Effects of continuous LHRH infusion on plasma levels of LH and FSH in males, before and after oestrogen or anti-oestrogen treatment

In order to study the role of oestrogens on gonadotrophin release in the human male, LHRH was administered as an infusion at a constant rate of 0.5 micrograms/minute for 4 hours to 7 normogonadotrophic oligozoospermic men, 6 eugonadal male-to-female transsexuals and 9 eugonadal male volunteers. In agreement with in vitro data a biphasic release pattern of both LH and FSH was observed in eugonadal transsexuals as well as in normogonadotrophic oligozoospermic men. In the latter the release of LH was greater than in eugonadal transsexual males and volunteers, which points to a different functioning of the hypothalamic-pituitary unit in normogonadotrophic oligozoospermic men. On the other hand the FSH response to LHRH stimulation was normal in these men. Three months' treatment with the oestrogen-receptor antagonist tamoxifen (TAM) (10 mg twice daily) in the normogonadotrophic oligozoospermic men stimulated basal LH, FSH and testosterone (T) levels. The fact that gonadotrophin levels rose in spite of increased T levels, suggests a role of endogenous oestrogens in the negative feedback regulation of gonadotrophin release in these men. Upon TAM treatment the first phase, the plateau and the second phase of LH release were augmented, whereas only the plateau and the second phase of FSH release were increased. Six weeks' administration of the oestrogen ethinyloestradiol (EE) (10 micrograms three times a day) in the eugonadal transsexual males suppressed basal T and oestradiol (E2) levels without affecting basal gonadotrophin levels significantly. In EE-treated males the first phase of LH release tended to be lower, whereas the plateau of LH had decreased significantly. The second phase of LH was unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of naloxone infusion on plasma levels of LH, FSH, and in addition TSH and prolactin in males, before and after oestrogen or anti-oestrogen treatment

The inhibitory action of endogenous opioids on gonadotrophin release is now well documented. Since LHRH-producing neurons do not possess oestrogen-receptors, it is likely that some other compound mediates the negative feedback action of oestrogens on the gonadotrophin release in the male. To test the hypothesis that endogenous opioids are implicated in this negative feedback action in the human male, the opioid receptor antagonist naloxone (2 mg/h for 4 h) was infused into 7 normogonadotrophic oligozoospermic men before and after 6 weeks of treatment with the oestrogen-receptor antagonist tamoxifen (TAM) (10 mg twice daily) and 6 eugonadal transsexual males before and after 6 weeks of administration of ethinyloestradiol (EE) (10 micrograms three times a day). The effects of naloxone on TSH and prolactin (PRL) release were also studied. Naloxone administration resulted in a significant release of gonadotrophins, but not of TSH and PRL. Administration of oestrogen and anti-oestrogen did not significantly affect the response of gonadotrophins to naloxone infusion and no evidence of consistently antagonistic effects of oestrogen and anti-oestrogen on the naloxone-induced gonadotrophin release was obtained. This shows that endogenous opioids are probably not intermediary in the negative feedback control of oestrogens on gonadotrophin release in the human male. Surprisingly, in contrast to the eugonadal transsexual males, FSH levels in the oligozoospermic men did not respond to naloxone administration. As naloxone is thought to exert its action on gonadotrophin release via a disinhibition of endogenous LHRH release, this finding is unexpected. Exogenous LHRH administration leads to a normal response of FSH in normogonadotrophic oligozoospermic men. No plausible explanation for this finding can presently be offered.     

Prolactin after baclofen in healthy subjects and prolactinoma patients

Serum prolactin (PRL) levels in basal conditions (two samples) and 30, 60, 90, 120, 150 e 180 minutes after oral administration of baclofen (20 mg) were evaluated in 6 healthy subjects and in 10 patients with prolactinoma. The effect of baclofen (20 mg by mouth) on the PRL secretion cimetidine (400 mg i.v.) or domperidone (20 mg i.v.) induced were evaluated in 9 healthy women by administration of baclofen 60 minutes before cimetidine or domperidone. Baclofen was unable to significantly rise serum PRL levels in healthy subjects and in patients affected by prolactinoma and furthermore did not interfere with PRL rise domperidone induced. On the contrary baclofen decreased PRL rise cimetidine induced. It was concluded that: in basal condition, GABAb receptor don't play an obvious role in modulation of PRL secretion; when H2 istaminergic inhibition on PRL secretion is blocked (at an hypothalamic site), a GABA inhibition, b receptor mediated, on PRL secretion became more clear; the domperidone blockade of hypophysial dopaminergic receptors suggests that GABAb modulation of prolactin secretion don't obtain itself by dopaminergic pathways.     

