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Biomedical subjects

L Lazarus

Publications and source records attributed to L Lazarus.

At least 19 recordsLinked to original sources
PubMed1992

The impact of recent advances in diagnostic technology on the clinical presentation of phaeochromocytoma.

OBJECTIVE: To examine the impact of recent advances in diagnostic technology on the spectrum of clinical and biochemical features of patients presenting with a new diagnosis of phaeochromocytoma. DESIGN: A retrospective review of the clinical and biochemical features of patients diagnosed by our laboratory as having phaeochromocytoma within a 27-month period up to December, 1990. Noradrenaline, adrenaline and dihydroxyphenylglycol were assayed in 24-hour urine specimens (19 patients) or plasma (1 anuric patient) by gas chromatography/mass spectrometry. SETTING: A tertiary level chemical pathology department. PATIENTS: Twenty patients with a new diagnosis of phaeochromocytoma. RESULTS: The classic, episodic adrenergic symptoms traditionally associated with phaeochromocytoma were absent in 9 of the 20 patients (45%). "Atypical" phaeochromocytoma presented as a mass on computed tomography imaging (6 patients, 30%), "phaeochromocytoma crisis" (4 patients, 20%) or family screening (1 patient, 5%). Excessive adrenaline production was found in 11 patients (55%) and six (30%) had predominantly adrenaline-secreting tumours. The urinary noradrenaline:dihydroxyphenylglycol ratio was raised in all nine patients with predominantly noradrenaline-secreting tumours but was not raised in nine out of ten patients with adrenaline-secreting phaeochromocytoma. Adrenaline excretion was significantly correlated with tumour size (r = 0.8; P less than 0.05). CONCLUSIONS: Advances in diagnostic technology, particularly specific adrenaline assays and computed tomography, have made possible the early diagnosis of patients with phaeochromocytoma presenting in ways previously thought to be uncommon. All patients with adrenal masses noted incidentally on CT scan should be investigated for phaeochromocytoma. Adrenaline-secreting tumours are common and both noradrenaline and adrenaline should be assayed in all patients investigated for phaeochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1992

Biochemical diagnosis of pheochromocytoma by simultaneous measurement of urinary excretion of epinephrine and norepinephrine.

The utility of specific assay of urinary catechols in pheochromocytoma diagnosis was examined by reviewing our data on the investigation of pheochromocytoma in a population of 2476 patients investigated over a six-year period. We used specific gas-chromatographic/mass-spectrometric (GC/MS) analysis for the simultaneous measurement of norepinephrine, dopamine, and the neuronal metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in all samples; the last two years of data collection (from 1101 patients) also included the specific GC/MS assay of epinephrine. The importance of assaying epinephrine as well as norepinephrine was shown by these latter data. During this latter period, 19 of 1101 patients were found to have pheochromocytoma; of these, nine had tumors that exclusively secreted norepinephrine, six had tumors that exclusively secreted epinephrine, and four exhibited excess production of both norepinephrine and epinephrine. Neither dopamine nor DOPAC was useful in the diagnosis of pheochromocytoma. A substantial proportion of patients may have uniquely epinephrine-secreting pheochromocytomas, previously considered a rarity. Thus we recommend that the biochemical testing for pheochromocytoma include the specific measurement of both norepinephrine and epinephrine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women.

