Different sensitivity to sodium valproate in healthy, non-tumoral and tumoral hyperprolactinemic subjects

GABAergic drugs affect PRL secretion in both rat and man. Sodium valproate (SV) inhibits GABA transaminase so increasing the endogenous GABAergic tone. The aim of this study was to evaluate the effects of SV at low and high doses on PRL release in healthy subjects and hyperprolactinemic patients. Fifteen patients with prolactinomas, 8 patients with non-tumoral hyperprolactinemia and 10 healthy subjects were studied: in non consecutive days, all subjects received placebo and SV at the dose of 400 and 800 mg po. Serum PRL levels were assessed 30, 15 and 5 min before and every 30 min for 4 hours after administration. SV at the dose of 400 mg induced a significant decrease of serum PRL in healthy subjects (p < 0.05), whereas no effect was noted in both tumoral and non-tumoral hyperprolactinemia. The administration of 800 mg SV induced a significant decrease of PRL levels in healthy subjects and in patients with non-tumoral hyperprolactinemia (p < 0.05). Conversely, in prolactinomas a paradoxical increase of serum PRL concentration (p < 0.05) was observed 120 min after the administration of the drug. These data confirm the inhibitory activity of SV on PRL release in healthy subjects, and suggest the existence of a partial resistance to GABA in non-tumoral hyperprolactinemia. In prolactinomas, the paradoxical PRL increase after high dose of SV suggests the existence of a complete pituitary resistance to GABA. This finding might be explained by the appearance of the stimulatory effect of GABA at hypothalamic level that could have been unmasked by the lack of pituitary GABA effects on adenomatous lactotrophs.     

Altered growth hormone and prolactin responsiveness to TRH in the infant rat

12-day-old female and male pups were killed 10 min after the injection of either saline or thyrotropin releasing hormone (TRH), and plasma growth hormone (GH) and prolactin (PRL) levels were measured by radioimmunoassay (RIA). At all doses used (0.15, 0.3, 0.6 and 1.5 mug/100 g b.w.i.p.), TRH induced a significant, although not dose-related, increase in plasma GH levels, but was effective in releasing PRL only at the greatest dose level (1.5 mug/100 g b.w.). The GH-releasing effect of TRH was even more evident in 12-day-old pups subjected to central sympathectomy of 6-hydroxydopamine (6-OHDA, 60 mug/10 mul intraventricular route) 1 week before; in these animals, TRH was ineffective in releasing PRL even at the greatest dose level (1.5 mug/100 g b.w.). In pups pretreated with 6-OHDA, the GH-lowering effect of insulin hypoglycemia or cold exposure was markedly reduced, while the PRL responses were unmodified. Baseline plasma PRL levels were markedly increased following 6-OHDA administration. It is proposed that in the infant rat the greater GH than PRL responsiveness to TRH, which opposed the pattern of response present in the adult animal, may be due to the existence of a 'physiologic' functional disconnection between the central nervous system (CNS) and the anterior pituitary (AP). Results obtained following central sympathectomy by 6-OHDA, which further disrupted CNS-AP links, substantiate this view.     

Effects of synthetic human gastrin I on movements on water, electrolytes, and glucose across the human small intestine

The effect of graded doses (0.125, 0.500, 1.00 and 2.00 mug per kg per hr) of intravenous synthetic human gastrin I (SHG) on jejunal transport of water, electrolytes, and glucose from a glucose-saline solution (solution II) was studied in 12 healthy volunteers, using an intestinal perfusion technique with a proximal occluding balloon. SHG when infused at rates of 0.500 mug per kg per hr or greater significantly reduced water and electrolyte absorption; this effect was linearly related to the dose and reached 40 to 60% of basal absorption (and only 10% for glucose) with the highest dose; insorption of sodium and water were significantly decreased by SHG. In a further group of 9 subjects no effect of SHG (2 mug per kg per hr) was found on jejunal absorption from a mannitol-saline solution (solution I) and on ileal absorption from solutions I and II; in 5 additional subjects, SHG did not decrease jejunal transit time of intraluminal fluid. There was no increase in serum thyrocalcitonin during SHG infusion. It is proposed that SHG selectively depresses the glucose-stimulated sodium transport as suggested by the reduction of the rate of net sodium absorption per micromole of glucose absorbed during SHG infusion. Physiological and pathological implications of these findings are discussed, especially in the light of the circulating levels of immunoreactive gastrin achieved during SHG infusion.     

