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Improvement of Growth Hormone Deficiency in Patients with Primary Hyperparathyroidism after Parathyroidectomy: Results of a Prospective Study

Department of Endocrinology and Metabolism (E.C., M.Ga., F.B., L.G., M.Ge., C.M., A.P., E.M.), University of Pisa, 56124 Pisa, Italy; Division of Endocrinology (M.P.), University of Turin, Turin, Italy; and Division of Endocrinology (L.B.), University of Insubria, 21100 Varese, Italy

Address all correspondence and requests for reprints to: Prof. Enio Martino, Dipartimento di Endocrinologia e Metabolismo, Università di Pisa, Ospedale Cisanello, Via Paradisa, 2 56124, Pisa, Italy. E-mail: e.martino{at}endoc.med.unipi.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
GH secretion is impaired in most patients with primary hyperparathyroidism (PHP), although the secretion of the other anterior pituitary hormones is unaffected. However, whether restoration of euparathyroidism is associated with reversal of GH deficiency in PHP patients is not known. To address this issue, we studied 30 consecutive patients with PHP due to a single parathyroid adenoma before and after parathyroidectomy. GH secretion was evaluated by peak serum GH after the maximal GHRH + arginine (Arg) stimulation test. A group of 35 age- and sex-matched normal subjects served as controls. Serum IGF-I concentration was below the normal age- corrected values in six of 30 patients before surgery and in four of 30 patients after parathyroidectomy (P = not significant). Mean serum peak GH values after the GHRH + Arg test were 17.5 ± 2.8 µg/liter before surgery and 23.8 ± 2.5 µg /liter after surgery (P = 0.0008). The GH response to the GHRH + Arg test was reduced in 20 (67%) and normal in 10 (33%) of 30 PHP patients at baseline; after surgery, 22 of 30 (73%) PHP patients had a normal GH response to the GHRH + Arg test, and only eight (27%) had an impaired GH secretion (P < 0.02).

In conclusion, this study confirms that GH secretion is impaired in PHP patients and indicates that it is reversed in many patients after parathyroidectomy.

Accordingly, GH deficiency in PHP patients must be considered a functional phenomenon for which GH therapy is not recommended.

	Introduction

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GROWTH HORMONE (GH) secretion is regulated by several factors, including stimulatory GHRH, inhibitory IGF-I, and somatostatin (1). Several additional factors, including neurotransmitters, neuropeptides, and calcium (2, 3, 4, 5, 6, 7, 8) also play an important regulatory role both in vivo and in vitro. Rats treated with an infusion of calcium chloride have a suppressed or blunted response to the release of anterior pituitary hormone (9). Increased calcium levels might stabilize secreting granule membranes and decrease protein kinase activity, which are important steps in the secretory mechanism (10, 11). Recently, the role of either intracellular or extracellular calcium concentration in somatotrophs and lactotrophs has been confirmed (12)

We recently reported that primary hyperparathyroidism (PHP) is associated with an impaired GH production, as indicated by a reduced 24-h GH secretion and a decrease in the GH response to the GHRH + arginine (Arg) stimulation test (13). Secretion of other pituitary hormones is not influenced by PHP (14). It is unclear whether this impairment of GH secretion is a transient or a persistent phenomenon in PHP due to the lack of follow-up studies after PHP surgical correction.

The aim of the present study was to evaluate GH secretion before and after PHP cure by parathyroidectomy. The results indicate that GH secretion impairment is generally reversed by restoration of euparathyroidism.

	Patients and Methods

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Patients

Thirty consecutive PHP patients [23 women (of whom 20 were postmenopausal) and seven men; mean age, 57 yr; range, 23–75 yr] were enrolled between June 2001 and June 2002. In all cases, PHP was due to a single parathyroid adenoma. Diagnosis was based on the increased serum ionized calcium and PTH levels, and supported by the presence of a hypoechoic posterior nodule in the thyroid bed by ultrasonography, and by a positive sestamibi parathyroid scan. PHP was asymptomatic in nine patients in whom diagnosis was initially suspected on the basis of increased serum calcium concentration during a routine blood test. In the remaining 21 patients, who had complications due to osteoporosis or nephrolithiasis, disease lasted for 1–4 yr (Table 1). No patients had history of head trauma, and pituitary magnetic resonance imaging was normal in all patients. No clinical and biochemical thyroid, adrenal, gonadal, renal, liver, or cardiac abnormalities were found. No patients were taking drugs known to affect GH secretion or bone mineral metabolism. Body mass index ranged from 22–28 kg/m², with a mean of 25.3 ± 0.4 kg/m².

