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Effect of Glucocorticoids on Thyroid Function of Cattle1
E F F E C T OF G L U C O C O I ~ T I C O I D S ON T H Y R O I D F U N C T I O N OF C A T T L E ' 1 C. W. TURNER, G. W. P I P E S , A~D B. N. PREMACI-IANDRA~ Department of Dairy Husbandry, University of Missouri, Columbia SUMMARY
The influence of two glucocorticoids upon the thyroidal-I1~1 release rate of cattle is reported. After the normal release rate of each animal was determined during a five-day period (recycling of 118~blocked by a goitrogen), seven cows were injected with hydrocortisone at the rate of 75 rag/l(}0 lb. body weight per day for six days. Of these cows, five showed varying degrees of depression of thyroidal-Ilu release, whereas two showed an increased release rate. Metieorton, a synthetic glucocorticoid, injected in eight heifers at the rate of 40 rag/100 lb. body weight per day, showed a variable increased release rate in six animals, whereas two showed a slight depression. These data suggest that hydrocortisone at the level administered tends to depress thyrotropin and thyroxine secretion, whereas meticorten tends to stimulate thyroid function. The causes of the individual differences in response in cattle to these glueocortieoids is not known, but may be related to individual secretion rates of other hormones. It is suggested that cattle with low thyroxine secretion rate, which is further depressed by increased secretion of hydroeortisone associated with parturition, would show low PBI and high 17-hydroxy-corticosteroid values characteristic of cows with ketosis.
The relation of the p i t u i t a r y adreno-corticotropic hormone ( A C T t t ) to the regulation of secretion of the glucocorticoids has been considered generally to be related to the phenomenon of stress and to that extent unfavorably influences both growth and milk secretion. However, it should be recognized that the hormones of the adrenal cortex are essential for life, for upon adrenalectomy survival is of short duration without replacement therapy. Thus, the secretion of the hormones of the adrenal cortex are of fundamental importance in normal animals. Further, the adrenal cortical hormones play an important role in the lactation process. I n hypophysectomized animals, lactation can be initiated (7, 13) or maintained (5) only by the simultaneous administration of lactogen and A C T H or the adrenal cortical hormones. The adrenal glucocorticoids received their name from their capacity to cause the deamination of amino acids. Following the removal of the NH2 group, the carbohydrate residue of m a n y amino acids can be converted to glucose in the liver. As a result, the blood glucose can be increased and, thus, glucocorticoids are useful in the treatment of ketosis in cattle (23), or the excess glucose can be stored in the body as glycogen. The deamination of amino acids, however, decreases their availability for somatic growth or the synthesis of milk proteins and thus depresses growth and milk secretion. Received for publication June 4, 1960. 1Contribution from the Missouri Agricultural Experiment Station. Journal Series No. 2168. Approved by the Director. ~Aided in part by a grant from the U.S. Atomic Energy Commission [Contract No. AT (11-1)-301]. 163
16~
C. W. TUIgNER, G. W. PIPES, AND B. N. PREMACttANDRA
In our study of factors influencing the thyroxine secretion rate of dairy cattle, it has been shown that estrogen at a level of .3 mg/day/100 lb. body weight stimulated a significant increase in thyroidal-1131 release rate (15). In a further study, estrogen was shown to increase thyroxine secretion rate (16). These data suggest that the increased secretion of estrogen in late pregnancy (6) not only stimulates increased secretion of laetogenic hormone, but thyrotropie hormone and thyroxine as well. It has been suggested by some that parturition is a stressful condition and as such it would be expected that increased release of ACTH and increased secretion of glueoeortieoids would be stimulated (21). Brush (4) reported a rise in plasma glueoeortieoicls in some cows a few days before calving, in one case in association with a difficult parturition, and in others for several days after calving. In spite of the possible increase in glucocorticoids postpartum, ketosis occurs most frequently during the first 3 wk. following calving. Robertson et al. (19, 20) noted that plasma 17-hydroxyeortieosteroid values of cows with ketosis were significantly higher than for normal cows, whereas the P B I values were lower for cows with ketosis than for normal cows. These observations are of significance in the iight of the observation by Reece (18) that thyroprotein was of value in the treatment of ketosis. The beneficial effect of thyroxine in ketosis may be due to the increase in blood sugar observed by Graham et al. (8) and Smith and Dastur (24) upon the administration of thyroxine. These data arc of interest and significance in relation to the generM problem of the interrelation of the adrenal cortex and its hormones and the thyroid gland and thyroxine secretion. Money (11) and Ingbar and Freinkel (10) have reviewed the literature in this field. During recent years, with t ~at available, three indices of thyroid gland function have been suggested; namely, I ~ uptake, thyroidal-P al release rate (with and without recycling depressed with a goitrogen), and thyroxine secretion rate determination. The literature concerning