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GH Secretion Is Impaired in Patients with Primary Hyperparathyroidism

Departments of Endocrinology (M.G., E.C., L.G., R.C., C.M., E.M.) and Surgery (P.M.), University of Pisa, 56124 Pisa, Italy; Chair of Endocrinology (L.B.), University of Insubria, 21100 Varese, Italy; and Division of Endocrinology (G.A., F.B., E.G.), University of Turin, 10126 Turin, Italy

Address all correspondence and requests for reprints to: Enio Martino, M.D., Dipartimento di Endocrinologia e Metabolismo, Ortopedia e Traumatologia, Medicina del Lavoro, University of Pisa, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy. E-mail: . emartino{at}endoc.med.unipi.it

Abstract

The activity of the GH/IGF-I axis as a function of parathyroid activity and calcium metabolism in humans has never been assessed. To address this issue, we studied 18 patients (5 men, 13 women; age range, 23–76 yr; mean, 61 yr) with primary hyperparathyroidism (PHP) due to solitary parathyroid adenoma. GH secretion was evaluated by serum IGF-I levels, spontaneous mean GH secretion over two morning hours, and GH response to arginine (ARG) alone or combined with GHRH. In five patients, serum GH concentrations were measured every 20 min for 24 h, and deconvolution analysis was performed. A group of 35 age- and sex-matched normal subjects served as controls.

Mean serum IGF-I levels in PHP were lower than in normal controls, and in six PHP patients individual serum IGF-I levels were below the age-related normal range. The mean (±SE) peak GH response to ARG alone in PHP patients was significantly lower than in normal subjects (4.0 ± 1.0 vs. 22.0 ± 1.3 µg/liter; P < 0.001). Likewise, the mean (±SE) peak GH response to ARG plus GHRH was reduced in PHP patients (9.9 ± 0.9 vs. 38.0 ± 3.5 µg/liter; P < 0.001). The mean GH concentration over two morning hours in PHP was lower (0.20 ± 0.05 vs. 1.34 ± 0.31 µg/liter; P < 0.001). The mean GH concentration over 24 h in five PHP patients was lower than in six normal controls (0.3 ± 0.1 vs. 0.7± 0.1 µg/liter; P < 0.05); the deconvolution analysis showed that 24-h GH production rate (3.0 ± 1.7 vs. 28.2 ± 4.7 µg/liter·d; P < 0.05) and mean secretory burst mass (1.2 ± 0.7 vs. 10.5 ± 2.6 µg/liter; P < 0.05), but not pulse frequency, were lower in PHP patients than in normal controls. GH half-life and approximate entropy values of 24-h GH profiles were similar in PHP patients and normal controls. No correlation was found between serum-ionized calcium or PTH levels and spontaneous or stimulated GH levels in PHP patients.

In conclusion, this study demonstrates that PHP patients have a reduction in both spontaneous and stimulated GH secretion. Accordingly, PHP should be mentioned as a further example of a metabolic condition in which GH secretion in adults is reduced.

GH SECRETION IS mainly dependent on hypothalamic control by the stimulatory GHRH and the inhibitory somatostatin, which in turn are under the influence of several neurotransmitters and neuropeptides (1, 2).

Among metabolic factors of GH secretion, the role of calcium in the regulation of GH secretion has been studied in vitro at the intracellular level. The acute exposure of rat, ovine, and human cell cultures to calcium was reported to be associated with an enhanced GH release (1, 2, 3, 4, 5), whereas calcium antagonists were shown to reduce the GH stimulation by various stimuli (6, 7, 8).

In vivo, in humans, studies on the effects of acute calcium excess or deprivation on GH secretion have provided contradictory results. In fact, in patients with primary hyperparathyroidism (PHP) after parathyroidectomy, both decreased (9) and increased (10) serum GH concentration have been reported. On the other hand, the influence of chronic hypercalcemia on the activity of the GH/IGF-I axis is basically unknown (11).

