The glycopeptide moiety of vasopressin-neurophysin precursor is neurohypophysial prolactin releasing factor

All of the classically-described hypothalamic, hypophysiotropic factors that regulate anterior pituitary hormone secretion have now been isolated and identified except for prolactin releasing factor. We report here that the 39-amino acid glycopeptide comprising the carboxyterminus of the neurohypophysial vasopressin-neurophysin precursor stimulates prolactin release from cultured pituitary cells as potently as does thyrotropin releasing hormone but has no effect on the secretion of other pituitary hormones. Furthermore, antisera to the glycopeptide administered to lactating rats attenuated suckling-induced prolactin secretion. Thus, this glycopeptide appears to be the neurohypophysial prolactin releasing factor.     

Effect of bombesin on basal and stimulated secretion of some pituitary hormones in humans

The effect of bombesin (5 ng/kg/min X 2.5 h) on basal pituitary secretion as well as on the response to thyrotropin releasing hormone (TRH; 200 micrograms) plus luteinizing hormone releasing hormone (LHRH; 100 micrograms) was studied in healthy male volunteers. The peptide did not change the basal level of growth hormone (GH), prolactin, thyroid-stimulating hormone (TSH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH). On the contrary, the pituitary response to releasing hormones was modified by bombesin administration. When compared with control (saline) values, prolactin and TSH levels after TRH were lower during bombesin infusion, whereas LH and FSH levels after LHRH were higher. Thus bombesin affects in man, as in experimental animals, the secretion of some pituitary hormones.     

Effect of histamine and acetylcholine on hypophysial stalk plasma dopamine and peripheral plasma prolactin levels.

To further define the role of dopamine in the regulation of prolactin secretion, we studied the effect on prolactin and hypothalamic dopamine secretion of histamine and acetylcholine (ACh) injected into the lateral ventricle of urethane anesthetized diestrus-1 rats. Histamine (10 μg) caused a 592% increase in plasma prolactin levels and a 26% decrease in stalk plasma dopamine levels. ACh (50 μg) caused a 2090% increase in plasma prolactin levels but no significant change in stalk plasma dopamine concentration.To determine if the 26% fall in stalk plasma dopamine following histamine administration could account for the 6-fold increase in plasma prolactin, we measured the effect on prolactin secretion of a similar decrease in administered dopamine. During an infusion of physiologic levels of dopamine, a 25% decrease in arterial plasma dopamine concentration resulted in only a 2-fold increase in prolactin secretion.The results of these experiments suggest that the effect of histamine on prolactin secretion may be mediated in part by decreased hypothalamic secretion of dopamine but that an additional hypothalamic hormone is probably involved. The stimulatory effect of ACh on prolactin secretion is not mediated by dopamine. These data are consistent with the growing evidence for the participation of multiple hypothalamic factors in the regulation of prolactin secretion.     

Episodic and TRH induced growth hormone release in primary hypothyroidism of man and rat.

In 27 hypothyroid subjects studied over 20 to 120 minutes, the concentration of serum growth hormone (GH) was variable with the amplitude and frequency of the secretory patterns similar to those reported by others for normal individuals. Serum GH, after the administration of thyrotropin releasing hormone (TRH) did not differ from values observed as spontaneous surges, in contrast to a consistent increase in thyrotropin and prolactin. Episodic secretion of GH persisted in thyroidectomized rats and did not differ significantly from that present in intact controls. It is concluded that episodic GH secretion is not abolished in primary hypothyroidism and that TRH is not a constant GH secretagogue in human subjects with hypothyroidism.     

Effects of the dopamine agonist cabergoline on the pulsatile and TRH-induced secretion of prolactin, LH, and testosterone in male beagle dogs

