Sex differences in the development of prolactinoma in mice overexpressing hCGβ: role of TGFβ1

Abstract

Female transgenic mice that overexpress the human chorionic gonadotrophin β subunit (hCGβ+) develop prolactinomas, whereas hCGβ+ males do not. The high levels of circulating hCG induce massive luteinization in the ovary of hCGβ+ females, and progesterone becomes the primary steroid hormone produced, but estradiol remains at physiological level. The involvement of high levels of progesterone in lactotroph proliferation is not clearly understood; hence, the pathogenesis of prolactinomas in hCGβ+ females remains unclear. TGFβ1 is an inhibitor of lactotroph function, and the reduced TGFβ1 activity found in prolactinomas has been proposed to be involved in tumor development. The aim of the present work was to study the role of TGFβ1 in the gender-specific development of prolactinomas in hCGβ+ mice. We compared the expression of different components of the pituitary TGFβ1 system in males and females in this model. We found reduced TGFβ1 levels, reduced expression of TGFβ1 target genes, TGFβ1 receptors, , and in hCGβ+ female pituitaries. However, no differences were found between the transgenic and wild-type male pituitaries. We postulate that decreased pituitary TGFβ1 activity in hCGβ+ females is involved in the development of prolactinomas. In fact, we demonstrated that an treatment carried out for increasing pituitary TGFβ1 activity, was successful in reducing the prolactinoma development, and the hyperprolactinemia in hCGβ+ females. Moreover, the stronger TGFβ1 system found in males could protect them from excessive lactotroph proliferation. Sex differences in the regulation of the pituitary TGFβ1 system could explain gender differences in the incidence of prolactinoma.

Comparison of Male and Female Prolactinoma Patients Requiring Surgical Intervention

“…Other studies have presented evidence that differential expression of estrogen receptor α and transforming growth factor β 1 may play a role in the difference seen in tumor pathogenesis between the genders, though the results of these studies are yet to be confirmed. 13,26 Previous studies have also shown differences in disease history between men and women with prolactinomas. Specifically, men have been previously shown to have shorter duration of symptoms prior to surgery, higher levels of preoperative serum prolactin levels, and more medically refractory disease.…”

Participation of membrane progesterone receptor α in the inhibitory effect of progesterone on prolactin secretion

“…All primers showed similar efficiencies of ~95–100%. A housekeeping gene, Cyclophilin B ( Cyp B ), was used as an internal control to normalise differences in the amount of starting template between samples, as described previously . Target gene expression was quantified using the comparative CT method (ΔCT).…”

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens—An Insight From Translational Studies

“…In addition, FS cells produce numerous cytokines and growth factors, including interleukin-6 (IL-6), follistatin, basic fibroblast growth factor, transforming growth factor β (TGF β), VEGF and leukemia inhibitory factor, which all regulate lactotropic cell proliferation and prolactinoma development [47]. The TGFβ1 expression was reduced in human and animal prolactinomas [91,92]. Estradiol inhibits most of the components of the TGFβ1 system, and this mechanism seems to be of importance with regard to the balance and negative control of the function of lactotropic cells [40] (Figure 1).…”