HORMONAL CONTROL OF PITUITARY PROLACTIN-SECRETING TUMORS

Dipak K. Sarkar, Shane T. Hentges, Alok De and Raghaba H.R. Reddy

Department of Veterinary and Comparative Anatomy, Physiology and Pharmacology, Washington State University, Pullman, WA 99163-6540

Received 7/5/98 Accepted 7/15/98

4. PERSPECTIVE

Despite the many advances in recent years in the area of estrogen-induced tumorigenesis, there is still a great deal that is not understood about this process. Here we have outlined some of the factors relevant to estrogen action on cell transformation. A great deal of information of estrogen actions on prolactinomas is derived from the studies in Fischer F344 rats. These data suggest that estrogen mitogenic action on lactotropes is a multistep process (figure 1).

Figure 1. A schematic representation of putative mechanisms by which estrogen may induces tumors in pituitary lactotropes. Open circles are estrogen non-responsive lactotropes, middle strike circles are estrogen responsive lactotropes, half close circles are preneoplastic lactotropes and closed circles are neoplastic lactotropes.

The early events of estrogen action involves activation of estrogen receptors in a subset population of lactotropes, blocking the action of the inhibitory hypothalamic regulatory hormone dopamine, reducing the activity of negative growth regulator TGF-ß1 and stimulation of positive growth regulators (TGF-a and FGF). These early changes in hormonal control mechanisms lead to induction of PRL secretion and activation of cell cycle regulatory genes (e.g. c-fos, c-jun) and cell proliferation in a subset population of lactotropes. Persistent stimulation of these cellular processes is maintained due to continuous elevation of circulatory estrogen, and eventually induce spontaneous genetic errors leading to activation of oncogenes or inactivation of suppressor genes that may ultimately lead to genomic instability and transformation (26, 108, 113, 128, 129-133). The information presented represents only a portion of what is known about the actions of estrogen and there is still a larger amount that is not known. With recent technical advances including sophisticated animal models, transgenic cell lines, and new molecular techniques, the gap in our understanding of estrogen regulation of cell function should be narrowed as more questions can be addressed.