In the present study, the pulsatile serum profiles of prolactin, LH and testosterone were investigated in eight clinically healthy fertile male beagles of one to six years of age. Serum hormone concentrations were determined in blood samples collected at 15 min intervals over a period of 6 h before (control) and six days before the end of a four weeks treatment with the dopamine agonist cabergoline (5 microg kg(-1) bodyweight/day). In addition, the effect of cabergoline administration was investigated on thyrotropin-releasing hormone (TRH)-induced changes in the serum concentrations of these hormones. In all eight dogs, the serum prolactin concentrations (mean 3.0 +/- 0.3 ng ml(-1)) were on a relatively constant level not showing any pulsatility, while the secretion patterns of LH and testosterone were characterised by several hormone pulses. Cabergoline administration caused a minor but significant reduction of the mean prolactin concentration (2.9 +/- 0.2 ng ml(-1), p < 0.05) and did not affect the secretion of LH (mean 4.6 +/- 1.3 ng ml(-1) versus 4.4 +/- 1.7 ng ml(-1)) or testosterone (2.5 +/- 0.9 ng ml(-1) versus 2.4 +/- 1.2 ng ml(-1)). Under control conditions, a significant prolactin release was induced by intravenous TRH administration (before TRH: 3.8 +/- 0.9 ng ml(-1), 20 min after TRH: 9.1 +/- 5.9 ng ml(-1)) demonstrating the role of TRH as potent prolactin releasing factor. This prolactin increase was almost completely suppressed under cabergoline medication (before TRH: 3.0 +/- 0.2 ng ml(-1), 20 min after TRH: 3.3 +/- 0.5 ng ml(-1)). The concentrations of LH and testosterone were not affected by TRH administration. The results of these studies suggest that dopamine agonists mainly affect suprabasal secretion of prolactin in the dog.     

The ability of prolactin to change the sensitivity of the pituitary of the lactating rat to luteinising hormone releasing hormonein vitro

The ability of prolactin to influence the responsiveness of the lactating rat pituitary to luteinising hormone releasing hormone has been examinedin vitro. The pituitary responsivenessin vivo to luteinising hormone releasing hormone decreased as a function of increase in the lactational stimulus. Prolactin inhibited the spontaneousin vitro release of luteinising hormone and follicle stimulating hormone to a small extent, from the pituitary of lactating rats with the suckling stimulus. However, it significantly inhibited the release of these two hormones from luteinising hormone releasing hormone-stimulated pituitaries. The responsiveness of pituitaries of rats deprived of their litter 24 h earlier, to luteinising hormone releasing hormone was also inhibited by prolactin, although minimal. It was concluded that prolactin could be influencing the functioning of the pituitary of the lactating rat by (a) partially suppressing the spontaneous release of gonadotropin and (b) inhibiting the responsiveness of the pituitary to luteinising hormone releasing hormone.     

Neuroendocrinology of Teleosts

The nucleus preopticus has been shown to receive afferent inputfrom certain cranial nerves and the spinal cord. In addition,the nucleus preopticus and its tracts can synthesize and transporthormones about as rapidly as a mammal can. The nucleus preopticusis functionally involved in the spawning reflex behavior. The hypothalamic control of each of the adenohypophysial hormonesis discussed. There is conflicting and incomplete evidence forthe control of melanocyte-stimulating hormone (MSH), prolactin,and somatotropin. Secretion of prolactin and MSH may each becontrolled by an inhibitory factor. Corticotropin secretionhas been shown to be controlled by corticotropin releasing factor(CRF). There is a negative fedback effect by cortisol on thepituitary to suppress corticotropin secretion. Gonadotropinsecretion is controlled by gonadotropin releasing factor (GRF).A part of the nucleus lateralis tuberis is involved in the controlof gonadotropin secretion. A great deal of indirect evidenceindicates that a thyrotropin inhibitory factor (TIF) controlsthyrotropin secretion. There is a negative feedback effect bythyroxine on the pituitary to suppress thyrotropin secretionand a positive feedback effect on the hypothalamus to stimulateTIF secretion. The above findings are restricted to only one or two speciesin each instance. It is not known how general the above mechanismsof control are found throughout the teleosts.     

Growth hormone and prolactin response to thyrotropin releasing hormone and growth hormone releasing factor in the immature turkey

Synthetic thyrotropin releasing hormone (TRH) and human pancreatic growth hormone releasing factor (hpGRF) stimulated growth hormone (GH) secretion in 6- to 9-week-old turkeys in a dose-related manner. TRH and hpGRF (1 and 10 micrograms/kg, respectively) each produced a sixfold increase in circulating GH levels 10 min after iv injection. Neither TRH nor hpGRF caused a substantial change in prolactin (PRL) secretion in unrestrained turkeys sampled through intraatrial cannulas. However, some significant increases in PRL levels, possibly related to stress, were noted.     

Relation of endogenous opioid peptides and morphine to neuroendocrine functions.

