The steroid hormone receptors (SHRs), which include receptors for glucocorticoid-, estrogen, progesterone, and mineralocorticoid, represent a class of ligand-dependent intracellular transcription factors that selectively modulate gene expression in response to specific hormone ligands (Beato, Herrlich, & Schutz, 1995; Kumar and Thompson, 1999, Kumar and Thompson, 2012; Kumar et al., 2004; McKenna, Lanz, & O'Malley, 1999). These SHRs belong to the large superfamily of nuclear receptors (NRs) which includes receptors for thyroid hormone, vitamin-D, and peroxisome proliferator-activated receptors and the orphan receptors (for which ligands have not been identified) (Evans, 2003; Kumar & Thompson, 1999; Thornton, Need, & Crews, 2003; Yamamoto, 1985) among others. The SHRs play diverse physiological roles in various cells/tissues such as differentiation, development, proliferation, reproduction, immune responses, and energy metabolism (Bhasin & Jasuja, 2009; Briet & Schiffrin, 2010; Gronemeyer, Gustafsson, & Laudet, 2004; Kumar & McEwan, 2012; Okafor, Colucci, & Ortlund, 2019; Yang, Lamia, & Evans, 2007). They are also associated with numerous pathologies such as cancer, cardiovascular diseases, inflammation, metabolic syndromes, and reproductive abnormalities (Bhasin & Jasuja, 2009; McKenna & O'Malley, 2002). Thus, SHRs are not only required in a broad range of normal physiological processes but also represent therapeutic targets for a wide range of human diseases (Chawla, Repa, Evans, & Mangelsdorf, 2001; Kumar & Thompson, 2012; McDonnell & Wardell, 2010; McKenna & O'Malley, 2002; Nilsson, Koehler, & Gustafsson, 2011).

Deregulated actions of SHRs due, mainly, to altered receptor expression, transactivation functions, structural stability or sub-cellular localization are heavily implicated in the onset and progress of such pathological disorders of the target cells/tissues (Bhasin & Jasuja, 2009; Kumar & McEwan, 2012; Kumar & Thompson, 2012; McKenna & O'Malley, 2002; Okafor et al., 2019). The good and bad effects of steroids/hormones on physiology, pathophysiology, and in therapeutic uses are well known for decades (Hill, Roemer, Churchill, & Edwards, 2012; McDonnell & Wardell, 2010; Nilsson et al., 2011; Simons, Edwards, & Kumar, 2014). The differential effects of ligands, response element DNA sequences, and various other cofactors on the dynamic structure and functions of SHRs have provided essential knowledge for those seeking to design specific steroidal (and nonsteroidal) molecules as drug targets (Kumar, 2016; McDonnell & Wardell, 2010; Nilsson et al., 2011; Simons et al., 2014). Over years, the understanding of the SHR biology and mechanisms of their actions on target cells have led to many clinical applications and management of various endocrine-related disorders.

This knowledge has been helpful in the development of several therapeutic interventions particularly where SHR activity is needed to be curtailed, e.g., endocrine-related cancers, yet the full therapeutic potential of such interventions are desirable. Most notable are the clinical applications of tamoxifen and raloxifine, which have sufficient specificity for estrogen receptor and tissue-selective antiestrogenic actions to be used effectively in breast cancer therapy (Brzozowski, Pike, Dauter, et al., 1997; Klinge, 2018; McDonnell & Wardell, 2010; Nilsson et al., 2011; Shapiro, Mao, & Cherian, 2011; Wu, Yang, Ren, et al., 2005). Despite the effectiveness of SHR-based therapies in endocrine-related cancers, intrinsic and acquired resistance remain a clinical challenge (Klinge, 2018; Kumar & McEwan, 2012; McDonnell & Wardell, 2010; Nilsson et al., 2011; Shapiro et al., 2011). In this review article, we are discussing the up-to-date knowledge about the SHR actions with a particular emphasis on the structure and functions of the NTD/activation function-1 (AF1) in regulating the expression of target genes. Further, this review provides a new insight of how NTD/AF1 structural flexibility plays an important role in SHRs' actions.