the influence of either ACTH or the glucoeorticoids in respect to thyroid function is very confusing. The majority of the studies indicate that these compounds depress or have no influence on I ~31 uptake. In regard to thyroidal-P 3~ release rate, studies indicating a decreased release rate have been reported by Myant (12) in the rabbit, Brown-Grant (3) in the rat, Sherer and Siefring (22) in man, no effect by Perry (14) and Albert et al. (1) in the rat, and an increase by Beck (2). Due to the lack of uniformity in the literature in regard to the role of glueoeorticoids in thyroid function, it seemed desirable to study their influence in dairy cattle. It was hoped that the observations wouid contribute to an understanding of the influence of the stress of parturition upon thyroid function at this time. EXPEI~IMlgNTAL METHODS
Nonlactating, mature, and immature dairy animals of several breeds were given 300 ~c. of carrier-free NaI ~3~ intravenously. After maximum uptake of
THYROID
FUNCTION
IN CATTLE
165
I TM by the thyroid gland (three days) 24 g/day thiouracil was given by gelatin capsule to prevent recycling, and daily measurements of thyroidal-I TM were made (17) for a five-day control period. Hydrocortisone (cortisol-hydrocortone) at 75 rag/100 lb. body Weight or meticorten at 40 rag/100 lb.. was administered subcutaneously during a six-day test period. Potassium chloride was administered at the rate of 14 g. per 1,000 lb. body weight to prevent excess potassium loss due to the glucocorticoids. Release rates of thyroidal-I TM were calculated according to the method previously described (15), with the term k"4 being employed for release rate constant per hour during thiouracil administration. For comparison, the daily percentage release rate is presented. These values indicate the percentage of the total I TM present in the thyroid glands which is released each 24 hr. Comparison of the release during the control period, with the release during the administration of the glucocorticoids, indicates the effect of the hormone on the TSH secretion and, indirectly, on the secretion of thyroxine. RESULTS
The two chief glucoeorticoids secreted by the bovine adrenal gland are hydrocortisone and corticosterone in a ratio of 1:1(9). Hydrocortisone should, therefore, be representative of the natural hormone secreted by cattle when stimulated by ACTH. The release rate of thyroidal-ITM from the gland, when the recycling of I TM is prevented by a goitrogen, follows an exponential decline (a straight line when plotted on semilog paper). The release rate is believed to be dependent upon the rate of discharge of thyrotropic hormone (TSH). If hydrocortisone influences the rate of secretion or discharge of TSH, then the release of thyroidal-I TM will be increased or decreased accordingly. It will be noted that hydroeortisone, at the level administered, tended to depress thyroidal-P al release to varying degrees in five of the seven cows (Table 1). In two other cows, there was a slight increase ia one and a more marked increase in the second. These data indicate considerable variability in individual response in dairy cattle to hydrocortisone, although in the majority of the animals the tendency was to inhibit thyroidal-ITM release, which indicates depression of TSH secretion or release and, in turn, depression of thyroxine secretion. Meticorten (Prednisone). This is a synthetic cortisone-like compound produced by dehydrogenation at Positions One and Two of the cortisone nucleus (Figure 1). It has gluconeogenic action comparable to hydrocortisone but is claimed to be more potent. It has been suggested for use in treatment of ketosis in dairy cattle. In contrast to the effect of hydrocortisone, meticorten stimulated a variable increased release of thyroidal-I TM in six of eight experimental animals. Two animals showed a slightly depressed release rate (Table 2). These observations indicate that meticorten tends to increase thyroxine secretion in most, but not all, animals. Paired " t " tests of data (Tables 1 and 2) indicate with both compounds a lack of change of statistical significance. However, it is believed that the obser-
TABLE 1 Effect of hydrocortisone on thyroida]-I TM release rate Thyroidal-I ~ release rate--recycling blocked with thiouracil
Body Animal No. 38
Breed
weight (lb.)
Guernsey
1,300
601
Ho]ste:in
3625
Guernsey
Month TSR determined
TSR ~(rag/day/100 lb.)
December
0.4
760
February
0.5
1,] 25
February
0.4
348
Jersey
9~7
February
0.3
160
Jersey
1,197
February
0.3
Guernsey
1,200
February
0.6
456
February
0,5
3596 H,_,
Holstein
Hydroeortisone (administered in April) Control period Period k'4 k",i Difference ~*:* 0.006]4 (14.7¢o) ~ 0.00417 (10.0%) 0.00760 (18.2%) 0.00853 (20.4%) 0.00624 (14.9%) 0.00210 (5.04%) 0.00450 (10,8%)
0.00419 (10.0%) 0.00261 (6.3%) 0.00610 (14.6%) 0.00732 (]7.5%) 0.00580 (13.9%) 0.00330 (7.4%) 0.00770 (18.5%)
--0.00195 (4.7%) --0.00156 (3.7%) --0.00150 (3.6%) --0.00121 (2.9%) --0.00044 (1.0%) +0.00100 (2.4%) +0.00320 (7.7%)
* Each value in parentheses indicates the percentage of I TM present in the thyroid gland which is released each 24 hr. ----k'% × 24 × 100. *~ TSR = thyroxine secretion rate. **~ Paired " t ' ' test indicates a lack of change of statistical significance, l~hysiological effect of hydrocortisone is believed to be significant ia each animal.
TABLE 2 Effect of metieorten on thyroidal-I ~s~ release rate ThyroidM-IT M release rate--recycling blocked with thiouracil Animal No.