Estrogen deficiency may account for lower circulating GH and insulin-like growth factor I (IGF-I) concentrations in the menopause. Since the liver is the major source of circulating IGF-I and oral estrogens have nonphysiological effects on hepatic function, we have compared GH secretion over 24 h from 20 min sampling and serum IGF-I levels in premenopausal women (n = 7, follicular phase) and postmenopausal women before and after 2 months of cyclical replacement therapy with either oral ethinyl estradiol (EE, 20 micrograms daily; n = 7) or transdermal 17 beta-estradiol (E2, 100 micrograms patches applied twice weekly; n = 7). The extent of GH binding to its serum binding protein was also examined by measuring the percent specific binding of [125I] GH in serum. Mean 24-h serum GH and serum IGF-I were significantly lower (P less than 0.05) in postmenopausal than in premenopausal women. Oral and transdermal estrogen therapy resulted in a comparable degree of gonadotropin suppression. Oral EE treatment increased mean 24-h serum GH (2.0 +/- 0.4 to 7.0 +/- 0.6 mIU/L, P less than 0.0005) and mean pulse amplitude (5.3 +/- 1.2 to 11.2 +/- 2.5 mIU/L, P less than 0.01) but significantly reduced circulating IGF-I (0.70 +/- 0.09 to 0.47 +/- 0.04 U/mL, P less than 0.02) levels. Oral EE increased the percent specific binding of [125I]GH (22.0 +/- 1.6 to 32.0 +/- 1.9%, P less than 0.0005), however the derived mean 24-h free serum GH concentrations were significantly higher (P less than 0.0005) after treatment. By contrast, transdermal E2 administration, which restored circulating E2 concentrations to the midfollicular range, increased circulating IGF-I (0.86 +/- 0.15 to 1.10 +/- 0.14 U/mL, P less than 0.005) to levels that were not significantly different from those of premenopausal women (1.41 +/- 0.21 U/mL). This was not accompanied by changes in 24-h GH secretion or the percent specific binding of [125I]GH in serum. The route of administration is a major determinant of the effects of exogenous estrogens on the GH/IGF-I axis. Oral estrogen administration inhibits hepatic IGF-I synthesis and increases GH secretion through reduced feedback inhibition. Reduced GH secretion in the menopause is not explained by estrogen deficiency since GH secretion is not restored by the attainment of physiological E2 concentrations using the transdermal route. The contrasting route dependent IGF-I responses have important implications for the long-term benefit of hormone replacement therapy in the menopause.

Administration, Cutaneous↗
PubMed1990

Therapeutic efficacy of the somatostatin analog SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety.

STUDY OBJECTIVE: To determine the efficacy of stepwise incremental doses, to compare twice- with thrice-daily administration of the same total daily dosage of the long-acting somatostatin analog SMS 201-995 (octreotide, Sandoz Australia, Sydney, Australia), and to evaluate the risk for cholelithiasis after long-term therapy for acromegaly. DESIGN: Nonrandomized, controlled trial. SETTING: Tertiary care center at a medical research institute. PATIENTS: Sequential sample of 19 patients with active acromegaly. Twenty-five age-matched normal subjects were also studied to establish the normal range for growth hormone (GH) and insulin-like growth factor 1 (IGF-1). INTERVENTIONS: Eight patients (group 1) were treated with 100, 250, and 500 micrograms twice daily of octreotide, then switched to 333 micrograms three times daily, whereas 11 patients (group 2) were treated with 100, 200, 300, and 500 micrograms three times daily. Each treatment stage lasted 6 to 12 weeks. MEASUREMENTS AND MAIN RESULTS: Octreotide, 100 micrograms administered twice or thrice daily, significantly reduced mean 12-hour and nadir GH (P less than 0.01), IGF-1 (P less than 0.05), and hand volume (P less than 0.05). Dose increment to 500 micrograms in both groups did not further reduce mean 12-hour GH, nadir GH, or hand volume. Switching from 500 micrograms twice daily to 333 micrograms thrice daily resulted in significant (P less than 0.05) reduction of mean 12-hour GH, IGF-1, and hand volume. Normalization of mean 12-hour GH and IGF-1 occurred in 8 of 19 patients; 7 of the 8 patients had pretherapy mean 12-hour GH below 20 mIU/L. The pretherapy mean blood glucose was a significant negative predictor (r = -0.89) of the change in mean blood glucose during therapy. Gallstones were present in 9 of 18 patients after therapy. CONCLUSION: Thrice-daily was more effective than twice-daily administration of octreotide, and dose increments above 100 micrograms thrice daily did not confer additional benefit. Biochemical remission was achieved in 40% of patients and was dependent on the GH concentration at initiation of treatment. Cholelithiasis is a risk of octreotide therapy. Octreotide is effective and can be considered as a first-line therapy in patients with acromegaly with mean pretherapy GH concentrations below 20 mIU/L. In patients with mean GH over 20 mIU/L, octreotide may be used as an adjuvant to surgery or radiotherapy.

Acromegaly↗
PubMed1990

Effect of biosynthetic human growth hormone on insulin action in individual tissues of the rat in vivo.

