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Enhanced LH action in transgenic female mice expressing hCGbeta-subunit induces pituitary prolactinomas; the role of high progesterone levels.

ABSTRACT: The etiology of pituitary adenomas remains largely unknown, with the exception of involvement of estrogens in the formation of prolactinomas. We have examined the molecular pathogenesis of prolactin-producing pituitary adenomas in transgenic female mice expressing the human choriongonadotropin (hCG) beta-subunit. The LH/CG bioactivity is elevated in the mice, with consequent highly stimulated ovarian progesterone (P(4)) production, in the face of normal estrogen secretion. Curiously, despite normal estrogen levels, large prolactinomas developed in these mice, and we provide here several lines of evidence that the elevated P(4) levels are involved in the growth of these estrogen-dependent tumors. The antiprogestin mifepristone inhibited tumor growth, and combined postgonadectomy estradiol/P(4) treatment was more effective than estrogen alone in inducing tumor growth. Evidence for direct growth-promoting effect of P(4) was obtained from cultures of primary mouse pituitary cells and rat somatomammotroph GH3 cells. The mouse tumors and cultured cells revealed stimulation of the cyclin D1/cyclin-dependent kinase 4/retinoblastoma protein/transcription factor E2F1 pathway in the growth response to P(4). If extrapolated to humans, and given the importance of endogenous P(4) and synthetic progestins in female reproductive functions and their pharmacotherapy, it is relevant to revisit the potential role of these hormones in the origin and growth of prolactinomas.

SUBMITTER: Ahtiainen P

PROVIDER: S-EPMC2881531 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Enhanced LH action in transgenic female mice expressing hCGbeta-subunit induces pituitary prolactinomas; the role of high progesterone levels.

Ahtiainen Petteri P Sharp Victoria V Rulli Susana B SB Rivero-Müller Adolfo A Mamaeva Veronika V Röyttä Matias M Huhtaniemi Ilpo I

Endocrine-related cancer 20100603 3

The etiology of pituitary adenomas remains largely unknown, with the exception of involvement of estrogens in the formation of prolactinomas. We have examined the molecular pathogenesis of prolactin-producing pituitary adenomas in transgenic female mice expressing the human choriongonadotropin (hCG) beta-subunit. The LH/CG bioactivity is elevated in the mice, with consequent highly stimulated ovarian progesterone (P(4)) production, in the face of normal estrogen secretion. Curiously, despite nor ...[more]

PMID: 20453081

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Project description:Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2(-/-)) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia, which is stronger in females. TGF-?1 is a known inhibitor of lactotroph proliferation. TGF-?1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models. To understand the role of TGF-?1 in the gender-specific development of prolactinomas in Drd2(-/-) mice, we compared the expression of different components of the pituitary TGF-?1 system, including active cytokine content, latent TGF-?-binding protein isoforms, and possible local TGF-?1 activators, in males and females in this model. Furthermore, we evaluated the effects of dopamine and estradiol administration to elucidate their role in TGF-?1 system regulation. The expression of active TGF-?1, latent TGF-?-binding protein isoforms, and several putative TGF-?1 activators evaluated was higher in male than in female mouse pituitary glands. However, Drd2(-/-) female mice were more sensitive to the decrease in active TGF-?1 content, as reflected by the down-regulation of TGF-?1 target genes. Estrogen and dopamine caused differential regulation of several components of the TGF-?1 system. In particular, we found sex- and genotype- dependent regulation of active TGF-?1 content and a similar expression pattern for 2 of the putative TGF-?1 activators, thrombospondin-1 and kallikrein-1, suggesting that these proteins could mediate TGF-?1 activation elicited by dopamine and estradiol. Our results indicate that (1) the loss of dopaminergic tone affects the pituitary TGF-?1 system more strongly in females than in males, (2) males express higher levels of pituitary TGF-?1 system components including active cytokine, and (3) estradiol negatively controls most of the components of the system. Because TGF-?1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-?1 system in males could protect or delay the development of prolactinomas in Drd2(-/-) male mice.

Dataset Information

Enhanced LH action in transgenic female mice expressing hCGbeta-subunit induces pituitary prolactinomas; the role of high progesterone levels.

Publications

Enhanced LH action in transgenic female mice expressing hCGbeta-subunit induces pituitary prolactinomas; the role of high progesterone levels.

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