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Original Studies |
Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples (A.C., C.D.S., R.P., G.C., A.F., G.L.), Naples; the Department of Pediatric Endocrinology (S.L.), University of Cagliari, Cagliari; and the Department of Endocrinology, University of Turin (G.A., G.C., E.G.), Turin, Italy1
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, via S. Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it
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Abstract |
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On the basis of the GH response to arginine plus GHRH (ARG+GHRH), patients were subdivided into 4 groups: group 1 included 41 patients with a GH peak below 3 µg/L (0.9 ± 0.08 µg/L), defined as very severe GHD; group 2 included 25 patients with a GH peak between 3.1–9 µg/L (4.7 ± 0.4 µg/L), defined as severe GHD; group 3 included 18 patients with a GH peak between 9.1–16.5 µg/L (11.0 ± 0.3 µg/L), defined as partial GHD; and group 4 included 17 patients with a GH peak above 16.5 µg/L (28.3 ± 4.3 µg/L), defined as non-GHD. In all 35 controls (group 5), the GH response after ARG+GHRH was above 16.5 µg/L (40.7 ± 2.2 µg/L). In patients in group 1, circulating IGF-I (P < 0.001), IGFBP-3 (P < 0.05), osteocalcin (P < 0.001), and urinary Ntx levels (P < 0.001) were lower than those in group 3–5, which were not different from each other; the t score at the lumbar spine (-1.99 ± 0.2) and that at the femoral neck (-1.86 ± 0.3) were lower than those in groups 3 (-0.5 ± 0.7, P < 0.01 and -0.3 ± 0.7, P < 0.01, respectively), 4 (-0.5 ± 0.2, P < 0.01 and -0.3 ± 0.7, P < 0.01, respectively), and 5 (-0.5 ± 0.2, P < 0.001 and 0.0 ± 0.02, P < 0.001, respectively). In patients in group 2, circulating IGF-I and IGFBP-3 levels were not different from those in group 1, whereas the t scores at the lumbar spine (-1.22 ± 0.3) and femoral neck (-0.9 ± 0.3) were significantly higher and lower, respectively, than those in groups 1 and 5 (P < 0.05) but not those in groups 3 and 4, and serum osteocalcin and urinary Ntx levels were significant higher than those in group 1 and lower than those in groups 3–5 (P < 0.001).
To evaluate the effect of isolated GHD vs. MPHD, patients were subdivided according to the number of their hormonal deficits, such as panhypopituitarism with (10 patients) or without (31 patients) diabetes insipidus, GHD with 1 or more additional pituitary deficit(s) (36 patients), isolated GHD (7 patients), 1–2 pituitary hormone deficit(s) without GHD (10 patients), and normal anterior pituitary function (7 patients). The t score at the lumbar spine and femoral neck and the biochemical parameters of bone turnover were not significantly different among the different subgroups with similar GH secretions.
A significant correlation was found between the GH peak after ARG+GHRH and IGF-I, osteocalcin, urinary Ntx levels, and the t score at the lumbar spine, but not that at the femoral neck level. A significant correlation was also found between plasma IGF-I levels and the t score at the lumbar spine and femoral neck, serum osteocalcin, and urinary Ntx. Multiple correlation analysis revealed that the t score at the lumbar spine, but not that at the femoral neck, was more strongly predicted by plasma IGF-I levels (t = 3.376; P < 0.005) than by the GH peak after ARG+GHRH (t = -0.968; P = 0.338).
In conclusion, a significant reduction of BMD associated with abnormalities of bone turnover parameters was found only in patients with very severe or severe GHD, whereas normal BMD values were found in non-GHD hypopituitary patients. These abnormalities were consistently present in all patients with GHD regardless of the presence of additional hormone deficits, suggesting that GHD plays a central role in the development of osteopenia in hypopituitary patients.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In a previous study (9), we have shown that the degree of the GH response to an arginine plus GHRH (ARG+GHRH) test was correlated with the severity of the lipid profile abnormality, but not with changes in body composition. In addition, the peak GH response to ARG+GHRH was correlated with insulin-like growth factor I (IGF-I) concentrations (9).