Effectiveness of the dopamine agonist lisuride in the treatment of acromegaly and pathological hyperprolactinemic states

We have studied the effects of the chronic administration of the dopamine agonist lisuride (L) in 21 acromegalics (group 1) and in 25 patients with pathological hyperprolactinemia (group 2). Before starting the treatment levels of PRL and/or GH were determined during acute tests with L (0.3 mg po) or TRH (0.2 mg iv). L was given in doses ranging between 0.4 and 2.4 mg/day. GH and/or PRL were determined at monthly intervals, TRH (6 patients of group 1 and 10 of group 2) was repeated during L therapy. In 10 patients of group 1 GH levels were reduced below 10 ng/ml by L therapy; in the remaining patients GH levels were reduced by 50% of the pretreatment values or they were unchanged. The correlation (p less than 0.01) found between GH levels during acute and chronic L administration indicates that GH changes after acute test are predictive of the outcome of the treatment. In all patients PRL was reduced during the therapy to at least 50% of the basal values and in most patients PRL fell to the normal range. No correlation was found between PRL levels during acute and chronic L administration. During the therapy TRH still increased GH levels in most patients whereas it failed to raise PRL. The withdrawal of L was followed by a rapid return of GH to the pretreatment values whereas PRL showed a slower increase. In acromegalics whose GH was lowered by L there was also a marked amelioration of clinical and metabolic parameters. The lowering of PRL was accompanied by the resumption of ovulatory menses even in patients with tumoral hyperprolactinemia. Males reported improvement in sexual performance. An improvement of visual field occurred in 1 patient. In 1 patient with a large prolactinoma serial computerized tomography scans performed during 2 yr of treatment showed a marked reduction of the tumor size.     

Effects of growth hormone secretagogues on prolactin release in anesthetized dwarf (dw/dw) rats

In addition to stimulating GH release, GH secretagogues such as GH-releasing peptide-6 (GHRP-6) stimulate small amounts of ACTH and PRL release. Although the effects on ACTH have recently been studied, there is little information about the effects of GHRP-6 on PRL. We have now studied GHRP-6-induced GH and PRL release and their regulation by estrogen (E2) in anesthetized male and female rats and in GH-deficient dwarf (dw/dw) rats that maintain high pituitary PRL stores and show elevated hypothalamic GH secretagogue receptor expression. Whereas GHRP-6 (0.1-2.5 microg, i.v.) did not induce PRL release in normal male or female rats, significant PRL responses were observed in dw/dw females. These responses were abolished by ovariectomy and could be strongly induced in male dw/dw rats by E2 treatment. These effects could be dissociated from GHRP-6-induced GH release in the same animals, but not from PRL release induced by TRH, which was also abolished by ovariectomy and induced in males by E2 treatment. However, the effects of GHRP-6 on PRL were unlikely to be mediated by TRH because in the same animals, TSH levels were unaffected by GHRP-6 whereas they were increased by TRH. The increased PRL response could reflect an increase in GH secretagogue receptor expression that was observed in the arcuate and ventromedial nuclei of E2-treated rats. Our results suggest that the minimal PRL-releasing activity of GHRP-6 in normal rats becomes prominent in GH-deficient female dw/dw rats and is probably exerted directly at the pituitary; these GHRP-6 actions may be modulated by E2 at both hypothalamic and pituitary sites.     

