Lupus Disease

Age-related Changes in Serum Growth Hormone, Insulin-like Growth Factor-1 and Somatostatin in Systemic Lupus Erythematosus

Charles W Denko¹ and Charles J Malemud^{2   1}Department of Medicine/Division of Rheumatic Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106-5076 USA, ²Department of Medicine/Division of Rheumatic Diseases, and Department of Anatomy, Case Western Reserve University School of Medicine, Cleveland, Ohio, 44106-5076 USA, BMC Musculoskeletal Disorders 2004, 5:37doi:10.1186/1471-2474-5-37
© 2004 Denko and Malemud; licensee BioMed Central Ltd.   This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background of Systematic Lupus Erythematosus Study

Results and Discussion

Glucose and insulin concentration was determined in serum from normal female subjects and from patients with Systematic Lupus Erythematosus. No normal female subjects were excluded from the study as a result of detecting hyperglycemia or hyperinsulinemia However, 2 Systematic Lupus Erythematosus patients were excluded from the statistical analysis on this basis (data not shown).

Over the course of this study, Systematic Lupus Erythematosus patients received medical therapy with NSAIDs, prednisone (10–60 mg/day), hydroxychloroquine sulfate or methotrexate as well as combinations of these drugs. No Systematic Lupus Erythematosus patients were treated with azathioprine or cyclophosphamide during this study.

Previously it was shown that basal serum growth hormone levels among normal male and female subjects did not significantly differ on the basis of age [16]. As noted, Systematic Lupus Erythematosus has a high female to male prevalence ratio and is predominant in young females between 20 and 40 yrs of age [5,21]. Thus, it was critical to determine the extent to which serum growth hormone and IGF-1 differed among female normal subjects on the basis of age. Serum growth hormone levels did not correlate with age in normal female subjects between the ages of 20 and 80 (Figure 1A). However, a strong inverse correlation between age and IGF-1 levels (adjusted r² = 0.269) in this group of normal female subjects was found (Figure 1B).

Figure 1.      Return to text                                                                                           

Denko et al. BMC Musculoskeletal Disorders 2004 5:37   doi:10.1186/1471-2474-5-37

In contrast to the results obtained from basal serum growth hormone measurements in the entire normal female subject population (Figure 1A), a strong direct correlation (adjusted r² = 0.092) between age (age, 30.8 ± 7.0, mean ± SD; 95% confidence, 3.74) and basal serum growth hormone levels in the young female normal subjects was found (Figure 2A). However, the correlation between age and basal serum growth hormone levels was weak in the older (age, 60.6 ± 9.4; mean ± SD; 95% confidence, 3.29) normal female subjects (Figure 2B).

Figure 2.       Return to text

Denko et al. BMC Musculoskeletal Disorders 2004 5:37   doi:10.1186/1471-2474-5-37

Based on the above considerations, basal serum growth hormone and IGF-1 concentration was determined in study groups subdivided by age in normal female subjects and these values compared with basal serum growth hormone and IGF-1 levels in Systemic Lupus Erythematosus patients. The results showed that Systemic Lupus Erythematosus was not characterized by elevated serum growth hormone whether or not all normal female subjects or age-matched normal female subjects were employed as the comparison group (Table 1). Serum IGF-1 levels were significantly lower in the normal female subject group compared to Systematic Lupus Erythematosus patients (Table 1), but there was no significant difference if serum IGF-1 levels in the Systematic Lupus Erythematosus group were compared to serum IGF-1 levels in the age-matched normal female group (Table 1).

Table 1 Return to text

A trend towards elevated somatostatin levels in normal subjects as a function age was previously found [17]. In the present study, there was also a trend towards elevated serum somatostatin levels in the <45 yr old Systemic Lupus Erythematosus patient group or 45 – 55 yr old group compared to their age-matched normal counterparts (Table 1). However, a significant difference was found only in the older (>55 yrs) Systemic Lupus Erythematosus patients compared to their age-matched control counterparts (Table 1).

The results of the present study emphasized the critical requirement to control for age and gender when basal serum growth hormone and IGF-1 levels in normal subjects are compared to patients with autoimmune musculoskeletal diseases which, like Systemic Lupus Erythematosus, are characterized by a strong age and gender association.

Several studies from our laboratory have consistently shown basal serum growth hormone to be higher in females than in males [8,9,14]. One study, in particular, examined the correlation between age, gender and race with basal serum growth hormone and concluded that, in general, older Caucasian women had slightly higher growth hormone levels compared to older African-American women [8]. However, in that study (8) no statistical differences were shown when serum growth hormone levels in young Caucasian women (age, 28 ± 6; mean ± SD) were compared to serum growth hormone levels in African-American women (age, 34 ± 10). This finding is particularly noteworthy to studies of Systemic Lupus Erythematosus because, in most cases, Systemic Lupus Erythematosus onset is prominent among young females during their reproductive years, and African-American women are over-represented in the Systemic Lupus Erythematosus patient population [21].

The present analysis also extends the results of previous studies [8,9,14] and partially supports the conclusions of Ghigo et al. [22] who showed that basal growth hormone levels were similar in young and older individuals. Ghigo et al. [22] further suggested that the somatotroph response in young versus older individuals to the combined administration of arginine and growth hormone-releasing substance also did not vary with age.

In contrast, the present results do not support the conclusions that growth hormone decreases as a function of age as reported by Kelijman [23]. In fact, the results of the present study showed a strong correlation between age and serum growth hormone only in the circumscribed young normal female (age 20 – 46 yrs) group (Figure 1A).