The aim of the present study was to investigate the influence of chronic hypercalcemia due to PHP on adult somatotroph function by evaluating both spontaneous and stimulated GH secretion. The results obtained in PHP patients were compared with those in age-matched controls and referred to age-related normal limits of GH and IGF-I secretions of our laboratory (12, 13). Herein, we demonstrate that PHP patients show a reduction in either spontaneous or stimulated GH secretion and in IGF-I levels, suggesting that PHP is another condition associated with an impairment of GH secretion in adulthood.

Subjects and Methods

Subjects

The study group included 18 patients (5 men, 13 women) with PHP due to solitary parathyroid adenoma. Ages ranged from 23–76 yr (mean, 61 yr). Clinical signs and symptoms, including kidney stones, of PHP lasted for 1–4 yr before diagnosis. Diagnosis was based on increased serum-ionized calcium and PTH levels (14) and was supported by the presence of one hypoechoic posterior nodule in the thyroid bed by ultrasound, positive at Sestamibi parathyroid scan. No patient had a history of head trauma. Pituitary computed tomography scan was performed in all patients but failed to detect any pituitary abnormality. No clinical or biochemical thyroid, adrenal, or gonadal abnormalities, as well as renal, liver, and cardiac abnormalities, were detected. Patients did not take drugs known to affect GH secretion. The body mass index was normal in all but one patient. Patients had received no treatment for at least 1 yr. All patients were submitted to video-assisted parathyroidectomy; PHP was cured by this procedure in all instances (15, 16).

The control group consisted of 35 normal age- and sex-matched subjects (12 men, 23 women; age range, 23–78 yr; mean, 59 yr), enrolled in the same period.

The clinical and biochemical features of the two groups are summarized in Table 1.

The study was approved by the Local Ethical Committee. An informed consent was obtained from all subjects.

Methods

Ionized calcium was measured by calcium ion selective method (Nova Biomedical, Waltham, MS); serum intact PTH was measured by specific immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA); and serum GH and IGF-I were measured by specific RIAs (Nichols Institute Diagnostics). To avoid interference of binding proteins, the samples were treated by acid ethanol. Normal values in our laboratory were as follows: ionized calcium, 1.13–1.30 mmol/liter; serum PTH, 10–65 pg/ml; serum IGF-I varied according to the age of subjects, as previously reported (13). Sensitivity of IGF-I assay was 0.3 µg/liter. Serum GH assay had a sensitivity of 0.15 µg/liter. Inter- and intra-assay coefficients of variation were: 5.6–6.2 and 1.8–3.3.% for PTH, 2.9–4.5 and 2.4–4% for GH, 7.6–15.5 and 10.1–15.7% for IGF-I, respectively.

Assays were done in duplicates in a single run for each subject.

Assessment of GH secretion

Spontaneous and stimulated GH secretion was assessed as follows:

Mean GH concentration over two morning hours. Serum GH was measured in the morning, starting from 0800–0830 h after an overnight fast, at 30-min intervals for 2 h. Values were expressed as mean GH concentrations over 2 h.

Arginine (ARG) test. Serum GH was measured at baseline and 30, 60, and 90 min after the iv 30-min infusion of arginine hydrochloric [0.5 g/kg body weight (BW); Damor, Naples, Italy].

ARG plus GHRH test. Serum GH was measured at baseline and 30, 60, and 90 min after the simultaneous iv 30-min infusion of arginine hydrochloric (0.5 g/kg BW) and GHRH (1 µg/kg BW as an iv bolus at 0 min; GHRH-29, Geref, Serono, Rome, Italy). The ARG plus GHRH test was performed 2 d after the ARG test.

Both tests were performed in the morning after an overnight fast. An indwelling catheter was placed in the antecubital vein and kept patent by a slow infusion of isotonic saline.

Circadian secretory pattern. Serum samples for GH measurement were drawn every 20 min for 24 h during normal diurnal activity and 7–8-h controlled nocturnal sleep. An indwelling catheter was placed in the antecubital vein and kept patent by a slow infusion of isotonic saline.

