Prolactinomas and resistance to dopamine agonists.

Among 288 patients with prolactinoma (aged 12-62 years; 242 women), 27 were diagnosed as resistant to bromocriptine as their plasma prolactin (PRL) levels remained elevated despite long-term (3 months or more) treatment at high doses (> or = 15 mg daily). These 18 women and 9 men, aged 29 +/- 9 years (mean +/- SD, range 13-50), followed-up for 8 +/- 4 years, had microadenomas (n = 6) or macroadenomas. They were treated by dopamine agonists alone (n = 6) or associated with surgical or radiation therapy. In 8 cases repetitive surgical treatments were necessary. Among the 24 patients who were treated with the nonergot dopamine agonist CV 205-502 after unsuccessful bromocriptine treatment, half of them (9 women, 3 men) resumed normal PRL levels on doses ranging from 0.15 to 0.45 mg/day. Despite daily doses of CV 205-502 from 0.3 to 0.525 mg, the remaining patients were not normalized by this drug which did not prevent tumor growth in 4 of them. Two patients died from invasive cerebral extensions of their tumor and a third had vertebral metastases with positive anti-PRL immunostaining. It is concluded that bromocriptine-resistant prolactinomas represent the most severe aspect of this disease and that a more powerful dopamine agonist like CV 205-502 is effective in only a fraction of these patients.     

EGF binding site number of rat anterior pituitary is increased by chronic administration with dopaminergic agonist, CV 205-502]

In order to assess whether a chronic treatment with a dopamine agonist, CV205-502, could modulate anterior pituitary epidermal growth factor (EGF) binding sites, female Wistar rats were treated or not (controls) with CV205-502 0.25 mg/kg/day sc for 8 days. This treatment significantly reduced rats' pituitary weight and plasma prolactin levels when compared to controls (weight: 10.4 +/- 0.1 vs 11.1 +/- 0.1 mg, p less than 0.01; prolactin: 1.2 +/- 0.2 vs 4.9 +/- 0.5 ng/ml, p less than 0.01). These decreases were associated with a significant stimulation of the number of pituitary EGF binding sites Bmax: 16.7 +/- 2.3 vs 11.3 +/- 1.9 fmoles/mg proteins, p less than 0.01) with no significant effect on their affinity (Kd: 0.94 +/- 0.17 vs 0.95 +/- 0.14 nM). Therefore, the modulation of pituitary EGF binding sites might be one of the mechanisms by which the dopamine agonist, CV205-502, exerts its pharmacological effects on hormonal secretions and/or cell multiplication in the pituitary.     

Effects of a dopaminergic stimulant,amfonelic acid,on anterior pituitary hormone release in conscious rats

The response of plasma LH, Prolactin, GH and TSH levels to systematic administration of a specific central dopaminergic stimulant, amfonelic acid (AFA), by intravenous pulse injection in ovariectomized (OVX) and OVX estrogen-progesterone primed conscious rats has been evaluated. Intravenous injection of 0.2 mg/kg of AFA had no influence on plasma LH concentration until 60 min after injection when it was significantly elevated. Increasing the dose to 1 mg/kg reduced LH titers at 15 and 30 min with a return to preinjection levels by 60 min. AFA produced a dose-dependent decrease in plasma prolactin levels; the decrease occurred as early as 5 min after injection. AFA, both at 0.2 and 1 mg/kg doses, was effective in producing a sharp, dose-related rise in plasma GH levels. By contrast, TSH levels were significantly suppressed by both doses of AFA. Injection of the 1 mg/kg dose of AFA did not modify plasma LH levels in OVX-steroid-primed animals, white producing a comparable effect on plasma prolactin, GH and TSH levels to that observed in OVX animals. The present results indicate that endogenously released DA can have profound effects on pituitary hormone release, inhibiting PRL and TSH discharge, stimulating GH release and either inhibiting or stimulating LH release.     

Usefulness of CV 205-502 in a case of allergy to ergot-derived drugs.