Circulating hormone levels in menopausal women receiving different hormone replacement therapy regimens. A comparison

OBJECTIVE: To measure and compare plasma levels of sex hormones after the administration of different hormone replacement therapy (HRT) regimens. STUDY DESIGN: Ninety women with natural menopause were randomized into this comparative study. Eighty-five women completed one year of follow-up. Patients were randomly assigned to five groups. The first received 0.6 mg/d of conjugated equine estrogen (CEE) cyclically (n = 15). The second received 50 micrograms/d of transdermal estradiol (E2) cyclically (n = 17), and the third received 0.6 mg/d of CEE continuously (n = 17). All these groups also received 2.5 mg of medroxyprogesterone acetate (MPA) sequentially for the last 12 days of HRT, while the fourth therapy group received 0.625 mg/d of CEE and 2.5 mg/d of MPA continuously (n = 19). The fifth group constituted a treatment-free control group (n = 22). Levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, estrone (E1), prolactin (PRL), testosterone (T), androstenedione (A4), dehydroepiandrosterone sulfate (DHEA-S) and sex hormone binding globulin (SHBG) were determined prior to HRT and during the last week of the 6th and 12th months of HRT, between days 21 and 24 of estrogen administration. RESULTS: After HRT we found decreases in FSH, LH and PRL levels, increases in E2, E1 and SHBG, and no modifications in T, A4 and DHEA-S plasma levels. There were no significant differences between the treatment groups in FSH, LH, E2, PRL, T, A4 or DHEA-S. E1 and SHBG were significantly higher in the groups with oral HRT. CONCLUSION: All the observed changes in hormone levels are to be expected after HRT except for the decrease in PRL levels. Finally, although MPA dosage was not the focus of the present study, our results suggest that the dosage of 2.5 mg/d of MPA in sequential regimens is clearly inadequate to protect the endometrium from hyperplastic changes.     

Biochemical parameters in the anterior pituitary during the course of tumorigenesis induced by diethylstilbestrol treatment

Treatment of F344 rats with diethylstilbestrol (DES) for 1-2 months induces a prolactin (PRL)-secreting pituitary adenoma. After 8 weeks of DES treatment, we have shown that the ratio of regulatory subunits of the cAMP-dependent protein kinase (RI/RII) increased in the tumors. Presently we report the variations in RI/RII ratio, pituitary weight, DNA content, serum PRL, nuclear estrogen receptor (E2R) and of ornithine decarboxylase (ODC) activity from the time of DES pellet implantation until 8 weeks. Pituitary weight, DNA content and serum PRL rose significantly at 4 weeks with a maximum at 6-8 weeks, and significantly correlated with each other. E2R and ODC activity increased from week 1 onwards, with a maximum at 2 weeks and decreased at 8 weeks. Both variables showed a positive correlation but neither E2R nor ODC activity correlated with pituitary weight, DNA or serum PRL. Values for RI remained stable with time, but RII decreased progressively. The RI/RII ratio was maintained around unity between 1-4 weeks, increasing to 1.6-2 thereafter. This ratio positively correlated with pituitary weight and DNA. It is suggested that during tumor induction by estrogen in a sensitive strain of rats, growth signals with different time-courses become activated. Increases in pituitary weight and DNA content, indicators of mammotroph hypertrophy and hyperplasia, were preceded by early rises in E2R and ODC activity. Increases in the RI/RII ratio accompanied the adenomatous change, suggesting their role in cell transformation after 6 weeks of estrogen exposure.     