Excessive endogenous production or exogenous administration of human growth hormone (hGH) causes insulin resistance at both the hepatic and extrahepatic levels. However, which extrahepatic tissues are involved have not been defined. We have examined the diabetogenic action of authentic biosynthetic hGH on whole body glucose disposal, hepatic glucose output, and glucose metabolism in individual peripheral tissues. The use of a highly purified preparation of the hormone allowed us to examine the isolated effects of 22K hGH. The euglycemic hyperinsulinemic (approximately 100 mU/L) clamp plus 3H-2-deoxyglucose technique was used to quantitate the effects of hGH on insulin action in vivo. Administration of biosynthetic hGH at a dose of 10 IU/kg/24 h for 48 hours in male Wistar rats (approximately 340 g) produced a highly significant decrease in the steady state clamp glucose infusion rate (GIR) when compared with controls (8.1 +/- 0.6 v 18.7 +/- 0.7 mg/kg/min, P less than .001), reduced insulin-mediated suppression of hepatic glucose output (Ra) (3.9 +/- 0.6 v 0.7 +/- 0.3 mg/kg/min, P less than .05) and a decreased clamp glucose disposal rate (Rd) (12.0 +/- 0.4 v 18.10 +/- 1.1 mg/kg/min, P less than .001). There was a significant decrease in insulin-mediated glucose uptake as indicated by tissue accumulation of [3H]-2-deoxyglucose phosphorylation in diaphragm and hindlimb muscles. Insulin action was more substantially reduced in muscles (approximately 50%) than in adipose tissues (approximately 20%). These studies confirm that the diabetogenic action of hGH in the rat is due to a combination of inhibition of insulin suppression of hepatic glucose output and inhibition of the uptake and subsequent utilization of glucose in skeletal muscles.

Adipose Tissue↗
PubMed1989

The pharmacokinetics, safety and endocrine effects of authentic biosynthetic human growth hormone in normal subjects.

The pharmacokinetics, safety and endocrine effects of an authentic human growth hormone (bio-hGH), produced by the expression of genomic hGH in a mammalian cell line, were studied in six healthy young men who were administered 0.2 U/kg/day subcutaneously for five consecutive days. Changes in sodium balance and in thyroid function were studied during the week of bio-hGH administration and safety parameters were monitored over a 3-week period. Growth hormone levels reached a mean (+/- SD) peak of 106 +/- 10 mIU/l at 3.3 +/- 0.5 h following the first dose and resulted in a significant rise of somatomedin C. free fatty acids, fasting blood glucose and insulin concentrations. Bio-hGH administration resulted in a significant increase in body weight (80.0 +/- 4.5 to 81.1 +/- 4.3 kg; P less than 0.01) which was associated with a marked reduction in urinary sodium excretion (196 +/- 38 to 45 +/- 20 mmol/day; P less than 0.025). Serum T3 increased during bio-hGH administration and was associated with reciprocal changes in free thyroxine and TSH concentrations. Cardiac, hepatic, renal, biochemical, haematological, endocrinological and immunological functions remained normal throughout the study. No antibodies to hGH or to host cell protein developed during the study. The results show that bio-hGH is safe in the short term, well tolerated, possesses pharmacokinetic and biological properties similar to pituitary hGH, and has distinct effects on sodium balance and on thyroid function. This study stresses the need to monitor patients for effects on sodium retention, carbohydrate metabolism and thyroid function when using hGH doses of 1.0 U/kg/week (40 U/m2/week) or more in patients with GH responsive short stature.

Adult↗
PubMed1989

Resolution of apparent growth hormone-dependent growth failure during puberty: a case report.

A prepubertal boy with apparent growth hormone (GH)-dependent growth failure displayed a marked increase in growth velocity, normal GH responses to arginine/insulin infusion and a fourfold increase in spontaneous 24-hour GH secretion following the onset of normal puberty. The case supports earlier observations of a transient form of GH insufficiency in some short prepubertal children, but represents the first evidence that puberty restores spontaneous as well as stimulated GH secretion in such patients.

Adolescent↗
PubMed1988

Measurement of norepinephrine and 3,4-dihydroxyphenylglycol in urine and plasma for the diagnosis of pheochromocytoma.

We compared the value of plasma samples with that of 24-hour urine samples in identifying patients with pheochromocytoma among those with hypertension. We employed specific gas chromatographic-mass spectrometric analysis of both urine and plasma for simultaneous assay of norepinephrine and its neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG). The study population consisted of 1086 patients with hypertension, among them 25 patients with proved pheochromocytoma. Reference ranges for free norepinephrine and DHPG in plasma and urine were established. Measurement of free norepinephrine in 24-hour urine samples provided the best index of a pheochromocytoma. This technique had 100 percent sensitivity and 98 percent specificity among 1192 urine samples, as compared with 82 percent sensitivity and 95 percent specificity among 358 plasma samples. Simultaneous measurement of norepinephrine and DHPG in urine further improved specificity (to 99 percent), but the use of the ratio of norepinephrine to DHPG reduced sensitivity (to 95 percent), since some patients with pheochromocytoma secrete large amounts of DHPG. We therefore recommend measurement of 24-hour urinary levels of free norepinephrine for the diagnosis of pheochromocytoma and suggest that simultaneous analysis for DHPG may sometimes prove useful in reducing the rate of false positive results.