Effect of sulpiride on serum growth hormone and prolactin concentrations following L-DOPA administration in man.

The effect of chronic administration of sulpiride on serum human growth hormone (hGH), prolactin and thyroid stimulating hormone (TSH) was examined in 6 normal subjects. Sulpiride was given orally at a dose of 300 mg (t.i.d.) for 30 days. Sulpiride raised serum prolactin levels in all subjects examined. In addition, sulpiride suppressed hGH release induced by L-dopa, although the basal hGH level was not changed. Sulpiride treatment appeared to antagonize partially the inhibitory effect of L-dopa on prolactin release. Following thyrotropin-releasing hormone (TRH) injection, the percent increment in prolactin levels from the baseline in sulpiride-treated subjects was less than in controls without sulpiride. In contrast, both the basal and TRH-stimulated TSH levels were not influenced by sulpiride. These observations suggest that sulpiride suppresses L-dopa-induced hGH release and stimulates prolactin release, presumably by acting against the dopaminergic mechanism either on the hypothalamus or on the pituitary. The decreased prolactin response to TRH after sulpiride treatment may indicate a diminished reserve capacity in pituitary prolactin release.     

Clinical use of metoclopramide test in the diagnosis of women with hyperprolactinemia

14 women with elevated prolactin (PRL) serum levels (greater than 25 ng/ml) were given 2.5 mg of metoclopramide, by bolus intravenous injection, to evaluate its diagnosic potential as a stimulus for PRL release. Following metoclopramide injection there was a prompt increase in serum PRL in normal subjects and in patients with moderate PRL elevations associated with galactorrhea-oligomenorrhea. The women with amenorrhea-galactorrhea regardless of the presence of absence of a pituitary tumor, showed a blunted response. Metoclopramide failed to induce TSH secretion in all cases. In conclusion: the use of the metoclopramide test provides no additional clinical information to that furnished by the basal serum PRL concentration for the hyperprolactinemic patient.     

Role of aging on growth hormone and prolactin release after growth hormone-releasing hormone and domperidone in man

Growth hormone (GH) and prolactin (PRL) secretion after GH-releasing hormone (GHRH) and domperidone (DOM), an antidopaminergic drug which does not cross the blood-brain barrier (BBB), was evaluated in 8 healthy elderly men (65-91 years) and in 7 young adults (23-40 years). All received in random order at 2-day intervals: GHRH(1-40) (50 micrograms i.v.) bolus, DOM (5 mg/h) infusion, GHRH(1-40) (50 micrograms i.v.) plus DOM (5 mg/h i.v.), saline solution. In elderly men GH increase after GHRH was significantly lower than in young men. DOM alone did not change GH secretion in either of these groups, whereas it increased the GH response to GHRH only in young adults. PRL levels increased in both young and elderly men during both DOM and GHRH plus DOM, but the PRL release was more marked in young than in elderly men. Both integrated secretion of GH after GHRH and of PRL after DOM were inversely correlated to chronological age. Our data show an impairment of GH rise after GHRH and of PRL after DOM in elderly adults. It is also stressed that peripheral blockade of dopamine receptors by DOM is unable to amplify the GH response to GHRH only in elderly men. A reduction in GH release after GHRH might be related to aging, perhaps through a reduction of dopaminergic tonus.     

The role of domperidone in the regulation of prolactin release in rats

Effects of domperidone, a dopamine antagonist, on prolactin release in female rats were studied. Oral administration of domperidone for 14 days caused a significant increase in serum prolactin levels in mature female rats. The routes by which domperidone exerted its effects on prolactin release were studied by a in vitro incubation system using rat pituitary tissues. Pituitary halves were incubated with (1) domperidone, (2) dopamine, (3) dopamine plus domperidone, (4) hypothalamic extracts from rats which had been treated with control meal (control hypothalamic extract), (5) control hypothalamic extract plus domperidone, and with (6) hypothalamic extract from rats which had been treated with domperidone for 14 days (domperidone-treated hypothalamic extract). Pituitary halves, when incubated alone, released a significant amount of prolactin into the incubation medium after 24 hours incubation, which was completely inhibited by dopamine or control hypothalamic extract. The addition of domperidone could not reverse the inhibitory effect of dopamine or control hypothalamic extract. On the other hand, domperidone-treated hypothalamic extract showed no inhibitory effects on prolactin release. These results indicated that domperidone could increase serum prolactin levels in female rats by acting primarily at the hypothalamus.     