Changes in the weight of the adrenal glands and in the concentration of plasma corticosterone in perinatal rats after prenatal treatment with oestadiol benzoate

A comparison was made of gonadotropin release after an iv bolus of large (150 mug) and small (10 mug) doses of LRF during various phases of the menstrual cycle and in primary hypogonadal women. Gonadotropin release was quantitatively similar to small and large doses of LRF in hypogonadal women with low estradiol levels. In contrast, normal women from the early to late follicular phase of the cycle, the gonadotropin response to a small dose of LRF (10 mug) was not as great as that observed with a large dose of LRF (150 mug) and did not elicit the augmented gonadotropin response of the late follicular phase. During the mid-luteal phase, a significant enhancement of responses to small doses of LRF was observed. The sustained gonadotropin release induced by the large dose of LRF in the late follicular phase was no longer apparent during the mid-luteal phase, although the dose-related discrimination of LH release was maintained. These dose-related disparities in the gonadotropin release to LRF might represent functional expressions of the two-pool dynamics of the gonadotrophs induced by ovarian steroids.     

Circadian responsiveness of the hypothalamic-pituitary axis

Five healthy men 25-38 years old were subjected to simultaneous composite intravenous stimulation tests of insulin hypoglycemia (0.1 U/kg), thyrotropin-releasing hormone (TRH, 100 mug), and luteinizing hormone-releasing hormone (LHRH, 50 mug) at weekly intervals to study the circadian responsiveness of the hypothalamic-adenohypophyseal axis at 0600, 1200, 1800, and 0000 hours. Blood sugar (BS), LH, follicle-stimulating hormone, TSH, prolactin, cortisol (C), growth hormone, and testosterone (T) levels were estimated before and after the administration of drugs. Comparisons were made between basal and delta values (difference between basal and peak or nadir levels) at different tests. Significant circadian variations in BS, GH, C, and, to a lesser extent PRL, responses were observed 0600 h basal and delta BS values were the lowest, delta BS was highest at 0000 h accompanied by maximal hypoglycemic symptoms; the delta values of both C and GH were significantly higher at 0600 h and 0000 h; highest mean delta PRL was observed at 0600; at 1800 h the basal plasma PRL level was maximum but the delta PRL was lowest. Plasma TSH, LH, and FSH responses did not show significant circadian variations. These results suggest that circadian variations are evident when stimuli act through central or hypothalamic mechanisms; however, direct stimulation of the adenohypophysis resulted in indentical responses at different periods tested.     

Prolactin and thyrotropin responses to thyrotropin-releasing hormone in patients with secondary amenorrhea: the effect of bromocriptine

Prolactin (PRL) and thyrotropin (TSH) responses to a 200 mug intravenous thyrotropin-releasing hormone (TRH) bolus were measured by radioimmunoassay in 11 women with hyperprolactinemic amenorrhea and 9 with normoprolactinemic amenorrhea. In all cases, the tests were carried out under basal conditions and repeated during bromocriptine treatment. In women whose basal PRL level was normal; TRH caused a maximal PRL increment of 85 +/- 25.2 mug/l (mean +/- SE), while those women whose basal PRL level was raised showed a smaller increase (5.2 +/- 11.9 mug/l) (P=0.02). The peak levels were not significantly different in these two groups (95.0 +/- 26.7 and 134.6 +/- 35.9 mug/l) (P is greater than 0.1). During bromocriptine treatment, the raised PRL levels decreased in all cases, but levels over 30 mug/l remained in 3 patients, one of whom turned out to have a pituitary tumor. Prolactin responses to TRH were markedly inhibited in normoprolactinemic patients by the dose of bromocriptine used. The mean maximal net increase of PRL was 2.0 +/- 0.9 mug/l in normoprolactinemic patients and 11.0 +/- 8.1 mug/l in hyperprolactinemic patients taking bromocriptine. After TRH stimulation during bromocriptine, the peak PRL levels in hyperprolactinemic patients were higher (32.7 +/- 10.5 mug/l) than in normoprolactinemic patients (7.2 +/- 1.5 mug/l). Unlike what has been described for hypothyroid patients, the basal TSH level in euthyroid amenorrhea patients was not affected by bromocriptine, and we found that bromocriptine has no effect on the TRH-TSH response.     

