Victor S. Fang

Thyroid Dysfunction in Chronic Renal Failure: A STUDY OF THE PITUITARY-THYROID AXIS AND PERIPHERAL TURNOVER KINETICS OF THYROXINE AND TRIIODOTHYRONINE

Thyroid function was evaluated in 46 patients with end-stage kidney disease and 42 normal subjects. Patients were studied before and after the institution of maintenance hemodialysis (HD) and after renal transplantation (RT). Serum total triiodothyronine concentrations (TT(3), ng/100 ml, mean+/-SD) were 63+/-17 and 83+/-22 in the non-HD and HD groups, respectively. Values from normal subjects were 128+/-25 and from RT patients 134+/-20. The TT(3) was in the hypothyroid range (<78 ng/100 ml; 2 SD below normal mean) in 80% of non-HD and 43% of HD patients. Mean serum total thyroxine concentration (TT(4)), although within the normal range, was lower than the control value. T(4)-binding globulin capacity was also slightly lower but the difference was not statistically significant. Among patients whose TT(4) was 1 SD below the normal mean, the free T(4) index was equally depressed, suggesting that factors other than decreased binding capacity might be responsible for the low TT(4). In addition, there was a 37% incidence of goiter. Mean serum thyroid-stimulating hormone (TSH) was not elevated and the TSH response to thyrotropin-releasing hormone (TRH) was distinctly blunted, suggesting the possibility of pituitary dysfunction as well. In vivo (125)I-l-T(4) and (131)I-l-T(3) kinetics during 0.2 mg/day of l-T(4) replacement showed marked reduction in T(3) turnover rate in the uremic patients, both before and during HD; the values (mug T(3)/day, mean+/-SD) for the different groups were as follows: normal, 33.8+/-6.1; non-HD, 13.5+/-2.6; HD, 12.9+/-3.1; and RT, 30.3+/-7.1. The low T(3) turnover rate was due to impaired extrathyroidal conversion of T(4) to T(3). The mean percent+/-SD of metabolized T(4) converted to T(3) was 37.2+/-5.8 in normal subjects, 15.7+/-3.1 in non-HD, 12.8+/-1.7 in HD, and 34.0+/-14.7 in RT patients. In contrast, thyroidal T(3) secretion rate was not different between the control and the three patient groups. Thus, it appears that uremia affects thyroid function at several levels: (a) subnormal pituitary TSH response to TRH; (b) possible intrathyroidal abnormalities as suggested by slightly decreased TT(4) and high incidence of goiter; and (c) abnormal peripheral generation of T(3) from T(4). Restoration of renal function with RT resulted in normalization of all parameters of thyroid function with the exception of blunted or absent TSH response to TRH. The latter may be a direct consequence of glucocorticoid administration.

Gonadal dysfunction in uremic men: A study of the hypothalamo-pituitary-testicular axis before and after renal transplantation

Evaluation of testicular function in 13 hemodialyzed patients revealed the following: plasma testosterone (ng/100 ml) was low (less than 300 ng/100 ml) in 6 and low normal in 7 patients; sperm counts ranged from 0 to 8 million/ml and motility from 0 to 8 per cent; testicular tissue from 2 patients showed an abnormal histologic picture ranging from hypospermatogenesis to germinal cell aplasia. Follicle-stimulating hormone (FSH, ng/ml) was normal in eight (10 to 217 ng/ml), and persistently eveated in five patients (265 to 760 ng/ml). Of the latter five patients, two were azzoospermic, one had germinal cell aplasia on postmortem examination, one had virtually no viable sperms, and the other was never able to furnish ejaculate for examination. Luteinizing hormone (LH, mg/ml) was high (more than 210 ng/ml) in five and normal in eight patients. Six patients when given clomiphene showed the normal response of increased FSH and LH release. Four of the 13 patients, when restudied 6 to 12 months later and while still on dialysis, showed further deterioration of plasma testosterone and sperm counts. Four of the patients subsequently underwent successful renal transplantation. All showed improvement in sperm counts (20 to 40 million/ml, motility 40 to 90 per cent) and plasma testosterone (440 to 850 ng/100 ml). These data suggest that both germinal cell and leydig cell functions were impaired among uremic men. These dysfunctions were not correctable by hemodialysis, but were completely reversed by renal transplantation. The high FSH among patients with azzospermia indicates a responsive pituitary. The positive response to clomiphene suggests that storage as well as release of both hypothalamic and pituitary hormones were normal. Attempts to localize a single defect at the testis failed to explain the post-transplant surge of FSH which invariably proceded improvement in spermatogenesis. It is therefore postulated that a defect in that portion of the hypothalamus involved in the receipt and/or interpretation of message might be at fault in uremia.

