Steroid hormone mechanism of action and metabolism




Mechanisms of steroid action


Steroid hormones exert their effects via a unifying basic mechanism: the induction of new protein synthesis in their target cells. These induced proteins may be hormones themselves or other molecules important to cell function, such as enzymes. It is the newly synthesized proteins that are ultimately responsible for steroid hormone activity (Fig. 3.1).


Once a steroid hormone is secreted by its endocrine gland of origin, 95–98% of it circulates in the bloodstream bound to a specific transport protein. The remaining 2–5% is free to diffuse into all cells. Once inside the cell, a steroid can only produce responses in cells that have specific intracellular receptors for that hormone. Specific receptor binding is key to the action of steroids in their target tissues. Thus, estrogen receptors are found in the brain and in target cells specific to female reproduction, such as the uterus and breast. Facial hair follicles and penile erectile tissue contain androgen receptors. Glucocorticoid receptors are found in all cells because glucocorticoids are necessary to regulate global functions like metabolism and stress.


All members of the major classes of sex steroids (e.g., androgens, estrogens and progestins) act through a similar sequence of events to exert cellular responses: (i) transfer of the steroid into the nucleus; (ii) intranuclear receptor binding; (iii) alterations in receptor conformation that convert the receptor from an inactive to an active form; (iv) binding of the steroid–receptor complex to regulatory elements on deoxyribonucleic acid (DNA); (v) transcription and synthesis of new messenger ribonucleic acid (mRNA); and (vi) translation of mRNA with new protein synthesis in the cell. The mechanisms of action of glucocorticoids and mineralocorticoids differ from those of the sex steroids. Glucocorticoids and mineralocorticoids bind to their receptors in the cell cytoplasm. Hormone–receptor complexes are subsequently transported to the nucleus where they bind to the DNA.


There are three important structural domains in each steroid hormone receptor that correspond to the molecule’s three functions: (i) steroid hormone binding; (ii) DNA binding; and (iii) promotion of gene transcription. It is therefore not surprising that all steroid hormone receptors have remarkable structural similarities at the copy DNA (cDNA) level. The receptors for thyroid hormone, vitamin D and vitamin A also have similar DNA binding domains. Together with the sex hormone receptors, these receptors form a “superfamily” of nuclear receptors in which the thyroid hormone and vitamin A and D receptors are thought to be the most evolutionarily primitive. The latter three receptors are highly conserved, likely a result of their importance in early embryonic development. Glucocorticoid and progesterone receptors arose more recently in evolution. Their actions are less global, regulating acute metabolic changes in highly differentiated cells.


Expression of genes regulated by steroid hormones is controlled by four specific elements: (i) promoters; (ii) steroid-responsive enhancers; (iii) silencers; and (iv) hormone-independent enhancers. Steroid-responsive enhancers are DNA binding sites for activated steroid–receptor complexes and are known as steroid response elements (SREs). SREs are a very important component of hormone-responsive genes; they determine steroid specificity.



Agonists and antagonists


Steroid hormone potency depends on a combination of the affinity of the receptor for the hormone or drug, the affinity of the hormone–receptor complex for the SRE, and the efficiency of the activated hormone–receptor complex in regulating gene transcription. Molecules with high affinities for a receptor and whose subsequent hormone–receptor complex has high affinity for an SRE lead to prolonged occupancy of the SRE and sustained gene transcription. Such molecules act as agonists for the parent compound. Other molecules may have a high affinity for a receptor, but the hormone–receptor complex binds inefficiently to the SRE. Still others occupy the steroid receptor in a way that allows them to bind to the SRE but prevents RNA polymerase from coupling with factors necessary for gene transcription. The latter act as antagonists to the parent compound. An example of a compound with mixed agonist/antagonist properties is the drug tamoxifen. Tamoxifen is an antiestrogen that acts as a potent antagonist to the estrogen receptor in breast tissue and as an agonist in uterus and bone. Such tissue-specific effects are dependent upon specific silencers and hormone-independent enhancers present in each tissue. Another widely used agonist/antagonist is the non-steroidal compound clomiphene citrate. Clomiphene can be used to induce ovulation, although its actions are complex. Clomiphene’s interactions with estrogen receptors in the pituitary gland and hypothalamus result in binding of receptors, but without subsequent efficient stimulation of estrogen-associated gene transcription. The hypothalamus senses this as a hypo-estrogenic state and gonadotropin-releasing hormone (GnRH) pulse frequency increases. Pituitary follicle-stimulating hormone (FSH) production is stimulated and increased FSH release drives ovarian production of estrogen. When clomiphene is stopped, the hypothalamic estrogen receptors are again available for estrogen binding and appropriate SRE responses. The hypothalamus is able to respond normally to the high concentrations of circulating estrogen from the ovaries and an ovulatory luteinizing hormone (LH) surge occurs (Chapter 14).

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Jun 17, 2017 | Posted by in NURSING | Comments Off on Steroid hormone mechanism of action and metabolism

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