To look for a possible correlation between the extent of the GH response to ARG+GHRH and the severity of bone mass and turnover impairment, we measured the BMD at the levels of lumbar spine and femoral neck together with biochemical parameters of bone turnover in a large series of adult hypopituitary patients. The effects of isolated GHD and MPHD were also evaluated in patients subdivided according to their hormonal deficits.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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One hundred and one hypopituitary patients (46 males and 55
females; age, 16–73 yr) and 35 healthy subjects (15 males and 20
females; age, 18–70 yr) entered this study after their informed
consents had been obtained. None of the subjects of this study had
taken any drug or medication known to affect skeletal or mineral
metabolism. In addition, none of the 136 subjects had habitual
ingestion of coffee greater than 4 cups/day or more than 2 alcohol
containing beverages/day. Seventy-six patients and 19 controls were
nonsmokers, and the remaining subjects were mild smokers (<15
cigarettes/day). Furthermore, none of the patients had active peptic
ulcer disease or abnormal renal and/or hepatic function. All patients
had been previously operated on via the transsphenoidal and/or
transcranic route for nonfunctioning pituitary adenoma, meningioma, or
craniopharyngioma, and 17 of them had also been irradiated. A variable
degree of pituitary insufficiency was found in the 101 patients, as
shown in Table 1
. Hormone replacement
therapy with L-T4 (50–100 µg daily, orally),
cortisone acetate (25–37.5 mg/day), and intranasal desmopressin (5–20
µg/day) was given where appropriate. Males with hypogonadism were
treated with testosterone enanthate (250 mg monthly, im), whereas
premenopausal females were given estro-progestinic replacement. The
adequacy of hormone replacement therapy was periodically assessed by
means of serum free thyroid hormones, testosterone, urinary free
cortisol, and serum and urinary Na+ and K+
measurements. At study entry, these hormonal parameters were in the
normal range for age in all patients. None of the patients had ever
received GH treatment.
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At study entry, serum calcium, phosphorus, and creatinine and circulating alkaline phosphatase, intact PTH, and osteocalcin (OC) were assayed twice in a single sample. Urinary cross-linked N-telopeptides of type I collagen (Ntx), calcium, phosphorus, and creatinine were assayed in the 24-h urinary collection the day before the study. Assay of IGF-I and IGF-binding protein-3 (IGFBP-3) levels and assessment of BMD measured at the lumbar spine and femoral neck levels were performed in all patients. All subjects were tested with ARG+GHRH. ARG (arginine hydrochloride, Damor, Naples, Italy) was administered at a dose of 0.5 g/kg up to a maximal dose of 30 g slowly infused from 0–30 min; GHRH (1–29, Geref, Serono, Rome, Italy) was given at a dose of 1 µg/kg as an iv bolus at time zero. Blood samples were taken every 15 min from -15 to 90 min. According to recent studies (9, 10, 11, 12), showing that adult patients with a GH peak after an insulin tolerance test of less than 3 µg/L had a GH response to ARG+GHRH below 9 µg/L, whereas normal subjects had a GH response after ARG+GHRH always greater than 16.5 µg/L, we classified the GH response after ARG+GHRH in our 101 subjects as follows: very severe GHD (GH peak, <3 µg/L), severe GHD (GH peak, 3.1–9 µg/L), partial GHD (GH peak, 9.1–16.5 µg/L), and normal (GH peak, >16.5 µg/L).
Assessment of BMD
In all patients and controls, BMD was assessed by dual x-ray absorptiometry. Measurement of the integral bone density in the lumbar spine (L1–L4) and femoral neck was performed using a Hologic QDR 1000 analyzer (Hologic, Inc., Waltham, MA). Data were expressed as the t score and as grams per cm2. Patients were considered osteopenic when the t score was between -1 and -2.5 and were considered osteoporotic when the t score was lower than -2.5.