Morphine and the endogenous opioid peptides (EOP) exert similar effects on the neuroendocrine system. When adminstered acutely, they stimulate growth hormone (GH), prolactin (PRL), and adrenocorticotropin (ACTH) release, and inhibit release of luteinizing hormone (LH), follicle stimulating hormone (FSH),and thyrotropin (TSH). Recent studies indicate that the EOP probably have a physiological role in regulating pituitary hormone secretion. Thus injection of naloxone (opiate antagonist) alone in rats resulted in a rapid fall in serum concentrations of GH and PRL, and a rise in serum LH and FSH, suggesting that the EOP help maintain basal secretion of these hormones. Prior administration of naloxone or naltrexon inhibited stress-induced PRL release, and elevated serum LH in castrated male rats to greater than normal castrate levels. Studies on the mechanisms of action of the EOP and morphine on hormone secretion indicate that they have no direct effect on the pituitary, but act via the hypothalamus. There is no evidence that the EOP or morphine alter the action of the hypothalamic hypophysiotropic hormones on pituitary hormone secretion; they probably act via hypothalamic neurotransmitters to influence release of the hypothalamic hormones into the pituitary portal vessels. Preliminary observations indicate that they may increase serotonin and decrease dopamine metabolism in the hypothalamus, which could account for practically all of their effects on pituitary hormone secretion.     

Failure to confirm consistent stimulation of growth hormone by diazepam

Diazepam has been reported to influence pituitary hormone secretion, with several studies claiming that diazepam provokes growth hormone release. Normal volunteers were therefore examined for anterior pituitary responsiveness to 10 mg diazepam i.v. and p.o. The drug had no significant effect on the secretion of prolactin or thyrotropin when compared to control saline injections in all subjects. Growth hormone response was variable; serum growth hormone increased significantly in only 4 of 10 patients after i.v. diazepam and in only 1 of 7 subjects tested with oral diazepam. Serum cortisol rose in only 1 subject, precluding a stress-related explanation for the increase in growth hormone. We conclude that diazepam inconsistently stimulates growth hormone secretion and should not be relied upon as a test of growth hormone reserve.     

TRH-Gly, a precursor of TRH, alters GH secretion in acromegaly

We explored effects of a precursor of thyrotropin (TSH)-releasing hormone (TRH), TRH-Gly, on growth hormone (GH) secretion in acromegaly. Intravenous injection of TRH-Gly produced a profound increase in GH secretion in eight, decrease in two, and no response in five out of a total fifteen patients. The magnitude of GH responsiveness to TRH-Gly was significantly correlated with that induced by TRH (r = 0.824, P less than 0.01). In contrast, TRH-Gly did not induce secretion of TSH or prolactin. The present data suggest that TRH-Gly may participate in regulating GH secretion in some patients with acromegaly and that TRH-Gly-induced GH secretion may be due at least in part to TRH-associated mechanisms underlying GH secretion.     

Aminergic regulation of neuroendocrinological functions: theoretical background and some clinical examples

Remarkable progress has been made during recent years in the central regulation of the hypothalamic releasing and inhibiting factors and the respective anterior pituitary hormones. There are two nearly universal inhibitory organizations: short tuberoinfundibular dopamine (TIDA) neurons and somatostatinergic system originating from the periventricular hypothalamus and terminating to the median eminence. It is now known that e.g. dopamine, noradrenaline and acetylcholine enhance while 5-hydroxytryptamine and GABA inhibit somatostatin secretion. These transmitters are also involved in the regulation of all releasing factors and pituitary hormones. Clinical applications have been developed based on the regulation of prolactin and growth hormone. Inhibitory TIDA neurons are undoubtedly the major determinants of prolactin secretion. Hyperprolactinaemia is one of the most common endocrinological side-effects of the drugs antagonizing dopaminergic transmission. Expectedly, dopaminergic drugs (bromocryptine, lergotrile, piribedil, dopamine and levodopa) are quite effective in reducing high prolactin levels regardless of the reason. The secretion of growth hormone is predominantly under dual dopaminergic control: hypothalamic stimulation and pituitary inhibition. The former masters the function of the normal gland, while the peripheral inhibitory component takes over in acromegalic gland. Hence dopaminergic drugs are able to reduce elevated growth hormone levels in 30-50% of the acromegalic patients. In normal man, dopamine agonists increase growth hormone levels. An analogous situation can be seen in Cushing's disease regarding ACTH secretion.     

Diabetes insipidus and galactorrhea caused by histiocytosis X.

A 44-year-old woman with diabetes insipidus of 3 years duration was found to have histiocytosis X. This was based on clinical, radiological and pathological findings consistent with the diagnosis. Furthermore, she developed spontaneous galactorrhea during the course. Endocrine studies of hypothalamic-pituitary function revealed completely impaired secretion of gonadotropin, growth hormone and anti-diuretic hormone, and possible partial impairment of adrenocorticotropic hormone secretion, while thyroid stimulating hormone secretion remained intact. Persistently elevated plasma levels of human prolactin were also demonstrated, which were unaffected by administration of either thyrotropin releasing hormone, l-DOPA or water loading, but suppressed significantly by CB-154, an ergot alkaloid. These results suggest that abnormalities of the patient's endocrine function may be mainly accounted for by a single hypothalamic lesion.     

