The Effect of Growth Hormone on Parathyroid Function in Rats* STUART R. LANCER, E. NELSON BOWSER, GARY K. HARGIS, AND GERALD A. WILLIAMS Section of Endocrinology, Departments of Medicine and Nuclear Medicine, VA West Side Hospital and University of Illinois College of Medicine, Chicago, Illinois iPTH during administration of the higher dose, and also a significantly increased parathyroid gland weight and PTH content. The concomitant increase in serum Ca and iPTH suggest that GH stimulates the parathyroid glands to increase PTH secretion, which in turn causes an increase in serum Ca. The parathyroid response increases with the increase in dose and duration of GH stimulus. The data suggest that the hypercalcemia often observed in acromegaly may be due, at least in part, to GHinduced excessive secretory activity of the parathyroid glands. (Endocrinology 98: 1289, 1976)
ABSTRACT. The effect of excessive growth hormone (GH) on parathyroid function in rats was evaluated in order to determine whether the GHinduced increase in serum calcium (Ca) may be mediated via stimulation of parathyroid hormone (PTH) secretion. Rats receiving injections of bovine GH 2 mg daily for 4 weeks showed a progressive significant increase in both serum Ca and immunoreactive PTH (iPTH) after the second week. Rats receiving daily injections of rat GH, 0.25 mg daily for 3 weeks, followed by 0.5 mg daily for 3 additional weeks, showed a significant increase in serum
I
T is well established that several aspects of calcium (Ca) metabolism are modified by growth hormone (GH) (1-15). Several investigators have reported the occurrence of borderline or definitely elevated serum Ca concentrations in acromegalic patients, the incidence varying from 16% in one series (1) to as high as 32% in another series (2). Following the treatment of the acromegaly, the elevated serum Ca returned to normal in many of the patients. Nadarajah et al. (1) reported that only half of their acromegalic patients with hypercalcemia returned to normocalcemia after successful treatment of the acromegaly. They concluded that the remainder probably had concomitant primary hyperparathyroidism. However, Brown and Singer (2) found that 12 of 13 acromegalic patients whose serum Ca concentration ranged from 10.1 to 11.5 mg/100 ml had a reduction of serum Ca after apparent successful therapy of the acromegaly. They concluded that the excessive GH in some patients causes parathyroid hyperplasia and Received August 4, 1975. * VA Research Program, MRIS No 9420-12. Reprints: Gerald A. Williams, M.D., VA West Side Hospital (M.P. 172), P.O. Box 8195, Chicago, Illinois 60680.
possibly adenoma with increased parathyroid hormone (PTH) secretion. They also concluded that the duration and severity of the acromegaly are major factors which influence Ca metabolism in acromegaly. Summers, et al. (3) reported 3 acromegalic patients with hypercalcemia, 2 of which had histologically proven parathyroid hyperplasia. Although some investigators have attributed the elevated serum Ca levels in acromegaly to the direct effect of excess GH on bone resorption (6-8) or to a combined genetic defect (15), others have postulated that GH may stimulate parathyroid function, resulting in the observed hypercalcemia (1-5). This question has thus far not been clarified by direct measurement of parathyroid function in the presence of known excessive GH. The present study was undertaken to determine whether excessive GH stimulates PTH secretion and therefore, to clarify whether the observed GH-induced hypercalcemia may be mediated, at least in part, by stimulation of parathyroid function. Materials and Methods Two related experiments were carried out. In experiment I, bovine (b) GH was adminis-
1289
1290
LANCER, BOWSER, HARGIS AND WILLIAMS
