Effects of estradiol and progesterone on parathyroid hormone secretion from human parathyroid tissue.

Estrogens have been used to treat the hypercalcemia in primary hyperparathyroidism. Estrogens and progesterone both stimulate PTH secretion from bovine parathyroid tissue. The effects of these agents on PTH secretion from human parathyroid tissue are not known. In this study, we evaluated the effects of 17 beta-estradiol and progesterone on PTH secretion from abnormal parathyroid tissue from seven patients (four adenomas, three hyperplasia). Both estradiol (10(-9)-10(-6) mol/L) and progesterone (10(-7) and 10(-6) mol/L) significantly stimulated PTH secretion in a time- and dose-dependent manner during a 3-h period. These results indicate the need for a careful evaluation of serum PTH levels and other parameters of parathyroid function in estrogen- and/or progesterone-treated patients with primary hyperparathyroidism.

Parathyroid hormone secretion: effect of estradiol and progesterone.

Previous studies have shown that estrogen therapy in postmenopausal women results in an increase in serum immunoreactive parathyroid hormone (iPTH) levels. It has been assumed that this effect of estrogen on PTH secretion is indirect, being mediated via mild hypocalcemia resulting from an inhibition of bone resorption. We evaluated the direct effect of 17 beta-estradiol (E2) and of progesterone (Prog) on secretion of PTH from bovine parathyroid tissue in vitro. Both E2 and Prog caused a significant stimulation of PTH secretion within one hour, which was progressive for the three-hour observation period. The responses were dose-related from 10(-7) to 5 X 10(-10) mol/L. There was no PTH response to 10(-7) mol/L alpha-E2, 3-methoxy estriol, estrone, testosterone, or 20-alpha-hydroxy progesterone, indicating specificity of the responses to E2 and Prog. There was a minimal PTH secretory response to 10(-6) mol/L cortisol and 10(-6) mol/L estrone. The E2 receptor antagonist tamoxifen did not inhibit the E2 effect on PTH secretion. This observation plus the rapid PTH response suggests that this hormonal effect may not be via the conventional intracellular E2 receptor. Therefore, E2 and Prog can stimulate PTH secretion by rapid, direct, and specific effects on parathyroid cells. These gonadal hormones may, therefore, be important in calcium homeostasis via their direct stimulatory effect on PTH secretion.

Prolonged effect of estradiol on calcitonin secretion.

Incubation of thyroparathyroid gland from 8-day-old rats with estradiol (10(-7) and 10(-9) M) and progesterone (10(-9) and 3 X 10(-10) M) resulted in stimulation of CT secretion. The effect of the gonadal steroids on CT secretion occurred at near physiological concentrations and persisted for at least 73 h. The studies demonstrate that exposure to gonadal steroids results in direct and prolonged stimulation of CT secretion. Therefore the decrease in bone resorption observed after the administration of gonadal steroids in vivo may at least in part be mediated via stimulation of CT secretion.

Effects of estradiol and progesterone on calcitonin secretion.

Estrogen therapy has been used to inhibit bone resorption and prevent osteoporosis in postmenopausal women. Previous studies have disagreed as to whether the mechanism of estrogen action involves stimulation of calcitonin (CT) secretion. We evaluated the direct effects of 17 beta-estradiol (E2) and progesterone (Prog) on CT secretion from the thyroid C cells of 8-day-old rats in vitro. Both E2 and Prog caused a significant stimulation of CT secretion within 1 h, which was progressive for the 3-h observation period. The responses were dose related from 10(-7) to 5 X 10(-10) M. There was no CT response to 10(-7) M alpha-estradiol, estriol, 3-methoxyestriol, estrone, testosterone, or 20 alpha-hydroxyprogesterone, indicating specificity of the responses to E2 and Prog. There was a minimal CT secretory response to 10(-6) M cortisol. The E2 receptor antagonist tamoxifen did not inhibit the E2 effect on CT secretion. This observation plus the rapid CT response suggest that this hormonal effect may not be via the conventional intracellular E2 receptor. Therefore, E2 and Prog can stimulate CT secretion by rapid, direct, and specific effects on the thyroid C cell. The gonadal hormones may, therefore, be important in inhibiting bone resorption via their direct stimulatory effect on CT secretion.

Parathyroid hormone and calcitonin secretion in man: effect of dopamine agonists and antagonists.