Lactational [correction of Lacational] anovulation in rats and its dependency on progesterone

The relationship between prolactin (PRL) secretion and anovulation in lactating rats was studied. Normal lactating rats and lactating rats treated with antiserum against luteinizing hormone-releasing hormone at the time of postpartal ovulation were used. Normal lactating rats were treated with either a dopamine agonist (CB-154, 150 micrograms/rat) on Day 10 or 13, or pups removal on Day 7 or 10, and thereafter luteolysis and inhibition on PRL secretion were assessed. With the CB-154 treatment, the incidence of luteolysis increased as the lactational period advanced (42% vs 72%), whereas it decreased (73% vs 14%) with the pups removal. Thus, dopamine effectively inhibited PRL secretion during the later lactational stage, but could not do so during the earlier stage when there were mechanisms other than dopamine stimulating PRL secretion. Following luteal regression induced by CB-154, ovulation did not occur if the rats were treated with CB-154 on Day 10, whereas 50% of the rats ovulated within 4 days if treated on Day 13. Furthermore, in the lactating rats treated with anti-luteinizing hormone-releasing hormone serum during late pregnancy, ovulation was not observed until Day 10 of lactation. Since the serum progesterone levels were low in these rats due to the absence of ovulation and lactational corpora lutea, the blockade of ovulation was not due to elevated circulating progesterone during the early lactational period. The mechanism of ovulation blockade during lactation thus seems to shift from being progesterone independent to progesterone dependent at a similar period when the neuroendocrine control of PRL secretion shifts from dopamine independent to dependent.     

The mechanisms by which vasoactive intestinal peptide (VIP) and thyrotropin releasing hormone (TRH) stimulate prolactin release from pituitary cells

The effect of vasoactive intestinal peptide (VIP) on prolactin (PRL) secretion from pituitary cells is reviewed and compared to the effect of thyrotropin releasing hormone (TRH). These two peptides induced different secretion profiles from parafused lactotrophs in culture. TRH was found to increase PRL secretion within 4 s and induced a biphasic secretion pattern, while VIP induced a monophasic secretion pattern after a lag time of 45–60 s.The secretion profiles are compared to changes in adenylate cyclase activity, production of inositol polyphosphates, changes in intracellular calcium concentrations and changes in electrophysiological properties of the cell membrane.Abbreviations AC adenylate cyclase - DG diacyglycerol - GH growth hormone - GTP guanosine trisphosphate - G_i GTP binding proteins that mediate inhibition of adenylate cyclase and that are pertussis toxin sensitive - G_s GTP binding protein that mediates stimulation of adenylate cyclase - GH cells clonal rat pituitary tumor cells producing PRL and/or growth hormone - GH₃ GH₄C₁ and GH₄B6 subclones of GH cells - PKA protein kinase A - PKC protein kinase C - PLC phospholipase C - PRL prolactin - TPA 12-O-tetradecanoyl phorbol 13-acetate - TRH thyrotropin releasing hormone - VIP vasoactive intestinal peptide     

Scientific Foundations of Oncology

The effect of somatostatin on the thyrotropin (TSH), prolactin, growth hormone (GH) and insulin responses to the combined administration of thyrotropin releasing hormone (TRH) and arginine was studied in six healthy subjects, three hypothyroid patients and three acromegalic patients. Similar inhibition by somatostatin of the TSH and insulin responses was observed in the three groups. While the tetradecapeptide had no significant effect on the prolactin response in the healthy and acromegalic subjects, it caused an unexpected inhibition of the prolactin response in two of the hypothyroid subjects. Contrary to the findings in the healthy and hypothyroid subjects, somatostatin did not inhibit the GH response in the acromegalic patients. Normal inhibition by somatostatin of the insulin response, followed by a rebound in insulin secretion, was observed in all subjects. These preliminary data indicate increased sensitivity of the prolactin-secreting cells to somatostatin in hypothyroidism and suggest that decreased responsiveness of the somatotrophs to somatostatin could play a role in the pathogenesis of acromegaly.     