Thirty-five normal subjects age- and sex-matched (23 women and 12 men; mean age, 59 yr; range, 23–78 yr) served as controls.

The study was approved by the local ethical committee, and all patients provided their informed consent.

Assays

Serum ionized calcium, PTH, IGF-I, and GH were measured as previously reported (13, 14). Stimulated GH secretion was evaluated after iv administration of GHRH + Arg as previously reported (13, 16, 17). Briefly, serum GH concentrations were measured at baseline and 30, 60, and 90 min after the simultaneous iv 30-min infusion of Arg hydrochloride (0.5 g/kg body weight) and GHRH (1 µg/kg body weight as an iv bolus at 0 min; GHRH-29, Geref, Serono, Rome, Italy). Blood samples for basal hormone measurements and stimulation tests were carried out at 0800 h after an overnight fast. GH measurements were carried out in a single run for each patient; serum GH assay had a sensitivity of 0.15 µg/liter; the sensitivity of the IGF-I assay was 0.3 µg/liter. Inter- and intraassay coefficients of variation were 2.9–4.5 and 2.4–4% for GH and 7.6–15.5 and 10.1–15.7% for IGF-I, respectively.

Normal values in our laboratory are as follows for ionized calcium, 1.13–1.30 mmol/liter; serum PTH, 10–65 pg/ml; serum IGF-I, 182–780 µg/liter; 16–24 yr, 90–492 µg/liter; 25–50 yr, 71–290 µg/liter; and more than 50 yr. The lower value of serum GH after GHRH + Arg test in normal subjects was 16.5 µg/liter as previously reported (18).

Statistics

Data were reported as mean ± SE; differences for quantitative variables before and after parathyroid surgery were evaluated using the ANOVA for repeated measures; differences for qualitative variables were measured by the ² test.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
As illustrated in Table 1, all patients had increased serum ionized calcium (1.53 ± 0.03 mmol/liter; range, 1.32–1.96 mmol/liter) and PTH (mean, 155 ± 20 pg/ml; range, 66–540 pg/ml) concentrations. Serum IGF-I concentration was 145 ± 14 µg/liter (range, 52–315 µg/liter) and was below the normal age-corrected values in six of 30 patients before surgery. Table 1 indicates that all patients had normal serum ionized calcium (mean, 1.23 ± 0.07 mmol/liter; range, 1.14–1.29 mmol/liter; P < 0.0001 vs. preoperative values) and PTH (mean, 41 ± 2 pg/ml; range, 17–61 pg/ml; P < 0.0001 vs. preoperative values) concentrations after parathyroidectomy. Postoperative serum IGF-I values were 143 ± 11 µg/liter and were below the normal age-corrected values in four of 30 (range, 64–324 µg/liter; P = 0.813 vs. preoperative values). Evaluation of serum GH was superimposable to that of peak GH in almost all patients (data not shown).

Before surgery, the GH response to the GHRH + Arg stimulation test was reduced in 20 of 30 PHP patients (67%) and within the normal range in 10 patients (33%). After parathyroidectomy, abnormal responses to GHRH + Arg were observed in eight of 30 patients (27%), although the remaining 22 patients (73%) had normal peak GH values (² = 5.45; P < 0.02 vs. baseline). All 10 patients with a normal preoperative GH response also had a normal postoperative test; a normalization of GH response was observed in 12 of 20 patients (60%) with an abnormal preoperative GH response.

Mean peak GH values after GHRH + Arg stimulation within the whole group were 17.5 ± 2.8 µg/liter (range, 1.1–56.8 µg/liter) before surgery and 23.8 ± 2.5 µg/liter (range, 4.3–53 µg/liter) after surgery (P = 0.0008). As illustrated in Fig. 1, preoperative impaired GH responses to GHRH + Arg were observed in three of nine (33%) asymptomatic patients and in 17 of 21 (81%) symptomatic patients. After restoration of euparathyroidism, all nine asymptomatic patients had a normal GH response, whereas an impaired GH response was still present 1 yr after restoration of euparathyroidism in eight of 21 (38%) symptomatic patients (Fig. 1).