Adrenal Gland Neoplasms↗
PubMed1988

Visual field area in phakic, aphakic, and pseudophakic individuals.

Goldmann perimetry was done on 11 pseudophakic subjects and results were compared to those of age-matched phakic subjects and a third group of aphakic individuals who were wearing rigid gas permeable contact lenses. Testing showed that the I-3 and I-4 fields of the subjects who had had cataract surgery were generally constricted when compared to the normal phakic population. Possible explanations for this include media clarity not being as important a factor in determining field size as was previously thought, peripheral retinal changes, and implant material affecting contrast sensitivity.

Aged↗
PubMed1988

A comparison of the dynamics of secretion of human growth hormone and LH pulses.

Patterns of hypothalamic stimulation causing pituitary hormone release cannot be studied directly in humans; one possible approach is to make inferences from the nature of the response of the target organ as revealed by patterns of pituitary hormones in blood. Replicated, precise assay of LH in frequently sampled blood of women at differing stages of the menstrual cycle has demonstrated previously that secretion of this hormone is compatible with a model of discrete, instantaneous episodes of LH output, which are assumed to be stimulated by isolated bursts of increased stimulatory hypothalamic gonadotrophin-releasing hormone. However, similarly detailed measurements of the dynamic secretion patterns of GH in women reported here, revealed much slower rates of increase of GH concentrations (median time to maximum concentration 38 min) in comparison with LH (13 min) assayed in the same blood samples. These rise rates of GH were uncorrelated with the final amplitude of the peak and were observably discontinuous in half the peaks. Simultaneous i.v. injection of a bolus of mixed GRF and GnRH produced similar dynamics of pituitary release of GH and LH. Thus differences in patterns of natural release of the two hormones appear to be contributed to by differences in the modes of hypothalamic stimulation. Current understanding of control of GH release in animal models suggests that the slow-rising, frequently discontinuous natural peaks of GH in human blood are likely to be caused by interaction between the withdrawal of inhibitory hypothalamic somatostatin and the increased secretion of stimulatory GRF.

Female↗
PubMed1987

Methionine oxidation in human growth hormone and human chorionic somatomammotropin. Effects on receptor binding and biological activities.

The oxidation of the methionine residues of human growth hormone (hGH) and human chorionic somatomammotropin (hCS) to methionine sulfoxide by hydrogen peroxide has been studied. The kinetics of oxidation of individual methionine residues has been measured by reverse-phase high pressure liquid chromatography tryptic peptide mapping. Met-170 is completely resistant to oxidation in both hormones. The other 3 methionine residues in hCS (Met-64, Met-96, and Met-179) have markedly different reaction rates. Oxidation of the methionine residues does not appear to cause gross conformational changes in either hGH or hCS, as judged by CD and 1H NMR spectroscopy. Oxidation of Met-14 and Met-125 in hGH has little effect on affinity of the hormone for lactogenic receptors or on its potency in the Nb2 rat lymphoma in vitro bioassay for lactogenic hormones. The oxidation of Met-64 and/or Met-179 in hCS reduces profoundly both its affinity for lactogenic receptors and its in vitro biological potency. It is inferred by induction that residues 64 and/or 179 are critical for the binding of both hGH and hCS to lactogenic receptors and the expression of lactogenic biological activity.

Animals↗
PubMed1986

Normal lactotroph sensitivity to graded low-dose dopamine infusions in pathological hyperprolactinemia.

The question as to whether there is lactotroph resistance to dopamine (DA) in pathological hyperprolactinemia (PHP) is unresolved. Previous studies utilizing low-dose DA infusions to study lactotroph function have not considered the diurnal changes in prolactin (PRL) secretion that occur in normals but which are lost in PHP. As PRL levels show a fall in the hours after waking, studies performed during this time of day will falsely show a greater fall of PRL in normals than in PHP patients. The aim was to readdress the issue of lactotroph sensitivity using a study designed to minimize the problem arising from diurnal PRL changes. Eight normal subjects, 17 patients with PHP, and 6 hyperprolactinemic patients with nonfunctioning pituitary tumors (NFTs) were studied with three graded doses of DA - (0.01, 0.05, and 0.5 micrograms/kg X min) - by relating the changes induced by each dose to the maximal spontaneous fall in PRL that occurred during a 3-hour control saline study. The mean +/- SE maximal fall in PRL during control saline infusion to 46.0 +/- 4.1% of basal in normal subjects was significantly greater (p less than 0.001) than the fall in patients with PHP (88.0 +/- 1.0%) or NFTs (87.5 +/- 2.6%). The apparent fall in PRL was significantly greater in normals during the two lower infusion doses, but not at the highest dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Modulation of lactogenic receptors by progestins in cultured human breast cancer cells.