Dose-response of prolactin and thyrotropin to N3im-methyl-thyrotropin releasing hormone in euthyroid men

The synthetic N3im-methyl analogue of thyrotropin releasing hormone (methyl-TRH) was administered intravenously to 15 euthyroid men, ages 36-62, in graded doses from 6.25 mug to 500 mug in order to establish the range of response of prolactin (PRL), TSH, T3 and T4 to various doses of methyl-TRH. There was a dose-related rise in serum TSH, PRL, T3, and T4 which gave a nearly linear relationship when the integrated area of response was used as an index of response to the various doses of methyl-TRH. All 15 men had a clear elevation in TSH, PRL, T3 and T4 following the lowest dose of methyl-TRH TESTED (6.25 mug). There was considerable variability in the response to methyl-TRH among the individuals. One hundred mug of methyl-TRH gave a maximum TSH response; a 25 mug dose elicited a maximum PRL response.     

Estrogen improves performance of reinforced T-maze alternation and prevents the amnestic effects of scopolamine administered systemically or intrahippocampally

In a previous study, administration of high doses of estradiol benzoate (100 microgram/kg for 3 days im) to ovariectomized Long-Evans rats counteracted impairments of reinforced T-maze alternation induced by systemic administration of scopolamine, a muscarinic receptor blocker. In the current study, daily administration of lower doses of estradiol benzoate (5 microgram/kg for 3 weeks sc) increased the number of correct reinforced alternations during T-maze acquisition in ovariectomized rats compared to oil-treated controls and prevented impairments of reinforced alternation induced by injection of scopolamine hydrobromide (0.2 mg/kg ip). Furthermore, scopolamine (20 microgram) delivered bilaterally to the dorsal hippocampus reduced reinforced T-maze alternation in ovariectomized rats previously trained to complete this task while daily treatment with estradiol benzoate (5 microgram/kg sc) for 1 week prior to scopolamine infusion counteracted this impairment. In summary, physiological levels of estrogen improved performance during acquisition of reinforced T-maze alternation and prevented impairments induced by scopolamine administered systemically or intrahippocampally.     

Gentamicin intravenous infusion rate: effect on interstitial fluid concentration

To assess the possible role of intravenous (i.v.) infusion rate as a determinant of degree and rate of interstitial fluid penetration, six rabbits, each with four intraperitoneal implanted capsules, were studied by crossover design after a single dose of 1.7 mg of gentamicin per kg by either slow 2.5-min i.v. bolus or 30 min i.v. infusion. The mean serum peak antibiotic level after slow bolus was 17.4 mug/ml. After 30 min of infusion, mean serum peak was 8.3 mug/ml (P < 0.025). Mean capsule fluid antibiotic levels at 30 min, 1, and 2 h were 0.9 mug/ml, 1.6 mug/ml, and 1.8 mug/ml, respectively, after slow bolus and 0.6 mug/ml, 0.9 mug/ml, and 1.3 mug/ml after 30-min infusion (P < 0.05 at 30 min, P < 0.001 at 1 h, and P < 0.05 at 2 h). Comparison of capsule levels beyond 2 h revealed no significant differences, and peak capsular concentrations achieved by the two methods were similar. Slow 2.5-min i.v. bolus administration of gentamicin established higher interstitial fluid levels during the first 2 h of therapy and may be the preferred mode of delivery when rapid extravascular penetration is desired.     

The effect of an original analog of the C-terminal fragment of vasopressin on the behavior of white rats