tered daily for 4 weeks. In experiment II, rat GH was administered at lower doses and for longer duration than with bGH in order to evaluate any qualitative or quantitative differences based on the species of GH administered, and to obtain inferences as to the effect of the dose and duration of GH on PTH response. Experiment I. Male albino Sprague-Dawley rats initially weighing approximately 200 g received bGH (supplied by NIAMD Pituitary Hormone Distribution Program as NIH-GH-B-17, potency 0.92 IU/mg) 2.0 mg SC daily for 4 weeks. Control rats of the same age and weight received daily SC injections of alkaline saline diluent. Both groups of rats were maintained on a nutritionally complete diet containing 1.7% Ca, 0.8% phosphorus (P), and 148 IU vitamin D/100 g diet. Weights were determined daily. All animals had 1.8 ml blood withdrawn weekly, by orbital sinus puncture after an overnight fast of 16-20 h, for determination of serum immunoreactive PTH (iPTH) and Ca. After 4 weeks, the animals were sacrificed, blood being obtained for serum P and proteins as well as PTH and Ca. The parathyroid glands were then removed immediately with fine dissecting instruments under a dissecting microscope. The pair of glands from each rat was immediately sealed in tared aluminum foil envelopes to prevent drying and weighed on a Cahn electrobalance, Model G. The parathyroid glands from each group of rats were then pooled and homogenized in cold 20% acetone in 1% acetic acid (0.1 ml extracting solution per mg wet wt of tissue) (16). The homogenate was centrifuged at 2200 x g for 15 min at 4 C and the supernatant was immunoassayed for iPTH. Experiment II. The protocol for this study was basically the same as that in experiment I except that: a) rat GH (supplied by NIAMDD Rat Pituitary Hormone Distribution Program as NIAMD-Rat GH-B-3, potency 0.9 IU/mg) rather than bGH was used; b) the experiment continued for 6 weeks rather than 4 weeks; c) the dose of rat GH was 0.25 mg SC daily (Vs the dose of bGH by wt) for the first 3 weeks and 0.5 mg SC daily {lA the dose of bGH) during the second 3 weeks of the study; and d) analyses of serum Ca, P, and proteins were not carried out. At the end of 6 weeks, the rats were sacrificed and the para-
Endo • 1976 Vol 98 • No 5
thyroid glands removed for study as in experiment I. In both experiments the serum was separated within 2 h of bleeding and was frozen until subsequent analyses. Serum Ca and P concentrations were determined with the Technicon AutoAnalyzer by the method of Kessler and Wolfman (17). Serum and parathyroid gland extract iPTH were determined by a sensitive radioimmunoassay technique for rat iPTH developed by Hargis et al. (18) in this laboratory. The inter-assay coefficient of variation for bovine or rat iPTH is 8%. Serum proteins were determined by refractometry (American Optical Corp., Buffalo, N.Y.). The serum Ca, iPTH, P, and protein values for both the control and GH-treated groups of rats at each weekly bleeding, were expressed as the group mean ± SE. The group values were statistically compared by Student's t test.
Results The mean weight gain of the control and GH-treated rats was not significantly different in either experiment. Experiment I As shown in Fig. 1, after 1 week of bGH treatment the serum Ca concentration in the bGH-treated group was slightly but not significantly greater than that of the control rats. However, after the second week of treatment, the serum Ca was significantly (P < 0.05) greater than that of the control group. After the third and fourth weeks of treatment the serum Ca of the bGH-treated group was further increased (P < 0.001) above the control level. The concomitant changes in serum iPTH concentration are shown in Fig. 2. As was observed for serum Ca, the concomitant serum iPTH concentration was minimally, but not significantly, greater than that of the control group of rats after 1 week of bGH treatment. However, after 2 weeks of treatment, the serum iPTH was significantly (P < 0.02) greater than that of the control group. After 3 and 4 weeks of treatment, the serum iPTH of the
EFFECT OF GH ON PTH SECRETION •
|
12 II 10 9 8
3g6 SJ 4 2 I0-
•
Control
Y71 bGH-Treoted
1
1
1
1
2
3
U\ bGH-Treated
is *
o
6
4 S 3 2 I 0
1
2
3
4
Weeks of Treatment
FIG. 2. Comparison of the effect of bGH or diluent (control) on serum iPTH concentration. Dosage, injection and bleeding schedule, and expression of the data are the same as in Fig. 1. There were 7 animals in each group.