Studies of anterior pituitary-grafted rats: I. Abnormal prolactin response to thyrotropin releasing hormone,clonidine, insulin,and fasting

Although the rat implanted with extra anterior pituitary glands (AP) under the kidney capsule has been widely used as a model of chronic hyperprolactinemia, its hormonal status has not been fully characterized. Using conscious, unrestrained female pituitary-grafted rats and sham-operated littermates, we investigated prolactin (PRL) secretion in response to the following stimuli: thyrotropin releasing hormone (TRH), clonidine, insulin, and fasting. The AP-implanted rats had a greater and more sustained rise in serum PRL after TRH than control rats, reflecting a direct effect of TRH on the ectopic lactotropes. In contrast after clonidine, which acts via the hypothalamus, the serum PRL rose to much higher levels in sham-operated rats than in rats bearing ectopic pituitary tissue. Both insulin-induced hypoglycemia and fasting decreased serum PRL in control rats, but the AP-implanted animals manifested a rise in serum PRL in response to these stimuli. Thus, the AP-implanted rat is not only a valid model of excess and abnormal PRL secretion, but it may also be useful for distinguishing between stimuli requiring an intact hypothalamic-pituitary unit and agents which act directly on the pituitary gland.     

Size heterogeneity of plasma prolactin in the rat: TRH and serotonin-induced changes

Synthetic thyrotropin releasing hormone (TRH, 1 μg/rat) and serotonin (5-HT, 10 mg/kg body weight), when administered intraarterially to separate groups of ovariectomized, estrogen-treated rats, induced rapid and marked elevations in plasma prolactin which were essentially equal in magnitude and time of onset. However, gel filtration chromatography of the plasma on Sephadex G-100 indicated that different molecular forms of prolactin were induced by these two secretagogues. These findings suggest that these agents have different mechanisms of action and that there are secretory mechanisms in the pituitary for prolactin that operate independently of secretion rate.     

Influence of endogenous opiates on anterior pituitary function

In general, the endogenous opioid peptides (EOP), morphine (MOR), and related drugs exert similar effects on acute release of pituitary hormones. Thus administration of opiates produces a rapid increase in release of prolactin (PRL), growth hormone (GH), adrenocorticotropin (ACTH), and antidiuretic hormone (ADH), and a decrease in release of gonadotropins and thyrotropin (TSH). Although not yet fully established, there is growing evidence that the EOP participate in the physiological regulation of pituitary hormone secretion. Thus naloxone (NAL), a specific opiate antagonist, has been shown to reduce basal serum levels of PRL and GH, and to elevate serum levels of LH and follicle stimulating hormone in male rats. Other reports have shown that NAL can inhibit the stress-induced rise in serum PRL, raise the castration-induced increase in serum LH to greater than normal castrate values, and counteract the inhibitory effects of estrogen and testosterone on LH secretion. Opiates appear to have no direct action on the pituitary, but there is evidence that they can alter activity of hypothalamic dopamine and serotonin in modulating secretion of pituitary hormones.     

Artificial induction of lactation in ewes: the role of prolactin.

The mammary glands of 30 non-pregnant, intact ewes were developed by subcutaneously injecting oestrogen plus progesterone at intervals of 3 days from day 0 to day 27. Two days later (day 29), 15 ewes were injected subcutaneously with 18 mg ergocryptine, to inhibit specifically secretion of prolactin. Then groups of ewes, each comprising five ergocryptiine-treated and five untreated ewes, were injected from days 30 to 34 with either four intravenous injections each day of 1 i.u. syntocinon, one subcutaneous injection each day of 10 mg dexamethasone trimethylacetate, or two subcutaneous injections each day of 2-5 mg oestradiol benzoate plus 6-25 mg progesterone. All ewes were milked by hand on days 30-50. Within 24 h of injecting ergocryptine, levels of prolactin in serum were reduced to negligible values (less than 2 ng/ml). Comparison of results for ewes not receiving ergocryptine showed that syntocinon, dexamethasone and oestradiol benzoate plus progesterone, at the doses used, were equally effective in initiating milk secretion. Peak yields of 0-23-0-27 kg/day were achieved. On the other hand, ewes treated with ergocryptine before syntocinon or dexamethasone produced peak yields of only 0-12-0-13 kg/day and ewes treated with ergocryptine before oestradiol benzoate plus progesterone produced negligible amounts of secretion. The results suggest that syntocinon and dexamethasone were either lactogenic per se or effected the release of hormones of the lactogenic complex other than prolactin. However, oestradiol benzoate plus progesterone appeared to be lactogenic by virtue of the influence of oestrogen on the secretion of prolactin.