, acts within the central amygdala to vagally stimulate gastric contractility.