This study reports a case of allergy to ergot-derived drugs in a patient with a prolactin (PRL)-secreting microadenoma. The anamnesis revealed allergic reactions to the administration of analgesics and antibiotics. The administration of dopamine agonist drugs, such as bromocriptine (BRC; 2.5 mg) or lisuride (0.2 mg), induced after a few minutes the appearance of nausea, vomiting, postural hypotension, headache, edema of the glottis with dispnea and acroedema. The edemas disappeared a few hours after the administration of antihistaminic drugs while nausea, vomiting, postural hypotension and headache persisted for a few days. Therefore, the patient was tested with another dopamine agonist non-ergot-derived drug, quinagolide (CV 205-502), which did not cause side effects or allergic reactions. Furthermore, not only was the responsiveness to the drug optimal but it also normalized the PRL levels, and menses reappeared after more than a 5-year amenorrhea. This report suggests that ergot-derived drugs, such as lisuride and BRC, seldom induce allergic reactions apart from common side effects. Consequently, the feasibility of using a new drug with a different molecular structure (non-ergot derived) effective in the therapy of hyperprolactinemic syndromes represents a good alternative to conventional therapy.     

Participation of voltage-sensitive calcium channels in pituitary hormone release

The role of extracellular Ca2+ in pituitary hormone release was studied in primary cultures of rat anterior pituitary cells. The basal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH), and adrenocorticotropin (ACTH) secretion were independent of extracellular Ca2+ concentration ([Ca2+]e). In contrast, the basal levels of growth hormone (GH) and prolactin (PRL) release showed dose-dependent increases with elevation of [Ca2+]e, and were abolished by Ca2+-channel antagonists. Under Ca2+-deficient conditions, BaCl2 mimicked the effects of calcium on PRL and GH release but with a marked increase in potency, and also increased basal LH and FSH release in a dose-dependent manner. In the presence of normal [Ca2+]e, depolarization with K+ maximally increased cytosolic [Ca2+] ([Ca2+]i) from 100 to 185 nM and elevated LH, FSH, TSH, ACTH, PRL, and GH release by 7-, 5-, 4-, 3-, 2-, and 1.5-fold, respectively. These effects of KCl were abolished in Ca2+-deficient medium or in the presence of the Ca2+-channel antagonist, Co2+, and were diminished by the dihydropyridine Ca2+-channel antagonist, nifedipine. The Ca2+-channel agonist BK 8644 (100 nM) enhanced the hormone-releasing actions of 25 mM KCl upon PRL, LH, FSH, GH, TSH, and ACTH by 2.3-, 2.0-, 1.8-, 1.7-, 1.6-, and 1.4-fold, respectively. The dose- and voltage-dependent actions of BK 8644 were specific for individual cell types; BK 8644 enhanced GH, PRL, TSH, LH, and ACTH secretion in the absence of any depolarizing stimulus, with ED50 values of 8, 10, 150, 200, and 400 nM, respectively. However, in the presence of 50 mM KCl, the ED50 values for BK 8644 were 1.5, 2, 3, 5, and 7 nM for GH, PRL, ACTH, TSH, and LH, respectively. [3H]BK 8644 bound specifically to pituitary membranes with Kd values of 0.8 nM and concentrations of about 900 channels per cell. These observations provide evidence for the presence and participation of voltage-sensitive calcium channels in the secretion of all five populations of anterior pituitary cells.     

Oral thyrotropin-releasing hormone (TRH) test in acromegaly

The effects of 40 mg oral and 200 microgram intravenous TRH were studied in patients with active acromegaly. Administration of oral TRH to each of 14 acromegalics resulted in more pronounced TSH response in all patients and more pronounced response of triiodothyronine in most of them (delta max TSh after oral TRh 36.4 +/- 10.0 (SEM) mU/l vs. delta max TSH after i.v. TRH 7.7 +/- 1.5 mU/l, P less than 0.05; delta max T3 after oral TRH 0.88 +/- 0.24 nmol/vs. delta max T3 after i.v. TRH 0.23 +/- 0.06 nmol/l, P less than 0.05). Oral TRH elicited unimpaired TSH response even in those acromegalics where the TSH response to i.v. TRH was absent or blunted. In contrast to TSH stimulation, oral TRH did not elicit positive paradoxical growth hormone response in any of 8 patients with absent stimulation after i.v. TRH. In 7 growth hormone responders to TRH stimulation the oral TRH-induced growth hormone response was insignificantly lower than that after i.v. TRH (delta max GH after oral TRH 65.4 +/- 28.1 microgram/l vs. delta max GH after i.v. TRH 87.7 +/- 25.6 microgram/l, P greater than 0.05). In 7 acromegalics 200 microgram i.v. TRH represented a stronger stimulus for prolactin release than 40 mg oral TRH (delta max PRL after i.v. TRH 19.6 +/- 3.22 microgram/, delta max PRL after oral TRH 11.1 +/- 2.02 microgram/, P less than 0.05). Conclusion: In acromegalics 40 mg oral TRH stimulation is useful in the evaluation of the function of pituitary thyrotrophs because it shows more pronounced effect than 200 microgram TRH intravenously. No advantage of oral TRH stimulation was seen in the assessment of prolactin stimulation and paradoxical growth hormone responses.     

