Pituitary secretion after administration of a new cerebroactive drug, fipexide.

The effect of a single oral dose of 400 mg fipexide on pituitary secretion was investigated in 10 elderly non-endocrine patients. Fipexide induced significant decrease (P less than 0.05) in serum prolactin (PRL) values at 90 and 120 min after drug administration, without affecting serum growth hormone (GH), gonadotropin (LH and FSH), thyrotropin (TSH) and cortisol values. Fipexide was unable to modify metoclopramide-induced PRL release in five of these patients. Our results show that this drug acts as a mild dopamine (DA) agonist, probably not directly affecting hypothalamic and/or pituitary DA receptors but indirectly via a reduced DA re-uptake at the pre-synaptic level.     

Involvement of brain catecholamines and acetylcholine in growth hormone deficiency states. Pathophysiological, diagnostic and therapeutic implications.

A cohort of brain neurotransmitters, especially catecholamines and acetylcholine, play a crucial role in the control of neurosecretory growth hormone-releasing hormone (GH-RH)- and somatostatin (SS)-producing neurons, and hence growth hormone (GH) secretion. Stimulation of alpha 2-adrenoceptors or of muscarinic cholinergic receptors in the hypothalamus stimulates GH release, probably via stimulation of GH-RH and inhibition of somatostatin release, respectively. Additionally, stimulation of dopamine receptors is stimulatory to GH release, while activation of beta-receptors inhibits GH release via stimulation of hypothalamic somatostatin function. As a corollary, in GH deficiency states drugs affecting catecholaminergic and cholinergic functions may be exploited for diagnostic and/or therapeutic purposes, and may be useful for a better understanding of the underlying pathophysiology. Levodopa (L-dopa) [125 to 500mg orally], the physiological precursor of the catecholamines, administered either alone or in combination with carbidopa (50mg orally), to prevent its peripheral decarboxylation to dopamine, and/or the beta-adrenoceptor antagonist propranolol (0.75 mg/kg orally), and the alpha 2-adrenoceptor agonist clonidine (0.15 mg/m2 orally), are a fairly reliable stimulus of GH release. In normal subjects, however, false-negative GH responses and wide inter-individual variability may occur with these drugs. Additionally, the GH secretory response to these provocation tests is a poor predictor of endogenous 24-hour GH secretion, since levodopa or clonidine may elicit a response within normal limits in children of short stature with reduced 24-hour GH secretion and good responsiveness to GH therapy. The availability of GH-RH, a direct probe of pituitary somatotrophs, held out promise of unravelling the hypothalamic or pituitary origin of GH secretory disturbance. It soon became apparent, however, that this was not the case, because of the wide inter- and intraindividual variation in the GH response. However, the coadministration of GH-RH and muscarinic cholinergic agonists, for example pyridostigmine (which deprive the pituitary of hypothalamic SS inhibitory influences), is a useful diagnostic probe. In a large group of normal children and adolescents who received an intravenous injection of GH-RH, preceded by oral administration of pyridostigmine (60mg orally), none gave a false-negative response; this was also true for a group of short children with different forms of GH disturbances, in whom 8-hour nocturnal GH secretion was within normal limits. However, some false-negative responses occurred in children following testing with GH-RH, clonidine or pyridostigmine alone. Interestingly, the cut-off point for normality following pyridostigmine + GH-RH was as high as 20 ng/ml, while for the other provocation tests it is only 5 to 10 ng/ml. Responses lower than 20 ng/ml were present in all children with organic and most of the children with idiopathic GH deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)     

Serum concentrations of PRL,GH, LH,FSH, TSH and cortisol after single administration to man of a new synthetic narcotic analgesic butorphanol

Summary The i.m. administration to 6 healthy adult male volunteers of 2 mg butorphanol, a potent synthetic opiate analgesic, resulted in a significant rise in serum PRL level, without affecting GH, LH, FSH, TSH or cortisol secretion. These effects indicate that in man butorphanol exerts an opiate agonist rather than an opiate antagonist effect at the hypothalamic and/or pituitary level.     

