The effect of somatostatin analogs on vitamin D and calcium concentrations in patients with acromegaly.

PURPOSE: The goals of this study were to determine: (1) 25OH vitamin D (25OHD) and calcium levels in patients with acromegaly and their association with insulin-like growth factor (IGF-1) and (2) whether somatostatin analog (SSA) therapy effects calcium and 25OHD levels. METHODS: 125 patients with acromegaly were studied. Serum calcium and 25OHD levels were compared prior to and after vitamin D supplementation between patients receiving versus not receiving SSA in whom medical therapy included pegvisomant and/or dopamine agonists. Calcium and 25OHD levels were also evaluated longitudinally prior to and during short-term (mean 3 months, range 1-5) and long-term (mean 49 months, range 7-180) SSA administration. Vitamin D2 50,000 units weekly were given to 3 patients in the cross sectional and 1 in the longitudinal group; 400-4,000 units/day of D3 were given to 11 and 5 in respective groups. RESULTS: In patients with a comparable mean IGF-1 index and season of testing, mean serum levels of 25OHD prior to vitamin D supplementation did not differ in patients receiving versus not receiving SSA (30 ± 3 vs. 30 ± 1 ng/ml, p = 0.99) and the prevalence of vitamin D sufficiency was similar between SSA and non SSA groups (42 vs. 57%, p = 0.20), prior to vitamin D supplementation. In patients with a comparable mean IGF-1 index and season of testing, mean serum 25OHD levels in patients increased after vitamin D supplementation in both those who were (37 ± 2 ng/ml, N = 23, p = 0.007) and were not receiving SSA (35 ± 1 ng/ml, N = 69, p = 0.005) compared to pre-D supplementation levels but were not different between these groups, p = 0.95) after D supplementation. Calcium and albumin were normal throughout longitudinal follow up. Calcium correlated with IGF-1 index (ρ = 0.29, p = 0.001, N = 125). In the longitudinal subset, serum calcium decreased transiently, in patients receiving short-term SSA (pretreatment 9.9 ± 0.1 mg/dl vs. short-term SSA 9.5 ± 0.1, p = 0.004). After long-term SSA therapy, calcium increased compared to levels on short-term therapy (9.8 ± 0.1 mg/dl vs. 9.5 ± 0.1, p = 0.017) and were unchanged compared to baseline. Mean vitamin D levels were sufficient at baseline prior to SSA therapy (33 ± 5.0 ng/ml), and did not change during short term (29 ± 6 ng/ml, p = 0.85) and long term SSA therapy (35 ± 5 ng/ml, p = 0.43). CONCLUSIONS: Prior to and after vitamin D supplementation, patients with acromegaly receiving long-term SSA had vitamin D levels similar to those receiving other therapies, suggesting that long-term SSA therapy does not affect serum vitamin D. However, given the limitations of this retrospective study, further prospective studies evaluating the impact of SSA on vitamin D levels are necessary to confirm these findings definitively. Calcium levels are positively associated with IGF-1 index in patients with acromegaly. There is a transient decrease in calcium levels with short-term SSA use. The acute effect of SSA on calcium does not appear to be mediated by albumin, 25OHD or PTH and resolves with long-term SSA treatment. The transient decrease in calcium with short-term SSA use resolved with long-term SSA therapy.

Investigation of impulsivity in patients on dopamine agonist therapy for hyperprolactinemia: a pilot study.

The use of dopamine agonists (DAs) has been associated with increased impulsivity and impulse control disorders in several diseases, including Parkinson's disease. Such an effect of DAs on impulsivity has not been clearly characterized in hyperprolactinemic patients, where DAs are the mainstay of therapy. We studied the effects of DAs on impulsivity in hyperprolactinemic patients treated at a tertiary pituitary center, using validated psychometric tests. Cross-sectional study. Impulsivity was evaluated in 30 subjects, 10 hyperprolactinemic patients on DAs compared to two control groups; one comprising untreated hyperprolactinemic patients (n = 10) and a second group consisting of normoprolactinemic controls with pituitary lesions (n = 10). Measures of impulsivity included both self-report questionnaires as well as laboratory-based tasks. Hyperprolactinemic patients on DAs had a higher score (mean ± SD) in one self-report measure of impulsivity, the attention subscale of the Barratt Impulsiveness Scale (16.2 ± 2.7), as compared to the hyperprolactinemic control group (12.3 ± 2.5) and the normoprolactinemic group (14.7 ± 4.4) (p = 0.04). No statistically significant difference was found between groups with regards to the other impulsivity scales. In the DA-treated group, a correlation was observed between increased impulsivity (as assessed in the Experiential Discounting Task) and higher weekly cabergoline dose (r(2) = 0.49, p = 0.04). The use of DAs in hyperprolactinemic patients is associated with an increase in one aspect of impulsivity. This effect should be further characterized in larger, longitudinal studies.

MANAGEMENT OF ENDOCRINE DISEASE: Impulse control disorders in patients with hyperpolactinemia treated with dopamine agonists: how much should we worry?

Dopamine agonists (DAs) represent a cornerstone in the management of patients with hyperprolactinemia and have an important role in the treatment of neurologic disorders, including Parkinson's disease and restless legs syndrome. A growing body of evidence has identified impulse control disorders (ICDs) as possible adverse effects of DA therapy. A variety of ICDs may occur in patients treated with DA, including compulsive shopping, pathologic gambling, stealing, hypersexuality and punding (repetitive performance of tasks, such as collecting, sorting, disassembling and assembling objects). These behaviors can have devastating effects on patients' life and family. In the present review article, we summarize available data on ICDs in patients with hyperprolactinemia as well as other disorders. Possible risk factors for the emergence of ICDs in patients treated with DA are discussed and the putative pathophysiologic mechanisms underlying the development of ICDs in this setting are reviewed. In addition, strategies for the early identification and management of ICDs in patients on DA are discussed. In conclusion, a wide variety of ICDs can occur in patients treated with DA, including those with hyperprolactinemia. The development of ICDs can have serious implications for patients' well-being and family. Endocrinologists and other physicians involved in the care of patients on DA therapy must be aware of this potential adverse effect, counsel patients regarding pertinent symptoms and regularly evaluate treated patients for the development of ICDs. Early detection of ICDs and discontinuation of DA therapy can mitigate the potential harms associated with ICDs in these patients.