each of the fourth, fifth, and sixth weeks of treatment. The mean parathyroid gland weight of the 6-weeks rat GH-treated animals was significantly (P < 0.02) greater than that of the control group (Fig. 4). The iPTH ex-
TfMtMl
I
4-
Experiment II As indicated in Fig. 3, the lower dose of rat GH (0.25 mg/day) for 3 weeks caused only a slight increase in serum iPTH above the control value, which was statistically significant (P < 0.02) only after the third week of treatment. However, during subsequent treatment with the larger dose of rat GH (0.5 mg/day), the serum iPTH in the rat GH-treated rats was significantly (P < 0.001) greater than the control level after
i
M
II
7
Weeks of Treatment
bGH-treated group was further increased (P < 0.001) above the control group values. There were no group differences in serum P or proteins after 4 weeks of bGH treatment. The mean parathyroid gland weight of the bGH-treated rats was slightly, but not significantly, greater than that of the control rats. The iPTH extracted from the pooled parathyroid tissue from the bGH-treated rats was slightly greater than that of the control rats (37 and 34 pg eq bovine iPTH/ mg wet wt, respectively).
Control
= 10 "** 9
4
FIG. 1. Comparison of the effect of bGH or diluent (control) on serum Ca concentration. bGH, 2 mg, or alkaline saline diluent was given SC daily for 4 weeks, the rats being bled weekly for Ca analysis. Each bar represents the mean Ca concentration with its SE. There were 7 animals in each group. *above a pair of bars indicates a statistically significant difference between control and bGH-treated values.
1291
1
2
3 4 Wttto d7 Trtqtmwtf
0.25 mg. Rot GH
1 5
0,5 mg RatGH
FIG. 3. Comparison of the effect of rat GH or diluent on serum iPTH concentration. Rat GH, 0.25 mg, or alkaline saline was given SC daily for 3 weeks, followed by rat GH, 0.5 mg, or alkaline saline daily for 3 weeks, the animals being bled weekly for iPTH determination. Each bar represents the mean iPTH concentration with its SE for 8 animals.
LANCER, BOWSER, HARGIS AND WILLIAMS
1292
1.2 1.0 OB
0.4-
Q2-
Control
Rat GH
Treatment FIG. 4. Comparison of the effect of rat GH or alkaline saline diluent (control) on weight of parathyroid glands. Other details as in legend to Fig. 3.
tracted from the pooled parathyroid glands from the rat GH-treated animals was almost double that of the control group (48.2 and 28.1 pg eq bovine PTH/mg wet wt, respectively). Discussion The observations from experiment I indicate that in rats, bGH given in daily doses of 2 mg caused significant increases in both serum Ca and iPTH after 2 weeks, with further increases noted in the ensuing 2 additional weeks of therapy. Because serum Ca and iPTH increased in parallel, it is most likely that bGH stimulated the parathyroid glands to increase PTH secretion, which, in turn, caused an increase in serum Ca. If the increased serum Ca were caused by some mechanism other than by increased circulating PTH, one would expect the elevated serum Ca to suppress parathyroid function with, in contrast to the observed results, a decrease in serum iPTH. Subsequently, a decrease in size and hormone content of the parathyroid glands would be
Endo • 1976 Vol 98 • No 5
expected, rather than the slight increase which was observed. The observations from experiment II using rat GH support the observations and conclusions of experiment I. Because comparable doses of bovine and rat GH were not used, the study does not allow consideration of comparable biological potency of the two species of hormone on parathyroid function in the rat. Also the design of this study does not allow for distinguishing between dose-response and duration-response effects. The fact that the larger dose of rat GH was associated with a greater iPTH response than occurred during the lower dose suggests that the GH-induced stimulation of parathyroid function maybe dose-related. However, the greater response seen when the larger dose of rat GH was given may be partially dependent upon duration, rather than upon the dose of GH administered, because the same animals first received the lower and then the larger dose of rat GH. An effect of duration of GH treatment is suggested by the observation that the weights of the parathyroid glands were significantly increased and the iPTH content was doubled after 6 weeks of rat GH treatment, with only minimal increases noted after 4 weeks of bGH treatment; however, potency differences between the 2 species of hormones cannot be discounted. These observations indicate that at least part of the effect of excessive GH on Ca metabolism is mediated via stimulation of parathyroid function, and suggest that the hypercalcemia often observed in acromegaly may be caused, at least in part, by GH-induced excessive secretory activity of the parathyroid glands. Acknowledgment We thank Ms. Bertha L. Jackson and Ms. Roberta Weber for valuable technical assistance.