Analysis of 24-h GH secretion

Multiparameter deconvolution analysis, as proposed by Veldhuis et al. (17) was used to quantitate pulsatile GH secretion and estimate the corresponding hormone half-life. Basal hormone secretion represents the calculated time-invariant interpulse component of the release profile. The daily pulsatile production rate is the product of the number of secretory bursts and the mean mass of GH released per pulse. Secretory pulse identification required that secretory-burst amplitudes and the basal secretion rate exceeded 0 by 95% statistical confidence. The analyst was blinded to the randomization scheme.

Approximate entropy (ApEn)

ApEn was used as a scale-and-model independent statistic that is complementary to deconvolution analysis (18). ApEn quantifies the serial order lines or pattern regularity of hormone measurements. Normalized ApEn parameters of m = 1 (series length) and r = 20% (threshold) of the intraseries SD were used as previously validated for 24-h time series (19). This statistic is thus designated ApEn (1.20%). Increased ApEn (at equal series length and similar parameter values, as used here) indicates greater secretory process irregularity consistent with altered within-axis feed-forward, feed-back control (18). The results are reported as the mean ± SE of absolute values, as well as areas under the curve calculated by trapezoidal integration.

Statistical analysis

Ionized calcium, serum GH, PTH, and IGF-I were expressed as mean ± SE. Differences between groups were analyzed by t test for unpaired data. A P value less than 0.05 was considered as significant.

Results

As illustrated in Table 1, increased values of ionized calcium and serum PTH were found in all PHP patients, with mean values of 1.53 ± 0.03 mmol/liter and 159 ± 19 pg/ml, respectively. These values were significantly higher than those in normal controls (ionized calcium, 1.19 ± 0.03 mmol/liter, P < 0.001; serum PTH, 42.0 ± 3.0 pg/ml, P < 0.001). Serum IGF-I concentration, corrected for age, was decreased in 6 patients and was within the normal range in 12 patients.

Mean serum GH over two morning hours was significantly reduced in PHP patients compared with normal controls (0.20 ± 0.05 vs. 1.34 ± 0.31 µg/liter; P < 0.01). Figure 1 shows that GH secretory peak after ARG stimulation test was below the lower normal limit in all PHP patients; the mean GH peak values were significantly reduced compared with normal controls (4.0 ± 1.0 vs. 22.0 ± 1.3 µg/liter; P < 0.001). Similar results were obtained with the ARG plus GHRH test (PHP patients, 9.9 ± 0.9 µg/liter; controls, 38.0 ± 3.5 µg/liter; P < 0.01) (Fig. 1).

View larger version (14K): [in this window] [in a new window]   Figure 1. Individual values of serum GH after ARG stimulation test (top) and ARG plus GHRH stimulation test (bottom) in PHP patients and controls. Mean (±SE) GH peak after ARG was 4.0 ± 1.0 µg/liter in patients and 22.0 ± 1.3 µg/liter in controls. Mean (±SE) GH peak after ARG plus GHRH was 9.9 ± 0.9 µg/liter in patients and 38.0 ± 3.5 µg/liter in controls. The boxes represent normal ranges.

View larger version (16K): [in this window] [in a new window]   Figure 2. Mean (±SE) spontaneous GH secretion in five patients with PHP and six controls.

Discussion

The results of the present study demonstrate that PHP patients show a clear reduction in the GH response to provocative tests. This impaired GH response even to a maximal provocative test is associated with a reduction in spontaneous 24-h GH secretion as well as in some cases in serum total IGF-I concentration. To our knowledge, the activity of the GH/IGF-I axis in PHP had never systematically been assessed before. In a previous report, Kovacs et al. (10) evaluated basal GH levels before and after parathyroidectomy for PHP and found that serum GH secretion had increased after parathyroid surgery.