Breed
264
Body weight (lb.)
~[onth TS]~ determined
Meticorten (administered in May) TSR** Control period Period (rag/day/100 lb.) k"4 k"4 Difference***
650
February
0.5
601
Holstein
760
February
0.5
H1
Guernsey
400
February
0.4
38
Guernsey
1,300
December
0.4
41
Guernsey
1,250
November
0.5
260
Holstein
650
February
0.5
263
Holstein
780
February
0.5
265
Holstein
850
February
0.4
0.00655 (15.7%) ~ 0.00699 (16.8%) 0.00660 (15.8%) 0.00240 (5.8%) 0.00180 (4.3%) 0.00263 (6.3%) 0.00400 (9.6%) 0.00435 (10.4%)
0.01174 (28.2%) 0.01147 (27.5%) 0.00950 (22.8%) 0.00380 (9.1%) 0.00310 (7.4%) 0.00288 (6.9~,~) 0.00358 (8.6%) 0.00331 (7.9%)
+0.00519 (12.5%) +0.00448 (10.7%) +0.00290 (7.0%) +0.00140 (3.3%) +0.00130 (3.1%) +0.00025 (0.6%) --0.00042 (1.0%) --0.00104 (2.5%)
* Each value in parentheses indicates the percentage of 11'~1present in the thyroid gland which is released each 24 hr. ~ k"4 X 24 X 100. ~* TSR = thyroxine secretion rate. ~ Paired " t " test indicates a lack of change of statistical significance. Physiological effect of meticorten is believed to be of significance in each animal.
168
c. w, TURNEI~,
G, W . PIPES,
AND
B. N. PI~E~IACIIANDI~A
I H20H
H20H
IC=O H O ~ ~
Z~4-PREGNENE-11~t~-17#L , 21-TRIOL-3, 20- DIONE 17-HYDROXYCORTICOSTERONE
(HYDROCORTISONE)
0 . ~ ~
OH
OH
A1,4_p REGNADIENE- 17~.~ 21- DIOL- 3, 11, 20-TRIONE (METICORTEN)
~IG. 1. Structural formula of hydroeortisone ~md synthetic glueocorticoid, metieorte~t compared.
rations are physiologically significant ill spite of the variation of response observed. It s suggested that individual animal differences in the interaction o6 the various hormones play a role in the observed results. Thus, it is possible that the glucocorticoids syncrgize with other hormones in producino' effects upon T S H secretion. I f such hormones are secreted in optimal amounts the g'lucocorticoid response might be increased, whereas if other hormones are secreted at low levels the response might be minimal or reversed. This possibility will be explored. DISCUSSION
The relation of the adrenal glucocortieoids to the functional activity of the thyroid gland is of great interest. Is there a tendency for these hormones to stimulate or depress thyroxine secretion? Under situations of stress, where it is expected that increased secretion of the glucocorticoids would be observed, the stressful condition itself might influence thyroxine secretion as well. In the present experiment, the direct administration of the glucocorticoid should indicate its uneolnplicatcd effect on thyroid function. These data show that hydrocortisone tended to depress thyroidal-1131 release and T S t t and thyroxine secretion in most of the animals. The cause of the variability in response of the individual animals is not evident. The normal thyroxine secretion rate of each of these animMs is presented (Table 1). It will be noted that the two animals which showed increased thyroidal-P al release were relatively higher seeretors of thyroxine, but one animal in the other group secreted thyroxine at the same level. Our data suggest that at the time of parturition thyroxine secretion tends to be increased as a result of estrogen. To the extent that increased secretion of glueocortieoids is stimulated by stress or other related conditions, an opposing depression of thyroxine secretion might occur in many animals. Thus, in cows
THYI%OID FUNCTION IN CATTLE
169
with a low normal thyroxine secretion, the f u r t h e r depression of thyroxine secretion by hydroeortisone associated with parturition might be a factor in the etiology of ketosis at this time. I n other words, physiological ketosis might be due, primarily, to a low normal thyroxine secretion rate, f u r t h e r depressed by increased secretion of the adrenal glucocorticoids. I f this is true, then ketosis would be favorably influenced by thyroxine or by the feeding of thyroprotein. This would explain the favorable report of Reeee (18). Since ketotie cows show a low blood sugar level and Graham et al. (8) and Smith and Dastur (24) showed that thyroxine increased the blood sugar level of cows, the low thyroxine secretion rate could have a depressing effect on blood sugar. I f this is true, the restoration of normal blood thyroxine levels would have a favorable effect on blood sugar. This would be augmented by the effect of the glucocortieoids in their capacity to provide blood glucose from deaminated amino acids. The observation that meticorten tends to stimulate an increased release of thyroidal-I lsl (and thyroxine secretion) in six of eight cows is quite surprising in relation to our observations on hydrocortisone. Both compounds have gluconeogenic properties and react similarly in respect to other biological functions. I t is possible, of course, since both compounds show variability in response from depression to stimulation of thyroidal-1131 release, that no true difference exists between the compounds and that the variation observed is due to as yet unrecognized differences in the endocrine balance of the animals, causing in some a stimulation and in others a depression of thyroid function. The present data, however, indicate that meticorten tends to stimulate thyroxine secretion and, if so, would have a more favorable action in the treatment of ketosis, to the extent that low thyroxine secretion is related to the etiology of ketosis. REFERENCES (1) ALBEI%T,A., TENI~y, A., ~kNDFORD, E. The Effect of Cortisone and Corticotrophin on the
Biological Decay of Thyroidal Radloiodine. Endocrinology, 50: 324. 1952. (2) BECK, R. N. The Effect of Cortisone and Corticotropin on the Release and Peripheral
Metabolism of Thyroid Hormone. Endocrinology, 62: 9. 1958. (3) B~OwN-G~ANT,K. Inhibition of the Release of Thyroidal Radioiodine in the Rat by Cortisone. Endocrinology, 56: 607. 1955. (4) B~ust{, M. G. Adrenocortieal Activity in Bovine Pregnancy and Parturition. J. Endocrino]., 17: 381. 1958. (5) COWlE, A. T. The Maintenance of Lactation in the Rat after Hypophysectom$. J. Endocrlnol., 16: 135. 1957. (6) EL-A
Missouri Agr. Exp. Sta., Research Bull. 641. 1957. (7) GOlgEz, E. T., AND TUIZNER, C. W. Non-effect of Estrogenic Hormones on Mammary Gland of tIypophyseetomized Guinea Pig. Proc. Soc. Exptl. Biol. Me(]., 34: 320. 1936.