The neuroendocrinological profile of roxindole,a dopamine autoreceptor agonist,in schizophrenic patients

Roxindole is a potent autoreceptor-selective dopamine agonist with additional properties as a serotonin reuptake inhibitor and 5-HT_1A agonist. In order to get more insight into its mode of action in various psychiatric populations, we evaluated the effects of subchronic roxindole treatment on pituitary and adrenal hormone secretion, i.e. release of prolactin, thyroid stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH), and cortisol. Fifteen schizophrenic patients with positive and negative symptomatology, respectively, were treated with roxindole for 28 days. Both basal and thyrotropin releasing hormone (TRH) -induced prolactin secretion diminished significantly to 26.4% and 22.8% of baseline levels, respectively, under roxindole. Basal GH secretion was insignificantly elevated by 89%, whereas GH levels increased nearly 3-fold after stimulation by TRH. TSH levels decreased insignificantly to 57.5% of baseline levels, while TRH-induced TSH release was not affected by subchronic roxindole. Roxindole treatment influenced neither LH secretion nor cortisol release. Our results indicate that roxindole's dopaminergic actions might prevail over its serotonergic effects, at least as far as the regulation of anterior pituitary hormone secretion is concerned.     

Discovery of iodinated somatostatin analogues selective for hsst2 and hsst5 with excellent inhibition of growth hormone and prolactin release from rat pituitary cells

Inhibition of growth hormone (GH) and prolactin (PRL) release from the anterior pituitary gland is mediated through somatostatin receptor subtypes sst2 and sst5. It has been found that somatostatin (SS) analogues that are selective for both receptor subtypes are more effective at inhibiting GH and PRL release than monospecific analogues alone. We synthesized several disulfide-bridged octapeptide SS analogues. Iodinated compounds 7, (4-amino-3-iodo)-d-Phe-c[Cys-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2, and 9, (4-amino-3-iodo)-d-Phe-c[Cys-(3-iodo)-Tyr-d-Trp-Lys-Val-Cys]-Thr-NH2, were as potent as somatostatin in binding at receptors hsst2 and hsst5 and inhibited GH and PRL release from rat pituitary cells as potently as somatostatin.     

Effect of hydrocortisone on the pituitary response to growth hormone releasing hormone

RATIONALE: In depression, the growth hormone (GH) response to clonidine and L-tryptophan (L-TRP) is reduced, suggesting reduced alpha2-adrenergic and serotonin (5-HT)1A receptor function. Pretreatment with hydrocortisone (100 mg, orally 11 h before) also blunts the GH response to L-TRP. This effect may be mediated at the hypothalamic level via reduced 5-HT1A receptor function or at the pituitary level, either by a direct effect on somatotrope cells or via enhanced insulin-like growth factor-1 (IGF-1) or somatostatin (SS) release. OBJECTIVES: To examine the effects of acute and chronic exposure to hydrocortisone on baseline and stimulated GH release from the pituitary. METHODS: Twelve healthy male volunteers received pretreatment with acute hydrocortisone (100 mg, 11 h before), chronic hydrocortisone (20 mg twice a day for 1 week) and placebo in a double blind, balanced order, crossover design. Serial measurements of plasma GH, IGF-1 and thyroid stimulating hormone (TSH) levels were made at baseline and following intravenous administration of 1 mcg/kg GHRH. RESULTS: The GH response to growth hormone releasing hormone (GHRH) was significantly blunted by pretreatment with both acute and chronic hydrocortisone. Baseline IGF-1 levels were significantly lower at baseline after chronic hydrocortisone compared with placebo. Baseline TSH levels were significantly lower after acute hydrocortisone compared with placebo, suggesting an increase in somatostatin levels. CONCLUSIONS: These data suggest that hydrocortisone acts at the pituitary level to reduce GH release. The TSH and IGF-1 data support the hypothesis that hydrocortisone reduces GH release by enhancing somatostatin and IGF-1 release.     

Selective and extremely long inhibition of prolactin release in man by 1-ethyl-3-(3''-dimethylaminopropyl)-3-(6''-allylergoline-8''-beta- carbonyl)-urea-diphosphate (FCE 21336)

The effects on anterior pituitary function of FCE 21336 (1-ethyl-3-(3'-dimethylaminopropyl)-3-(6'-allylergoline-8'-beta-ca rbonyl)-urea- diphosphate), a synthetic ergoline derivative with selective dopamine agonistic properties, were studied. Circulating PRL, GH, TSH, cortisol and LH levels were determined up to 96 h after single oral doses of 50, 100, 200 and 300 micrograms of the compound to eight healthy males, and up to 168 h after single oral doses of 400 and 600 micrograms to six healthy males, according to double-blind, within subjects, experimental designs vs placebo. Vital signs, ECG, laboratory tests and the appearance of newly observed signs and symptoms were monitored. A dose-related decrease of serum PRL in comparison with both basal and post-placebo levels was observed after 200 micrograms and greater doses of the compound, with inhibition of spontaneous circadian rhythm. Maximal inhibition (PRL less than 2 ng ml-1) was observed in one out of five subjects after 200, three out of seven subjects after 300, four out of six after 400 and five out of six subjects after 600 micrograms. The effect was of rapid onset and long duration; the maximum or nearly maximum decrease was observed within 3 h after dosing as well as up to 96 h (200 and 300 micrograms) and up to 168 h (400 and 600 micrograms). No modifications of GH, TSH, LH and cortisol as well as of vital signs, ECG and laboratory tests were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sauvagine induces release of adrenocorticotropin, beta-endorphin and corticosterone in rats

