Unsuppressed prolactin secretion in the male rat is pulsatile

The pattern of prolactin (Prl) secretion was studied in several different situations. In normal and castrated male rats, the plasma Prl level gently fluctuated along the course of time. When the presumed hypothalamic Prl inhibitory factor was suppressed by treatment with a pharmacological agent, pimozide (Pim), the plasma Prl concentration was elevated and the elevated plasma level fluctuated in an irregular and pulsatile manner. Another situation was examined. First, baseline Prl concentration was elevated by implantation of estradiol, which also caused a moderate fluctuation of the circulating Prl level. The Prl level was then lowered from the elevated plateau level by administration of a dopaminergic receptor agonist, ergocristine. During this partial blockade, the plasma Prl level fluctuated in episodic bursts. It is suggested that the inherent, unsuppressed secretion of Prl is pulsatile in nature, but that this pulsatile pattern is normally suppressed under the inhibiting influence of the hypothalamus.     

Adenohypophysial dopamine content and prolactin secretion in the aged male and female rat

In male rats the concentrations of dopamine (DA) in the adenohypophysis and of PRL in serum increase progressively with age. The increase in the DA content is not a consequence of reduced metabolism of DA, since the activities of the enzymes that deaminate (monoamine oxidase) and O-methylate (catechol-O-methyltransferase) this amine are not reduced in the anterior pituitary of aged male rats; indeed, both type A and B monoamine oxidase activities are increased in the pituitaries of aged rats. The increased DA present in the aged adenohypophysis is not in a static pool but, as in young rats, is rapidly decreased by pharmacological treatments that reduce the activity of tuberoinfundibular DA neurons (gamma-butyrolactone), reduce the synthesis of DA in these neurons (alpha-methyltyrosine), or block DA receptors (haloperidol) in the adenohypophysis. All of these treatments increased serum PRL levels and reduced DA concentrations in the adenohypophysis of both young and aged rats. Similarly, in female rats, where age-related differences in BW and body composition are minimized, serum PRL concentrations and DA concentrations in the adenohypophysis of both young and aged rats changed in the same way after the administration of a DA agonist (apomorphine) or a DA antagonist (haloperidol). Apomorphine reversed the alpha-methyltyrosine-induced increase in serum PRL concentrations and the decrease in anterior pituitary DA content in both young and aged rats, although the latter animals appear to be more responsive to this drug. Similarly, aged rats were more sensitive to the increase in serum PRL concentrations and the decrease in anterior pituitary DA content caused by haloperidol. The actions of acute and chronically administered haloperidol are reversible, with the reduced DA content of the adenohypophysis and the elevated serum concentrations of PRL returning to respective pretreatment levels in both young and aged rats once treatment stops. The time course for recovery of serum PRL levels and anterior pituitary DA contents after both the acute and chronic haloperidol treatment is of longer duration in the aged rat, which is consistent with a decreased rate of clearance of haloperidol in these animals. Twelve daily injections of bromocriptine, a DA agonist, reduced serum PRL and anterior pituitary DA concentrations in both young and aged rats, and these effects persisted for up to 7 days after the injections were stopped.(ABSTRACT TRUNCATED AT 400 WORDS)     

The lipocorticotropic system and prolactin secretion

Administration of ACTH beta 1-24 (0.25 mg, i.m.) in six healthy subjects reduces blood prolactin response to sulpiride (100 mg, i.m.). Dexamethasone (2 mg, orally, given at 11.00 p.m. of preceding day) blocks blood prolactin response to insulin-induced hypoglycemia (0.20 U. kg of "Actrapid" Novo, i.v.) in six voluntary healthy subjects. Intravenous naloxone (0.4 mg/Kg of body weight) blocks in man blood prolactin response to insulin-induced hypoglycemia. On the basis of the above data we can hypothesize that ACTH and dexamethasone have influenced by a feed-back mechanism the lypocorticotropic system. Such system by beta-endorphin release can modulate the secretion of prolactin. Thus inhibition of the lipocorticotropic system may be responsible for the reduced response of the prolactin system to stimulation by sulpiride or hypoglycemic stress.     