Assays
All hormone measurements were performed using the same reagents in two laboratories at the Department of Molecular and Clinical Endocrinology and Oncology, University Federico II of Naples, and the Department of Endocrinology, University of Turin. Assay performances were similar in the two laboratories. Serum GH levels were measured by immunoradiometric assay (IRMA) using commercially available kits. The sensitivity of the assay was 0.2 µg/L. The intra- and interassay coefficients of variation (CVs) were 4.5% and 7.9%, respectively. Plasma IGF-I was measured by IRMA after ethanol extraction. The normal ranges in 20- to 30-yr-old, 31- to 40-yr-old, 41- to 50-yr-old, and over 50-yr-old men were 108–458, 92–483, 100–316, and 78–213 µg/L, respectively, whereas in women these values were 118–523, 112–506, 96–288, and 78–268 µg/L, respectively. The sensitivity of the assay was 0.8 µg/L. The intraassay CVs were 3.4%, 3.0%, and 1.5% for low, medium, and high points of the standard curve, respectively. The interassay CVs were 8.2%, 1.5%, and 3.7% for low, medium, and high points of the standard curve. Plasma IGFBP-3 was measured by RIA after ethanol extraction. The normal ranges in 20- to 30-yr-old, 31- to 40-yr-old, 41- to 50-yr-old, and over 50-yr-old subjects were 2.1–7.6, 1.7–7.3, 2.1–4.3, and 2–4 mg/L, respectively. The sensitivity of the assay was 0.5 µg/L. The intraassay CVs were 3.9%, 3.2%, and 1.8% for low, medium, and high points of the standard curve, respectively. The interassay CVs were 0.6%, 0.5%, and 1.6% for low, medium, and high points of the standard curve. PTH was assayed by the IRMA method; the normal range was 9–55 pg/mL. Serum OC levels were measured by RIA; the normal range was 3.0–13.0 µg/L. Urinary Ntx levels were measured by enzyme-linked immunosorbent assay; the normal ranges were 23–110 and 13–96 nmol bone collagen equivalent (BCE)/mmol in males and females, respectively. Urinary and serum calcium, phosphorus, creatinine, and alkaline phosphatase were assayed using standard methods in our laboratory.
Statistical analysis
ANOVA followed by Newman-Keuls test was used for the intergroup comparison to calculate the t scores for the lumbar spine and femoral neck among groups. Regression analysis was performed to correlate bone parameters to GH peak after ARG+GHRH and IGF-I levels. Multiple regression analysis was performed, taking the GH peak after ARG+GHRH as the dependent variable vs. age, disease duration, t score at the lumbar spine and femoral neck, serum OC, and urinary Ntx as independent variables by calculating the coefficient for the variables related to GH peak after ARG+GHRH at the linear correlation. Data are reported as the mean ± SEM. The limit of significance was set at 5%.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Plasma IGF-I concentrations in patients in groups 1 (76.5 ± 7.6 µg/L) and 2 (80.3 ± 7.5 µg/L) were similar and lower (P < 0.001) than those in groups 3–5, which were not different from each other (170.9 ± 40.6, 186.5 ± 20.1, and 188.8 ± 11.1 µg/L, respectively). IGF-I concentrations were below the normal range for age in 28 patients in group 1 (68.3%), 15 in group 2 (60%), and 2 in group 3 (11.1%) and were normal in all subjects in groups 4 and 5. Similarly, IGFBP-3 concentrations in groups 1 (2.1 ± 0.3 mg/L) and 2 (2.2 ± 0.3 mg/L) were similar and lower than those in groups 3 (3.5 ± 0.7 mg/L; P < 0.05), 4 (3.6 ± 0.8 mg/L), and 5 (3.8 ± 0.2 mg/L; P < 0.05). Plasma IGFBP-3 concentrations were below the normal range for age in 24 patients in group 1 (58.3%), 10 in group 2 (40%), and 1 in group 3 (5.5%) and were normal in all subjects in groups 4 and 5.
PTH, urinary and serum calcium, phosphorus, and creatinine, and alkaline phosphatase were similar in the five groups of patients (data not shown).
In group 1, the t scores at the lumbar spine (-1.99 ±
0.2) and femoral neck (-1.86 ± 0.3) were lower than those in
groups 3 (-0.5 ± 0.7, P < 0.01 and -0.3
± 0.7, P < 0.01, respectively), 4 (-0.5 ± 0.2,
P < 0.01 and -0.3 ± 0.7, P <
0.01, respectively), and 5 (-0.5 ± 0.2, P <
0.001 and 0.0 ± 0.02, P < 0.001, respectively;
Fig. 1). Serum OC levels were lower in
patients in group 1 (1.7 ± 0.1 µg/L) than in those in groups
3–5 (5.6 ± 0.4, 6.1 ± 0.3, and 7.4 ± 1.1 µg/L,
respectively; P < 0.001; Fig. 2). Similarly, urinary Ntx were lower in
patients in group 1 (20.1 ± 1.0 nmol BCE/mmol creatinine) than in
those in groups 3–5 (50.7 ± 1.1, 91.9 ± 3.2, and 96.1
± 1.0 nmol BCE/mmol creatinine, respectively; P <
0.001; Fig. 2). Patients in group 2 had t scores at the
lumbar spine (-1.22 ± 0.3) and femoral neck (-0.9 ± 0.3)
significantly higher and lower, respectively, than those in groups 1
and 5 (P < 0.05, respectively; Fig. 1), but not those
in groups 3 and 4. Conversely, in group 2, serum OC and urinary Ntx
levels were significantly higher than those in group 1 and were lower
than those in groups 3–5 (2.6 ± 0.1 µg/L and 30.5 ± 0.8
nmol BCE/mmol creatinine, respectively; P < 0.001;
Fig. 2).