The effect of sauvagine, a frog skin peptide, on ACTH, beta-endorphin and corticosterone secretion, was studied in rats. A subcutaneous injection of 5 micrograms kg-1 of sauvagine in rats produced a prompt increase in immunoreactive plasma concentration of ACTH and beta-endorphin, which reached a peak value 15-30 min after the peptide injection. The stimulatory action of sauvagine on ACTH and beta-endorphin secretion was dose related. Intensity and duration of corticosterone secretion, produced by sauvagine mediated ACTH release, was dose-dependent, the threshold dose being 0,5 microgram kg-1 s.c. Pretreatment of rats with dexamethasone-21-phosphate, prevented the corticosterone releasing effect of sauvagine. Sauvagine perfusion (2,1 nM/h) of biogel columns containing isolated and dispersed anterior pituitary cells induced a sharp increase of ACTH levels in the eluate. Considering the high corticotropin releasing potency of sauvagine and its chemical similarity to ovine CRF, it is interesting to hypothesize whether this peptide may represent, in lower vertebrates, an ancestral form of the mammalian hypothalamic releasing factor.     

去脑重体大鼠细胞因子水平的变化

目的 探讨脑垂体对细胞因子水平的影响。方法 采用生物活性法检测去脑垂体大鼠血清细胞因子IL－2、IL－6、TNF水平及应用放射免疫分析法检测垂体GH、TSH、PRL水平。结果 SD大鼠切除脑垂体后血清中GH、TSH、PRL水平均显著下降,血清中细胞因子IL－2、TNF活性均显著性降低,但IL－6无明显改变。结论 切除大鼠脑垂体后将影响了其免疫功能,证明脑垂体分泌正常的GH、TSH、PRL水平对维持正常的细胞因子水平有重要的作用。     

内分泌激素水平检测在垂体瘤治疗中的临床观察

目的 探讨内分泌激素水平检测在垂体瘤临床治疗中的应用价值.方法 回顾性分析我院2008年6月至2011年6月收治的112例垂体瘤切除手术患者的临床资料,观察并分析手术前后血清泌乳素(PRL)、生长激素(GH)、甲状腺功能(T3、T4)、促甲状腺素(TSH)、血皮质醇(F)和促肾上腺皮质激素(ACTH)的变化情况.结果 垂体PRL和GH瘤患者术后的PRL和GH值低于术前(P<0.05),尤其是全切组(P<0.01);11例术前垂体功能低下患者,术后T3低于术前的正常值.结论 手术治疗可明显改善垂体腺瘤患者术前高激素水平状态,垂体激素水平的动态监测町作为评估肿瘤手术切除程度重要指标,对垂体瘤的综合治疗有重要临床意义.     

Lack of effect of deflazacort,a novel glucocorticoid,on basal and TRH-stimulated prolactin and thyrotropin levels in healthy subjects

Summary The possible relationship between cortisol inhibition induced by deflazacort, a new glucocorticoid, and impairment of prolactin (PRL) and thyrotropin (TSH) secretion in healthy volunteers has been investigated. In 8 healthy subjects deflazacort pretreatment partly inhibited cortisol secretion but did not affect basal or TRH-stimulated secretion of PRL and TSH in comparison to placebo. After dexamethasone, there was the anticipated complete suppression of cortisol secretion, no change in PRL secretion, either in basal conditions or after TRH, and significant inhibition of the TSH response to TRH. No significant change in GH, aldosterone or renin secretion was observed after deflazacort or dexamethasone.     