Episodic prolactin secretion in the adult male rat is affected by orchidectomy and testosterone replacement

To characterize the plasma PRL pattern in adult male rats and elucidate the modulatory effects of testosterone on this circulating PRL pattern, serial blood samples were obtained from both intact rats and rats orchidectomized and given various doses of testosterone via sustained release polydimethylsiloxane implants. Adult male rats were equipped with chronic indwelling jugular catheters. One week later the animals were orchidectomized and given either empty (12-mm) or testosterone-filled polydimethylsiloxane implants measuring 3, 5, or 12 mm that maintain plasma testosterone at 0%, 20%, 30%, or 60%, respectively, of those concentrations found in normal animals. Plasma samples for PRL RIA were obtained every 5-10 min for 3 h, before (intact control) and 3, 6, 9, 15, 21, and 28 days after orchidectomy and testosterone replacement. The plasma PRL pattern in intact animals was pulsatile; on the average, three or four pulses per 3 h, with amplitudes of 3.6 ng/ml on a 2.7 ng/ml nadir, were seen. After orchidectomy PRL pulse nadir, peak, and amplitude were rapidly attenuated. These parameters stabilized between days 6 and 15 at levels approximately 40% of those recorded in intact rats. In contrast, PRL pulse frequency remained in the control range for the first 9 days after orchidectomy. Thereafter, pulse frequency accelerated and reached stable plateau levels by day 15 at 145% of the values seen before orchidectomy. The administration of 3-mm testosterone implants completely prevented the effects of orchidectomy on PRL pulse nadir, peak, and amplitude, but only partially prevented the postorchidectomy rise in pulse frequency. Although the two larger implants (5 and 12 mm) had no further effect on pulse nadir, peak, and amplitude over that seen with the 3-mm implant, only the 12-mm implant completely prevented the acceleration in PRL pulse frequency accompanying orchidectomy. These results indicate that testosterone is intimately involved in regulation of the circulating PRL pattern and that this steroid has effects on the neuroendocrine system controlling PRL pulse frequency independent of those regulating pulse nadir, peak, and amplitude.     

Dermorphin stimulates prolactin secretion in the rat

The effect of dermorphin, a new opioid peptide originally isolated from amphibian skin, on the release of prolactin (Prl) was studied in vivo and in vitro. In vivo experiments: subcutaneous administrations of different doses of dermorphin ranging from 0.1 to 5 mg/kg body weight to normal male rats induce a statistically significant, dose-related increase in serum Prl levels. Pretreatment with the specific opioid antagonist, naloxone (2 mg/kg i.p.) completely prevents the rise in serum Prl, induced by 2 mg/kg of dermorphin. In normal male rats, the intraventricular injection of 0.25 micrograms/kg of dermorphin is not able to induce any significant changes in serum Prl levels 10 min after injection. Serum Prl levels show a significant enhancement 30 min after the administration of this dose of dermorphin, and return to control values at 60 min. On the contrary, 1 microgram/kg of dermorphin significantly elevates Prl concentrations 10 min after injection, leaving serum Prl levels unchanged 30 and 60 min after the administration. Naloxone (25 and 100 micrograms/kg) alone does not substantially modify serum Prl concentrations at any time interval considered. Treatment with either dose of naloxone performed together with either 0.25 or 1 microgram/kg of dermorphin completely counteracts the stimulatory effect of the peptide at all time intervals in which dermorphin was active when given alone. In orchidectomized (3 weeks) rats, the intraventricular administration of dermorphin at the dose of 0.25 micrograms/kg appears effective in enhancing Prl levels only 30 min after treatment. No statistically significant modifications are observed at 10 and 60 min with this dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for alpha-adrenergic regulation of episodic growth hormone and prolactin secretion in the undisturbed male rat

The present experiments were designed to study the effect of the centrally active alpha-adrenergic receptor agonist, clonidine, on episodic GH and PRL secretion in male rats after selective blockade of norepinephrine (NE) and epinephrine (EP) synthesis with the dopamine-beta-hydroxylase inhibitor, FLA-63. Freely behaving, chronically cannulated rats were maintained on a constant light-dark cycle in isolation test chambers. Beginning at 1000 h, blood samples were removed every 20 min for 5-h periods without disturbing the animal. FLA-63 was administered (10 or 20 mg/kg ip) at 0845 h. Clonidine (15 or 150 microgram/kg iv) was given at times that coincided with the spontaneous occurrence of episodic GH peaks or troughs observed in control animals. Results of the present study are summarized as follows: 1) selective blockade of NE and EP synthesis with FLA-63 (20 mg/kg) caused complete suppression of episodic GH but had no significant effect on PRL release; 2) clonidine (150 microgram/kg) restored the pulsatile pattern of GH secretion in FLA-63-treated rats, and 3) clonidine (15 and 150 microgram/kg) stimulated PRL release in a dose-dependent manner. These findings suggest a major stimulatory role of alpha-adrenergic receptors in episodic GH and PRL secretion.     