Influence of bupropion HCl (Wellbatrin), a novel antidepressant, on plasma levels of prolactin and growth hormone in man and rat.

Bupropion HCl (Wellbatrin®), a non-tricyclic compound with antidepressant effects in man, was evaluated for effects on plasma prolactin (PRL) and growth hormone (GH) levels in normal human subjects, and for effects on plasma PRL levels in a series of pharmacological studies in normal rats. Single oral doses of 50, 100 or 200 mg of bupropion given to male (n=6) and female (n=12) subjects produced a marked suppression (80% decrease) of PRL. Incomplete PRL recovery was observed at the end of 24 hours. One hour after drug administration there was a +0.56 correlation of percent decrease in PRL levels with bupropion plasma levels. GH showed only small and erratic changes in plasma levels at 1–4 hours post-dose. In the rat, single bupropion doses of 25 mg/kg, i.p., failed to lower basal PRL levels. Bupropion, however, significantly decreased PRL in rats in which plasma PRL was elevated by pretreatment with alphamethyltyrosine, 5-hydroxytryptophan or quipazine. Bupropion, on the other hand, did not counteract the PRL-elevating effect of haloperidol. Results in man and rat are consistent with the view that bupropion has significant dopamine mimetic properties. Whether bupropion is a direct dopamine receptor-stimulator or an indirectly acting agonist cannot be determined from the present results.     

Pharmacological activation of the GABAergic system does not affect GH and PRL release in acromegaly

An extensive hypothalamic neurotransmitter impairment has been proposed in acromegaly. However, at the moment, the hypothalamic GABAergic system has been little investigated in this disorder. Since GABA has been shown to modulate growth hormone (GH) and prolactin (PRL) secretion in human subjects, it seemed reasonable to investigate hypothalamic GABAergic functioning through the assessment of basal GH and PRL responses to pharmacological activation of this system. 800 mg of sodium valproate (SV), a drug with GABA facilitating properties, were administered orally to 7 acromegalic patients and 9 healthy volunteers. Blood samples were collected before and after the drug administration for the measurement of plasma GH and PRL levels. SV induced a clear-cut rise in basal GH and a decrease in basal PRL in healthy subjects, but it did not induce any change in the basal levels of these hormones in acromegalics. These results suggest that the response of GH and PRL to SV in acromegaly is qualitatively different from normal controls.     

Neuroendocrine and behavioral effects of m-chlorophenylpiperazine administration in rhesus monkeys

The effects of m-chlorophenylpiperazine (mCPP), a serotonin receptor agonist, on the release of plasma prolactin (PRL), growth hormone (GH), and cortisol in the rhesus monkey were studied. mCPP was administered intravenously at doses of 0.5, 1.5, and 3.0 mg/kg. GH and cortisol were increased significantly at all doses whike PRL was significantly increased only following administration of 3.0 mg/kg mCPP. mCPP administration also produced behavioral alterations in each monkey, including sedation, penile erection, and defecation. PRL, GH and behavioral responses to mCPP were completely blocked by pretreatment with the serotonin anatgonist metergoline (MTG). However, pretreatment with MTG failed to entirely antagonize the cortisol response to mCPP. These data suggest that mCPP has prominent neuroendocrine and behavioral effects which are mediated, in part, by serotonergic mechanisms.     

Growth hormone and prolactin secretion after metoclopramide administration (DA2 receptor blockade) in fertile women.