Effect of CRF on the release of anterior pituitary hormones in normal subjects and patients with Cushing's disease

Patterning of plasma ACTH, beta-EP/beta-LPH and cortisol in response to ovine CRF (1 microgram/kg b.w.t. injected i.v.), was studied in three normal subjects and in five patients with Cushing's disease, two of whom had undergone total bilateral adrenalectomy. CRF caused in all subjects a prompt and concurrent rise of plasma hormone levels. The hormonal response was of the same magnitude in normal controls and in the three untreated Cushing's patients, but was much greater in the two adrenalectomized subjects. No changes were noted, after CRF, in plasma levels of GH, PRL, TSH, LH and FSH. These findings indicate that CRF specifically promotes the pituitary release of ACTH and ACTH-related peptides both in normal subjects and patients with Cushing's disease. In view of the likely CRF hypersecretion of the adrenalectomized patients, their ACTH and beta-EP/beta-LPH hyperresponsiveness to exogenous CRF would denote that the peptide does not down regulate its own pituitary receptors.     

Narcotic analgesics and endorphins and the release of pituitary hormones (author's transl)

This report concerns a review of the neuroendocrine effects of narcotic analgesics and endorphins. Acute administration of narcotic analgesics to rats increases the blood levels of ACTH, GH and prolactin, and decreases levels of LH and TSH, however, there is no general consensus regarding changes in serum FSH, ADH and oxytocin as induced by narcotics in rats. In humans, the narcotic analgesic increases in serum prolactin, decreases in serum LH and has no effect on the release of other known pituitary hormones. Endorphins mimic morphine regarding hormonal effects. Effects of naloxone on the basal levels of prolactin, LH or GH were inverse to the effects seen with narcotics and endorphins, therefore endorphins may play a role in regulating the basal levels of these hormones. Narcotics analgesics depress the increased blood levels of prolactin, gonadotropins or TSH elicited by specific measures. While chronic administration of morphine results in tolerance to the stimulant effect of ACTH, and possibly of prolactin secretion, tolerance does not develop to the stimulant effect on GH secretion. The analgesic potency of narcotic analgesics correlates with their suppressive effect on the pituitary-gonadal system and the potency with which endorphins bind to the opiate receptors correlates with their prolactin releasing activity. It is assumed that narcotic analgesics and endorphins exert their hormonal effects by altering the release of neurotransmitters in the CNS. Thus, a release of hypothalamic releasing hormones is involved rather than a direct action on the pituitary. The central neurotransmitter systems involved in the hormonal effects of narcotics are now being intensively investigated by various groups of workers.     

Effects of acute continuous exposure of the rat to cigarette smoke on amine levels and utilization in discrete hypothalamic catecholamine nerve terminal systems and on neuroendocrine function

Summary The effects of acute continuous exposure to the smoke from 1–4 cigarettes have been studied in the male rat in terms of hypothalamic catecholamine levels and utilization as well as the secretion of anterior pituitary hormones. Catecholamine levels in discrete hypothalamic catecholamine nerve terminal systems were studied by quantitative histofluorimetry. Catecholamine utilization was studied by means of the tyrosine hydroxylase inhibition method using -methyl-(±)-p-tyrosine methyl ester. The serum hormone levels of adenohypophyseal hormones and of corticosterone were measured by the use of radioimmunoassay procedures. The results show that acute continuous exposure to unfiltered but not to filtered (Cambridge glass fibre filters) cigarette smoke leads to small but dose-dependent reductions of amine levels in most of the hypothalamic noradrenaline and dopamine nerve terminal system. These effects were associated with an enhancement of regional hypothalamic noradrenaline utilization but not of dopamine utilization in the median eminence. Furthermore, a reduction of TSH and prolactin serum levels was noted as well as increases in ACTH secretion. These results are partly different from those previously obtained with rats acutely exposed to intermittent unfiltered cigarrete smoke. This difference is suggested to be due to a temporary blockade of catecholamine release following acute continuous exposure to cigarette smoke.This work has been supported by a grant (1223) from the Council for Tobacco Research, New York, USA and by a grant from the Svenska Tobaks monopolet Send offprint requests to K. Andersson at the above address     

Selective neuroendocrine effects of low-dose haloperidol in normal adult men

The neuroendocrine effects of haloperidol, usually reported as side effects of this drug when given in antipsychotic doses, have not been systematically investigated. In the present study five normal adult men were administered saline and two doses of haloperidol (0.25 mg, 0.5 mg) intramuscularly in a double-blind randomized block design. The anterior pituitary hormones GH, LH, FSH, and PRL were measured in blood samples taken every 20 min for several hours thereafter.The low doses of haloperidol used have been shown by others to alter the human EEG; in our subjects these doses produced no objective or subjective clinical effects. There were no drug related changes in GH, LH, or FSH. PRL, however, showed a prompt, statistically significant, dose-related increase in plasma levels, with a return to baseline within 5h.Haloperidol has strong dopamine-blocking effects, and the hypothalamic inhibitory mechanism for PRL release is believed to be dopamine-mediated. The results of this study suggest that haloperidol may have utility in low doses primarily for its hypothalamic neuroendocrine effects, and that dose-related PRL release may be a useful paradigm for comparing dopamine-blocking antipsychotic agents in humans.     