The results of the present study suggest that PHP may represent a further example of a metabolic condition in which GH secretion in adulthood is reduced. The latter should be suspected on clinical grounds and supported by appropriate dynamic tests. In fact, serum IGF-I concentrations, as well as spontaneous GH secretion, are low in patients with GH deficiency but are insufficient to establish the correct diagnosis due to substantial overlapping with values found in normal controls (12, 13, 17, 18, 19, 20). Among provocative tests, the ARG test provides reliable information on the presence of GH deficiency (20), but sensitivity and specificity are increased by the combined stimulation of ARG and GHRH (21). Provided that the response to the above provocative tests, as well as the evaluation of the spontaneous GH secretion over 2 h, support the diagnosis of adult GH deficiency, the results observed in our series of PHP patients indicate that the latter disease should be regarded as a possible condition predisposing to GH deficiency. In fact, a significant reduction in spontaneous GH secretion over two morning hours was observed in all PHP patients, as well as a decreased response to both ARG and ARG plus GHRH provocative tests. Effectively, 7 of 11 patients had a minimal response, suggesting the presence of severe GH deficiency. Although the mean GH concentration over two morning hours does not necessarily reflect the daily mean GH secretion (2), the finding in a subset of PHP patients that the 24-h mean serum GH concentration was reduced reinforces the concept that PHP is characterized by an impairment of both spontaneous and stimulated GH secretion.

The finding that 5 of 11 PHP patients had reduced serum IGF-I concentrations further supports the diagnosis of GH deficiency. The high prevalence of decreased serum IGF-I levels is remarkable in view of the observation that even in severe adult GH deficiency, only about half of the patients show serum IGF-I concentrations below the normal limits (12).

The direct role of PHP in causing this situation in our patients seems to be supported by the absence of other conditions associated with GH deficiency in adults, such as previous head traumas, pituitary abnormalities (empty sella, pituitary tumors, previous pituitary surgery or irradiation, etc.), or obesity.

Regarding the potential mechanisms involved in the pathogenesis of GH deficiency in PHP patients, some neuroendocrine insight may derive from the deconvolution analysis of 24-h GH profiles. Despite the absence of changes in GH pulse frequency and half-life, PHP patients showed a significant reduction in 24-h GH production rate and mean secretory burst mass. This may suggest an impaired activity of hypothalamic GHRH-secreting neurons or GH-stimulating peptide neurons or failure of the somatotrophs to respond to GHRH or other GH secretagogues (22). However, the pathophysiological mechanisms leading to GH deficiency remain to be clarified. Actually, our findings indicate that the activity of the GH/IGF-I axis in PHP does not seem to be correlated with parameters of calcium metabolism and serum PTH levels. To clarify these aspects and the reversibility of this situation, it will be necessary to verify whether GH deficiency can be corrected after successful removal of parathyroid adenoma. In addition, it will be appropriate to investigate whether the impairment of GH secretion is correlated with PHP duration. Finally, GH secretion should be assessed in hypercalcemic conditions associated with normal to low PTH levels. Both studies are in progress. The real pathophysiological significance of GH deficiency in PHP remains to be clarified because, as far as we presently know, it might represent a physiological and normal reaction. Because GH deficit is likely to be reverted by correction of PHP, treatment of GH deficiency in PHP should coincide with parathyroidectomy. Accordingly, at the present state of knowledge, the use of GH replacement therapy should be discouraged in patients with hyperparathyroidism and GH deficiency.

In conclusion, this study represents the first demonstration that PHP is associated with the impairment of GH secretion and should be mentioned as a further example of a metabolic condition in which GH secretion in adults is impaired.

Footnotes

This work was supported in part by grants from the Ministero della Università e della Ricerca Scientifica e Tecnologica, Rome, Italy (to E.M.).

Abbreviations: ApEn, Approximate entropy; ARG, arginine; BW, body weight; PHP, primary hyperparathyroidism.

Received May 21, 2001.

Accepted January 24, 2002.

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