Endocrine Abstracts

Hypercalcaemia is a prevalent complication in malignancies as a consequence of tumor secretion of parathyroid hormone related peptide (PTHrP). This complication is also associated with ovarian dysgerminomas but is much less common than for other tumours. To investigate this further we have studied 10 cases of dysgerminoma, assessing biochemical parameters and analysing mRNA and protein expression in tissue biopsies. Pathological reports show raised serum calcium and 1,25(OH)₂D₃levels: 11-17.8 mg/dL (normal range 8.5-10.5 mg/dL and 63-198 pg/ml (normal range 15-60 pg/ml respectively), with normal PTH and PTHrP levels. Analysis of the expression of vitamin D-associated genes (1alpha-hydroxylase, vitamin D receptor (VDR) and 24-hydroxylase) in the dysgerminomas (n=10) was carried out using quantitative real-time RT-PCR analysis and compared to data from normal ovaries (n=5). Results indicated mRNA for all three genes (normalised to 18S rRNA) was significantly upregulated (p<0.001) in dysgerminomas (1alpha-hydroxylase, 164-fold plus/minus 1.57; 24-hydroxylase, 29-fold plus/minus 2.28; VDR 36-fold plus/minus 1.97 respectively) compared to normal ovaries. Immunohistochemistry and enzyme activity assays confirmed that expression of 1alpha-OHase and synthesis of 1,25(OH)₂D₃ is upregulated in dysgerminomas. This was associated with a 163-fold induction (plus/minus 2.46) in expression of CD45, the common leukocyte antigen. Likewise semi-quantitative RT-PCR analysis showed increased tumour expression of CD14, a macrophage-specific marker. These data indicate a possible role for tumour-associated macrophages as a source of dysregulated 1alpha-hydroxylase activity in dysgerminomas. We therefore propose that hypercalcaemia associated with dysgerminomas is similar to that previously reported for the inflammatory disease sarcoidosis, with abnormal extra-renal synthesis of active vitamin D being the central defect.