References 1. Nadarajah, A., M. Hartog, B. Redfern, N. Thalassinos, A. D. Wright, G. F. Joplin, and T. R. Fraser, BrMedJ 4: 797, 1968.
EFFECT OF GH ON PTH SECRETION 2. Brown, J., and F. R. Singer, Br MedJ 2: 50, 1969. 3. Summers, V. K., W. R. Hunter, L. J. Hipkin, and J. C. Davis, Lancet 2: 601, 1966. 4. Harrison, M., and R. Fraser, BrMedJ 2: 535,1960. 5. Houssay, B. A., Harvey Led 31: 116, 1936. 6. Gershberg, H., A. Hecht, and Z. Javier, / Clin Endocrinol Metab 27: 1492, 1967. 7. Riggs, B. L., R. V. Randall, H. W. Wahner, J. Jowsey, P. J. Kelly, and M. Singh, J Clin Endocrinol Metab 34: 911, 1972. 8. Bell, N. H., and F. C. BartterJ Clin Endocrinol Metab 27: 178, 1967. 9. Molinatti, G. M., F. Camanni, O. Losana, and M. Olivetti, Ada Endocrinol (Kbh) 36: 161, 1961. 10. Bryson, M. F., G. B. Forbes, G. H. Amirhakimi, and J. C. Reina, Pediatr Res 6: 743, 1972.
1293
11. Forbes, G. B., F. A. Smith, and M. F. Bryson, CalcifTiss Res 11: 301, 1973. 12. Sjoberg, H. E., Horm Metab Res 1: 136, 1969. 13. Males, J. L., and J. L. Townsend, South MedJ 65: 321, 1972. 14. Gordon, D. A., F. M. Hill, and C. Ezrin, Can MedAssocJ 87: 1106, 1962. 15. Vancil, M., and W. Locke, Am J Surg 110: 495, 1965. 16. Silverman, R., and R. S. Yalow, J Clin Invest 52: 1958, 1973. 17. Kessler, G., and M. Wolfmann, Clin Chem 10: 686, 1964. 18. Hargis, G. K., E. N. Bowser, W. J. Henderson, and G. A. Williams, Endocrinology 94: 1644,1974.
ABSTRACT. The effect of excessive growth hormone (GH) on parathyroid function in rats was evaluated in order to determine whether the GHinduced increase in serum calcium (Ca) may be mediated via stimulation of parathyroid hormone (PTH) secretion. Rats receiving injections of bovine GH 2 mg daily for 4 weeks showed a progressive significant increase in both serum Ca and immunoreactive PTH (iPTH) after the second week. Rats receiving daily injections of rat GH, 0.25 mg daily for 3 weeks, followed by 0.5 mg daily for 3 additional weeks, showed a significant increase in serum
I
T is well established that several aspects of calcium (Ca) metabolism are modified by growth hormone (GH) (1-15). Several investigators have reported the occurrence of borderline or definitely elevated serum Ca concentrations in acromegalic patients, the incidence varying from 16% in one series (1) to as high as 32% in another series (2). Following the treatment of the acromegaly, the elevated serum Ca returned to normal in many of the patients. Nadarajah et al. (1) reported that only half of their acromegalic patients with hypercalcemia returned to normocalcemia after successful treatment of the acromegaly. They concluded that the remainder probably had concomitant primary hyperparathyroidism. However, Brown and Singer (2) found that 12 of 13 acromegalic patients whose serum Ca concentration ranged from 10.1 to 11.5 mg/100 ml had a reduction of serum Ca after apparent successful therapy of the acromegaly. They concluded that the excessive GH in some patients causes parathyroid hyperplasia and Received August 4, 1975. * VA Research Program, MRIS No 9420-12. Reprints: Gerald A. Williams, M.D., VA West Side Hospital (M.P. 172), P.O. Box 8195, Chicago, Illinois 60680.
