Endocrine Abstracts

Prolactinomas are the commonest type of functioning pituitary adenoma in man. High circulating oestrogen levels are associated with lactotroph proliferation and increased PRL secretion essential for lactation. In vitro, oestradiol induces proliferation of the rat pituitary somatolactotroph GH3 cell line, and chronic oestrogen treatment of Fischer-344 rats in vivo results in lactotroph hyperplasia and adenoma formation, though the mechanisms responsible remain elusive.

We conducted a microarray gene expression study to seek novel genes and pathways involved in oestrogen-induced lactotroph hyperplasia. Female Fischer-344 rats were treated with 10 mg diethylstilboestrol pellets for 3 weeks, and pituitaries were removed for analysis. Pituitary weight increased by 3.7-fold, and PRL mRNA increased by 1.8-fold as judged by qPCR analysis. Using an affymetrix array (rat genome array 230, version 2.0) we detected altered expression of a series of genes. Notably we detected up-regulation of two Wnt ligands, Wnt-4 and Wnt-10a (4-fold and 10-fold induction respectively). GH3 cells proliferate slowly in response to oestradiol, doubling in cell number over 7 days. A 2-3-fold induction of Wnt-4 and Wnt-10a mRNA was shown by qPCR analysis in GH3 cells treated with oestradiol for 72 h. Similarly, in primary cultures of dissociated pituitary cells from Fischer-344 rat pituitaries, oestradiol increased expression of both Wnt-4 and Wnt-10a mRNA by 120 h. Western blotting confirmed expression of Wnt-4 protein in GH3 cells, which was increased 2.1-fold by oestradiol treatment over 72 h.

In conclusion, Wnt-4 and Wnt-10a are expressed in the adult rat pituitary, and Wnt-4 is induced during oestrogen-induced proliferation. Wnt-4-deficient mice exhibit pituitary hypoplasia, but little is known of Wnt ligand function in the adult pituitary. These findings suggest that Wnt signalling pathways are involved in oestrogen-induced lactotroph proliferation. It is likely that these developmental pathways are utilised in adult pituitary remodelling, and may therefore be relevant to understanding pituitary adenoma pathogenesis.