Ethinylestradiol (EE) has evident paradoxical effects on cancer risk for human breast and hepatic cancer which parallel in some respects its effects on estrogen-induced neoplasms in the hamster kidney and liver. EE has been shown to be only weakly carcinogenic in the hamster kidney, but the most potent carcinogenic estrogen in the hamster liver following prolonged treatment. Unexpectedly, when EE and potent carcinogenic estrogens, such as diethylstilbestrol (DES), 17beta-estradiol (E2) and Moxestrol (MOX), are administered concomitantly, estrogen-induced carcinogenesis in the kidney is completely prevented. In studying this novel finding, we found that, compared with E2 exposure alone, EE at 0.05 and 1.0 nM significantly (P < 0.001) inhibited the rise in proliferation of cultured primary hamster proximal renal tubular (PRT) cells in the presence of E2 (1.0 nM). Consistent with these findings, combined EE + DES treatment for 5.0 months reduced hamster kidney c-myc, c-fos and c-jun RNA expression to 43, 37 and 52%, respectively, compared with levels observed after DES treatment alone. Interestingly, TAM + DES treatment for the same period also resulted in the same low level of RNA expression of these proto-oncogenes. c-MYC, c-FOS and c-JUN protein products were comparably reduced after either EE + DES or TAM + DES treatment. It appears that c-fos expression and c-FOS protein levels in the hamster kidney were more responsive to TAM inhibition. These data demonstrate that EE possesses unique anti-tumorigenic properties in vivo in the hamster kidney. Additionally, the observed anti-estrogen-like effect of EE on cell proliferation of cultured PRT cells suggests that EE may interfere critically with estrogen receptor (ER)-mediated mitogenic pathway(s) affected by potent carcinogenic estrogens, thus preventing subsequent gene dysregulation and, hence, tumor development. Based on competition studies, the differential binding of EE to hamster kidney ER relative to that of the other estrogens (E2, DES, MOX) appears not to contribute to the prevention of estrogen carcinogenesis at this organ site by EE.     

Rat Hsp20 confers thermoresistance in a clonal survival assay, but fails to protect coexpressed luciferase in Chinese hamster ovary cells

The effect of stress-like concentrations of cortisol (C) on estrogen-dependent expression of GnRH receptor was evaluated using orchidectomized sheep (wethers; n = 6 animals per group). C (5.0 mg/50 kg per hour; groups 1-4) or a comparable volume of vehicle (groups 5-8) was delivered by continuous infusion for 48 h. During the final 24 h of infusion, animals received concurrent infusion of estradiol (E2) at rates of 0 (groups 1 and 5), 0.5 (groups 2 and 6), 2.0 (groups 3 and 7), or 8.0 (groups 4 and 8) microg/50 kg per hour. Pituitary tissue was collected at the end of infusion. Although C did not affect (p > 0.05) the basal concentration of GnRH receptor or GnRH receptor mRNA, it reduced (p < 0.05) the increase in receptor and receptor mRNA induced by concurrent administration of 0. 5 microg E2/50 kg per hour. In contrast, the increase in GnRH receptor expression induced by higher levels of estrogen stimulation was not affected (p > 0.05) by concurrent administration of C. The effect of C on the temporal pattern of E2-dependent increase in GnRH receptor expression was assessed using wethers receiving E2 (0.5 microg/50 kg per hour) by continuous infusion for 0 (groups 1 and 5), 24 (groups 2 and 6), 48 (groups 3 and 7), or 72 h (groups 4 and 8). Animals received C (5.0 mg/50 kg per hour; groups 1-4) or vehicle (groups 5-8) beginning 24 h before, and continuing throughout, the E2 delivery period. Stress-like concentrations of C reduced (p < 0. 05) the increase in GnRH receptor and receptor mRNA induced after 24 h of E2 stimulation. However, the suppressive effect of C was transient, and tissue levels of GnRH receptor and receptor mRNA were comparable after 72 h of E2 infusion in animals receiving C or vehicle alone. Collectively these observations demonstrate that C suppresses estrogen-dependent increase in tissue concentrations of GnRH receptor and receptor mRNA. However, this effect of C is transient and not evident in animals receiving moderate to high levels of estrogen stimulation. This transient suppression of GnRH receptor expression may account, at least in part, for the anti-gonadal effect of glucocorticoids.     