possibly adenoma with increased parathyroid hormone (PTH) secretion. They also concluded that the duration and severity of the acromegaly are major factors which influence Ca metabolism in acromegaly. Summers, et al. (3) reported 3 acromegalic patients with hypercalcemia, 2 of which had histologically proven parathyroid hyperplasia. Although some investigators have attributed the elevated serum Ca levels in acromegaly to the direct effect of excess GH on bone resorption (6-8) or to a combined genetic defect (15), others have postulated that GH may stimulate parathyroid function, resulting in the observed hypercalcemia (1-5). This question has thus far not been clarified by direct measurement of parathyroid function in the presence of known excessive GH. The present study was undertaken to determine whether excessive GH stimulates PTH secretion and therefore, to clarify whether the observed GH-induced hypercalcemia may be mediated, at least in part, by stimulation of parathyroid function. Materials and Methods Two related experiments were carried out. In experiment I, bovine (b) GH was adminis-
1289
1290
LANCER, BOWSER, HARGIS AND WILLIAMS
tered daily for 4 weeks. In experiment II, rat GH was administered at lower doses and for longer duration than with bGH in order to evaluate any qualitative or quantitative differences based on the species of GH administered, and to obtain inferences as to the effect of the dose and duration of GH on PTH response. Experiment I. Male albino Sprague-Dawley rats initially weighing approximately 200 g received bGH (supplied by NIAMD Pituitary Hormone Distribution Program as NIH-GH-B-17, potency 0.92 IU/mg) 2.0 mg SC daily for 4 weeks. Control rats of the same age and weight received daily SC injections of alkaline saline diluent. Both groups of rats were maintained on a nutritionally complete diet containing 1.7% Ca, 0.8% phosphorus (P), and 148 IU vitamin D/100 g diet. Weights were determined daily. All animals had 1.8 ml blood withdrawn weekly, by orbital sinus puncture after an overnight fast of 16-20 h, for determination of serum immunoreactive PTH (iPTH) and Ca. After 4 weeks, the animals were sacrificed, blood being obtained for serum P and proteins as well as PTH and Ca. The parathyroid glands were then removed immediately with fine dissecting instruments under a dissecting microscope. The pair of glands from each rat was immediately sealed in tared aluminum foil envelopes to prevent drying and weighed on a Cahn electrobalance, Model G. The parathyroid glands from each group of rats were then pooled and homogenized in cold 20% acetone in 1% acetic acid (0.1 ml extracting solution per mg wet wt of tissue) (16). The homogenate was centrifuged at 2200 x g for 15 min at 4 C and the supernatant was immunoassayed for iPTH. Experiment II. The protocol for this study was basically the same as that in experiment I except that: a) rat GH (supplied by NIAMDD Rat Pituitary Hormone Distribution Program as NIAMD-Rat GH-B-3, potency 0.9 IU/mg) rather than bGH was used; b) the experiment continued for 6 weeks rather than 4 weeks; c) the dose of rat GH was 0.25 mg SC daily (Vs the dose of bGH by wt) for the first 3 weeks and 0.5 mg SC daily {lA the dose of bGH) during the second 3 weeks of the study; and d) analyses of serum Ca, P, and proteins were not carried out. At the end of 6 weeks, the rats were sacrificed and the para-
Endo • 1976 Vol 98 • No 5
thyroid glands removed for study as in experiment I. In both experiments the serum was separated within 2 h of bleeding and was frozen until subsequent analyses. Serum Ca and P concentrations were determined with the Technicon AutoAnalyzer by the method of Kessler and Wolfman (17). Serum and parathyroid gland extract iPTH were determined by a sensitive radioimmunoassay technique for rat iPTH developed by Hargis et al. (18) in this laboratory. The inter-assay coefficient of variation for bovine or rat iPTH is 8%. Serum proteins were determined by refractometry (American Optical Corp., Buffalo, N.Y.). The serum Ca, iPTH, P, and protein values for both the control and GH-treated groups of rats at each weekly bleeding, were expressed as the group mean ± SE. The group values were statistically compared by Student's t test.
