1 Department of Physiology, The mechanism that
causes hypercalcitonemia in female rats and is associated with aging
was investigated. Young (3 mo), adult (8 mo), middle-aged
(12 mo), and old (21 mo) rats were infused with
CaCl2 and were bled from a jugular
catheter after a CaCl2 challenge.
To mimic some of the hormonal changes caused by aging, the anterior
pituitary (AP)-grafted ovariectomized rats with hyperprolactinemic syndrome were used to mimic the physiological status of aging. The rat
thyroid gland was incubated with or without ovine prolactin (oPRL; 40 or 80 ng/ml) at 37°C for 30 min. Old rats possessed the lowest
levels of plasma estradiol and progesterone yet had the highest levels
of plasma prolactin and calcitonin (CT) compared with young, adult, and
middle-aged rats. The basal release of thyroid CT in vitro in thyroid
glands gradually increased with age. Compared with cortex (CX)-grafted
rats, the AP-grafted rats possessed higher levels of plasma PRL, basal
and CaCl2-induced levels of plasma
CT, and the release of thyroid CT in thyroid glands. After stimulation
with oPRL, the in vitro release of thyroid CT increased in both CX- and
AP-grafted rats. These results suggest that the hypersecretion of CT in
old rats is due at least in part to hyperprolactinemia.
prolactin
AGE-ASSOCIATED or age-specific physiological changes in
hormone secretion have been investigated previously in both humans and
experimental animals. For example, the levels of plasma prolactin (PRL)
in aged humans (26) and rats (10) are higher than in young humans and
rats, respectively. Serum immunoreactive parathyroid hormone levels are
elevated with age in both humans (27) and rats (13, 20, 30).
There are also age-related changes in calcitonin (CT) levels in both
humans (22) and rats (8, 13, 20, 25, 30). In humans, there is a
progressive decrease in plasma CT with age, and it is possible that
aging itself may generally decrease the secretory capacity of the C
cells (7). Hypercalcitonemia occurs in aged rats (8, 13, 20, 25, 30),
and the increased secretion of CT is probably due to It is well known that the level of plasma CT is influenced by ovarian
steroid hormones. Both estradiol and progesterone have been shown to
cause an increase of in vitro CT release from the thyroid C cells of
8-day-old rats (12). Regardless of the presence of estradiol,
administration of progesterone in ovariectomized (Ovx) rats resulted in
an increase of the basal and calcium-induced secretion of CT (14).
Clinical studies have indicated that postmenopausal estrogen
replacement therapy is effective in the prevention of rapid bone loss
(3, 9). Because estrogen regulates CT secretion in postmenopausal
women, CT might be a mediator of estrogen action on bone (3, 9). Thus
ovarian steroids may be an age-related physiological regulator for CT
secretion. However, the aged rats possess either higher (15) or lower
(11, 25) plasma levels of estradiol and lower levels of plasma
progesterone (11, 15, 25); therefore, hypercalcitonemia in aged rats
cannot be explained by an effect of ovarian steroids.
In addition to the changes of ovarian steroid hormones, PRL is also an
age-associated factor in regulating CT secretion that has been
investigated in both humans (24) and experimental animals (1). It has
been shown that the basal plasma CT levels are slightly reduced in
hyperprolactinemic women (24). The serum levels of CT have also been
shown to decrease in Buffalo rats bearing an MMQ tumor, a
pituitary cell line derived from the 7315a tumor, with
hyperprolactinemic syndrome (1). The hyperprolactinemia caused by an MMQ tumor does not increase plasma levels of CT; therefore, it does not explain the reasons for hypercalcitonemia in
aged rats. Thus another model of hyperprolactinemia has to be selected
to study the effects of aging on CT secretion.
This study investigated the mechanism of the effects of aging on the
secretion of CT both in vivo and in vitro in female rats. The models of
hyperprolactinemia and hypogonadism were used to mimic the hormonal
changes caused by aging. The role of PRL in regulating CT secretion in
vitro in rats was studied.
Animals. The rats were purchased from
the animal center of National Yang-Ming University. Old (21 mo), middle
(mid)-aged (12 mo), adult (8 mo), and young (3 mo) female rats of
Sprague-Dawley strain were housed in a temperature-controlled room (22 ± 1°C) with 14 h of artificial illumination daily
(0600-2000) and were provided food and water ad libitum. Vaginal
smears were taken before the experiment. Young and adult rats at
diestrus stage on the experimental day were used. Old rats in the
persistent diestrous stage were employed. Both the constant diestrous
(60%) and the constant estrous (40%) mid-aged rats were employed in this study.