Changes in pituitary hormone levels induced by met-enkephalin in man—The role of dopamine

The interaction of dopamine with the effects of the opiate agonist peptide D-Ala²-MePhe⁴-met-enkephalin-O-o1 (DAMME) on anterior pituitary hormone secretion was investigated in normal male subjects. DAMME produced clear elevations in prolactin, growth hormone and thyroid-stimulating hormone, while inhibiting the release of luteinising hormone and cortisol. There was no change in follicle stimulating hormone. The elevations in prolactin and TSH were enhanced by the dopamine antagonist, domperidone, and blocked by an infusion of dopamine. Neither dopamine nor domperidone modulated the changes in growth hormone, luteinising hormone or cortisol. The data are comptible with the association of the release of prolactin and TSH by opiate peptides with decreased hypothalamic dopaminergic activity; changes in the other anterior pituitary hormones seem to involve different mechanisms.     

Metoclopramide potentiates the hypophyseal reactions to oestradiol

Male rats to which oestradiol benzoate was administered intramuscularly twice a week for three weeks in 1 mg doses as an aqueous microcrystal suspension showed an increase in adenohypophyseal weight, in the number of lactotropic cells in the adenohypophysis (demonstrated by immunohistochemical detection of prolactin) and in polyphenol oxidase (ceruloplasmin) activity in the blood and hypothalamus. The simultaneous administration of metoclopramide (methoxychloroprocainamide) in doses of 10 mg/rat per day in food potentiated the adenohypophyseal reaction to oestradiol (weight and the number of lactotropic cells), but potentiated the polyphenol oxidase reaction only little or not at all. Metoclopramide thus has an anti-dopaminergic effect similar to that of perphenazine and other inhibitors of dopaminergic neurones.     

Complex role of 5-HT in the regulation of TSH secretion in the male rat

The role of 5-hydroxytryptamine (5-HT) in the regulations of TSH secretion was studied in male rats using both peripheral and central administration of the drugs. Basal TSH levels were not modified by moderate doses of 5-HT (subcutaneously) or its precursors or antagonists (intraperitoneally) given 1 h before decapitation. The cold-stimulated TSH secretion was decreased by L-tryptophan (L-TRP, 400 mg/kg i.p.), quipazine (10 mg/kg i.p.) and 5-HT (1 or 5 mg/kg s.c. or i.v.) as well as by p-chlorophenylalanine (pCPA, 20 or more mg/kg i.p.) when the drugs were given 1 h before sampling. pCPA (100-400 mg/kg i.p.) was active 24-48 h after the injection but repetitive administration did not affect TSH levels. 5-HT (5 mg/kg s.c.) was effective also in pinealectomized animals. L-TRP and 5-hydroxytryptophan potentiated the TRH-stimulated TSH secretion when given 1 h before killing. 5-HT (10 microgram/rat) infused into the third ventricle enhanced the cold-stimulated TSH secretion when given 30-45 min before sampling. When injected into the medial basal hypothalamus, 50-HT (1-10 microgram/rat) had no effect on basal or stimulated TSH levels. The results suggest: (1) 5-HT does not play any role in the regulation of basal TSH secretion; (2) in the cold-stimulated TSH secretion 5-HT has a stimulatory action evidently inside the blood-brain barrier and also an inhibitory effect obviously outside this barrier.     