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).
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). Multiple correlation
analysis revealed that the t score at the lumbar spine, but
not at the femoral neck, was more strongly predicted by plasma IGF-I
levels (t = 3.376; P < 0.005) than by
the GH peak after ARG+GHRH (t = -0.968;
P = 0.338).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this cross-sectional study we have shown that only patients with very severe or severe GHD have a significant reduction of BMD, associated with abnormalities of bone turnover parameters. These abnormalities were found in all patients with GHD regardless of the presence of additional hormone deficits. Normal BMD values were found in non-GHD hypopituitary patients, thus indicating that GH plays a central role in the development of osteopenia in patients with hypopituitarism. This hypothesis in substantiated by the observation that the GH response to ARG+GHRH was directly correlated with the degree of bone loss. In fact, patients with partial GHD (group 3) had normal BMD values, and their serum IGF-I concentrations were not different from those in non-GHD hypopituitary patients and control subjects. As the effect of GHD on bone is principally mediated by IGF-I (1, 2), the normal BMD values of this group may be explained by their normal IGF-I concentrations. However, we have previously shown that adults with GHD have subtle abnormalities of lipid metabolism (9). It is tempting to speculate that a slightly reduced GH secretion may have direct effects on lipid metabolism but is still capable of maintaining normal IGF-I production, thus explaining the different clinical findings between partial and severe GHD.
Bone metabolism is influenced by virtually all pituitary hormones, either directly or via their target organ products. Although overt hyperthyroidism has clearly negative effects on bone mass, the skeletal effects of T4 administration are more controversial (25). Mild chronic overreplacement with thyroid hormones is also associated with accelerated bone loss (26, 27). Recently, Hanna et al. (27) reported that replacement doses of T4 had no adverse effects on the spine, femoral neck, or total hip in patients with central hypothyroidism (27). The effect of replacement therapy with glucocorticoids on bone mass in patients with hypocortisolism is limited. Patients with Addison’s disease may have an increased incidence of osteoporosis as a consequence of mild subclinical glucocorticoid overreplacement during a period of many years (28). On the other hand, glucocorticoid replacement therapy has no adverse effects on BMD in patients with 21-hydroxylase deficiency (29), but a 30% reduction in daily hydrocortisone dose leads to a 19% rise in OC levels, indicating increased bone formation (30). Hypogonadism causes osteoporosis in men and women (31), and replacement therapy with sex hormones increases bone turnover and bone mass (32, 33). A recent study reported significant bone impairment in patients with central diabetes insipidus, which was not prevented or reversed by standard dose replacement with intranasal desmopressin (34).
Interestingly, all non-GHD patients had normal BMD, leading us to hypothesize that they were receiving appropriate replacement treatments.
In conclusion, a significant reduction of BMD associated with abnormalities of bone turnover parameters was found only in patients with very severe or severe GHD, whereas normal BMD values were found in non-GHD hypopituitary patients. These abnormalities were consistently present in all patients with GHD regardless of the presence of additional hormone deficits, suggesting that GHD, probably via reduced IGF-I production, plays a central role in the development of osteopenia in hypopituitary patients.
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Acknowledgments |
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Footnotes |
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Received December 3, 1998.
Revised February 24, 1999.
Accepted March 1, 1999.
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References |
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B. M. K. Biller, G. Sesmilo, H. B. A. Baum, D. Hayden, D. Schoenfeld, and A. Klibanski Withdrawal of Long-Term Physiological Growth Hormone (GH) Administration: Differential Effects on Bone Density and Body Composition in Men with Adult-Onset GH Deficiency J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 970 - 976. [Abstract] [Full Text]
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