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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
After secretion into the bloodstream, GnRH travels via the portal blood to the pituitary gland where it acts on its own receptor known as the Gonadotropin-Releasing Hormone Receptor (GnRHR), a seven-transmembrane G-Protein-Coupled receptor (Figure 8.24). This stimulates production of the beta-isoform of Phosphoinositide Phospholipase C, which then mobilizes calcium and Protein Kinase C. This results in the activation of proteins involved in the synthesis and secretion of the two pituitary hormones, Luteinizing Hormone and Follicle-Stimulating Hormone from the anterior pituitary. These hormones induce the production of estrogen and progesterone in the ovaries in females, and testosterone in the testes in males. This, in turn, induces ovulation in females and gametogenesis in males. GnRH is the target of various regulatory processes within the hypothalamic–pituitary–gonadal axis, and is inhibited by rising levels of estrogen or testosterone in females and males, respectively (i.e., via a feedback loop).
Dissemination and adhesion of peritoneal cancer cells to the peritoneal wall
Published in Wim P. Ceelen, Edward A. Levine, Intraperitoneal Cancer Therapy, 2015
Elly De Vlieghere, Marc Bracke, Laurine Verset, Pieter Demetter, Olivier De Wever
Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase associated with integrins and growth factor receptors. Elevated FAK expression correlates with poor survival in ovarian cancer patients [58]. FAK inhibition can lead to its relocalization to the nucleus and modulates gene expression and cell survival, affecting anchorage-independent ovarian carcinoma cell survival and growth. Ward et al. tested a small molecule FAK inhibitor (PF-271) that selectively prevents anchorage-independent cell growth by inhibition of FAK tyrosine (Y397) phosphorylation, resulting in increased tumor cell apoptosis and prevention of peritoneal metastasis in vitro and in vivo [58]. CD44 expression in cancer cells is not correlated with a bad prognosis. However, high expression of its ligand hyaluronate in the stroma is a poor prognosis marker [27]. Experimental data and correlative histological studies suggest CD44 as an interesting therapeutic drug candidate. Intraperitoneal injection of 36M2 positive cells (highly positive CD44 ovarian cancer cells) together with neutralizing monoclonal anti-CD44 inhibited the number of peritoneal implants by 70% without reducing the growth rate of tumors [50]. β1-integrin interacts with six divergent α-integrins covering the majority of ECM adhesion molecules (Table 6.2). Targeting β1-integrin for blocking adhesion is consequentially a logical approach in antiperitoneal metastasis therapy. Cheung et al. [55] blocked integrin adhesion in SK-OV-3 and Coav-3 by siRNA and blocking antibodies. Blocking β1-integrin inhibited adhesion of type I collagen, fibronectin, and laminin by 89%, while blocking α2-integrin decreased adhesion to type I collagen by 98%, and blocking α5 decreased adhesion to fibronectin by 94%. Inhibition of gonadotropin-releasing hormone receptor by siRNA (upstream of α2β1- and α5β1-integrin) in Coav-3 resulted in fewer peritoneal implants in a mouse model [55]. Cancer cells can adhere to mesothelial cells and to ECM via a wide range of adhesion molecules (Table 6.1), but do not form a homogeneous population: free cancer cells from similar tumor origin can use different molecular mechanisms to adhere. Besides this phenomenon, cancer cells show high phenotypic plasticity [49]. Blocking one adhesion molecule is inefficient; however, simultaneous targeting of several molecules could have a better result. Strobel et al. [50] combined neutralizing antibodies for β1-integrin and CD44 and found reduced adhesion of 36M2, CAOV-3, and SK-OV-3 ovarian cancer cells to human mesothelial cells compared to single antibody treatment [50].
Activation of Gonadotropin-releasing Hormone Receptor Impedes the Immunosuppressive Activity of Decidual Regulatory T Cells via Deactivating the Mechanistic Target of Rapamycin Signaling
Published in Immunological Investigations, 2022
Xuejin Wang, Liangying Zhong, Qiaodan Liu, Peiya Cai, Peiru Zhang, Zhilan Lu, Xiaoqin Li, Jin Liu
Gonadotropin-releasing hormone receptor (GnRHR) is mainly expressed on pituitary gonadotrope cells. Its ligand, GnRH, is secreted by hypothalamus, pituitary, and non-hypothalamic reproductive tissues such as ovaries, placenta, endometrium, oviducts, testes, prostrate, and mammary glands (Ramakrishnappa et al. 2005). In contrast with non-pregnant women, GnRH is measurable with pulsatile fluctuations in maternal blood during pregnancy (Petraglia et al. 1994). Upon binding to gonadotropin-releasing hormone (GnRH), GnRHR is activated to regulate the synthesis and secretion of the gonadotropins (Flanagan and Manilall 2017). Previous studies indicated the presence of GnRHR mRNA in human peripheral blood mononuclear cells (Chen et al. 1999). Recent studies suggested that GnRHR agonists might induce pro-inflammatory differentiation of T cells (N. Sung et al. 2015, 2016). However, the role of GnRHR in the modulation of immune cell functions is poorly understood. Particularly, the effect of GnRHR on the development and immunosuppressive activity of Tregs remains completely unknown.
Prevalence of primary aldosteronism without hypertension in the general population: Results in Shika study
Published in Clinical and Experimental Hypertension, 2018
Shigehiro Karashima, Mitsuhiro Kometani, Hiromasa Tsujiguchi, Hiroki Asakura, Shigeru Nakano, Mikiya Usukura, Shunsuke Mori, Masashi Ohe, Toshitaka Sawamura, Rika Okuda, Akinori Hara, Toshinari Takamura, Masakazu Yamagishi, Hiroyuki Nakamura, Yoshiyu Takeda, Takashi Yoneda
There have been previous reports of aberrant G-protein-coupled receptors (including luteinizing hormone-chronicgonadtropin receptor (LHCGR) and gonadotropin-releasing hormone receptor (GnRHR) in both human normal adrenal tissue and APA (34–38). It is quite possible that high levels of LH and GnRH after menopause cause aldosterone over-production from the adrenal gland in a subtype of normotensive PA.
Current approaches to overcome the side effects of GnRH analogs in the treatment of patients with uterine fibroids
Published in Expert Opinion on Drug Safety, 2022
Mohamed Ali, Mohamed Raslan, Michał Ciebiera, Kornelia Zaręba, Ayman Al-Hendy
New GnRH antagonists are oral, non-peptide, and gonadotropin-releasing hormone receptor antagonists. Elagolix and relugolix are approved for the treatment of heavy menstrual bleeding associated with UFs. The use of low-dose hormonal ABT has shown efficacy in reducing hypoestrogenic side effects. Therefore, all approved drugs are in combination with ABT of estradiol and norethindrone acetate.