Parathyroid responsiveness to hypocalcemic and hypercalcemic stimuli in adult growth hormone deficiency after growth hormone replacement

Abstract

. Parathyroid responsiveness to hypocalcemic and hypercalcemic stimuli in adult growth hormone deficiency after growth hormone replacement. Am J Physiol Endocrinol Metab 286: E986 -E993, 2004; 10.1152/ajpendo. 00325.2003.-Adult growth hormone deficiency (AGHD) is associated with osteoporosis. Previous reports have suggested that alterations in parathyroid gland responsiveness to changes in calcium concentration may play a role in the genesis of osteoporosis in untreated AGHD patients. We investigated the endogenous parathyroid hormone ] response to hypocalcemic and hypercalcemic stimuli induced by sodium EDTA and calcium gluconate infusion, respectively, and to PTH-(1-34) infusion in AGHD patients before and during GH replacement (GHR). We have demonstrated that the maximum PTH-(1-84) stimulation and suppression occurred at significantly higher calcium concentrations and in response to smaller changes in calcium concentrations after GHR. The calcemic response to the effects of PTH-(1-34) infusion significantly increased after GHR. The calcium set point (the calcium concentration at which the rate of PTH secretion is one-half of its maximal value) significantly increased in all groups after 3 mo on GHR, and it increased further at 12 mo. Our results suggest increased parathyroid gland sensitivity to smaller changes in serum calcium and increased endorgan sensitivity to the effects of PTH in AGHD patients after GHR. These findings may help us to understand the mechanisms underlying the genesis of osteoporosis in AGHD patients. sodium ethylenediaminetetraacetic acid; calcium gluconate; parathyroid hormone-(1-84); parathyroid hormone-(1-34); calcium set point EXTRACELLULAR IONIZED CALCIUM concentration is maintained near constancy via a complex homeostatic mechanism, which includes the calcium-sensing receptors found in the parathyroid glands (15), and by an effector system with specialized cells in the kidneys, bone, and intestines that responds to calciotropic hormones with changes in the transport of mineral ions so as to restore calcium and phosphate concentrations toward normal (13). The parathyroid gland calcium-sensing receptor cell is remarkably sensitive to alterations in extracellular calcium concentration, and an inverse sigmoidal relationship has been shown between parathyroid hormone (PTH) release and extracellular calcium concentration in normal and abnormal parathyroid tissue (12).Extracellular ionized calcium concentration is generally regarded as the principal regulator of PTH secretion in vivo (34). However, it has been suggested that changes in maximal PTH secretion, slope of the PTH secretory curve at the calcium set point (the calcium concentration at which the rate of PTH secretion is one-half of its maximal value) (17), and the calcium set point and maximum suppressibility of PTH release might all contribute to PTH secretion (12). On a quantitative basis, changes in calcium set point have been shown to produce the largest alteration in PTH secretory rate for a given change in the value of a p...

PTH Circadian Rhythm and PTH Target-Organ Sensitivity Is Altered in Patients With Adult Growth Hormone Deficiency With Low BMD

“…The study size was determined by a power calculation that was based on previous studies performed at our center ( 3–5,24 ). Using the normogram presented by Altman,( 25 ) the power derived with eight patients in each group, at a significance level of 0.05, was >95%.…”

“…GHR also increases the maximal renal tubular phosphate reabsorption (TmPO 4 ), thereby resulting in an increase in serum phosphate (PO 4 ) concentration ( 5,6 ). It has been suggested that the increase in PTH target‐organ sensitivity and parathyroid gland calcium sensing receptor (CaSr) sensitivity, together with restoration toward normal of the Ca and PO 4 metabolism, may result in a positive effect on bone remodeling and subsequent increase in BMD, which has been consistently reported in patients with AGHD after GHR ( 3,5 ). PTH plays an important role in the physiology of bone remodeling ( 7 ).…”

Effect of Oral Phosphate and Alendronate on Bone Mineral Density When Given as Adjunctive Therapy to Growth Hormone Replacement in Adult Growth Hormone Deficiency

“…However, the mechanism that results in benefit differs between therapies. Previous studies have suggested that GHR alone may lead to an increase in bone turnover and consequently BMD by improving target-organ sensitivity to PTH (12)(13)(14)(15). In keeping with these studies, the initiation of GHR alone in our previously untreated AGHD patients did result in an increase in PTH target-organ sensitivity, as demonstrated by a decrease in PTH with simultaneous increase in NcAMP, ACa, 1,25(OH) 2 D, and markers of bone turnover, together with a decrease in urine calcium excretion.…”

“…Temporal fluctuations in PTH secretion are particularly important in bone remodeling (9). The nocturnal rise in PTH concentration is absent in postmenopausal osteoporotic women (9,10), and blunting of the nocturnal PTH rise has been reported in patients with untreated AGHD (11)(12)(13)(14)(15).…”

“…Patients with untreated AGHD have a reduction in the sensitivity of the kidney and bone to the effect of PTH, as evidenced by higher PTH concentration in the presence of lower nephrogenous cAMP (NcAMP; marker of PTH activity at the kidney), together with lower bone turnover markers and serum adjusted calcium concentration than healthy controls-a change that may be reflected in the reduction in bone turnover and BMD (11)(12)(13)(14)(15). GH replacement (GHR) in AGHD results in an increase in PTH target-organ sensitivity, as evidenced by a decrease in PTH with simultaneous increase in NcAMP, markers of bone turnover and serum adjusted calcium, and this may lead to the increase in bone turnover and BMD consistently reported after GHR (12,14,15).…”