Effects of methysergide,bromocriptine and naloxone on prolactin,growth hormone and TSH release induced by d-Met2,Pro5-enkephalinamide in man

d-Met²,Pro⁵-enkephalinamide (EA) 10 mg, given SC, induced a dramatic rise in serum prolactin (PRL) and growth hormone (GH) levels in healthy male volunteers. The TSH content was also moderately elevated. Naloxone 0.8 mg administered IV abolished these effects. Bromocriptine 2.5 mg given per os also antagonized EA-induced PRL and TSH release but potentiated the GH surge. Methysergide 2.0 mg administered orally partially reversed EA-elicited PRL release, further augmented GH liberation and did not modify TSH output. The data indicate that inhibition of the dopaminergic tone and/or activation of certain serotonergic mechanisms play an important role in the EA-induced release of PRL and TSH. However, primarily other neurotransmitters might mediate the GH liberation elicited by this opioid peptide. Offprint requests to: J. Földes     

Endosulfan effects on pituitary hormone and both nitrosative and oxidative stress in pubertal male rats

The present study was undertaken to investigate in pubertal male rats possible effects of endosulfan administered throughout lactation and gestation on: (a) pituitary gene expression of prolactin, luteinizing hormone (LH), growth hormone (GH) and thyroid stimulating hormone (TSH); (b) circulating levels of these hormones; and (c) expression of nitric oxide synthase 1 and 2 (NOS1 and NOS2), and heme oxygenase-1 (HO-1) at pituitary level. Endosulfan was administered orally at the doses of 0.61 mg/kg/day or 6.12 mg/kg/day, and possible toxic effects were studied in pubertal male pups (at postnatal day 30). Gene expression was evaluated by RT-PCR and plasma hormone levels by RIA. Exposure to both administered doses down-regulated LH, GH and TSH. Treatment with 0.61 mg endosulfan/kg/day decreased prolactin expression, although its plasmatic concentration was decreased by both administered doses. LH secretion was stimulated by both doses, whereas the highest dose increased GH levels and decreased plasma TSH concentration. Endosulfan up-regulated NOS1 and NOS2. We can conclude that in pubertal male rat, prenatal and lactational exposure to endosulfan modifies expression and release of prolactin, LH, GH and TSH, and pituitary NOS1 and NOS2 mRNA levels, suggesting that nitrosative stress can be implicated in the endocrine toxicity of endosulfan at pituitary level.     

Suppression of the Luteinizing Hormone Surge by Chlordimeform in Ovariectomized,Steroid-Primed Female Rats

Abstract: The midcycle surge of luteinizing hormone (LH) from the pituitary provides the physiological trigger in the mammalian female for the process of ovulation. Accordingly, any agent that compromises the LH surge could function as a reproductive toxicant. Since ovariectomized (OVX) rats implanted with oestradiol capsules will exhibit daily afternoon surges, such animals can serve as a useful model for the investigation of toxicant-induced alterations in this functional hormonal event. The acaricide chlordimeform (CDF) has previously been found to decrease serum LH, probably by altering the hypothalamic noradrenergic transmitter control of LH secretion. Consequently, the present study focused on the effect of acute CDF administration on the appearance of the induced LH surge. Single intraperitoneal injections of CDF (0, 10, 25, 50 mg/kg) in OVX, oestradiol-implanted female Long-Evans rats approximately 5 hr prior to the expected surge caused a complete suppression at 25 and 50 mg/kg. Ten mg/kg had no effect on surge amplitude, but advanced the LH peak by 2 hr. The observed suppression did not persist beyond the day of CDF administration. Earlier dosing at 11 or 18 hr prior to the surge was without effect. Since CDF has been found to elevate serum corticosterone (CORT), 10 mg CORT/rat were given at different times prior to the surge. Twenty hr after administration only a partial lowering was seen; 5 hr exposure were ineffective. This indicates that an indirect adrenal effect was not the principal route, but may accompany an action of CDF on the hypothalamic mechanisms regulating the surge and becomes evident after more prolonged exposure.