Possible direct effect of serotonin on pituitary prolactin secretion: in vivo and in vitro studies

In this work we analyze the possibility of serotonin (5-HT)-releasing prolactin (PRL) through a direct action at the pituitary level. 5-HT (2 mg/kg i.v.) stimulates PRL secretion in hypophysectomized autotransplanted animals (HAG) significantly and this effect was not influenced by pretreatment with the dopaminergic antagonist domperidone. In perifused pituitaries, 5-HT administration (0.01, 0.1 and 1 microM for 90 min, or 1, 10, 100 microM for 15 min) was ineffective in stimulating PRL release. In pituitaries obtained from animals previously treated with the neurotoxic 5,7-dihydroxytryptamine (5,7-DHT) or vehicle and incubated in the presence of 5-HT (2.5, 5 and 10 microM), no response in PRL secretion was observed. These results suggested that 5-HT does not release PRL through a direct pituitary action, and that the effect observed in HAG animals could be mediated through the release of a PRL-releasing factor after 5-HT administration.     

Plasma aldosterone response to metoclopramide is unmodified by hyperprolactinemia

It has been previously demonstrated that patients with hyperprolactinemia have impaired PRL response to dopaminergic blockade and increased TSH response. Since inhibitory dopaminergic modulation of aldosterone is well established, we have examined whether prolactinoma patients have an altered aldosterone response to dopaminergic blockade. To investigate this possibility we compared the plasma PRL, TSH and aldosterone responses to the dopamine (DA) antagonist metoclopramide (MCP; 10 mg i.v.) in 10 women with prolactinomas and 7 healthy female controls. Basal PRL levels in prolactinoma patients were elevated and showed a blunted rise following MCP. Although basal TSH levels were similar in the 2 groups of subjects, they significantly increased (p = 0.017) in prolactinoma patients while in contrast they did not significantly change in control subjects. Basal supine plasma aldosterone was similar in patients with prolactinomas (0.23 +/- 0.03 nmol/l) and in healthy subjects (0.25 +/- 0.04 nmol/l) and the increased aldosterone concentrations from 15 to 120 min following MCP were not significantly different in prolactinoma patients and in control subjects. It is concluded that in patients with prolactinomas, the alteration in the dopaminergic regulation is specifically related to the lactotroph.     

Inhibition of prolactin secretion by gastrin releasing peptide (GRP) in the rat

Synthetic gastrin releasing peptide (GRP) injected intraventricularly (1 microgram/rat), but not intravenously, suppressed rat prolactin (PRL) release induced by a Met-enkephalin analog, FK33-824 (10 micrograms/100 g body wt., iv). GRP also blunted PRL release induced by a dopamine antagonist, domperidone (1 microgram/100 g body wt., iv). In contrast, GRP did not suppress elevated plasma PRL levels sustained by a large dose of domperidone (10 micrograms/100 g body wt., iv). GRP (10(-5) M) had no effect on PRL release from superfused pituitary cells in vitro. These results suggest that GRP inhibits PRL secretion in the rat by acting through the brain to stimulate the dopaminergic mechanism.     

Cimetidine and hyperprolactinemia

Plasma TSH was determined in 12 normal subjects before and after administration of mg 400 of cimetidine i.v., an H2-receptor antagonist. TSH concentration remained unchanged. In 7 normal subjects, pretreated with bromocriptine; variation of plasma prolactin were studied before and after administration of mg 400 and 800 of cimetidine. Bromocriptine inhibited the increase of prolactin secretion, induced by cimetidine. It can be assumed that: a) cimetidine doesn't release hypothalamic TRH in portal vessels; b) that drug has no direct effect on pituitary cells; c) hypothalamic H2-receptor blockade by cimetidine decreases dopamine release from hypothalamus to pituitary gland.     

Effect of caerulein on pituitary response to TRH in humans

The effect of caerulein (100 ng/kg/h X 1 h) on basal as well as on thyrotropin-releasing hormone (TRH)-stimulated prolactin and thyroid-stimulating hormone (TSH) secretion was studied in healthy male volunteers. The peptide did not change the basal levels of prolactin and TSH. However, during the infusion of caerulein, prolactin response to TRH was significantly increased whereas the TSH response was decreased. These data, showing an action of caerulein (a frog peptide which mimics the biological actions of cholecystokinin) on prolactin and TSH release, suggest that cholecystokinin may be involved in the physiological control of human pituitary secretion.     