Interaction of estradiol and LHRH on LH release in rhesus females: evidence for a neural site of action

The effects on LH release of infusing luteinizing hormone-releasing hormone (LHRH 80 mug/20 min) into the third ventricle, the pituitary, and the peripheral circulation were compared in spayed rhesus monkeys. Within 30 min after iv administration, serum LH concentrations increased to twice to preinfusion levels, and by 120 min declined to original values. Intraventricular or intrapituitary infusions of LHRH resulted in similar LH increments, but the peaks occurred somewhat later (70 to 90 min) and the elevations persisted beyond 200 min. Estradiol-17beta (E2) administered by a sc silastic capsule caused a 5-fold increase in serum E2 within 1 h and reduced serum LH levels by 65% within 4 h. The LH release caused by intrapituitary LHRH was significantly suppressed by maintaining for 72 h E2 concentrations near 100 pg/ml, a level inadequate for stimulating an LH surge. A comparable E2 treatment before intraventricular infusion of LHRH, however, did not inhibit LH release. This difference between the effects of intrapituitary and intraventricular LHRH was demonstrable only in E2-treated monkeys. Moreover, the release of LH after intraventricular infusion of LHRH in E2-treated females was blocked (P less than 0.001) by a single iv injection (90 min before LHRH) of haloperidol (1 mg/kg BW) or phentolamine (5 mg/kg), but was not altered by phenoxybenzamine (3 mg/kg) or propranolol (5 mg/kg). Without E2 pretreatment, LH release after intraventricular LHRH was enhanced by each drug. Phentolamine, injected into both E2- and non-E2-treated monkeys 90 min before an intrapituitary infusion of LHRH had no demonstrable effects on the patterns of serum LH. Our interpretation of these data is that E2 at a concentration below the level that triggers an LH surge has a dual action on LHRH-induced LH release in monkeys: an inhibitory effect exerted directly on the pituitary and a stimulatory effect on the brain. Furthermore, the paradoxical effects of the drugs with and without E2 are due to the involvement of two distinct neuronal systems. The postulated neural effects of both E2 and these drugs can be explained either by an increase in the quantity of injected or secreted LHRH which ultimately binds to LH-secreting cells or by the release of additional endogenous LH-stimulating agents together with ventricular LHRH.     

Activity and tolerance of a continuous subcutaneous infusion of interferon-alpha2b in patients with chronic hepatitis C

We administered interferon-alpha2b (IFN-alpha2b) by continuous subcutaneous infusion (60,000 IU/h, or 10 million IU/week) over 3 months to 7 patients with chronic hepatitis C. All had previously responded, as assessed by normalization of transaminases to the same dose of IFN administered by intermittent injection over 6 months, but had relapsed after cessation of therapy. The continuous infusion was tolerated well at the site of infusion, and the systemic side effects were similar in type but were lesser in intensity than with intermittent dosage. Four of 7 subjects had normalization of transaminase at the end of week 12 of therapy. Serum HCV RNA and HCV by PCR decreased with treatment, and there was a prompt and sustained increase in serum beta2-microglobulin and of 2', 5' OAS activity. The level of the latter appeared to correlate with response of the transaminase. Serum IFN concentrations were low but detectable throughout therapy. After stopping IFN administration, the transaminases in responders increased again to pretreatment levels.     

Preparation and stereoconfigurations of heterodimers of pyrimidines

Plasma levels of growth hormone (GH) and prolactin (PRL) were measured in twelve acromegalic patients after acute administration of an ergoline derivative (methergoline) which has been proposed as a specific serotoninergic blocking agent. The administration of methergoline (4 mg p.o.) was followed by a significant decrease in plasma GH and PRL concentrations. The administration to the same subjects of CB 154 (2.5 mg p.o.), a known stimulator of dopaminergic receptors, led to results almost superimposable to those obtained with methergoline although the suppressive effect of CB 154 on GH and PRL levels was more sustained. Also on the ground of results obtained in these patients with the use of cyproheptadine, phentolamine, or pimozide, we have concluded that methergoline inhibition of GH and PRL release is, in acromegalic patients, most probably due to a dopaminergic mechanism of action.     