Results The mean weight gain of the control and GH-treated rats was not significantly different in either experiment. Experiment I As shown in Fig. 1, after 1 week of bGH treatment the serum Ca concentration in the bGH-treated group was slightly but not significantly greater than that of the control rats. However, after the second week of treatment, the serum Ca was significantly (P < 0.05) greater than that of the control group. After the third and fourth weeks of treatment the serum Ca of the bGH-treated group was further increased (P < 0.001) above the control level. The concomitant changes in serum iPTH concentration are shown in Fig. 2. As was observed for serum Ca, the concomitant serum iPTH concentration was minimally, but not significantly, greater than that of the control group of rats after 1 week of bGH treatment. However, after 2 weeks of treatment, the serum iPTH was significantly (P < 0.02) greater than that of the control group. After 3 and 4 weeks of treatment, the serum iPTH of the
EFFECT OF GH ON PTH SECRETION •
|
12 II 10 9 8
3g6 SJ 4 2 I0-
•
Control
Y71 bGH-Treoted
1
1
1
1
2
3
U\ bGH-Treated
is *
o
6
4 S 3 2 I 0
1
2
3
4
Weeks of Treatment
FIG. 2. Comparison of the effect of bGH or diluent (control) on serum iPTH concentration. Dosage, injection and bleeding schedule, and expression of the data are the same as in Fig. 1. There were 7 animals in each group.
each of the fourth, fifth, and sixth weeks of treatment. The mean parathyroid gland weight of the 6-weeks rat GH-treated animals was significantly (P < 0.02) greater than that of the control group (Fig. 4). The iPTH ex-
TfMtMl
I
4-
Experiment II As indicated in Fig. 3, the lower dose of rat GH (0.25 mg/day) for 3 weeks caused only a slight increase in serum iPTH above the control value, which was statistically significant (P < 0.02) only after the third week of treatment. However, during subsequent treatment with the larger dose of rat GH (0.5 mg/day), the serum iPTH in the rat GH-treated rats was significantly (P < 0.001) greater than the control level after
i
M
II
7
Weeks of Treatment
bGH-treated group was further increased (P < 0.001) above the control group values. There were no group differences in serum P or proteins after 4 weeks of bGH treatment. The mean parathyroid gland weight of the bGH-treated rats was slightly, but not significantly, greater than that of the control rats. The iPTH extracted from the pooled parathyroid tissue from the bGH-treated rats was slightly greater than that of the control rats (37 and 34 pg eq bovine iPTH/ mg wet wt, respectively).
Control
= 10 "** 9
4
FIG. 1. Comparison of the effect of bGH or diluent (control) on serum Ca concentration. bGH, 2 mg, or alkaline saline diluent was given SC daily for 4 weeks, the rats being bled weekly for Ca analysis. Each bar represents the mean Ca concentration with its SE. There were 7 animals in each group. *above a pair of bars indicates a statistically significant difference between control and bGH-treated values.
1291
1
2
3 4 Wttto d7 Trtqtmwtf
0.25 mg. Rot GH
1 5
0,5 mg RatGH
FIG. 3. Comparison of the effect of rat GH or diluent on serum iPTH concentration. Rat GH, 0.25 mg, or alkaline saline was given SC daily for 3 weeks, followed by rat GH, 0.5 mg, or alkaline saline daily for 3 weeks, the animals being bled weekly for iPTH determination. Each bar represents the mean iPTH concentration with its SE for 8 animals.
LANCER, BOWSER, HARGIS AND WILLIAMS
1292
1.2 1.0 OB
0.4-
Q2-
Control
Rat GH
Treatment FIG. 4. Comparison of the effect of rat GH or alkaline saline diluent (control) on weight of parathyroid glands. Other details as in legend to Fig. 3.
