Steroid Hormone Mechanism Of Action And Metabolism
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 trans- port 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).
Steroids in the circulation
Steroid hormones are transported in the bloodstream bound to specific proteins. Protein-bound hormone does not traverse the plasma mem- brane of the cell. Nearly 70% of circulating testosterone and estradiol is bound to a β globulin known as sex hormone-binding globulin (SHBG). Another 30% is loosely bound to albumin, leaving only 1–2% unbound and capable of entering cells. SHBG binds all other estrogens and androgens to varying degrees; less than 10% of any steroid is free in the bloodstream. Pregnancy, estrogen and hyperthyroidism all increase SHBG synthesis. Androgens, progestins, corticoids and growth hormone all decrease SHBG. Weight gain can also decrease SHBG through an insulin-mediated effect on its synthesis. In keeping with the law of mass action, changes in the concentration of SHBG will affect the amount of free, unbound circulating steroid. Changes in SHBG will therefore affect the biologic action of steroids by altering the amount available to cells.
Unlike the other sex steroids, progesterone is carried in the blood by a glycoprotein, corticosteroid-binding globulin (CBG). CBG is also known as transcortin. As suggested by its name, it binds and carries glucocorticoids.
With the exception of the progestins, androgens are obligatory precursors of all other steroid hormones. Therefore, androgens are made in all steroid-producing tissues including the testis, ovary and adrenal gland. The major circulating androgen in men is testosterone which is produced by the testes. Testosterone is the most potent androgen. Its hormonal action is produced either directly through binding to the androgen receptor or indirectly after conversion to dihydrotestosterone (DHT) within the target tissue. Testosterone acts directly on the internal genital tract in male fetuses during sexual differentiation (Chapter 6) and on skeletal muscle to promote growth. DHT acts on the genital tracts of male fetuses to stimulate differentiation of the external genitalia. In adult men, DHT acts locally to maintain masculinized external genitalia and secondary sexual characteristics such as facial and pubic hair. Other major circulating androgens in men include androstenedione, androstenediol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S).
All of the above androgens, including testosterone and DHT, can be found in the circulation of women. With the exception of androstenedione, the concentrations of the androgens are considerably lower in women than in men. Androstenedione is unique in that only about 4% of it is bound to SHBG in the circulation in women. The remainder is bound more loosely to albumin. Circulating androstenedione functions largely as a prohormone and is converted within target tissues to testosterone, estrone and estradiol.
Estradiol (E2) is the major estrogen secreted by the ovary. Estrone (E1) is also secreted by the ovary in significant amounts. Estriol (E3), by contrast, is not produced in the ovary at all. Estriol is produced from estradiol and estrone in peripheral tissues and from androgen in the placenta; it is considered a less active “metabolite” of the more potent estrogens. Direct conversion of androgens into estrone can occur in skin and adipose tissue. This has important clinical implications in the obese female. In all women, the daily production of the prohormone androstenedione is 10 times higher than that of estradiol. In obese women, conversion of androgens to estrone in adipose tissue can become a major source of excessive amounts of circulating estrogen.
The adrenal gland is an important source of sex steroids in both men and women. Androstenedione, DHEA and DHEA-S are the major circulating androgens of adrenal origin and adrenal androgen production follows a circadian rhythm that parallels cortisol secretion. Adrenal androgens assume an important role in the postmenopausal woman. In the absence of ovarian estrogen production, adrenal androgens act as a major source for estrogen precursors.
The most abundant progestin in the circulation is progesterone. The ovary, testis, placenta and adrenal gland can all produce progesterone. 17-Hydroxyprogesterone of adrenal and ovarian origin represents the other major circulating progestin. Both progestins are largely bound by transcortin.
Steroids are excreted in urine and bile. Prior to elimination, most active steroids are conjugated as either sulfates or glucuronides. Some sulfated conjugates such as DHEA-S are actively secreted. These conjugated hormones can serve as precursors to active hormone metabolites in target tissues that have the enzymes to hydrolyze the ester bonds involved in the conjugation.