Progesterone receptors (PgR) are present in many breast cancers, but few specific actions of progestins in breast cancer cells have been reported. We now report that progestins specifically modulate lactogenic receptor expression in cultured T-47D and MCF-7 human mammary carcinoma cells. When T-47D cells were preincubated for 24 h with 1 nM medroxyprogesterone acetate (17 alpha-acetoxy-6 alpha-methyl-4-pregnene-3,20-dione), specific binding of [125I]human GH ([125I]hGH) and [125I]human PRL was increased to 205 +/- 22% (+/- SE) (P less than 0.01) and 175 +/- 32% (P less than 0.05), respectively, of that in control cultures. There was no significant effect on cell number and no significant enhancement of specific binding of [125I]porcine insulin, [125I]salmon calcitonin, [125I]human transferrin, or [3H] Concanavalin A. Lactogenic receptor number was increased from 6,490 +/- 500 (n = 12) to 13,180 +/- 3,270 (n = 7; P less than 0.01) sites/cell, with no significant change in affinity for hGH. Progesterone, which is readily metabolized by these cells, was less potent than the synthetic progestins (medroxyprogesterone acetate, R 5020 (17 alpha, 21-dimethyl-19-norpregn-4,9-diene-3,20-dione), and ORG 2058 (16 alpha-ethyl-21-hydroxy-19-norpregn-4-en-3,20-dione), but physiological concentrations of progesterone (1 nM) significantly enhanced specific binding of [125I]hGH to 153 +/- 23% of the control value (n = 6; P less than 0.05). Physiological concentrations of androgens, estrogens, and glucocorticoids had no significant effect. MCF-7 cells were considerably less sensitive to these effects of progestins than T-47D cells, probably due to the lower PgR concentration in MCF-7 cells. These observations, which indicate that lactogenic receptor expression is controlled, at least in part, by progestins in these mammary carcinoma cell lines, may have important implications in the management of human breast cancer, where high levels of this receptor may reflect a functional PgR and a highly hormone-dependent phenotype.

Breast Neoplasms↗
PubMed1986

Progestin regulation of epidermal growth factor receptor in human mammary carcinoma cells.

Epidermal growth factor (EGF) receptors are present in human breast cancer and probably mediate the effects of EGF and the autocrine effects of alpha-transforming growth factors, produced by breast cancer cells. Steroid hormones influence the growth of some human cancers, and both direct and indirect effects on cell proliferation have been proposed. One potential indirect effect of steroids would be to augment sensitivity to other endocrine and autocrine factors by up-regulation of their receptors. We therefore investigated the effects of various steroids on EGF receptor expression in T-47D, MCF-7, and BT 20 human mammary carcinoma cells in culture. Preincubation of T-47D cells for 24 h with a series of androgens, estrogens, glucocorticoids, and progestins resulted in a significant enhancement of specific 125I-EGF binding in the presence of progestins only. Increased binding of EGF was associated with neither a change in cell number nor changes in the specific binding of concanavalin A, insulin, or calcitonin but was accompanied by an increase in lactogenic receptor expression. When assayed at 20 degrees C, increased EGF binding was due to an increase in receptor number (33,380 +/- 7,410 sites/cell in control cultures; 67,460 +/- 20,330 sites/cell in cultures treated with 1 nM medroxyprogesterone acetate for 24 h; P less than 0.05) without a change in receptor affinity. Two- to 3-fold increases in receptor number were also apparent when binding was measured at 4 degrees C, indicating that the effect was due to an increase in expression of receptor at the cell surface rather than progestin effects on internalization and degradation. These data illustrate that the expression of EGF receptor in some breast cancer cells is regulated in part by mechanisms mediated via the progesterone receptor, since the effect was confined to progestins, potency among a series of progestins was correlated with their affinities for progesterone receptor, and sensitivity among the three cell lines studied was related to the presence and concentration of cellular progesterone receptor.