In this report, we will describe the results of a cross-sectional study to assess PRL and GH secretion during the early follicular phase in 22 fertile patients after metoclopramide administration in order to achieve a dopaminergic DA2 receptor blockade. Blood samples were collected at - 15, 0, 15, 30, 45 and 60 minutes. PRL, GH, estradiol, IGF-I, TSH, glucose, and insulin were measured in the samples taken at - 15 and 0 minutes. The existence of a correlation between GH and PRL secretion was investigated. All patients presented normal serum levels of estradiol, prolactin, insulin, fasting glucose and IGF-I. Serum GH levels were not changed after metoclopramide infusion (p = 0.302), but there was a significant alteration in serum PRL (p = 0.0001) with the highest levels after 30 (mean: 237.20 ng/ml +/- 95.86) and 45 (mean: 211.80 ng/ml +/- 83.24) minutes. Serum GH levels did not correlate with serum PRL levels after the dopaminergic DA2 blockade. We conclude that GH secretion was not modulated by a direct effect of type 2 dopamine receptor.     

Serum prolactin levels and prolactin binding activity in adrenals and kidneys of male rats after dehydration, salt loading, and unilateral nephrectomy.

Serum prolactin (PRL) levels and PRL binding activity in microsomal membranes from kidneys and adrenals were measured in control, water-deprived, unilaterally nephrectomized, and salt-loaded male rats. Unilateral nephrectomy and water deprivation increased serum prolactin levels significantly. Unilateral nephrectomy did not alter PRL binding activity in the kidneys, but significantly increased it in the adrenal glands. Salt loading had no effect on serum prolactin levels or PRL binding in the kidneys; but significantly increased PRL binding in the adrenal glands. Inhibition curves and tests of cross reactivity with LH, FSH, TSH, and GH showed that binding of PRL to its receptors in the kidneys and adrenals was specific. These observations suggest that PRL has a role in salt and water metabolism and that PRL receptors in the kidney and adrenals participate in this regulatory system.     

Comparison of pituitary responses to physical exercise in athletes and sedentary subjects

Serum growth hormone (GH), prolactin (PRL), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH) levels were evaluated before and after a bicycle ergometer exercise test in 8 male competitive volleyball players and in 8 sedentary healthy males of the same age. Increased serum GH and cortisol values after exercise in both groups were found, whereas an exercise-induced PRL release was observed in athletes only. Serum levels of LH, FSH and TSH were unaffected by the test in all subjects. A possible role of training in conditioning the hypothalamopituitary exercise-induced secretion is suggested.     

Ontogeny of endocrine responses to methadone in rats

The effects of methadone (METH) on serum levels of prolactin (PRL), growth hormone (GH), corticosterone (CS) and TSH were determined in developing rats. METH increased PRL, GH and CS and decreased TSH at all ages tested, but the time course and magnitude of these effects changed during ontogeny. METH effects on day 10 were lower in magnitude than those observed in adults. In 20 day old pups, METH effects on GH and CS were comparable to those of adults, but TSH effects were still blunted. METH effects on hormone secretion in both 10 and 20 day old pups lasted longer than those observed in adults. Naloxone blocked all hormonal responses in adults, but did not completely block METH effects on CS secretion in 10 day old pups.     

Serum thyrotropin response to combined arginine and thyrotropin-releasing hormone administration provides evidence for an altered somatostatinergic tone in acromegaly.

The aim of this study was to evaluate plasma thyrotropin (TSH), prolactin (PRL) and growth hormone (GH) responses to the TSH-releasing hormone (TRH) test and to a combined arginine-TRH test (ATT-TRH) in 10 normal subjects and in 15 acromegalic patients. In controls, TSH responsiveness to TRH was enhanced by ATT (p less than 0.001). When considering the 15 acromegalic patients as a whole, no significant difference in TSH responses was detected during the two tests. However, patients without suppression of plasma GH levels after oral glucose load showed an increased TSH responsiveness to the ATT-TRH test if compared to TRH alone (p less than 0.025), while patients with partial suppression of plasma GH levels after glucose ingestion showed a decreased TSH responsiveness to ATT-TRH (p less than 0.05). No difference was recorded in PRL and GH responses, evaluated as area under the curve, during TRH or ATT-TRH tests in controls and in acromegalics. In conclusion, (1) normal subjects have an enhanced TSH response to the ATT-TRH test and (2) acromegalic patients without suppression of GH levels after oral glucose load show a TSH responsiveness to the ATT-TRH test similar to that of controls, while acromegalics with partial GH suppression after oral glucose load have a decreased TSH responsiveness to the ATT-TRH test. These data suggest that acromegaly is a heterogeneous disease as far as the somatostatinergic tone is concerned.     