Effect of the circulating renin-angiotensin system on prolactin release in humans

We recently reported that renin, angiotensinogen, and angiotensin-converting enzyme were present in normal human pituitary lactotroph cells and PRL-secreting adenomas. Angiotensin-II and -III have also been shown to modulate PRL release in vitro. The present study was designed to determine whether angiotensin modulates PRL secretion in vivo. In 36 hypertensive patients with widely varying renin levels, active renin and basal PRL levels did not correlate. In 10 normal volunteers, both a sustained infusion of angiotensin-II and a graded infusion of angiotensin-III induced a 2- to 3-fold increase in aldosterone levels, but had no effect on PRL secretion. Administration of the angiotensin-converting enzyme inhibitor captopril had no effect on PRL circadian rhythm in 10 normal subjects or on PRL concentrations in 11 patients with PRL-secreting adenomas. Cross-over administration of placebo and captopril did not affect the peak PRL level measured after TRH treatment in 10 hypertensive men (placebo, 43.1 +/- 5.4; captopril, 40.0 +/- 6.2 micrograms/L; P = NS) or the rise in PRL induced by doperidone in 6 normal women (placebo, 129.5 +/- 16.2; captopril, 150.0 +/- 35.7 micrograms/L; P = NS). Further, administration of enalapril for 30 days to 6 hypertensive patients did not alter basal PRL concentrations or the peak concentrations induced by TRH. These data indicate that in humans the circulating renin-angiotensin system does not interact with diurnal PRL release or with the response to TRH or domperidone.     

Corticosteroid regulation of gonadotropin and prolactin secretion in the rat

The purpose of this study was to determine if glucocorticoids had any direct effects on the release of gonadotropin. In estrogen-primed ovariectomized immature rats, triamcinolone acetonide and deoxycorticosterone (1 mg/kg BW) caused a surge in both serum LH and FSH levels. Dexamethasone treatment (0.05 mg/kg BW) resulted in a highly significant selective release of FSH. Cortisol (1 mg/kg BW) suppressed serum FSH levels. A systematic dose-response study showed that triamcinolone acetonide significantly released LH and FSH and suppressed PRL at all doses tested (range, 0.25-4 mg/kg BW). Deoxycorticosterone was not as potent as triamcinolone acetonide and only doses greater than 0.8-1 mg/kg BW significantly released LH and FSH. Dexamethasone selectively released FSH at low doses (0.01, 0.02, 0.05, and 0.1 mg/kg BW) and inhibited LH at higher doses (0.5 and 1.0 mg/kg BW). A single low dose of dexamethasone (0.02 mg/kg BW) was found to significantly release LH. With respect to PRL secretion, a biphasic effect of dexamethasone was observed in that the lowest dose (0.01 mg/kg BW) stimulated PRL release while the highest dose (1.0 mg/kg BW) significantly inhibited PRL release. Triamicolone acetonide and deoxycorticosterone were found to require estrogen priming for their effects on gonadotropin secretion. The findings in this study raise the possibility that the beneficial effects seen with corticosteroids in inducing ovulation in polycystic ovarian syndrome may be due, in part, to their direct effects upon the release of gonadotropins.     

Interaction of putative endogenous tryptolines with the hypothalamic serotonergic system and prolactin secretion in adult male rats