Effect of chronic metoclopramide therapy on serum pituitary hormone concentrations

The effect of chronic (3--9 months) therapy with metoclopramide on serum levels of pituitary and thyroid hormones was studied in 4 males and 1 female. The mean serum prolactin concentration during metoclopramide therapy was significantly higher than after discontinuation of metoclopramide. Serum prolactin concentrations increased acutely after each dose of metoclopramide. Serum prolactin concentrations increased acutely after each dose of metoclopramide, and gradually returned to normal by 6--12 h. There was no sifgnificant differences in the serum TSH, T3, T4, GH, and gonadotrophin levels during and after metoclopramide administration. In the male subjects the mean serum testosterone was normal, but significantly lower during metoclopramide therapy.     

Variations of prolactin content in human cerebrospinal fluid after metoclopramide and morphine

Serum and cerebrospinal fluid (CSF) prolactin (PRL) concentrations were determined in fourteen patients of both sexes suffering from hydrocephalus, in basal conditions and after i.m. administration of 10 mg metoclopramide or 10 mg morphine. A significant increase in both serum and CSF hormone values was found after administration of both drugs. Serum and CSF PRL values after metoclopramide administration increased earlier and to a greater extent than after morphine. Furthermore, the metoclopramide induced CSF PRL increase immediately followed the serum peak, whereas after morphine administration an evident delay in the CSF hormone peak with respect to the serum increase was found. These data suggest that PRL entry in the CSF compartment is subject to a controlling mechanism which acts at the blood/brain barrier.     

Effect of metoclopramide-induced prolactin on aldosterone secretion in normal subjects

We investigated the role of prolactin (PRL) on modurating the secretion of aldosterone in normal male subjects. Metoclopramide (5mg) which causes a significant rise of PRL was given by intravenous injection. The peak of PRL level at 30 min. after i.v. injection of metoclopramide (20.0 ± 1.6 ng/ml, mean ± S.E.) was significantly higher than the basal level (6.4 ± 2.1 ng/ml, P < 0.01), but plasma aldosterone, serum sodium, potassium and plasma renin activity did not change significantly throughout the period of the study. Cortisol levels, however, reduced significantly after 30 min. and remained significantly low, probably because of diurnal variation. Present results suggest that PRL might at least not play a physiological role on regulating the secretion of aldosterone in man.     

The effect of various prostaglandins and a prostaglandin synthetase inhibitor on rat anterior pituitary cyclic AMP levels and hormone release in vitro (38475).

(U)Prostaglandins E-1, E2,F-1alpha or F-2 alpha significantly increased the release of GH, with a parallel increase in intracellular cAMP concentrations, while they only protentiated HE-stimulated TSH release. (2) None of the prostaglandins examined consistently effected either the basal or HE-altered release of LH,FSH or prolactin. (3) The prostaglandin synthetase inhibitor, indomethacin, inhibited GH and TSH release and, at high doses of the drug, inhibited prolactin release. In contrast, the drug appeared to potentiate both He and sLRF-stimulated gonadotropin release. It had no significant effect on intracellular cAMP concentration.     

Effect of bromocriptine on serum TSH in euthyroid patients with endocrine disorders

In 10 euthyroid subjects a single 2.5 mg per os dose of bromocriptine caused rapid and remarkable decreases in serum TSH. As much as a 0.85 +/- 0.18 (s.d.) microU/ml decrease from the basal level (56 +/- 9%) was observed at 5 hours. A good correlation was observed between the basal TSH level and the TSH decrease after bromocriptine (r = 0.786). In 4 patients taking 5 to 15 mg bromocriptine daily (chronic administration group), another 2.5 mg bromocriptine also caused significant decreases in serum TSH, but the degree (0.42 +/- 0.03 microU/ml, 43 +/- 26% of basal) and duration (maximal at 4 hours) were less than those observed in the untreated group. The lowest TSH levels in these two groups did not differ significantly (0.80 +/- 0.45 and 0.78 +/- 0.53 microU/ml, respectively). The TSH decrease after bromocriptine in the untreated group was found not to correlate significantly with TRH induced TSH increase (r = 0.300). TRH induced TSH increase in the chronic administration group was similar to or greater than that of control subjects with matched basal TSH. The TSH lowering effects of per os prednisolone and triiodothyronine were also studied. Prednisolone exerted a quite similar effect to bromocriptine, but a certain time lag was observed in the case of triiodothyronine. A single dose of bromocriptine was found to lower serum TSH levels even in euthyroid subjects. The effect was considered to be independent of TRH-TSH regulation and to act directly on the TSH release.