Influence of prostaglandins and thyrotropin releasing hormone (TRH) on hormone secretion and growth in wether lambs.

A series of experiments were conducted in ewes and whether (castrate male) lambs to evaluate the influence of prostaglandins on secretion of anabolic hormones and to determine if repeated injections of prostaglandin (PG) F2alpha would chronically influence the secretion of these hormones and perhaps growth rate as well. A single intravenous injection of PGA1 and PGB1 (100 microgram/kg) exerted no significant (P greater than .10) influence on plasma concentrations of prolactin (PRL), growth hormone (GH) or thyrotropin (TSH) in ewes. PGA1, but not PGB1, stimulated an increase in the plasma concentration of insulin. Infusion of PGF2alpha for 5.5 hr into ewes resulted in increased (P less than .05) plasma concentrations of both GH and ARL while TSH and insulin were not significantly influenced. Prostaglandin F2alpha, when injected subcutaneously into wether lambs (10 mg twice weekly) stimulated (P less than .05) plasma GH concentrations after the first injection, but not after 3 weeks of treatment. Changes in plasma PRL or TSH were not observed consistently in the lambs treated chronically with PGF2alpha or TRH. Prostaglandin F2alpha, in the present studies, and PGE1 in previously reported studies (1-3), has been demonstrated to be stimulatory to the secretion of PRL and GH. In contrast, PGA1 and PGB1, which lack an 11-hydroxyl group, failed to influence the secretion of either PRL or GH. It would, therefore, appear that the 11-hydroxyl group is a structural requirement for prostaglandins to influence the secretion of these two hormones in sheep. Treatment with thyrotropin releasing hormone (TRH), alone or in combination with PGF 2alpha, significantly (P less than .05) increased growth rate (average daily gains) while PGF2alpha did not, despite the fact that both compounds exerted similar effects on plasma GH.     

Further studies on the effects of central administration of neuropeptide Y on neuroendocrine function in the male rat: relationship to hypothalamic catecholamines

Following intraventricular (i.v.t.) administration of increasing doses of neuropeptide Y (NPY; 7.5-750 pmol/rat) the catecholamine levels and turnover were quantitatively measured in discrete hypothalamic regions by means of histofluorometry. In the same rats the adenohypophyseal hormones as well as vasopressin, aldosterone (ALDO) and corticosterone (CORTICO) levels in serum were determined. Neuropeptide Y seems to induce a biphasic change in amine utilization in the tuberoinfundibular dopamine (DA) neurons and in the noradrenergic (NA) utilization in various hypothalamic areas. Thus, the lowest doses seem to inhibit the catecholamine utilization while higher doses seem to enhance it. NPY (250-750 pmol) reduced the serum levels of thyreotropine (TSH), prolactin (PRL) and growth hormone (GH) but increased CORTICO, adrenocorticotropin (ACTH) and ALDO serum levels. In conclusion, it is suggested that the NPY induced changes in DA utilization in the tuberoinfundibular DA neurons may contribute to the NPY induced changes in PRL and TSH secretion. The increases in paraventricular NA utilization may contribute to the increases in ACTH, ALDO and CORTICO secretion induced by NPY. These data give further support for NPY as an important neuroendocrine modulator.     

