Faraoni Erika Y, Camilletti María Andrea, Abeledo-Machado Alejandra, Ratner Laura D, De Fino Fernanda, Huhtaniemi Ilpo, Rulli Susana B, Díaz-Torga Graciela
Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
Instituto de Investigaciones FarmacológicasConsejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
J Endocrinol. 2017 Mar;232(3):535-546. doi: 10.1530/JOE-16-0371. Epub 2017 Jan 17.
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.
过表达人绒毛膜促性腺激素β亚基（hCGβ+）的雌性转基因小鼠会发生催乳素瘤，而hCGβ+雄性小鼠则不会。循环中高水平的hCG会诱导hCGβ+雌性小鼠卵巢大量黄体化，孕酮成为产生的主要甾体激素，但雌二醇水平维持在生理水平。高水平孕酮在催乳素细胞增殖中的作用尚不清楚；因此，hCGβ+雌性小鼠催乳素瘤的发病机制仍不明确。转化生长因子β1（TGFβ1）是催乳素细胞功能的抑制剂，催乳素瘤中发现的TGFβ1活性降低被认为与肿瘤发生有关。本研究的目的是探讨TGFβ1在hCGβ+小鼠催乳素瘤性别特异性发生中的作用。我们比较了该模型中雄性和雌性垂体TGFβ1系统不同成分的表达。我们发现hCGβ+雌性垂体中TGFβ1水平降低、TGFβ1靶基因、TGFβ1受体、 以及 的表达减少。然而，转基因和野生型雄性垂体之间未发现差异。我们推测hCGβ+雌性小鼠垂体TGFβ1活性降低与催乳素瘤的发生有关。事实上，我们证明通过 治疗提高垂体TGFβ1活性可成功减少hCGβ+雌性小鼠催乳素瘤的发生和高催乳素血症。此外，雄性中更强的TGFβ1系统可保护它们免受催乳素细胞过度增殖的影响。垂体TGFβ1系统调节中的性别差异可以解释催乳素瘤发病率的性别差异。
