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.
Steroid metabolism
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.
Steroid excretion
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.