The decrease in basal serum IGF-1 levels with age (Figure 1B) confirmed previous studies by Hochberg et al. [24] who studied patients with osteoarthritis of the knee as well as earlier studies by Ghigo et al. [22] who reported a significant difference in IGF-1 levels between young and older individuals. Thus, it was not unexpected that basal serum IGF-1 levels in Systemic Lupus Erythematosus was significantly elevated when compared to basal serum IGF-1 levels in the general population of normal subjects, but not so, when basal serum IGF-1 levels from Systemic Lupus Erythematosus patients were compared to their age-matched counterparts (Table 1). In this regard, Bennett et al. [25] also failed to find differences in serum IGF-1 levels when normal subjects (age, 45.1 ± 8.6) were compared to 15 age-matched Systemic Lupus Erythematosus patients (age, 42.5 ± 7.0).

The relationship between putative abnormalities in the hypothalamic-pituitary axis, systemic disturbances and Systemic Lupus Erythematosus pathogenesis and progression remains conjectural. In this regard, Rovensky et al. [26] found no correlation between plasma prolactin, growth hormone, interleukin-6, cortisol or C-reactive protein in adult Systemic Lupus Erythematosus patients. However, studies by Chikanza et al. [27] reached a different conclusion. They suggested that a "pro-inflammatory hormonal bias" existed in juvenile Systemic Lupus Erythematosus which was identical to adult Systemic Lupus Erythematosus. They also concluded that the role of the neuroendocrine-immune system in adult Systemic Lupus Erythematosus was, at the present time, limited to deficiencies in prolactin. Of note, two recent case reports suggested a link between growth hormone and exacerbation of lupus nephritis in a male teenager with Systemic Lupus Erythematosus [28] as well as in juvenile Systemic Lupus Erythematosus [29] where when growth retardation treated with growth hormone was terminated, clinical improvement in lupus symptoms was observed. These findings suggested that exogenously-administered growth hormone may result in "toxic" levels of growth hormone accompanied by lupus "flares" with progressive autoimmune dysfunction.

A recent study from this laboratory showed that the growth hormone to somatostatin ratio was skewed upward in patients with Rheumatoid Arthritis [17]. In the present study, somatostatin levels in the age groups encompassing the average age of the Systemic Lupus Erythematosus patients were not different from than of normal subjects (Table 1). Although previous studies have suggested that somatostatinergic activity increased with age [20], the present analysis (Table 1) does not support that view (at least from measurements of basal somatostatin levels) as lower somatostatin levels in the older Systemic Lupus Erythematosus patients reached statistical significance when compared to age-matched controls with the caveat that the present study did not relate changes in somatostatin to Systemic Lupus Erythematosus disease activity.

Although somatostatin may alter growth hormone effects and immune responses in chronic autoimmune diseases, the relationship between somatostatin and "specific" somatostatin receptor (sSR) in Systemic Lupus Erythematosus remains to be elucidated. In this regard, van Hagen [30] showed that 97% of patients with sarcoidosis, 100% of patients with tuberculosis or Wegener's granulomatosis, 75% of patients with Sjogren's syndrome but only 50% of Systemic Lupus Erythematosus patients exhibited sSRs on mitogen-activated human peripheral lymphocytes compared to 97% in normal individuals. Of note, somatostatin receptor levels appeared to be unrelated to disease progression or remission. In the present study, a trend towards reduced serum somatostatin levels was seen only in the older Systemic Lupus Erythematosus patients (Table 1). As functional somatostatin may change in autoimmunity and result in altered growth hormone release, reduced somatostatin levels could also influence basal levels of growth hormone in elderly Systemic Lupus Erythematosus patients. Thus, changes in somatostatin could be one of several environmental stress factors resulting in the progression of clinically active disease in older Systemic Lupus Erythematosus patients [31].

The therapeutic implications and diagnostic utility of serum growth hormone, IGF-1 and somatostatin measurements in Systemic Lupus Erythematosus as well as in other musculoskeletal disorders appears central to assigning a role for these factors in disease progression. Serum growth hormone remained elevated in some DISH and Osteoarthritis patients where clinical symptoms were significant [9,11,12]. Thus, single serum growth hormone determinations appear to accurately reflect a pattern of serum growth hormone levels associated with these clinical disorders. Further, improvement in the clinical symptoms in Osteoarthritis and DISH patients with medical therapy [10,13] resulted in a sustained reduction in serum growth hormone levels reaching levels comparable to those found in normal subjects. Although longitudinal measurements of serum somatostatin in Systemic Lupus Erythematosus and other rheumatic diseases have not yet been performed, reduced somatostatin levels appear to be most strongly associated with joint inflammation (as was seen in Rheumatoid Arthritis) [17] as well as in older patients (>55 yrs) with the inflammatory complications of knee Osteoarthritis (Denko and Malemud, submitted). Thus, it could be informative if elevated somatostatin levels correlated with clinical improvement in Systemic Lupus Erythematosus patients.

Competing Interests

The authors declare that they have no competing interests.

Authors' Contributions

CWD participated in the design of the study and performed the clinical analysis. CJM participated in the design of the study and performed the statistical analysis. All authors read and approved the final manuscript.

Acknowledgements

This study was supported, in part, by NIH P60 AR-20618 (Northeast Ohio Multipurpose Arthritis Center). The authors' thank Ms. Betty Boja for technical assistance and the personnel in the clinics at University Hospitals of Cleveland and Veterans Administration Medical Center for providing their support for this study.

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