This study was undertaken to evaluate the physiological role, if any, of dopamine (DA) in modulating parathyroid hormone (PTH) and calcitonin (CT) secretion in man. Infusion of DA (5 micrograms/kg/min) into 6 normal men, decreased serum immunoreactive prolactin (iPRL) and concomitantly increased serum iPTH to 140 +/- 6.8% of baseline (P less than 0.01) at 30 min, with decline thereafter, despite continuation of the DA infusion. Serum iCT levels did not significantly change. Chlorpromazine (50 mg IM), decreased serum iPTH to 75 +/- 5.4% and 79 +/- 3.7% of baseline (P less than 0.01) at 30 and 60 min, respectively, associated with an increase in iPRL. There was subsequent return of iPTH to baseline even though iPRL remained elevated. iCT levels did not significantly change. These observations would suggest that DA may play a physiological role in iPTH, but not iCT, secretion. However, infusion of more nearly physiological doses of DA (0.02, 0.2, and 2.0 micrograms/kg/min) lowered serum iPRL to levels similar to those after the larger DA dose, but with no concomitant increase in either iPTH or iCT. Also, 1) the DA agonist bromocriptine decreased serum iPRL without modifying iPTH or iCT; 2) the DA precursor, levodopa, and the DA antagonist, metoclopramide, had no effect on serum iPTH or iCT levels. These studies suggest that 1) the transient stimulatory effect of DA on iPTH secretion is pharmacological, and 2) DA does not have a physiological role in secretion of iPTH or iCT in man.

Effect of the parasympathetic system on secretion of parathyroid hormone.

This study evaluated the effect of parasympathetic agonists and antagonists on immunoreactive (i) PTH secretion in vitro and on serum iPTH in vivo in rats. In in vitro studies pilocarpine or bethanechol significantly inhibited PTH secretion. This inhibition was blocked by the simultaneous addition of atropine to the incubation medium. In in vivo studies, the cholinergic agonists pilocarpine and bethanechol and the cholinergic antagonist atropine were administered to rats by IV infusion. Blood was obtained before and again after two hours of infusion for analysis of iPTH. Pilocarpine or bethanechol significantly decreased serum iPTH. This inhibition by either agent was blocked by the simultaneous administration of atropine. Administration of atropine alone significantly increased serum iPTH above baseline. This stimulation of basal serum iPTH by parasympathetic blockade suggests that even basal PTH secretion may be influenced by endogenous parasympathetic tone. Therefore, the following conclusions were reached: (1) parasympathetic influences inhibit PTH secretion, and (2) endogenous parasympathetic tone may be an inhibitory modulator of basal secretion of PTH.

Effect of exercise on serum calcium and parathyroid hormone.

Previous studies have suggested a role for adrenergic stimuli in the regulation of PTH secretion. In the present studies, we evaluated the effect of endogenous catecholamine stimulation (by treadmill exercise) on serum calcium (Ca) and immunoreactive PTH (iPTH) in six healthy volunteers. Blood was collected for serum total Ca, ionized Ca, iPTH, cAMP, epinephrine, and norepinephrine before, during, and after exercise. As expected, plasma cAMP and catecholamine levels increased significantly during the exercise. In addition, there was an increase in serum total and plasma ionized Ca. However, serum iPTH levels did not change significantly at any of the times tested during and after exercise. The lack of change in serum PTH despite an increase in plasma catecholamines may be explained by 1) an increase in plasma ionized Ca by a separate mechanism (such as metabolic acidosis), which blocked an increase in serum iPTH, or 2) insufficient increase in plasma catecholamines to stimulate PTH secretion.

Calcium metabolism in diabetic mother, fetus, and newborn infant.

Peripheral blood levels of the minerals and hormones involved in calcium homeostasis were measured in insulin-dependent diabetic patients at delivery, and in umbilical arterial and venous blood. The minerals were also measured in neonatal blood at 24 hours of age. Insulin-dependent diabetic patients at delivery have depressed serum levels of parathyroid hormone, although serum total and ionized calcium levels are not different from those of nondiabetic patients. Fetuses of diabetic mothers are hypocalcemic and have reduced parathyroid hormone levels. Infants of diabetic mothers demonstrate early neonatal hypocalcemia. No differences between diabetic and control patients could be demonstrated in terms of calcitonin or phosphorus levels, in either mother, fetus, or neonate.

Effect of meal on serum parathyroid hormone and calcitonin: possible role of secretin.