A hyperprolactinemic rat model was used to mimic certain aspects of
aging and to eliminate the possible confounding effects of differences
in circulating gonadal steriods. All operations were performed under
ether anesthesia. The 3-mo-old rats were implanted with anterior
pituitary (AP) or brain cortex (CX, for control) under the capsule of
the kidney (2). Castrations were performed 2 wks before the experiment.
Six weeks after implantation, rats were decapitated and the blood
samples were collected. It has been shown that the levels of plasma PRL
increased in AP-grafted rats but not in CX-grafted animals (2).
In vivo experiments. Rats were
catheterized via the right jugular vein and left femoral vein under
ether anesthesia (14, 25). Twenty hours later,
CaCl2 (30 mg/kg body wt) was
infused (1 ml/30 min) via the femoral catheter connected to a
peristaltic pump (14, 25). Blood samples (0.6 ml each) were collected from the right jugular vein at 0, 30, 60, and 120 min
post-CaCl2 challenge (14, 25).
Plasma was separated by centrifugation at 10,000 g for 1 min and stored at
In vitro experiments. After
decapitation, rat blood samples were collected, and the concentrations
of CT, PRL, estradiol, and progesterone in the plasma were measured by
the RIA. Rat thyroparathyroid glands were excised, bisected, and
preincubated with Locke's solution containing 10 mM glucose, 0.003%
bacitracin, and 0.05% HEPES at 37°C for 90 min. Thyroparathyroid
glands were then incubated with vehicle (i.e., Locke's medium) or
ovine PRL (oPRL; 40 or 80 ng/ml, Sigma) for 30 min. At the end of
incubation the tissue was weighed, and the medium was collected and
measured for CT by the RIA.
RIAs. The CT concentrations in each
plasma and thyroid medium samples were measured by a human CT RIA kit
purchased from Nichols Institute Diagnostics as described elsewhere
(14, 25). The sensitivity was 4 pg/ml. The intra- and interassay
coefficients of variability were 6.7 and 8.3%, respectively.
The concentration of PRL in the plasma samples was determined by RIA as
described elsewhere (5). The rat PRL kit was provided by the National
Institute of Diabetes and Digestive and Kidney Diseases. Rat PRL-I-6
was used for radioiodination, whereas rat PRL-RP-3 was the standard.
The sensitivity of rat PRL RIA was 3 pg per assay tube. The intra- and
interassay coefficients of variability were 3.8 and 3.2% for PRL RIA, respectively.
The concentration of plasma progesterone was determined by RIA as
described elsewhere (14, 16). With anti-progesterone serum no. W5, the
sensitivity of progesterone RIA was 5 pg per assay tube. The intra- and
interassay coefficients of variability were 4.8 (n = 5) and 9.5%
(n = 4), respectively.
The concentration of plasma estradiol was determined by RIA as
described previously (14). With anti-estradiol serum no. W1, the
sensitivity of estradiol RIA was 1 pg per assay tube. The intra- and
interassay coefficients of variability were 6.0% (n = 5) and 5.9%
(n = 5), respectively.
Statistical analysis. The treatment
means were tested for homogeneity with ANOVA, and the difference
between specific means was tested for significance with Duncan's
multiple range test (23). A difference between two means was considered
significant when P < 0.05.
Effects of aging on plasma PRL, estradiol, and
progesterone in female rats. The thyroid weights were
17.11 ± 0.79 mg/thyroid in 3-mo-old rats, 23.87 ± 0.93 mg/thyroid in 8-mo-old rats, 26.23 ± 2.17 mg/thyroid in 12-mo-old
rats, and 35.92 ± 3.17 mg/thyroid in 21-mo-old rats (sample size:
7-8). The correlation coefficient for aged rats and weights of the
thyroid in rats was 0.80 (P < 0.01).
The levels of plasma PRL showed a gradual and an age-dependent increase
in the different age groups (correlation coefficient = 0.91, P < 0.01, Fig.
1, top).
Compared with young animals, the basal level of plasma PRL increased
2.5-fold in old rats (Fig. 1, top).
There was a significant difference (P < 0.05) in plasma PRL between young and adult, mid-aged, or old rats
or between adult and old animals (Fig. 1,
top). The levels of plasma estradiol (Fig. 1, center) and progesterone
(Fig. 1, bottom) showed a gradual and age-dependent decrease in the different age groups (correlation coefficients: estradiol,
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
-adrenergic
agonists (20), an aging-related decline in estrogen secretion (25), or
regulation of secretion by calcium (30). Although serum calcium itself does not change with age, hormones that regulate calcium metabolism do
change markedly with age in rats (13, 30). However, the mechanisms of
hypercalcitonemia regulated by aging in rats are still not clear.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
20°C for radioimmunoassay (RIA) of CT. Plasma calcium
concentration was determined by an automatic calcium analyzer (Calcette; Precision Systems, Natick, MA).
RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
0.41,
P < 0.01; and progesterone,
0.47, P < 0.05). There was a
significant difference (P < 0.05) in plasma estradiol and progesterone between young and old
rats and between adult and old animals (Fig. 1,
center and
bottom).
View larger version (24K):
[in a new window]
Fig. 1.
Concentration of plasma prolactin (PRL;
top), estradiol
(center), and progesterone
(bottom) in female rats of different
ages. Bars with similar superscripts were not different
(P > 0.05).
Response of CT to
CaCl2 challenge in female rats
with different ages. The changes of basal level of rat
plasma calcium (Fig. 2,
top) were not associated with age
(correlation coefficient = 0.35, P = 0.053). Compared
with young rats, the basal levels of plasma calcium decreased 4% in
old rats (Fig. 2, top). The basal
levels of plasma CT increased with age (correlation coefficient = 0.83, P < 0.01), and the lowest plasma CT
was in young rats (Fig. 2, bottom).
|
After 30 min of CaCl2 infusion, both calcium and CT increased in plasma (Fig. 2). Changes in plasma calcium after the challenge tended to differ according to age. At 30 min after the challenge, plasma calcium was higher in mid-aged rats than in young rats; however, this increase was not sustained in the old-age group. The plasma calcium had decreased more slowly in mid-aged and old rats than in the others at the end of calcium infusion. After this infusion, the maximal response of plasma CT showed an age-related increase. Meanwhile, the levels of plasma CT at 60 and 120 min after CaCl2 infusion were higher in mid-aged and old rats than in young rats. In young rats, the plasma CT levels were always significantly lower (P < 0.01) than in others. A maximal increase in plasma CT occurred in old rats.
Effect of aging on CT release in vitro. The release of CT from thyroid glands gradually increased with age (Fig. 3, correlation coefficient = 0.49, P < 0.01), and the maximal release of CT was observed in old rats (Fig. 3). Compared with young rats, the release of CT from thyroid glands increased 26, 71, and 94% in adult, mid-aged, and old rats, respectively.
|
Response of CT to CaCl2 challenges in hyperprolactinemic rats. The levels of plasma PRL were higher in AP-grafted (85.70 ± 7.67 ng/ml) than in CX-grafted (64.07 ± 4.33 ng/ml) rats. Compared with CX-grafted rats, the basal levels of plasma calcium were not different from AP-grafted rats (Fig. 4, top). The basal levels of plasma CT were higher (P < 0.05) in AP-grafted (35.80 ± 4.25 pg/ml) than in CX-grafted (23.08 ± 2.75 pg/ml) rats.
|
After CaCl2 infusion for 30 min, plasma calcium levels increased in all animals. The maximal increase of plasma calcium in response to CaCl2 infusion from 0 to 30 min was greater (33.5%, P < 0.01) in AP-grafted than in CX-grafted Ovx rats (Fig. 4, top). Thereafter, calcium levels returned to basal level at 60 min or were below the basal level at 120 min (Fig. 4, top).
Infusion of CaCl2 for 30 min increased plasma concentration of CT in all rats (Fig. 4, bottom). The maximal increase of plasma CT in response to CaCl2 infusion from 0 to 30 min was greater (40.8%, P < 0.05) in AP-grafted than in CX-grafted Ovx rats (Fig. 4, bottom). Both CaCl2-induced and post-CaCl2 levels (120 min) of plasma CT in Ovx rats were altered by hyperprolactinemia.
Effects of hyperprolactinemia on the release of CT in vitro. The basal release of CT from thyroid glands was higher in AP-grafted than in CX-grafted rats (Fig. 5). Administration of oPRL (80 ng/ml) increased the in vitro release of thyroid CT in CX- and AP-grafted rats. After oPRL (40 ng/ml) treatment, the release of CT from thyroid glands was also higher in AP-grafted than in CX-grafted rats. The correlation coefficients between oPRL and CT were 0.52 (P < 0.05) and 0.50 (P < 0.05) in AP- and CX-grafted rats, respectively.
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DISCUSSION |
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In this study we found that 1) the time it took for CaCl2-stimulated levels of plasma CT to return to pre-CaCl2 levels was longer in old and mid-aged than in young and adult rats; 2) the release of thyroid CT in thyroid glands was the greatest in old rats; 3) compared with CX-grafted rats, the AP-grafted rats possessed higher levels of plasma PRL and CT; 4) maximal increase of plasma CT in response to CaCl2 infusion was greater in AP-grafted than in CX-grafted rats; and 5) the release of thyroid CT in thyroid glands was greater in AP-grafted than in CX-grafted rats.