Extrapyramidal side effects and increased serum prolactin following fluoxetine, a new antidepressant

Fluoxetine (Lilly 110140) is a potent, specific serotonin (5-HT) uptake blocker which is being tested in man for antidepressant activity. One of 9 depressed patients receiving this drug developed a dystonic reaction, parkinsonian rigidity, and increased serum prolactin levels, all signs of decreased dopaminergic activity. Homovanillic acid levels also decreased in the cerebrospinal fluid of this subject. We postulate that fluoxetine, via the increase in 5-HT activity resulting from 5-HT uptake blockade, inhibited both the nigro-striatal and tubero-infundibular dopaminergic neurons. These results provide additional evidence for a linkage between serotonergic and dopaminergic neurons in man.

Plasma acth and cortisol levels in depressed patients: Relation to dexamethasone suppression test

Blood samples collected from normal subjects and newly hospitalized depressed patients at 8 AM on the day before and at 8 AM and 4 PM the day after receiving dexamethasone, 1 mg orally at 11 PM, were analyzed for ACTH and cortisol. The mean plasma ACTH values of these two groups were not significantly different at any of the times, while the cortisol levels of the depressed patients were significantly higher than those of the normal subjects at 8 AM pre-dexamethasone (P<0.001). There was no correlation between plasma ACTH and cortisol values in either group. The cortisol responses to dexamethasone in depressed patients revealed two subgroups. In one subgroup, the cortisol was suppressed as much as in normal subjects, but in the other, cortisol levels were not suppressed. The post-dexamethasone ACTH rebounded at 4 PM in the latter subgroup to higher values than in the subgroup with suppressed cortisol levels and in the normal subjects. After dexamethasone, the ACTH values were negatively correlated with plasma cortisol only in the normal subjects (P<0.01), not in the depressed patients. These results indicate that ACTH levels do not account for the elevated cortisol and the failure of dexamethasone to suppress cortisol levels in some depressed patients.

Effect of quipazine on rat plasma prolactin levels.

Abstract Quipazine (2-(1-piperazinyl) quinoline maleate), a serotonin agonist which also has other effects on serotonin metabolism, in doses from 2.5 – 20 mg/kg, i.p., was found to markedly increase plasma prolactin levels in male rats. This increase was blocked by the serotonin antagonists methysergide and brom-lysergic acid diethylamide and potentiated by para-chlorophenylalanine, an inhibitor of serotonin synthesis. These findings suggest that the increase in plasma prolactin levels is due to the serotonin agonist properties of quipazine. Apomorphine and 2-Br-α-ergocryptine pretreatment blocked the effect on plasma prolactin of quipazine, while apomorphine given 15 min after quipazine brought about a rapid decline in the elevated plasma prolactin levels produced by quipazine.

LH bioactivity increases more than immunoreactivity during puberty

We have measured bioactive LH in the plasma of 60 normal boys and 45 normal girls throughout puberty because the rise in immunoreactive LH has seemed too small to account for the profound changes in sexual maturation during adolescence. Bioactive LH was determined using an in vitro bioassay (rat interstitial cell testosterone production); I-LH was measured by radioimmunoassay using the same LH standard, LER 907. Bioactive LH was measurable in all 270 plasma samples; I-LH in 218. In both boys and girls, B-LH rose more than I-LH when compared to chronological age, bone age, and pubertal stage. In boys, B-LH increased 8.2-fold (P < 0.001) from prepuberty to late puberty, whereas I-LH rose 3.0-fold (P < 0.001). Similarly, in girls B-LH increased 23.1-fold (P < 0.001) while I-LH increased 4.9-fold (P < 0.001). Between pubertal stages there was less overlap of individual values of B-LH, in comparison to those of I-LH. We conclude that B-LH increases more than I-LH during normal puberty and is a more discriminating measure of maturation. One implication of these findings is that a qualitative change in gonadotropin secretion may occur during puberty.

Comparison of the effects of substituted benzamides and standard neuroleptics on the binding of 3H-spiroperidol in the rat pituitary and striatum with in vivo effects on rat prolactin secretion.