Purified secretin infused in an estimated physiological dose caused an increase in serum immunoreactive PTH (iPTH) and calcitonin (iCT) in man. Ingestion of a gastric acid-stimulating test meal, a procedure known to increase endogenous secretin, caused increases in serum iPTH and plasma iCT in normal subjects. Ingestion of antacid with the test meal blunted the increase in both iPTH and iCT. Ingestion of the test meal by pernicious anemia patients with achlorhydria caused no stimulation of either serum iPTH or plasma iCT. Therefore, based on the observations that 1) exogenous secretin stimulated iPTH and iCT, 2) an acid-stimulating test meal is known to stimulate endogenous secretin release (4), 3) the test meal increased both serum iPTH and iCT in normal man, an effect nullified by simultaneous antacid ingestion, and 4) the test meal caused no increase in either iPTH or iCT in achlorhydric patients, we conclude that endogenous secretin possibly mediates this effect of test meal and, therefore, may play a physiological role in modulating the secretion of PTH and CT.

Parathyroid hormone secretion: effect of beta-adrenergic blockade before and after surgery for primary hyperparathyroidism.

Serum immunoreactive parathyroid hormone (iPTH) response to beta-adrenergic blockade by propranolol infusion was determined in 11 normal subjects and 6 patients with primary hyperparathyroidism (PHPT) before and again after the surgical removal of abnormal parathyroid tissue. Propranolol infusion in PHPT patients before surgery resulted in no significant decrease in serum iPTH except at 2 h, when the mean value was 83 +/- 4.4% of baseline. After surgery and achieving a euparathyroid state, the same patients showed a significant propranolol-induced decrease in serum iPTH from baseline at all time periods tested, reaching the nadir value of 57 +/- 7.5% of baseline at 2 h after the start of the propranolol infusion. This response in PHPT patients after surgery was very similar to the response seen in normal subjects. Therefore, this impaired suppressibility of serum iPTH in PHPT is corrected after removal of the abnormal parathyroid tissue. The studies indicate that abnormal parathyroid tissue (either per se or via a metabolic state induced by it) is responsible for the impaired response to beta-adrenergic blockade. It therefore appears unlikely that the impaired beta-adrenergic responsiveness is involved in the pathogenesis of PHPT.

Effect of secretin on parathyroid hormone and calcitonin secretion.

The effect of secretin on secretion of parathyroid hormone (PTH) and calcitonin (CT) was evaluated by both in vitro and in vivo techniques. In in vitro studies with bovine parathyroid tissue, Secretin-Boots caused significant dose-related increases in PTH secretion. In in vitro studies with rat thyroparathyroid tissue, Secretin-Boots caused significant increases in both PTH and CT secretion. Infusion of Secretin-Boots or of synthetic secretin in biologically equivalent doses into rats caused similar increases in secretion of PTH and of CT. Infusion of multiple doses of synthetic secretin revealed a dose-related stimulation of both PTH and CT secretion. Infusion of Secretin-Boots into normal human subjects caused prompt and progressive significant increases in secretion of both PTH and CT, with return to baseline values within 90 min after termination of the infusion. These data suggest that secretin can stimulate hormonal secretion by parathyroid and thyroid C cells and that secretin may play a modulating role in the secretion of both PTH and CT.

Normal responsiveness of serum parathyroid hormone to beta-adrenergic blockade in patients with secondary hyperparathyroidism.

Infusion of calcium gluconate (15 mg Ca++/kg body weight in 4 h) to 6 patients with secondary hyperparathyroidism (due to mild renal insufficiency) decreased serum parathyroid hormone (PTH) levels to the same degree (on a percent basis) as in normal subjects. Serum PTH values at 4 h were 60 +/- 4.5 (SEM)% of baseline in the patients and 59 +/- 2.9% of baseline in the normal subjects. Infusion of propranolol (1 mg i.v. bolus followed by an infusion of 60 micrograms/min for 2 h) to 7 additional patients with secondary hyperparathyroidism also decreased serum PTH to the same degree as in normal subjects. Serum PTH values at 2 h were 68 +/- 10.4% of baseline in the patients and 68 +/- 3.3% of baseline in the normal subjects. The studies indicate normal responsiveness of serum PTH to calcium or beta-adrenergic blockade in secondary hyperparathyroidism due to mild renal insufficiency.

Parathyroid hormone secretion in normal man and in primary hyperparathyroidism: role of histamine H2 receptors.