Age-associated morphological and physiological changes of the thyroid have been known for some time. In elderly humans, thyroid weight has been shown to decrease, remain substantially unchanged, or increase; the last is unrelated to physiological aging but is rather the consequence of an increased prevalence of nodular goiter in the elderly (4, 17). An age-dependent increase in thyroid weight also occurs in rats (20, 21). This finding is similar to our results. Admittedly, a number of C cells have been shown to increase in rats from birth to 120 days (18). In humans, however, the number of C cells appears to decrease rather than increase with age (28, 29). This may be one of the reasons why the plasma levels of CT are decreased in elderly humans but increased in aged rats.
Age-associated or age-specific physiological changes in CT secretion
have been extensively investigated in both humans and experimental
animals. Deftos et al. (7) found that, irrespective of age, the
increase in CT in response to calcium infusion was greater in men than
in women but that basal levels of CT and the response to calcium waned
with age in both sexes. Queener et al. (20) found that
hypercalcitonemia occurs in aged Buffalo rats, as does
hyperparathyroidism, and further suggested that the concentrations of
CT in blood are modulated by -adrenergic agonists. In this study, we
found that the pre- and post-CaCl2
plasma CT and the in vitro release of CT reach the highest levels in
old rats compared with young rats. After
CaCl2 challenge, the plasma level
of calcium at 60 min was higher in mid-aged and old rats than in young
rats. Thus mid-aged and old rats had a low recovery ability on plasma calcium from CaCl2 stimulation.
The increased in vitro release of CT in aged rats has also been
observed by Wongsurawat and Armbrecht (30). Tsai et al. (25) have
reported that the basal CT secretion and the maximal CT level in female
rats during calcium infusion are increased with age. The link between
estrogen and the hypocalcemic effect of CT observed in rats is actually
an age-related phenomenon instead of a physiological regulation of all
ages (25). Thus hypercalcitonemia occurs in aged rats (20, 25, 30), and the increased secretion of CT is probably due to
-adrenergic agonists (20), an aging-related decline in estrogen secretion (25), or
regulation of secretion by calcium (30).
Previous studies have demonstrated that the circulating PRL concentration in rats (10) and humans (26) increases during aging. In humans, it has been shown that gonadal steroid deficiency may affect malfunction of CT secretion (9). Meanwhile, the basal plasma CT levels are slightly reduced in hyperprolactinemic women (24). These phenomena may explain why aged humans possessing low ovarian steroid hormones and high PRL have a low level of basal plasma CT.
In this study, we have confirmed that the level of plasma PRL is gradually and age-dependently increased and that the levels of plasma estradiol and progesterone are gradually and age-dependently decreased in rats. Because lower plasma levels of estrogen and/or progesterone result in a decrease of the levels of plasma CT in Ovx rats (6), the hypercalcitonemia in female rats during aging is not due to the decline of ovarian steroid hormones.
Previous studies have demonstrated that hyperprolactinemia is associated with decreased bone mineral density (24) and that plasma CT levels are slightly reduced in hyperprolactinemic women (24), which is similar to the CT levels in older humans. In this study, the hyperprolactinemic rats induced by AP graft were used as an aged-animal model. We found that the basal, CaCl2-induced, and oPRL-stimulated levels of CT release from thyroid glands were markedly higher in AP-grafted hyperprolactinemic rats than in CX-grafted animals. Furthermore, the in vitro release of CT was increased by oPRL in AP- or CX-grafted rats. The maximal increase of plasma calcium in response to CaCl2 infusion from 0 to 30 min was greater in AP-grafted than in CX-grafted rats and greater in the old than in the young rats. Recently, Ohkubo et al. (19) reported that the gene encoding the PRL receptor is expressed in the thyroid gland of the domestic chicken. These data indicate that hyperprolactinemia was involved in the mechanism regulating hypersecretion of CT in rats during aging.
In summary, the present results demonstrate that the hypersecretion of CT both in vivo and in vitro in female rats during aging is associated with an increase of the plasma PRL arising from hyperprolactinemia.
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ACKNOWLEDGEMENTS |
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The authors greatly appreciate A. L. Vendouris for English editorial assistance.
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FOOTNOTES |
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This study was supported by Grant CI-85-03 from the Yen Tjing Ling Medical Foundation and Grant NRICM-84104 from the National Research Institute of Chinese Medicine, Republic of China. This work was also supported by awards from the Medical Research and Advancement Foundation in memory of Dr. Chi-Shuen Tsou (ROC) to P. S. Wang.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: P. S. Wang, Dept. of Physiology, National Yang-Ming Univ., Shih-Pai, Taipei, Taiwan, Republic of China.
Received 20 March 1998; accepted in final form 15 July 1998.
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