Androgens↗
PubMed1986

Error in laboratory reference limits as shown in a collaborative quality-assurance program.

Laboratories participate in collaborative quality-assurance programs to maintain and improve the quality of their diagnostic assays, but little attention has been paid to diagnostic quality in these programs. We used a national quality-assurance program to assess the quality of laboratory reference intervals as exemplified by triiodothyronine, thyroxin, and thyrotropin immunoassays. The limits of the reference intervals used by laboratories bear virtually no relationship to laboratory bias, i.e., whether assays read "high" or "low." Further, correcting assay results from different laboratories for the reference limits used increases rather than decreases interlaboratory scatter. We conclude that the analytical quality of immunoassays now exceeds the quality of the reference limits supplied to clinicians to assist diagnosis, and that nationally or internationally defined reference limits would therefore provide more information at less cost than do individual laboratory reference limits.

Humans↗
PubMed1985

Regulation of growth hormone and epidermal growth factor receptors by progestins in breast cancer cells.

A 24 hr incubation of T-47D human breast cancer cells with R5020, a synthetic progestin, resulted in a 200-250% increase in the specific binding of human growth hormone (hGH) and epidermal growth factor (EGF) by these cells. This effect was specific for progestins in that similar responses were observed with progesterone, medroxyprogesterone acetate and ORG 2058 but no significant increases in hGH or EGF binding were observed in cells incubated with testosterone, estradiol or hydrocortisone. Increased binding was due to an increase in the concentration of receptors (hGH, control = 6,490 +/- 500, progestin treated = 13,180 +/- 3,270 sites/cell; EGF, control = 33,380 +/- 7,410, progestin treated = 67,460 +/- 20,330 sites/cell) while the affinity constants for the hormone-receptor interactions were unchanged by progestin treatment. The specific binding of insulin, calcitonin, transferrin and concanavalin A was unaffected by these treatments. It is concluded that expression of hGH and EGF receptors in this breast cancer cell line is regulated by progestins.

Breast Neoplasms↗
PubMed1985

The interaction of trh and dopaminergic mechanisms in the regulation of stimulated prolactin release in man.

The manner by which dopaminergic and TRH mechanisms interact to control PRL release is not known. Whilst dopamine receptor antagonists and TRH both release PRL, it is not known if the PRL released by these two mechanisms reflects similar aspects of physiological control, or if PRL responses to these mechanisms of release can be dissociated. We addressed this question by studying the PRL responses to maximal stimulatory dose of TRH and domperidone (a DA receptor antagonist), which were administered sequentially, simultaneously or separately on different occasions. Six normal volunteers undertook three sets of studies: (1) standard PRL stimulation tests to 400 micrograms TRH, 5 mg domperidone or simultaneous TRH/domperidone administration, (2) domperidone bolus-infusion study in which either 5 mg domperidone or 400 micrograms TRH was administered i.v. at 120 min during a 240 min infusion of domperidone (50 micrograms/min) which was preceded by a 5 mg i.v. bolus of the drug, and (3) TRH bolus-infusion study in which domperidone or TRH was administered i.v. at 120 min during a 240 min infusion of TRH (0.4 micrograms/min) which was preceded by a 400 micrograms i.v. bolus of the drug. In Study 1, simultaneous TRH/domperidone administration induced an incremental rise in PRL (5195 +/- 940 mIU/l) which was significantly greater (P less than 0.0005) than with either domperidone (3730 +/- 825 mIU/l) or TRH (1335 +/- 300 mIU/l) alone. In study 2, TRH administration at 120 min resulted in a significant rise (P less than 0.01) in PRL (delta PRL 960 +/- 232 mIU/l) whilst the second dose of domperidone did not, thus suggesting that the initial bolus and subsequent infusion had resulted in complete DA receptor blockade. In Study 3, domperidone administered at 120 min induced a marked rise in PRL (delta PRL 3609 +/- 963 mIU/l). In contrast, the corresponding TRH stimulus resulted in a small rise (delta PRL 142 +/- 32 mIU/l) suggesting that the PRL release induced by the initial bolus and subsequent infusion had been near maximal. Thus, TRH is able to induce significant PRL release in the presence of maximal DA receptor blockade, and domperidone, in the presence of maximal TRH stimulation, is also capable of inducing significant PRL release. These observations together with the ability of TRH/domperidone to induce a greater PRL response than either agent alone, suggest that each stimulus has a specific releasing action on a fraction of intracellular PRL which is not accessible to the other.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