The effect of 5-methoxytryptoline (5-MeOT), 5-hydroxytryptoline (5-OHT) and tryptoline (Tp), putative endogenous derivatives of the tryptamines, on plasma prolactin (PRL) concentrations has been investigated in the adult male rat. The possible involvement of the hypothalamic serotonergic system has been considered in the mediation of the hormonal effect of the tryptolines. Therefore, plasma PRL levels have been evaluated in rats receiving tryptolines after different pharmacological manipulations of central serotonergic function. Although the three compounds increased the plasma titers of PRL in a dose-dependent manner and enhanced the hypothalamic content of serotonin (5HT), they appear to affect the serotonergic system through different mechanisms. In particular, 5-OHT might act at a presynaptic level, since its hyperprolactinemic effect was antagonized both by the depletion of central 5HT content after p-chlorophenylalanine and by the degeneration of serotonergic terminals after 5,7-dihydroxytryptamine. In contrast, 5-MeOT behaved as if it had a postsynaptic site of action, being counteracted by the serotonergic postsynaptic antagonists metergoline and cyproheptadine. The unsubstituted tetrahydro-beta-carboline, Tp, is probably active at both pre- and postsynaptic sites. The enhancing effect of Tp on PRL secretion was antagonized by chronic treatment with p-chlorophenylalanine, while it was also maintained in 5,7-dihydroxytryptamine-lesioned rats. These findings suggest that tryptolines may play a functional role in PRL secretion by interacting with central serotonergic systems through different biochemical mechanisms.     

Serotoninergic stimulation of aldosterone secretion in the rat in vivo: role of the renin-angiotensin system.

Serotoninergic control of aldosterone secretion in vivo was investigated in conscious rats with indwelling arterial cannulae. Serial blood samples were taken from the animals before and after i.p. administration of 1 ml (4 g/l) 5-hydroxytryptophan (5-HTP), the precursor of serotonin, or saline and they were analysed for 5-HTP, serotonin, 5-hydroxyindoleacetic acid, plasma renin activity (PRA), corticosterone, aldosterone, sodium and potassium concentrations. The role of the renin-angiotensin system was investigated in animals pretreated for 1 week with the angiotensin-converting enzyme inhibitor captopril (25 mg/day). 5-HTP caused a significant increase in all parameters within 45 min except for sodium and potassium. Saline administration showed no significant effect. Captopril pretreatment did not impair the increase in any parameter by 5-HTP, with the exception of the aldosterone response which was significantly attenuated, though not completely. The results show that administration of 5-HTP, which increases serum serotonin levels, stimulates PRA, aldosterone and corticosterone secretion. Captopril pretreatment inhibits the aldosterone response, suggesting that the aldosterone stimulatory properties of 5-HTP require the presence of angiotensin II, although it is unclear whether it acts in a mediatory or permissive capacity. The failure of captopril to inhibit the aldosterone response completely suggests the involvement of other mechanisms such as the hypothalamo-pituitary adrenal axis or a direct action of serotonin on the adrenal.     

Kallikrein secretion by the isolated perfused rat kidney. Role of perfusion pressure and the renin-angiotensin system

The isolated perfused rat kidney (IPRK) releases kallikrein in urine and renin in perfusate. We have previously shown (Kidney Int 24: 58-65, 1983) and confirm here that kallikrein, as well as renin releases are influenced by changes in renal hemodynamics in this model: a rise in perfusion pressure (PP) from 80 to 98 mmHg increases renal perfusate flow (RPF) by 48 +/- 3 p. 100, inhibits renin release and stimulates kallikrein secretion to 234 +/- 84 p. 100 of control values (n = 8). Since the perfusate lacks angiotensinogen, we decided to study the effect on kallikrein of the reconstitution of the renin-angiotensin system in the IPRK by adding angiotensinogen + angiotensin converting enzyme (AG + ACE) to the perfusion medium. After AG + ACE, PP rose to 107 +/- 4 mmHg, RPF decreased by 82 +/- 3 p. 100 as a consequence of the vasoconstrictor effect of angiotensin II, and renin release was suppressed. Again kallikrein secretion was stimulated and increased to 333 +/- 153 p. 100 of control values (n = 4). It is concluded 1) that kallikrein release is influenced by changes in PP but not in RPF on the IPRK. 2) that reconstitution of the renin-angiotensin system by addition of AG + ACE to the perfusate leads to vasoconstriction, suppression of renin release and a marked increase in kallikrein secretion.     

The effect of exposure to ether on prolactin secretion and the half-life of endogenous prolactin in normal and castrated male rats

Normal and castrated male rats implanted with permanent right atrial cannulae were used, and sequential blood samples were taken every 2 min through the cannula. When the rats, both normal and castrated, were exposed to ether for 2 min, the prolactin (Prl) concentration in plasma was immediately and dramatically elevated. During 40 min of continuous ether anesthesia, plasma Prl concentration was not sustained. After the initial 'surge' of Prl secretion, which lasted about 15 min, the concentration returned to normal levels. Following the peak of the Prl 'surge', Prl disappeared from the circulation with a calculated half-life of 7 min (mean value: 6.9 min; confidence interval: 6.3-7.7).     

