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Biology of the endometrium
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
In addition to steroid hormones, their receptors play a key role in the regulation of cellular events in the endometrium. Estrogen and progesterone receptors are in tracellularly located ligand-inducible transcription factors that interact with specific hormone-response elements in target genes4,5. The three different domains of the receptor molecule possess specific functions (e.g. steroid and DNA-binding domains). A revolution in receptor studies was the realization that steroid hormone receptors are associated with non-steroid binding proteins that play a role in regulation of receptor function. Some of those proteins, such as heat shock protein 90, are speculated to stabilize the unactivated form of the steroid receptor in the absence of hormone6. The steroid-controlled regulatory genes can further regulate the expression of a multitude of genes either via transcription or post-transcriptional pathways. Some of the final protein products may remain intracellular; others are secreted and capable of mediating the steroid action to other cells. Figure 1 schematically represents a simplified model of signal transduction by steroid receptors. Despite many significant advances in the field of molecular biology, our understanding of how steroid receptors regulate gene transcription is still at an early stage.
Preclinical and clinical development of new progesterone receptor antagonists with high receptor specificity for breast cancer treatment
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
J. Hoffmann, H. Hess-Stumpp, R. B. Lichtner, U. Fuhrmann, G. Siemeister, M. R. Schneider
Endocrine therapies available to block steroid hormone receptor-mediated tumor growth are based on two principles: ligand depletion and receptor blockade. Ligand depletion can be achieved either by removal of steroid-producing glands or by inhibition of steroid biosynthesis (inhibitors of aromatase, or gonadotropin-releasing hormone (GnRH) agonists). Estrogen receptors can be blocked either with selective estrogen receptor modulators (SERMs) or by a new class of compounds, the pure antiestrogens.
Immunohistochem1Cal Studies with Antibodies to the Chicken Oviduct Progesterone Receptor
Published in Louis P. Pertschuk, Sin Hang Lee, Localization of Putative Steroid Receptors, 2019
Jean-Marie Gase, Etienne-Emile Baulieu
The detection of steroid hormone receptors in target cells has been the matter of numerous studies in recent years. Essentially all techniques have involved detection of hormone that is bound by the receptor and, therefore, only indirectly revealed this receptor in histological sections, smears, or cultured cells. Autoradiography with tritiated hormone has been successful in this respect. However, controversial results have been obtained1 with fluorescent hormone conjugates and with antibodies raised against hormonal ligands. These techniques and appropriate references are found in other chapters of this book.
From ligands to behavioral outcomes: understanding the role of mineralocorticoid receptors in brain function
Published in Stress, 2023
Huanqing Yang, Sowmya Narayan, Mathias V. Schmidt
Steroid hormone receptors are ligand-activated and switch from an inactive state to an active state by binding to their corresponding hormones (Torchia et al., 1998). Since MR LBD shares high homology with GR LBD, MR has two main endogenous ligands: aldosterone and cortisol in humans, or CORT in rodents (Baker et al., 2013). MR has a high affinity for cortisol (Kd = 0.5 nM), 10-fold higher than GR (Kd = 5 nM) (Meijer et al., 2018). The circulating concentration of cortisol in the blood is about 100–1000 times that of aldosterone (Syed & Qureshi, 2012). Even if only 5%-10% of cortisol is actively free, cortisol levels remain much higher than aldosterone in plasma (Cizza & Rother, 2012; Mifsud & Reul, 2018). Consequently, MR will be entirely occupied by cortisol except for when the circadian cycle of cortisol release is at its lowest point. Aldosterone has the same affinity for binding MR as cortisol, and since aldosterone dissociates from MR more slowly than cortisol, the aldosterone-MR complex is more stable and potent.
Improving the risk-to-benefit ratio of inhaled corticosteroids through delivery and dose: current progress and future directions
Published in Expert Opinion on Drug Safety, 2022
Piotr Damiański, Grzegorz Kardas, Michał Panek, Piotr Kuna, Maciej Kupczyk
FF is a synthetic, trifluorinated ICS approved for the once daily anti-inflammatory therapy in asthma and COPD [84]. It can be a good example of how a slight modification of a molecule can affect the PK/PD properties of the drug. It should be stressed that FF and FP are ICS with the structurally distinct molecules and different properties [85]. The 17α-furoate ester in FF has been shown to provide higher GR binding affinity, greater lipophilicity, and prolonged anti-inflammatory activity due to extended residence time compared to FP [86]. Interestingly, there is also growing evidence that unique structural modification in FF contributes to a therapeutic advantage over FP [87–89]. In addition, coupling the fluticasone backbone with the 17a-furoate ester in FF provides also the highest receptor selectivity for GR among the ICS currently available. Generally, this key pharmacological property reduces,,off target” interactions with other familiar steroid hormone receptors including mineralocorticoids receptors, progesterone receptors, estrogen as well as androgen receptors [87]. In summary, these properties of FF together with its negligible oral bioavailability, high systemic clearance and high-protein binding affinity (Table 1) determine favorable risk-to-benefit ratio.
Involvement of β-catenin in Androgen-induced Mesenchymal Transition of Breast MDA-MB-453 Cancer Cells
Published in Endocrine Research, 2021
Mamoun Ahram, Randa Bawadi, Mohammad S. Abdullah, Dana B. Alsafadi, Haneen Abaza, Sallam Abdallah, Ebtihal Mustafa
AR is a ligand-activated transcription factor that regulates the expression of numerous genes responsible for controlling cell proliferation and maturation.8 It is expressed in mammary tissue and plays important roles in the development of normal mammary glands.9–12 AR is the most widely expressed steroid hormone receptor in breast cancer with a higher prevalence among ER-positive tumors.13 In the context of ER-negative disease, the AR is expressed in 20–50% of the cases depending on the technique used (specifically, immunohistochemistry versus gene expression) and the studied population. In contrast to prostate cancer, the biological role of AR in breast cancer in general and in ER-negative/AR-positive subtype, in particular, has yet to be elucidated with preclinical studies reporting that AR has both proliferative and anti-proliferative effects.14–17