(8) Gm~A~{, W. R., JR., TURNER, C. W., AND GO~EZ, E. T. A Method for Obtaining Arterial Blood from the Goat. Missouri Agr. Exp. Sta., Research Bull. 260. 1937. (9) HE(]I-ITER,0., ZAFFA~0NI, A., JACOBSEN, R. P., LEVY, H., JEANLOZ, R. W., SCtIENKEF~, V., AND ]]INCUS, G. The Nature and the Biogenesis of the Adrenal Secretory Product.
Rec. Prog. I=[ormoneResearch, VI: 215. 1951.
170
C. W. TURNEI~, G. W. PIPES, AND B. N. PREMACHANDIgA
(10) I]~GBAR, S. R., AND FREINKEL, N. ACTH, Cortisone and the Metabolism of Iodine. Metabolism, 5" 652. 1956. (11) MONEY, W. L. The Interrelation of the Thyroid and the Adrenals. Brookhaven Symposia in Biology No. 7, The Thyroid, p. 137. 1955. (12) MYXNT, N. B. Comparison of the Effects of Thiouraeil, Thyroxine and Cortisone on the Thyroid Function of Rabbits. J. Physiol., 120: 288. 1953. (13) N~SON, W. O., ~ D GA~r*ST, R. Initiation of Lactation in the Hypophysectomized Guinea Pig. Proe. Soc. Exptl. Biol. Med., 34: 671. 1936. (14) PERaY, W. F. The Action of Cortisone and ACTH on Thyroid Function. Endocrinology, 49: 284. 1951. (15) PIPES, G. W., PR~AC~A~DRA, B. N., A~'*) T~RNER, C. W. Effect of Estrogen and Progesterone on Thyroid Funetion of Cattle. d. Dairy Sci., 41: 1387. 1958. (16) PIPES, G. W., PRE~*AC]~AN~)EA, B. N., AND TURNER, C. W. The Effect of Estradiol on the Thyroid Secretion Rate of Dairy Cattle. d. Dairy Sci., 43 : 862. 1960. (17) PIPES, G. W., ~ D TUIgNZR, C. W. The Effect of Thyroxine on Thyroid Function. Missouri Agr. Exp. Sta., ]~esea~eh Bull. 617. 1956. (18) REEOE, R. P. The Influence of Thyroprotein in the Ration of Dairy Cattle. d. Dairy Sci., 30: 574. 1947. (19) R0~ERTSON, W. G., LENtO*C, H. D., JR., BArnEY, W. W., A~qD MXXIqER, 3. P. Interrelationship Among Plasma 17-ttydroxyeorticosteroid Levels, Plasma Protein-Bound Iodine Levels, and Ketosis. 3. Dairy Sci., 40: 732. 1957. (20) I~OBEI~TSOlff,W° G., LENNON, H. D., Jig., AND MIXNEI~, J. P. Interrelation Among Plasma 17-Hydroxycorticoid Levels, Plasma Protein Bound Iodine Levels and Ketosis in Dairy Cattle. d. Dairy Sci., 38: 611. 1955. (21) SOHULTZg, A. B. Eosinophil Count and Glucose Level in Blood of Dairy Cattle During the F i r s t Pregnancy. J. Dairy Sci., 38: 611. 1955. (22) S*IERER, M. G., AN*) SIEF~NG, B. N. Effect of Prednisone and Prednisolone on Thyroid Function with Special Reference to Thyroxine-Bindlng Protein in Nephrosis. J. Clin. Endoerinol. Metabolism, 16: 643. 1956. (23) S~Aw, J. C. Ketosis in Dairy Cattle. A Review. 3. Dairy Sci., 39: 402. 1956. (24) S ~ I ~ , d. A. B., AND DAS~E, N. N. The Secretion of Milk Fat. I I I . The Effect of Thyroxine Administration on the Blood Lipids and the Nature of the Milk Fat. Biochem. d., 34: 1093. 1940.