Effects of growth hormone therapy on bone density and fracture risk in age-related osteoporosis in the absence of growth hormone deficiency: a systematic review and meta-analysis.

PURPOSE: In adults, growth hormone deficiency (GHD) has been associated with low bone mineral density (BMD), an effect counteracted by growth hormone (GH) replacement. Whether GH is beneficial in adults with age-related bone loss and without hypopituitarism is unclear. METHODS: We conducted a systematic literature search using Medline, Embase and the Cochrane Register of Controlled Trials. We extracted and analyzed data according to the bone outcome included [bone mineral content (BMC), BMD, and bone biomarker, fracture risk]. We performed a meta-analysis when possible. RESULTS: We included eight studies. Seven randomized 272 post-menopausal women, 61-69 years, to GH or control, for 6-24 months, and the eighth was an extension trial. Except for one study, all women received concurrent osteoporosis therapies. There was no significant effect of GH, as compared to control, on BMD at the lumbar spine (Weighted mean difference WMD = -0.01 [-0.04, 0.02]), total hip (WMD = 0 [-0.05, 0.06]) or femoral neck (WMD = 0 [-0.03, 0.04]). Similarly, no effect was seen on BMC. GH significantly increased the bone formation marker procollagen type-I carboxy-terminal propeptide (PICP) (WMD = 14.03 [2.68, 25.38]). GH resulted in a trend for increase in osteocalcin and in bone resorption markers. Patients who received GH had a significant decrease in fracture risk as compared to control (RR = 0.63 [0.46, 0.87]). Reported adverse events were not major, mostly related to fluid retention. CONCLUSION: GH may not improve bone density in women with age-related bone loss but may decrease fracture risk. Larger studies of longer duration are needed to further explore these findings in both genders, and to investigate the effect of GH on bone quality.

Effects of recombinant human growth hormone therapy on bone mineral density in adults with growth hormone deficiency: a meta-analysis.

OBJECTIVE: GH deficiency is associated with decreased bone mineral density (BMD) and increased fracture risk. Because the effects of recombinant human GH (rhGH) therapy on BMD and bone mineral content have not been systematically investigated, we conducted a meta-analysis of pertinent studies. DESIGN: A thorough search of the literature (MEDLINE, EMBASE, and the Cochrane Register) was performed. Relevant studies were divided and analyzed according to their design (randomized/controlled or prospective/retrospective) and duration of rhGH therapy (≤12 months and > 12 months). RESULTS: Administration of rhGH led to a significant increase in lumbar spine (LS) and femoral neck (FN) BMD in randomized/controlled studies of more than 1 year [weighted mean difference (95% confidence interval)] of 0.038 g/cm(2) (0.011-0.065) and 0.021 g/cm(2) (0.006-0.037) at the LS and FN, respectively, and a nonsignificant drop at the same sites in studies of shorter duration. In prospective studies, a significant increase in the LS and FN BMD was obtained. On meta-regression, a negative association was observed between the change in LS and FN BMD and subjects' age and a positive association between the BMD change and treatment duration. In a subgroup analysis, the increase in LS and FN BMD was significant in men [0.048 g/cm(2) (0.033-0.064) and 0.051 g/cm(2) (0.003-0.098), respectively] but not in women. CONCLUSION: This meta-analysis suggests a beneficial effect of rhGH replacement on BMD in adults with GH deficiency. This effect is affected by gender, age, and treatment duration. Larger studies are needed to evaluate the effect of rhGH on fracture risk.

25-hydroxyvitamin D assay variations and impact on clinical decision making.

CONTEXT: Laboratories are increasingly shifting to new automated 25-hydroxyvitamin D (25-OHD) assays, with subsequent variability in results. OBJECTIVE/SETTING: We describe the experience at our center with such a shift and illustrate its clinical implications. METHODS: 25-OHD levels were measured in 494 patients using Immunodiagnostic Systems RIA (IDS-RIA) and DiaSorin Liaison assays. Sources of variability between the assays were investigated in a subset of 83 samples, retested in the reference laboratory in the United States, and by reviewing the performance reports issued by the International Vitamin D External Quality Assessment Scheme, DEQAS. 25-OHD cut-points for target levels were used to compare the two assays. RESULTS: 25-OHD concentrations were significantly lower when measured with Liaison as compared to IDS-RIA: mean bias was -5 ng/ml, range was -38.1 to 18.7 ng/ml, P<0.001; the absolute bias was independent of 25-OHD value. Interassay variability was also detected in values obtained in the reference laboratory and in DEQAS reports. Using 20 ng/ml as the target 25-OHD level, 52% of patients required treatment when tested by Liaison, as opposed to 36% by IDS-RIA (P<0.001). Using 30 ng/ml as the desirable level, the proportions were 79 and 64%, respectively (P<0.001). The two assays agreed in only 41-68% of subjects, proportions that depended on criteria used to define agreement. CONCLUSION: A change in 25-OHD assays has a significant impact on results, patient classification, and treatment recommendations. Such variability cannot be ignored when deriving and applying vitamin D guidelines. It also renders universal assay standardization a pressing call.