tracted from the pooled parathyroid glands from the rat GH-treated animals was almost double that of the control group (48.2 and 28.1 pg eq bovine PTH/mg wet wt, respectively). Discussion The observations from experiment I indicate that in rats, bGH given in daily doses of 2 mg caused significant increases in both serum Ca and iPTH after 2 weeks, with further increases noted in the ensuing 2 additional weeks of therapy. Because serum Ca and iPTH increased in parallel, it is most likely that bGH stimulated the parathyroid glands to increase PTH secretion, which, in turn, caused an increase in serum Ca. If the increased serum Ca were caused by some mechanism other than by increased circulating PTH, one would expect the elevated serum Ca to suppress parathyroid function with, in contrast to the observed results, a decrease in serum iPTH. Subsequently, a decrease in size and hormone content of the parathyroid glands would be
Endo • 1976 Vol 98 • No 5
expected, rather than the slight increase which was observed. The observations from experiment II using rat GH support the observations and conclusions of experiment I. Because comparable doses of bovine and rat GH were not used, the study does not allow consideration of comparable biological potency of the two species of hormone on parathyroid function in the rat. Also the design of this study does not allow for distinguishing between dose-response and duration-response effects. The fact that the larger dose of rat GH was associated with a greater iPTH response than occurred during the lower dose suggests that the GH-induced stimulation of parathyroid function maybe dose-related. However, the greater response seen when the larger dose of rat GH was given may be partially dependent upon duration, rather than upon the dose of GH administered, because the same animals first received the lower and then the larger dose of rat GH. An effect of duration of GH treatment is suggested by the observation that the weights of the parathyroid glands were significantly increased and the iPTH content was doubled after 6 weeks of rat GH treatment, with only minimal increases noted after 4 weeks of bGH treatment; however, potency differences between the 2 species of hormones cannot be discounted. These observations indicate that at least part of the effect of excessive GH on Ca metabolism is mediated via stimulation of parathyroid function, and suggest that the hypercalcemia often observed in acromegaly may be caused, at least in part, by GH-induced excessive secretory activity of the parathyroid glands. Acknowledgment We thank Ms. Bertha L. Jackson and Ms. Roberta Weber for valuable technical assistance.
References 1. Nadarajah, A., M. Hartog, B. Redfern, N. Thalassinos, A. D. Wright, G. F. Joplin, and T. R. Fraser, BrMedJ 4: 797, 1968.
EFFECT OF GH ON PTH SECRETION 2. Brown, J., and F. R. Singer, Br MedJ 2: 50, 1969. 3. Summers, V. K., W. R. Hunter, L. J. Hipkin, and J. C. Davis, Lancet 2: 601, 1966. 4. Harrison, M., and R. Fraser, BrMedJ 2: 535,1960. 5. Houssay, B. A., Harvey Led 31: 116, 1936. 6. Gershberg, H., A. Hecht, and Z. Javier, / Clin Endocrinol Metab 27: 1492, 1967. 7. Riggs, B. L., R. V. Randall, H. W. Wahner, J. Jowsey, P. J. Kelly, and M. Singh, J Clin Endocrinol Metab 34: 911, 1972. 8. Bell, N. H., and F. C. BartterJ Clin Endocrinol Metab 27: 178, 1967. 9. Molinatti, G. M., F. Camanni, O. Losana, and M. Olivetti, Ada Endocrinol (Kbh) 36: 161, 1961. 10. Bryson, M. F., G. B. Forbes, G. H. Amirhakimi, and J. C. Reina, Pediatr Res 6: 743, 1972.
1293
11. Forbes, G. B., F. A. Smith, and M. F. Bryson, CalcifTiss Res 11: 301, 1973. 12. Sjoberg, H. E., Horm Metab Res 1: 136, 1969. 13. Males, J. L., and J. L. Townsend, South MedJ 65: 321, 1972. 14. Gordon, D. A., F. M. Hill, and C. Ezrin, Can MedAssocJ 87: 1106, 1962. 15. Vancil, M., and W. Locke, Am J Surg 110: 495, 1965. 16. Silverman, R., and R. S. Yalow, J Clin Invest 52: 1958, 1973. 17. Kessler, G., and M. Wolfmann, Clin Chem 10: 686, 1964. 18. Hargis, G. K., E. N. Bowser, W. J. Henderson, and G. A. Williams, Endocrinology 94: 1644,1974.