The influence of two glucocorticoids upon the thyroidal-I1~1 release rate of cattle is reported. After the normal release rate of each animal was determined during a five-day period (recycling of 118~blocked by a goitrogen), seven cows were injected with hydrocortisone at the rate of 75 rag/l(}0 lb. body weight per day for six days. Of these cows, five showed varying degrees of depression of thyroidal-Ilu release, whereas two showed an increased release rate. Metieorton, a synthetic glucocorticoid, injected in eight heifers at the rate of 40 rag/100 lb. body weight per day, showed a variable increased release rate in six animals, whereas two showed a slight depression. These data suggest that hydrocortisone at the level administered tends to depress thyrotropin and thyroxine secretion, whereas meticorten tends to stimulate thyroid function. The causes of the individual differences in response in cattle to these glueocortieoids is not known, but may be related to individual secretion rates of other hormones. It is suggested that cattle with low thyroxine secretion rate, which is further depressed by increased secretion of hydroeortisone associated with parturition, would show low PBI and high 17-hydroxy-corticosteroid values characteristic of cows with ketosis.
The relation of the p i t u i t a r y adreno-corticotropic hormone ( A C T t t ) to the regulation of secretion of the glucocorticoids has been considered generally to be related to the phenomenon of stress and to that extent unfavorably influences both growth and milk secretion. However, it should be recognized that the hormones of the adrenal cortex are essential for life, for upon adrenalectomy survival is of short duration without replacement therapy. Thus, the secretion of the hormones of the adrenal cortex are of fundamental importance in normal animals. Further, the adrenal cortical hormones play an important role in the lactation process. I n hypophysectomized animals, lactation can be initiated (7, 13) or maintained (5) only by the simultaneous administration of lactogen and A C T H or the adrenal cortical hormones. The adrenal glucocorticoids received their name from their capacity to cause the deamination of amino acids. Following the removal of the NH2 group, the carbohydrate residue of m a n y amino acids can be converted to glucose in the liver. As a result, the blood glucose can be increased and, thus, glucocorticoids are useful in the treatment of ketosis in cattle (23), or the excess glucose can be stored in the body as glycogen. The deamination of amino acids, however, decreases their availability for somatic growth or the synthesis of milk proteins and thus depresses growth and milk secretion. Received for publication June 4, 1960. 1Contribution from the Missouri Agricultural Experiment Station. Journal Series No. 2168. Approved by the Director. ~Aided in part by a grant from the U.S. Atomic Energy Commission [Contract No. AT (11-1)-301]. 163
16~
C. W. TUIgNER, G. W. PIPES, AND B. N. PREMACttANDRA
In our study of factors influencing the thyroxine secretion rate of dairy cattle, it has been shown that estrogen at a level of .3 mg/day/100 lb. body weight stimulated a significant increase in thyroidal-1131 release rate (15). In a further study, estrogen was shown to increase thyroxine secretion rate (16). These data suggest that the increased secretion of estrogen in late pregnancy (6) not only stimulates increased secretion of laetogenic hormone, but thyrotropie hormone and thyroxine as well. It has been suggested by some that parturition is a stressful condition and as such it would be expected that increased release of ACTH and increased secretion of glueoeortieoids would be stimulated (21). Brush (4) reported a rise in plasma glueoeortieoicls in some cows a few days before calving, in one case in association with a difficult parturition, and in others for several days after calving. In spite of the possible increase in glucocorticoids postpartum, ketosis occurs most frequently during the first 3 wk. following calving. Robertson et al. (19, 20) noted that plasma 17-hydroxyeortieosteroid values of cows with ketosis were significantly higher than for normal cows, whereas the P B I values were lower for cows with ketosis than for normal cows. These observations are of significance in the iight of the observation by Reece (18) that thyroprotein was of value in the treatment of ketosis. The beneficial effect of thyroxine in ketosis may be due to the increase in blood sugar observed by Graham et al. (8) and Smith and Dastur (24) upon the administration of thyroxine. These data arc of interest and significance in relation to the generM problem of the interrelation of the adrenal cortex and its hormones and the thyroid gland and thyroxine secretion. Money (11) and Ingbar and Freinkel (10) have reviewed the literature in this field. During recent years, with t ~at available, three indices of thyroid gland function have been suggested; namely, I ~ uptake, thyroidal-P al release rate (with and without recycling depressed with a goitrogen), and thyroxine secretion rate determination. The literature concerning the influence of either ACTH or the glucoeorticoids in respect to thyroid function is very confusing. The majority of the studies indicate that these compounds depress or have no influence on I ~31 uptake. In regard to thyroidal-P 3~ release rate, studies indicating a decreased release rate have been reported by Myant (12) in the rabbit, Brown-Grant (3) in the rat, Sherer and Siefring (22) in man, no effect by Perry (14) and Albert et al. (1) in the rat, and an increase by Beck (2). Due to the lack of uniformity in the literature in regard to the role of glueoeorticoids in thyroid function, it seemed desirable to study their influence in dairy cattle. It was hoped that the observations wouid contribute to an understanding of the influence of the stress of parturition upon thyroid function at this time. EXPEI~IMlgNTAL METHODS