The renin-angiotensin system and male reproduction: new functions for old hormones

The blood-borne renin-angiotensin system (RAS) is known best for its role in the maintenance of blood pressure and electrolyte and fluid homeostasis. However, numerous tIssues show intrinsic angiotensin-generating systems that cater for specific local needs through actions that add to, or differ from, the circulating RAS. The male reproductive system has several sites of intrinsic RAS activity. Recent focus on the epididymis, by our laboratories and by others, has contributed important details about the local RAS in this tIssue. The RAS components have been localized morphologically and topographically; they have been shown to be responsive to androgens and to hypoxia; and angiotensin has been shown to influence tubular, and consequently, fluid secretion. Components of the RAS have also been found in the testis, vas deferens, prostate and semen. Angiotensin II receptors, type 1 and, to a lesser extent, type 2 are widespread, and angiotensin IV receptors have been localized in the prostate. The roles of the RAS in local processes at these sites are still uncertain and have yet to be fully elucidated, although there is evidence for involvement in tubular contractility, spermatogenesis, sperm maturation, capacitation, acrosomal exocytosis and fertilization. Notwithstanding this evidence for the involvement of the RAS in various important aspects of male reproduction, there has so far been a lack of clinical evidence, demonstrable by changes in fertility, for a crucial role of the RAS in male reproduction. However, it is clear that there are several potential targets for manipulating the activity of the male reproductive system by interfering with the locally generated angiotensin systems.     

Anterolateral hypothalamic deafferentation inhibits histamine-induced prolactin secretion and potentiates TRH-induced thyrotropin secretion in male rats

We studied the effect of histamine on serum prolactin and thyrotropin (TSH) levels in male rats with anterolateral hypothalamic deafferentation of hypothalamic connections or anterolateral cut (ALC). The success of ALC was confirmed by immunohistochemistry of somatostatin (SRIF) in the medial basal hypothalamus. ALC did not affect basal prolactin or TSH levels. Thyrotropin-releasing hormone (TRH, 200 ng/rat, i.p.) did not affect prolactin secretion either in sham-operated or ALC rats. In sham-operated rats intracerebroventricularly administered histamine increased significantly prolactin levels. Hypothalamic deafferentation abolished the effect of histamine on prolactin levels. TRH increased significantly serum TSH levels both in sham-operated controls and ALC rats. In the latter, however, the TSH-secretory response to TRH was significantly (p less than 0.05) larger compared to the controls. Intracerebroventricularly infused histamine (2 micrograms/rat) did not change the TRH-induced TSH secretion in either group of rats. These results show that (1) the effect of histamine on prolactin secretion is mediated through nerve tracts which are destroyed by ALC, and (2) cutting of afferent TRH (through sensitization) and SRIF fibers (through lacking inhibition) entering medial basal hypothalamus may both contribute to the enhanced TSH response to exogenous TRH.     

The endogenous stimulatory rhythm regulating prolactin secretion is present in the lactating rat

Prolactin (PRL) secretion in the female rat is regulated by an endogenous stimulatory rhythm (ESR), which is normally under the tonic inhibition of dopamine (DA). The ESR consists of a nocturnal (N) component which peaks at approximately 03.00 h, and a diurnal (D) component which peaks at approximately 17.00 h. This ESR has been shown to be present in ovariectomized and cervically stimulated rats. We have proposed that the ESR is continuously present in the female rat and that any suppression of the tonic inhibitory influence on PRL secretion can reveal its existence. In this study, the effects of the DA-lowering stimulus of suckling was investigated at different times of day in lactating rats. In addition, the pattern of PRL secretion in freely lactating rats throughout a 24-hour period was studied. Female rats were separated from their pups for 6 h prior to reunion at either 03.00 (coincident with the N component), 12.00 (control) or 17.00 h (coincident with the D component) at various stages of lactation. Blood samples were collected from intra-atrial cannulae immediately before separation of pups and dams, immediately before reunion of pups and dams (0 time), and 15, 30, 60 and 120 min following reunion of pups and dams. Four days following parturition, dams suckled at either 03.00 or 17.00 h secreted significantly greater PRL than rats suckled at 12.00 h. Peak levels of PRL were 60-, 90- and 25-fold greater than 0 time levels, at 03.00, 17.00 and 12.00 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)