The effect of histamine and histamine H2 receptors on secretion off parathyroid hormone (PTH) was evaluated by 1) adding histamine phosphate (with or without the histamine H2 receptor antagonist, cimetidine) to the medium in in vitro incubation studies with bovine parathyroid tissue, 2) infusing histamine into rats, and 3) infusing the histamine H1 receptor antagonist, diphenhydramine, or cimetidine into normal men and patients with primary hyperparathyroidism. In vitro, histamine (10(-5)-10(-7) M) caused a dose-related significant stimulation of immunoreactive PTH (iPTH) secretion; this was blocked by the simultaneous addition of cimetidine (10(-5) M). Intravenous infusion of histamine significantly increased serum iPTH in rats. In normal man, infusion of diphenhydramine had no effect, but cimetidine (300 or 450 mg) significantly decreased serum iPTH. However, cimetidine had no effect on serum iTh in primary hyperparathyroid patients. The in vitro observations indicate that histamine can stimulate iPTH secretion by a direct effect on the parathyroid cell and that this is probably a specific effect via histamine H2 receptors because the effect was blocked by the H2 receptor antagonist, cimetidine. The observed inhibition of basal PTH concentration by cimetidine induced histamine H2 receptor blockade (but not by H1 blockade) in normal human subjects suggests that endogenous histamine with H2 receptor activation stimulates even basal PTH secretion and may serve as a modulator of PTH secretion in normal man. Loss of this modulating effect of H2 receptors on PTH secretion is a characteristic of primary hyperparathyroidism.

Maternal and fetal parathyroid hormone responsiveness in pregnant primates.

Maternal and fetal parathyroidd hormone (PTH) responsiveness to hypocalcemia induced by EDTA infusion (50 mg/kg over 2 h) was studied in rhesus monkeys in late pregnancy. Although baseline serum total calcium (Ca) levels in the fetus exceeded those in the mother (4.83 +/- 0.13 vs. 4.28 +/- 0.15 meq/liter; P < 0.001), PTH values were not significantly different (5.62 +/- 0.37 vs. 6.18 +/- 0.33 muleq/ml; P > 0.05). EDTA infusion directly to five fetuses produced significant hypocalcemia (maximal decline averaging 19 +/- 2%) and PTH response (maximal increase averaging 46 +/- 5%). In contrast, in four control studies involving fetal saline infusion, there were no significant changes in fetal Ca or PTH levels. Four maternal control infusions produced no significant changes in either Ca or PTH levels. A comparison of maternal and fetal PTH responses indicated considerable similarity, although fetal PTH levels tended to return to baseline somewhat more gradually after cessation of the hypocalcemic stimulus than did maternal levels. These studies indicate that fetal PTH secretion, both baseline and in response to hypocalcemia, is quantitatively similar to that of the adult, and thus, the fetal parathyroid does not appear to be suppressed by the relative hypercalcemia of late fetal life.

Mode of action of somatostatin in inhibiting parathyroid hormone secretion.

Effects of somatostatin on basal and low calcium-, isoproterenol- or dibutryl cyclic AMP (DBcAMP)-stimulated parathyroid hormone (PTH) secretion were evaluated in vitro with bovine parathyroid tissue. Low calcium, isoproterenol or DBcAMP alone significantly stimulated PTH secretion. Somatostatin 1 or 4 microgram/ml significantly inhibited these stimulated PTH secretions. Inhibition of isoproterenol-stimulated PTH secretion was more complete than was the inhibition of low calcium- or DBcAMP-stimulated secretion. The studies indicate that somatostatin inhibits PTH secretion by an action distal to cAMP generation. The more complete inhibition of isoproterenol-stimulated PTH secretion suggests that somatostatin may also have additional effects on or proximal to the formation of cyclic AMP.

Characterization of the beta-adrenergic receptor mediating secretion of parathyroid hormone.

In vitro incubation studies with bovine parathyroid gland slices compared the relative responsiveness of parathyroid hormone (PTH) secretion to isoprotherenol, epinephrine or norepinephrine. Isoproterenol was the most potent and norepinephrine the least potent of the three stimuli, suggesting a beta 2 type of an adrenergic response. However in this in vitro system, tazalol, a selective beta 1 adrenergic agonist significantly stimulated PTH secretion, whereas terbutaline, a selective beta 2 agonist had no effect. In addition, practolol, a selective beta 1 adrenergic antagonist blocked isoproterenol- or tazolol-stimulated PTH secretion. In vivo studies in normal human subjects showed that injection of te nonselective beta agonist, isoproterenol, (0.15 mg s.c.) significantly increased, whereas injection of the selective beta 2 agonist, terbulatine (0.3 mg s.c.) had no effect on serum PTH levels. These latter studies with putative selective beta adrenergic agents suggest that the beta adrenergic receptor mediating PTH secretion is of the beta 1 type (in contrast to the studies above with nonselective agents). The studies suggest that the beta adrenergic receptor mediating PTH secretion apparently differs from the classical beta 1 receptor described in th myocardium or the classical beta 2 receptor described in the bronchial smooth muscle.