Nonlactating, mature, and immature dairy animals of several breeds were given 300 ~c. of carrier-free NaI ~3~ intravenously. After maximum uptake of
THYROID
FUNCTION
IN CATTLE
165
I TM by the thyroid gland (three days) 24 g/day thiouracil was given by gelatin capsule to prevent recycling, and daily measurements of thyroidal-I TM were made (17) for a five-day control period. Hydrocortisone (cortisol-hydrocortone) at 75 rag/100 lb. body Weight or meticorten at 40 rag/100 lb.. was administered subcutaneously during a six-day test period. Potassium chloride was administered at the rate of 14 g. per 1,000 lb. body weight to prevent excess potassium loss due to the glucocorticoids. Release rates of thyroidal-I TM were calculated according to the method previously described (15), with the term k"4 being employed for release rate constant per hour during thiouracil administration. For comparison, the daily percentage release rate is presented. These values indicate the percentage of the total I TM present in the thyroid glands which is released each 24 hr. Comparison of the release during the control period, with the release during the administration of the glucocorticoids, indicates the effect of the hormone on the TSH secretion and, indirectly, on the secretion of thyroxine. RESULTS
The two chief glucoeorticoids secreted by the bovine adrenal gland are hydrocortisone and corticosterone in a ratio of 1:1(9). Hydrocortisone should, therefore, be representative of the natural hormone secreted by cattle when stimulated by ACTH. The release rate of thyroidal-ITM from the gland, when the recycling of I TM is prevented by a goitrogen, follows an exponential decline (a straight line when plotted on semilog paper). The release rate is believed to be dependent upon the rate of discharge of thyrotropic hormone (TSH). If hydrocortisone influences the rate of secretion or discharge of TSH, then the release of thyroidal-I TM will be increased or decreased accordingly. It will be noted that hydroeortisone, at the level administered, tended to depress thyroidal-P al release to varying degrees in five of the seven cows (Table 1). In two other cows, there was a slight increase ia one and a more marked increase in the second. These data indicate considerable variability in individual response in dairy cattle to hydrocortisone, although in the majority of the animals the tendency was to inhibit thyroidal-ITM release, which indicates depression of TSH secretion or release and, in turn, depression of thyroxine secretion. Meticorten (Prednisone). This is a synthetic cortisone-like compound produced by dehydrogenation at Positions One and Two of the cortisone nucleus (Figure 1). It has gluconeogenic action comparable to hydrocortisone but is claimed to be more potent. It has been suggested for use in treatment of ketosis in dairy cattle. In contrast to the effect of hydrocortisone, meticorten stimulated a variable increased release of thyroidal-I TM in six of eight experimental animals. Two animals showed a slightly depressed release rate (Table 2). These observations indicate that meticorten tends to increase thyroxine secretion in most, but not all, animals. Paired " t " tests of data (Tables 1 and 2) indicate with both compounds a lack of change of statistical significance. However, it is believed that the obser-
TABLE 1 Effect of hydrocortisone on thyroida]-I TM release rate Thyroidal-I ~ release rate--recycling blocked with thiouracil
Body Animal No. 38
Breed
weight (lb.)
Guernsey
1,300
601
Ho]ste:in
3625
Guernsey
Month TSR determined
TSR ~(rag/day/100 lb.)
December
0.4
760
February
0.5
1,] 25
February
0.4
348
Jersey
9~7
February
0.3
160
Jersey
1,197
February
0.3
Guernsey
1,200
February
0.6
456
February
0,5
3596 H,_,
Holstein
Hydroeortisone (administered in April) Control period Period k'4 k",i Difference ~*:* 0.006]4 (14.7¢o) ~ 0.00417 (10.0%) 0.00760 (18.2%) 0.00853 (20.4%) 0.00624 (14.9%) 0.00210 (5.04%) 0.00450 (10,8%)
0.00419 (10.0%) 0.00261 (6.3%) 0.00610 (14.6%) 0.00732 (]7.5%) 0.00580 (13.9%) 0.00330 (7.4%) 0.00770 (18.5%)
--0.00195 (4.7%) --0.00156 (3.7%) --0.00150 (3.6%) --0.00121 (2.9%) --0.00044 (1.0%) +0.00100 (2.4%) +0.00320 (7.7%)
* Each value in parentheses indicates the percentage of I TM present in the thyroid gland which is released each 24 hr. ----k'% × 24 × 100. *~ TSR = thyroxine secretion rate. **~ Paired " t ' ' test indicates a lack of change of statistical significance, l~hysiological effect of hydrocortisone is believed to be significant ia each animal.
TABLE 2 Effect of metieorten on thyroidal-I ~s~ release rate ThyroidM-IT M release rate--recycling blocked with thiouracil Animal No.
Breed
264
Body weight (lb.)