Localization of Carboxyl Ester Lipase in Human Pituitary Gland and Pituitary Adenomas

Carboxyl ester lipase (CEL) is an enzyme that hydrolyzes a wide variety of lipid substrates, including ceramides, which are known to show inhibitory regulation of pituitary hormone secretion in experimental models. Because no studies on CEL expression in human pituitary and pituitary adenomas have been reported in the literature, we investigated CEL expression in 10 normal pituitary glands and 86 well-characterized pituitary adenomas [12 FSH/LH cell, 17 α-subunit/null cell, 6 TSH cell, 21 ACTH cell, 11 prolactin (PRL) cell, and 19 GH cell adenomas] using IHC, immunoelectron microscopy, Western blotting, and quantitative RT-PCR. In normal adenohypophysis, CEL was localized in GH, ACTH, and TSH cells. In adenomas, it was mainly found in functioning GH, ACTH, and TSH tumors, whereas its expression was poor in the corresponding silent adenomas and was lacking in FSH/LH cell, null cell, and PRL cell adenomas. Ultrastructurally, CEL was localized in secretory granules close to their membranes. This is the first study demonstrating CEL expression in normal human pituitary glands and in functioning GH, ACTH, and TSH adenomas. Considering that CEL hydrolyzes ceramides, inactivating their inhibitory function on pituitary hormone secretion, our findings suggest a possible role of CEL in the regulation of hormone secretion in both normal and adenomatous pituitary cells. (J Histochem Cytochem 58:881–889, 2010)     

The pituitary-thyroid axis in acromegaly

The pituitary-thyroid axis of 12 acromegalic patients was evaluated by measurement of the serum concentrations (total and free) of thyroxine (T4), triiodothyronine (T3) and reverse T3 (rT3) and thyrotropin (TSH), growth hormone (GH) and prolactin (PRL) before and after iv stimulation with thyrotropin releasing hormone (TRH). Using an ultrasensitive method of TSH measurement (IRMA) basal serum TSH levels of the patients (0.76, 0.07-1.90 mIU/l) were found slightly, but significantly (P less than 0.01), lower than in 40 healthy controls (1.40, 0.41-2.50 mIU/l). The total T4 levels (TT4) were also reduced (84, 69-106 nmol/l vs 100, 72-156 nmol/l, P less than 0.01) and significantly correlated (P less than 0.02, R = 0.69) to the TSH response to TRH, suggesting a slight central hypothyroidism. The acromegalics had, however, normal serum levels of TT3 (1.79, 1.23-2.52 nmol/l vs 1.74, 0.78-2.84 nmol/l, P greater than 0.10), but significantly decreased levels of TrT3 (0.173, 0.077-0.430 nmol/l vs 0.368, 0.154-0.584 nmol/l, P less than 0.01) compared to the controls. The serum concentration of the free iodothyronines (FT4, FT3, FrT3) showed similar differences between acromegalics and normal controls. All the acromegalics showed a rise of serum TSH, GH and PRL after TRH. Positive correlation (P less than 0.05, R = 0.59) was found between the TSH and GH responses, but not between these two parameters and the PRL response to TRH. These findings may be explained by the existence of a central suppression of the TSH and GH secretion in acromegalic subjects, possibly exerted by somatostatin. Euthyroidism might be maintained by an increased extrathyroidal conversion of T4 to T3.     

Effects of phorbol ester on GH, TSH and PRL release by superfused rat adenohypophysis

The present study was undertaken to examine the effects of 12-0-tetradecanoyl-phorbol-13-acetate (TPA), one of the potent tumor promoting agents, on GH, TSH and PRL release by rat adenohypophyseal dispersed cells and fragments, using a superfusion technique. TPA (10(-6) to 10(-5) M) stimulated GH release from acutely dispersed rat adenohypophyseal cells. Neither TSH nor PRL was affected, but both were increased by TRH in a dose-dependent fashion (10(-9) to 10(-7) M). In fragments, TPA (10(-8) to 10(-6) M) elicited a dose-related release of GH. Exposure of the fragments to 10(-6) M TPA for 5 min promptly caused a 5-fold increase in GH release which continued for at least 40 min after stopping the stimulation. The addition of somatostatin (SRIF) (10(-7) M) decreased basal GH release and abolished GH release induced by 10(-6) M TPA. In contrast to GH, neither TSH nor PRL release was affected by TPA, but both were stimulated by TRH. These results indicate 1) that GH release is more sensitive to stimulation with TPA in normal rat anterior pituitaries in vitro than the release of TSH and PRL, and 2) that SRIF abolishes TPA-induced GH release.