Abstract The abilities of sulpiride, metoclopramide, clozapine, loxapine, chlorpromazine, thioridazine, fluphenazine, haloperidol, (+)-butaclamol and RMI 81,582 to displace 3H-spiroperidol from rat pituitary and striatal membranes in vitro were compared to their abilities to stimulate rat prolactin secretion in vivo. There was a significant correlation between the abilities of clozapine, chlorpromazine, thioridazine, fluphenazine, RMI 81,582, haloperidol and (+)-butaclamol to bind to pituitary and striatal spiroperidol binding sites and to stimulate rat prolactin secretion. Loxapine was somewhat more potent and sulpiride and metoclopramide were markedly more potent in their abilities to stimulate prolactin secretion than would be predicted on the basis of their abilities to bind to pituitary dopamine receptors as measured by antagonism of 3H-spiroperidol binding. The abilities of metoclopramide and sulpiride to increase prolactin secretion and to produce anti-psychotic and extrapyramidal effects may be mediated by action at dopamine receptors which differ from those at which classical neuroleptics act, and they may also be mediated by non-dopaminergic mechanisms. Potency as inhibitors of 3H-neuroleptic binding in the rat pituitary or striatum appears to have heretofore unappreciated limitations to predict physiological functions such as prolactin stimulation and anti-psychotic activity.

Clozapine increases rat serum prolactin levels

Abstract Clozapine differs from other anti-psychotic drugs in that is produces little or no extrapyramidal side effects. The effects of clozapine on rat brain dopamine differ markedly from those of the neuroleptic drugs. The neuroleptics increase rat serum prolactin levels which has been attributed to their dopamine receptor blocking properties. We found that clozapine markedly increased serum prolactin levels in male rats when injected intraperitoneally in doses of 5, 10, 50 and 100 mg/kg. Serum prolactin levels after 5 mg/kg clozapine were significantly less than in rats given 10, 50 and 100 mg/kg which did not significantly differ from each other. Serum prolactin after 10 mg/kg clozapine was significantly greater than after chlorpromazine, 5 mg/kg and haloperidol, 0.5 mg/kg. The increases in serum prolactin are attributed to clozapines ability to produce dopamine blockade or to inhibit nerve impulse-dopamine release, or both. The capacity of clozapine to affect brain serotonin and norepinephrine metabolism and its strong anti-cholinergic properties are probably not involved in its ability to increase serum prolactin.

Overexpression of vascular endothelin-1 and endothelin: A receptors in a fructose-induced hypertensive rat model

Objective To examine the temporal relationship between hyperinsulinemia and hypertension in the fructosehypertensive rat model and to study the function of endothelin-1 (ET-1) in fructose-induced hypertension. Design Since ET-1 induces insulin resistance in conscious rats, we tested the hypothesis that both hyperinsulinemia and hypertension developed in the fructose-hypertensive rat model might be the sequelae of an elevated tissue content of ET-1 and ETA receptors. Materials and methods Systolic hypertension was induced within 3 weeks in male Sprague–Dawley rats fed on a fructose-rich diet. After continual monitoring of blood pressure and plasma insulin concentrations, the animals were killed at the end of experiment to determine plasma levels of ET-1, the contractile response of aortic rings to ET-1, and ET-1 and ETA receptor gene expressions. In a separate experiment, BQ-610 was administered to lower the effect of ET-1 in rats with fructose-induced hypertension. Results Compared with control rats given normal chow, the fructose-fed rats developed systolic hypertension after 3 weeks of the diet (127 ± 3.7 versus 110 ± 5.5 mmHg, P < 0.01) and hyperinsulinemia both before (107.1 ± 32.5 versus 48.5 ± 14.3 pmol/l, P < 0.005) and after (96.6 ± 63.7 versus 50.4 ± 5.6 pmol/l, P < 0.05) they became hypertensive. Although plasma ET-1 levels did not differ between the rat groups, aortic ring contraction–concentration curves, indicating vessel contractility in response to ET-1, were significantly greater in these rats than in controls (F1,72 = 12.34, P < 0.00077). Messenger RNA extracted from the tail arteries and blotted with both ET-1 and ETA probes showed that fructose-fed rats had greater ET-1 and ETA-receptor gene expression than control rats. Concomitant administration of BQ-610 to rats fed on a fructose diet significantly reduced the hypertension. Conclusions These findings suggest that elevated vascular expression of ET-1 and ETA receptor genes may mediate the development of hypertension and hyperinsulinemia in rats fed a fructose-rich diet.

Lack of effect of tricyclic antidepressants on serum prolactin levels

A previous report indicated that the tricyclic antidepressants imipramine and amitriptyline markedly increased plasma prolactin levels in man. We found no increases after acute or chronic treatment with either drug in usual clinical doses. The results indicate that blockade of serotonin reuptake does not affect basal prolactin levels in man.