It is estimated that up to one in five individuals develops pituitary gland tumors, despite the common occurrence of these tumors, the pathogenetic mechanisms underlying their development mainly remain unknown. We studied the gene expression in null cell adenomas compared with normal pituitary by expressed sequence tags (EST) sequencing and cDNA microarray on large scale. Both approaches of EST sequencing and microarray analysis showed that 17 genes were differentially expressed in human null cell pituitary adenoma tissues, among which 14 genes were overexpressed and three genes were underpressed. Five of the genes with potential oncogenic significance by RT-real time quantitative PCR. Synaptotagmin (SYT) are integral membrane proteins of synaptic vesicles considered to serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis. Calcium binding to participates in triggering neurotransmitter release at the synapse. In view of our finding that SYT is overexpressed in null cell adenomas, these tumors may be capable of secreting some unknown hormones or peptides. ATP5B and MDH1 were involved in the energy metabolism, whose overexpression in null cell adenomas provide us with a new perspective of exploring the oncogenesis of these tumors. All of these data may contribute to the understanding of null cell adenoma formation and development.