Steroid hormone is a steroid that serves as a hormone. It can be divided into two groups: corticosteroids and sex steroids. Within these two classes, they are five types according to their receptors: glucocorticoids, mineralocorticoids, androgens, estrogen and progestogens. In human body, steroid hormones play an important part in metabolism, inflammation, immune functions, salt and water balance, development of sexual characteristics and the ability of withstanding illness and injury. The natural steroid hormones are generally synthesized from cholesterol in the gonads and adrenal glands. These hormones are lipophilic substance. They can pass through the cell membrane as they are fat-soluble, and then bind to steroid hormone receptors (which may be nuclear or cytosolic depending on the steroid hormone) to bring about changes within the cell. Steroid hormones are generally carried in the blood, bound to specific carrier proteins such as sex hormone-binding globulin, corticosteroid-binding globulin and albumin. The binding is beneficial to help improve the hormones’ solubility in water.
Most studies say that hormones can affect cells when they are not bound by serum proteins. In order to be active, steroid hormones must free themselves from their blood-solubilizing proteins and either bind to extracellular receptors, or passively cross the cell membrane and bind to nuclear receptors. This idea is called the free hormone hypothesis. One study has found that these steroid-carrier complexes are bound by Megalin, a membrane receptor, and are then taken into cells via endocytosis. One possible pathway is that once inside the cell these complexes are taken to the lysosome, where the carrier protein is degraded and the steroid hormone is released into the cytoplasm of the target cell.
After the steroid hormones are transported to the target tissues and cells, they bind to the corresponding hormone receptors. Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), and androgen receptor (AR) are classic members of the nuclear receptor superfamily, composing subfamily 3C. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) and 3-ketosteroids (group NR3C). In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.
Steroid Hormone Receptors and Regulators
Individually and in combination, these four receptors play pivotal roles in some of the most fundamental aspects of physiology such as the stress response, metabolism, immune function, electrolyte homeostasis, growth, development, and reproduction. Multiple signaling pathways have been established for all four receptors, and several common mechanisms have been revealed. One main signaling pathway is achieved by direct DNA binding and transcriptional regulation of responsive genes. Another is achieved through protein-protein interactions, mainly with other transcription factors such as nuclear factor-kB, activator protein-1, or signal transducer and activator of transcriptions, to regulate gene expression patterns. These pathways can be up-regulate or down-regulate gene expression. And they all require ligand activation of the receptor and interplay with multiple protein factors such as chaperone proteins and co-regulator proteins.
The GR, MR, PR, and AR share structural similarities, with all containing three functional domains, i.e., the N-terminal transactivation domain followed by the DNA-binding domain (DBD) and the C-terminal ligand binding domain (LBD). A hinge region links the DBD and the LBD. These four steroid hormone receptors also exemplify the tremendous capacity and precision of endocrine modulatory mechanisms. Patients carrying mutated receptors frequently experience severe complications, and transgenic animals lacking individual receptors frequently cannot reproduce and/or survive. Temporally controlled tissue distribution patterns during developmental stages, reproductive phases, and disease states contribute to the diverse activities of these receptors.GR is expressed in almost all tissues although tissue and cell cycle-specific regulation of GR levels. Glucocorticoids exert a vast of physiological functions via the GR. Glucocorticoids are essential regulators of carbohydrate, protein, and fat metabolism The major glucocorticoid in the human is cortisol, also called hydrocortisone, whereas in rodents the major glucocorticoid is corticosterone. The synthesis and secretion of glucocorticoids by the adrenal cortex are tightly regulated by the hypothalamo-pituitary-adrenal axis, which is susceptible to negative feedback by circulating hormones and exogenous glucocorticoids. MR is expressed in epithelial tissues, such as the distal nephron or colon. Aldosterone can moderate dietary salt intake and the balance of salt ions by regulating the epithelial sodium channel and Na+, K+-ATPase subunit genes. The most physiologically important mineralocorticoid is aldosterone. Aldosterone is synthesized in the adrenal cortex primarily under the regulation of the renin-angiotensin system, potassium status, and ACTH. Progesterone is the most important progestin in humans. It is synthesized in the ovary, testis, and adrenal gland. Substantial amounts are also synthesized and released by the placenta during pregnancy. In addition to having significant hormonal effects, progesterone serves as a precursor in the synthesis of estrogen, androgens, and adrenocortical steroids. PR is expressed in the female generative tract, mammary gland, brain, and pituitary gland. In many cells, estrogen induces expression of PR, and its presence is a common marker for estrogen action in both research and clinical settings. In many biological systems, progestin enhances differentiation and opposes the cell proliferation action of estrogen. In humans, the predominant androgen secreted by the testis or ovary and peripheral conversion of androstenedione produced by the adrenal gland is testosterone. Androgens serve critical functions at different stages of life in the male. During embryonic life, androgens virilize the urogenital tract of the male embryo, and their action is therefore essential for the development of the male phenotype. At puberty, androgens promote the development of secondary sexual characteristics. In addition to stimulating and maintaining sexual function in men, androgens may also be responsible in part for aggressive behaviors. Testosterone and androstenedione are precursors for estrogen biosynthesis. Testosterone and 5-dihydrotesterone also produce androgenic effects via the AR.
Cancer Risk Factors
According to previous studies, researchers find that glucocorticoids are a key to treating certain leukemia and are frequently included in chemotherapy regimens for their antiemetic, antiedema, and palliative properties. The study found that serum cortisol levels in patients with prostate cancer were significantly higher than those in prostate hyperplasia. Preoperative blood cortisol levels in the lung cancer group and the digestive tract cancer group were higher than those in the healthy control group. This may be due to the abnormal metabolism of the cancer itself and the influence of cancer tissue on the body, lead to endocrine or metabolic disorders. In breast cancer and ovarian cancer research, dexamethasone can rapidly inhibit ERK activity in a manner independent of glucocorticoid receptors, and may be involved in the process of inhibiting cell proliferation in human breast cancer cell lines. In the process of inhibition of brain tumors, it is found that the combination of glucocorticoids and various biological effects can inhibit the synthesis and biological effects of vascular endothelial growth factor (VEGF) in tumor cells, inhibit the action of oxygen free radicals, and act on inflammatory mediators and inhibit tumor cell production function. And the presence of the PR acts as a useful prognostic marker in breast cancer irrespective of the patient’s progestational status. Studies suggest that certain progestin plus estrogen replacement regimens in postmenopausal women may increase the incidence of breast cancer. In addition, recurrent prostate cancer seems to result from increased AR signaling caused by increased AR expression in the presence or absence of AR gene amplification. The onset of recurrent prostate cancer seems to involve increasing AR-dependent growth factor signaling that overcomes apoptosis induced by androgen depletion.