~[onth TS]~ determined
Meticorten (administered in May) TSR** Control period Period (rag/day/100 lb.) k"4 k"4 Difference***
650
February
0.5
601
Holstein
760
February
0.5
H1
Guernsey
400
February
0.4
38
Guernsey
1,300
December
0.4
41
Guernsey
1,250
November
0.5
260
Holstein
650
February
0.5
263
Holstein
780
February
0.5
265
Holstein
850
February
0.4
0.00655 (15.7%) ~ 0.00699 (16.8%) 0.00660 (15.8%) 0.00240 (5.8%) 0.00180 (4.3%) 0.00263 (6.3%) 0.00400 (9.6%) 0.00435 (10.4%)
0.01174 (28.2%) 0.01147 (27.5%) 0.00950 (22.8%) 0.00380 (9.1%) 0.00310 (7.4%) 0.00288 (6.9~,~) 0.00358 (8.6%) 0.00331 (7.9%)
+0.00519 (12.5%) +0.00448 (10.7%) +0.00290 (7.0%) +0.00140 (3.3%) +0.00130 (3.1%) +0.00025 (0.6%) --0.00042 (1.0%) --0.00104 (2.5%)
* Each value in parentheses indicates the percentage of 11'~1present in the thyroid gland which is released each 24 hr. ~ k"4 X 24 X 100. ~* TSR = thyroxine secretion rate. ~ Paired " t " test indicates a lack of change of statistical significance. Physiological effect of meticorten is believed to be of significance in each animal.
168
c. w, TURNEI~,
G, W . PIPES,
AND
B. N. PI~E~IACIIANDI~A
I H20H
H20H
IC=O H O ~ ~
Z~4-PREGNENE-11~t~-17#L , 21-TRIOL-3, 20- DIONE 17-HYDROXYCORTICOSTERONE
(HYDROCORTISONE)
0 . ~ ~
OH
OH
A1,4_p REGNADIENE- 17~.~ 21- DIOL- 3, 11, 20-TRIONE (METICORTEN)
~IG. 1. Structural formula of hydroeortisone ~md synthetic glueocorticoid, metieorte~t compared.
rations are physiologically significant ill spite of the variation of response observed. It s suggested that individual animal differences in the interaction o6 the various hormones play a role in the observed results. Thus, it is possible that the glucocorticoids syncrgize with other hormones in producino' effects upon T S H secretion. I f such hormones are secreted in optimal amounts the g'lucocorticoid response might be increased, whereas if other hormones are secreted at low levels the response might be minimal or reversed. This possibility will be explored. DISCUSSION
The relation of the adrenal glucocortieoids to the functional activity of the thyroid gland is of great interest. Is there a tendency for these hormones to stimulate or depress thyroxine secretion? Under situations of stress, where it is expected that increased secretion of the glucocorticoids would be observed, the stressful condition itself might influence thyroxine secretion as well. In the present experiment, the direct administration of the glucocorticoid should indicate its uneolnplicatcd effect on thyroid function. These data show that hydrocortisone tended to depress thyroidal-1131 release and T S t t and thyroxine secretion in most of the animals. The cause of the variability in response of the individual animals is not evident. The normal thyroxine secretion rate of each of these animMs is presented (Table 1). It will be noted that the two animals which showed increased thyroidal-P al release were relatively higher seeretors of thyroxine, but one animal in the other group secreted thyroxine at the same level. Our data suggest that at the time of parturition thyroxine secretion tends to be increased as a result of estrogen. To the extent that increased secretion of glueocortieoids is stimulated by stress or other related conditions, an opposing depression of thyroxine secretion might occur in many animals. Thus, in cows
THYI%OID FUNCTION IN CATTLE
169
with a low normal thyroxine secretion, the f u r t h e r depression of thyroxine secretion by hydroeortisone associated with parturition might be a factor in the etiology of ketosis at this time. I n other words, physiological ketosis might be due, primarily, to a low normal thyroxine secretion rate, f u r t h e r depressed by increased secretion of the adrenal glucocorticoids. I f this is true, then ketosis would be favorably influenced by thyroxine or by the feeding of thyroprotein. This would explain the favorable report of Reeee (18). Since ketotie cows show a low blood sugar level and Graham et al. (8) and Smith and Dastur (24) showed that thyroxine increased the blood sugar level of cows, the low thyroxine secretion rate could have a depressing effect on blood sugar. I f this is true, the restoration of normal blood thyroxine levels would have a favorable effect on blood sugar. This would be augmented by the effect of the glucocortieoids in their capacity to provide blood glucose from deaminated amino acids. The observation that meticorten tends to stimulate an increased release of thyroidal-I lsl (and thyroxine secretion) in six of eight cows is quite surprising in relation to our observations on hydrocortisone. Both compounds have gluconeogenic properties and react similarly in respect to other biological functions. I t is possible, of course, since both compounds show variability in response from depression to stimulation of thyroidal-1131 release, that no true difference exists between the compounds and that the variation observed is due to as yet unrecognized differences in the endocrine balance of the animals, causing in some a stimulation and in others a depression of thyroid function. The present data, however, indicate that meticorten tends to stimulate thyroxine secretion and, if so, would have a more favorable action in the treatment of ketosis, to the extent that low thyroxine secretion is related to the etiology of ketosis. REFERENCES (1) ALBEI%T,A., TENI~y, A., ~kNDFORD, E. The Effect of Cortisone and Corticotrophin on the
Biological Decay of Thyroidal Radloiodine. Endocrinology, 50: 324. 1952. (2) BECK, R. N. The Effect of Cortisone and Corticotropin on the Release and Peripheral
Metabolism of Thyroid Hormone. Endocrinology, 62: 9. 1958. (3) B~OwN-G~ANT,K. Inhibition of the Release of Thyroidal Radioiodine in the Rat by Cortisone. Endocrinology, 56: 607. 1955. (4) B~ust{, M. G. Adrenocortieal Activity in Bovine Pregnancy and Parturition. J. Endocrino]., 17: 381. 1958. (5) COWlE, A. T. The Maintenance of Lactation in the Rat after Hypophysectom$. J. Endocrlnol., 16: 135. 1957. (6) EL-A
Missouri Agr. Exp. Sta., Research Bull. 641. 1957. (7) GOlgEz, E. T., AND TUIZNER, C. W. Non-effect of Estrogenic Hormones on Mammary Gland of tIypophyseetomized Guinea Pig. Proc. Soc. Exptl. Biol. Me(]., 34: 320. 1936.