Coagulation studies and platelet function after somatostatin infusion

The effect of short- and long-term somatostatin (GIF) administration on haemostatic function in man was investigated. The dosage programme applied in this study was 250 mug GIF as a bolus injection and 250 mug GIF/h by way of infusion. In five healthy volunteers a short-term (3h) treatment resulted in a statistically significant drop of platelet count and impairment of platelet aggregation at the end of infusion. However, these changes were within the physiologically normal range and disappeared after two hours on all subjects. Other parameters such as bleeding time, thromboplastin and partial thromboplastin time, fibrinogen, fibrin/fibrinogen split products, plasma factor XIII, ethanol gelation test were not affected. In two patients with gastric haemorrhage and persistent amylasaemia a 67 or 120-h treatment induced no remarkable haemostatic defect. By contrast, peptic ulcer bleeding in one patient stopped 60 min after starting the GIF infusion. These studies indicated that somatostatin administration in man at the dosage programme used neither results in clinical evidence indicating bleeding tendency nor does it influence laboratory parameters in an apparent way.     

Abnormal twenty-four hour pattern of pulsatile luteinizing hormone secretion and the response to naloxone in women with hyperprolactinaemic amenorrhoea

OBJECTIVE: Hyperprolactinaemic amenorrhoea is associated with disturbances of pulsatile gonadotrophin secretion. The underlying mechanism remains unclear and the aim of this study was to investigate the 24-hour secretory pattern of gonadotrophins in women with hyperprolactinaemic amenorrhoea. The effect of opioid blockade using naloxone infusion on LH secretory pattern was also studied. DESIGN: The secretory patterns of LH, FSH, PRL and their responses to naloxone infusion were studied by serial blood samples collected at 10-minute intervals for 24 hours. On the following day, naloxone was infused at a dose of 1.6 mg per hour for 4 hours. PATIENTS: Eight women with hyperprolactinaemic amenorrhoea, two women hyperprolactinaemic but with normal ovarian cycles, and nine control subjects in the early follicular phase of menstrual cycle. MEASUREMENTS: Concentrations of LH, FSH and PRL were measured in plasma samples obtained at 10-minute intervals for 24 hours. In one woman, concentrations of urinary oestrone glucuronide were measured daily during treatment with pulsatile GnRH. RESULTS: The number of LH pulses per 24 hours was significantly fewer in women with hyperprolactinaemic amenorrhoea than in those with hyperprolactinaemia with normal cycles or control subjects (mean +/- SEM 4.5 +/- 2.4 vs 13.5 +/- 2.5 vs 17.3 +/- 0.8, P < 0.001). The magnitude of each episode of secretion was significantly higher in the hyperprolactinaemic amenorrhoeic women (P < 0.05) so the overall mean concentrations of LH throughout the 24-hour period was similar in the three groups (5.2 +/- 1.1, 4.8 +/- 0.8 and 5.2 +/- 0.4 U/l respectively). In women with hyperprolactinaemic amenorrhoea there was no significant change in the pattern of LH secretion during sleep in contrast to the control women in whom there was a slowing in the LH pulse frequency during the night. There was no significant change in the mean concentrations of LH, FSH and PRL during the naloxone infusion. There were also no significant changes in the LH pulse frequency in response to naloxone infusion when compared with an equivalent period of time in the previous 24 hours. In one hyperprolactinaemic amenorrhoeic woman, follicular development, ovulation and pregnancy were induced when gonadotrophin releasing hormone (GnRH) was infused in a pulsatile manner at a dose of 5 micrograms every 90 minutes. CONCLUSIONS: The suppression of normal ovarian cycles in women with hyperprolactinaemic amenorrhoea is due to a significant reduction in frequency of LH (GnRH) secretion which is not due to an increase in hypothalamic opioid activity. As normal ovarian cycles can occur or be induced by exogenous GnRH in hyperprolactinaemia, it is unlikely that a high level of prolactin by itself inhibits follicular development and ovulation.