Victoria Sy Lim

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.

Ovarian function in chronic renal failure: evidence suggesting hypothalamic anovulation.

The pathogenesis of ovarian dysfunction in uremia was evaluated in 24 patients by measurements of plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone, prolactin, estradiol, and progesterone basally and after clomiphene, ethinyl estradiol, and bromocriptine. In the 17 premenopausal women, levels of plasma estradiol, progesterone, and FSH were comparable to those found in normal women during the follicular phase of the ovarian cycle; plasma luteinizing hormone was slightly elevated. In most patients, there was an absence of cyclicity. After clomiphene, plasma levels of luteinizing hormone, FSH, and estradiol rose; after ethinyl estradiol, plasma luteinizing hormone levels failed to increase. In seven postmenopausal patients, plasma estradiol was undetectable and gonadotropin levels were markedly elevated. Although plasma prolactin was generally elevated, suppression of prolactin with bromocriptine resulted in resumption of ovulation in only one patient; the other 2 remained amenorrheic. In uremic women, the continued secretion of estrogen, the rise of plasma levels of luteinizing hormone, FSH, and estradiol after clomiphene, and the elevated gonadotropin levels during menopause suggest that the negative estradiol feedback, the tonic gonadotropin secretion, and the pituitary ovarian axis were normal. The positive estradiol feedback associated with cyclic release of luteinizing hormone, however, was impaired as indicated by the prevalence of acyclicity and the failure of luteinizing hormone levels, to rise after ethinyl estradiol.

Thyroid Function in a Uremic Rat Model: EVIDENCE SUGGESTING TISSUE HYPOTHYROIDISM

The main objective of this study was to determine whether the principal abnormality of thyroid function observed in patients with chronic renal failure, low serum triiodothyronine (T(3)) concentration, causes hypothyroidism at the tissue level. A partially nephrectomized (Nx) uremic rat model was developed and the following parameters of thyroid function were assessed: serum total thyroxine (TT(4)), total T(3) (TT(3)), and thyrotropin and liver T(3) content, and activity of two thyroid hormone-dependent enzymes, mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and cytosol malate dehydrogenase (MDH). The results were compared to those of intact control (C), thyroidectomized (Tx), and nephrectomized-thyroidectomized (NxTx) littermates.Results expressed as mean+/-SEM showed that Nx rats had a fivefold increase in blood urea nitrogen, (112+/-20 mg/dl in Nx, and 22+/-1 mg/dl in C) and manifested all the changes of of thyroid function observed in uremic men, including a low serum TT(3) level (30+/-7 ng/dl in Nx and 50+/-6 ng/dl in C). In the liver, T(3) was significantly reduced (18+/-2 ng/total liver in Nx and 35+/-3 ng/total liver in C) as well as the activities of alphaGPD (8.8+/-1.0 and 16.1+/-1.5 DeltaOD/min per total liver in Nx and C, respectively) and MDH (6.3+/-1.6 and 12.6+/-2.2 U/total liver in Nx and C, respectively). The reduction in liver enzyme activities correlated significantly with the decrease in T(3) content. The changes in Tx rats were as expected, showing a profound reduction in serum hormone levels, liver T(3) content, and liver enzyme activities. Serum thyrotropin was markedly elevated to 2,390+/-212 ng/ml as compared to 703+/-61 in C and 441+/-87 ng/ml in Nx rats. The NxTx rats showed the combined effects of nephrectomy and thyroidectomy; blood urea nitrogen was elevated to 203, and serum levels of TT(4), TT(3), and thyrotropin were 0.4, <10, and 2,525, respectively. Total liver T(3) and alphaGPD and MDH were strikingly low; the corresponding values were 3.5, 2.4, and 2.5.l-triiodothyronine replacement (0.4 mug/100 g body wt/d) for 4 wk in the Nx rats resulted in significant increases in liver enzyme activities, alphaGPD and MDH rose by 70 and 60% over their respective basal values without alteration in the severity of azotemia. From these data, we conclude that the reduction of liver T(3) content in the uremic rats, accompanied by a decrease in alphaGPD and MDH activity, indicates the presence of hypothyroidism at the tissue level. Restoration of enzyme activities toward normal levels after T(3) administration provided further supporting evidence that the diminution in liver enzyme activity was causally related to tissue T(3) deficiency.

Endocrine abnormalities associated with chronic renal failure.

It is evident that chronic renal failure has far-reaching metabolic consequences because endocrine aberrations are common. Uremia may alter endocrine function through its effect on the hypothalamopituitary axis, the individual end organs, and the peripheral metabolism of various hormones. Deficiency of some hormones and excess of others coexist in patients with renal failure. Since the physiologic effects of many of these abnormalities are still not well defined, no treatment is necessary with the exception of true deficiency states such as testosterone deficiency. In the latter instance, exogenous hormonal supplementation is recommended.