View larger version (20K): [in this window] [in a new window]   FIG. 1. Individual GH responses to GHRH + Arg in PHP patients before (•) and after () parathyroidectomy. The broken line represents the normal lower limit of serum GH peak after GHRH + Arg stimulation. Preoperative impaired GH responses to GHRH + Arg were observed in 33% of asymptomatic patients and 81% of symptomatic patients. After restoration of euparathyroidism, all asymptomatic patients had a normal GH response, whereas an impaired GH response was still present 1 yr after restoration of euparathyroidism in 38% of symptomatic patients.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In the present study, we evaluated GH secretion, as assessed by serum GH response to GHRH + Arg stimulation test, in a large series of consecutive patients affected with PHP due to parathyroid adenoma, before and after restoration of euparathyroidism. An impaired GH preoperative GH secretion was observed in two thirds of patients, confirming and expanding our previous results. In our previous study, we had shown that impaired GH secretion was due to a reduction in the 24-h GH production rate rather than to a decrease in GH half-life or approximate entropy values of 24-h GH profiles (13). The above results indicated that both spontaneous and stimulated GH secretion were impaired in PHP. Accordingly, in the present study, we limited our analysis to maximally stimulated GH secretion.

Owing to the cross-sectional feature of our previous report, it was not possible to ascertain whether the impairment of GH secretion was transient, i.e. restored after parathyroid hyperfunction, or permanent, i.e. not correctable by restoration of euparathyroidism. The results of the present study clearly indicate that decreased GH secretion observed in PHP is corrected, and, in many cases, parathyroid disease is cured by surgery, and that GH response to the GHRH + Arg stimulation test is not influenced by gender, age, or postmenopausal status. These findings are in keeping with the data by Kovacs et al. (19), who evaluated only baseline GH secretion in PHP patients and observed an improvement after parathyroidectomy; conversely, Schernthaner et al. (20) did not observe amelioration of GH secretion in PHP patients after parathyroidectomy.

It is worth noting that approximately one fourth of patients still had an abnormal GH response to GHRH + Arg at the end of the 1-yr follow-up period. Two explanations can be offered for this finding. First, it is possible that 1 yr of follow-up is not enough to normalize GH secretion after correction of PHP. Because our data are unsuitable on the time period required for normalization of GH secretion after restoration of euparathyroidism, further studies with a longer follow-up period will likely answer this question. A second explanation, not mutually exclusive with the previous one, might be that patients who still had an impaired GH secretion despite correction of PHP had a longer disease duration. An indirect support to this concept might come from the observation that asymptomatic patients, likely patients who had a shorter PHP duration, had both a higher rate of normal GH response to GHRH + Arg before parathyroidectomy and a normalization of GH response after surgery in all cases. As reported in our previous papers (13, 14) and also in the present series of PHP patients, the reduced GH concentrations were not invariably associated with serum IGF-I levels below the age-corrected values. This is in keeping with the concept that the overlap between normal and abnormal serum IGF-I values makes IGF-I determination not sufficient to establish the diagnosis of GH deficiency in adult subjects (21, 22, 23, 24).

The question of whether the impaired GH secretion observed in PHP is due to the increase in calcium or PTH concentrations, or both, is still unanswered by this study, because both serum PTH and calcium values normalized after parathyroid adenoma removal. A model that might help answer this question might be represented by familial hypocalciuric hypercalcemia, an autosomal dominant disorder due in the majority of cases to inactivating mutations of calcium receptor gene, characterized by asymptomatic hypercalcemia, relative hypocalciuria, and inappropriately normal serum PTH concentrations. In two families with familial hypocalciuric hypercalcemia, we recently assessed GH secretion and found it impaired in five of six subjects (25). This finding suggests that hypercalcemia rather than the elevated serum PTH levels might be responsible for the impaired GH secretion observed in PHP.

The present study lends further support to the concept that PHP is another metabolic condition responsible for GH deficit in adults. It is a functional disorder, not associated with a deficiency of other pituitary hormones (14). Correction of the primary parathyroid disorder is associated, in many cases (and, likely, in all cases if follow-up is long enough), with a normalization of GH secretion. This further underscores the fact that GH replacement therapy should be discouraged in PHP patients with GH deficiency.

	Footnotes

 
This work was partially supported by grants from the University of Pisa (Fondi di Ateneo) and Ministero dell’Istruzione, dell’Universita e della Ricerca, Rome (to E.M. and M.G.), and from the University of Insubria at Varese (to L.B.).

Abbreviations: Arg, Arginine; PHP, primary hyperparathyroidism.

Received September 12, 2003.

Accepted November 21, 2003.

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