(8) Gm~A~{, W. R., JR., TURNER, C. W., AND GO~EZ, E. T. A Method for Obtaining Arterial Blood from the Goat. Missouri Agr. Exp. Sta., Research Bull. 260. 1937. (9) HE(]I-ITER,0., ZAFFA~0NI, A., JACOBSEN, R. P., LEVY, H., JEANLOZ, R. W., SCtIENKEF~, V., AND ]]INCUS, G. The Nature and the Biogenesis of the Adrenal Secretory Product.
Rec. Prog. I=[ormoneResearch, VI: 215. 1951.
170
C. W. TURNEI~, G. W. PIPES, AND B. N. PREMACHANDIgA
(10) I]~GBAR, S. R., AND FREINKEL, N. ACTH, Cortisone and the Metabolism of Iodine. Metabolism, 5" 652. 1956. (11) MONEY, W. L. The Interrelation of the Thyroid and the Adrenals. Brookhaven Symposia in Biology No. 7, The Thyroid, p. 137. 1955. (12) MYXNT, N. B. Comparison of the Effects of Thiouraeil, Thyroxine and Cortisone on the Thyroid Function of Rabbits. J. Physiol., 120: 288. 1953. (13) N~SON, W. O., ~ D GA~r*ST, R. Initiation of Lactation in the Hypophysectomized Guinea Pig. Proe. Soc. Exptl. Biol. Med., 34: 671. 1936. (14) PERaY, W. F. The Action of Cortisone and ACTH on Thyroid Function. Endocrinology, 49: 284. 1951. (15) PIPES, G. W., PR~AC~A~DRA, B. N., A~'*) T~RNER, C. W. Effect of Estrogen and Progesterone on Thyroid Funetion of Cattle. d. Dairy Sci., 41: 1387. 1958. (16) PIPES, G. W., PRE~*AC]~AN~)EA, B. N., AND TURNER, C. W. The Effect of Estradiol on the Thyroid Secretion Rate of Dairy Cattle. d. Dairy Sci., 43 : 862. 1960. (17) PIPES, G. W., ~ D TUIgNZR, C. W. The Effect of Thyroxine on Thyroid Function. Missouri Agr. Exp. Sta., ]~esea~eh Bull. 617. 1956. (18) REEOE, R. P. The Influence of Thyroprotein in the Ration of Dairy Cattle. d. Dairy Sci., 30: 574. 1947. (19) R0~ERTSON, W. G., LENtO*C, H. D., JR., BArnEY, W. W., A~qD MXXIqER, 3. P. Interrelationship Among Plasma 17-ttydroxyeorticosteroid Levels, Plasma Protein-Bound Iodine Levels, and Ketosis. 3. Dairy Sci., 40: 732. 1957. (20) I~OBEI~TSOlff,W° G., LENNON, H. D., Jig., AND MIXNEI~, J. P. Interrelation Among Plasma 17-Hydroxycorticoid Levels, Plasma Protein Bound Iodine Levels and Ketosis in Dairy Cattle. d. Dairy Sci., 38: 611. 1955. (21) SOHULTZg, A. B. Eosinophil Count and Glucose Level in Blood of Dairy Cattle During the F i r s t Pregnancy. J. Dairy Sci., 38: 611. 1955. (22) S*IERER, M. G., AN*) SIEF~NG, B. N. Effect of Prednisone and Prednisolone on Thyroid Function with Special Reference to Thyroxine-Bindlng Protein in Nephrosis. J. Clin. Endoerinol. Metabolism, 16: 643. 1956. (23) S~Aw, J. C. Ketosis in Dairy Cattle. A Review. 3. Dairy Sci., 39: 402. 1956. (24) S ~ I ~ , d. A. B., AND DAS~E, N. N. The Secretion of Milk Fat. I I I . The Effect of Thyroxine Administration on the Blood Lipids and the Nature of the Milk Fat. Biochem. d., 34: 1093. 1940.