Steroid hormones are synthesized in the adrenal cortex, gonads, and placenta; all are derived from cholesterol and many are of clinical importance. Steroid hormones are synthesized in the mitochondria and the smooth endoplasmic reticulum. Because they are lipophilic, they cannot be stored in vesicles from which they would readily diffuse, and are therefore synthesized when needed as precursors. Upon stimulation of the stem cell, steroid hormone precursors are converted to active hormones and diffuse out of the stem cell by simple diffusion as their intracellular concentration increases.
Because all steroid hormones are derived from cholesterol, they are not soluble in plasma or other body fluids. As a result, the steroids bind to transport proteins that increase their half-life and ensure ubiquitous distribution. Protein-bound steroids are in equilibrium with a small fraction of free steroids, which are “active.” Steroids can act rapidly, by binding to cell surface receptors, or slowly, by binding to cytoplasmic or nucleic receptors, ultimately activating gene transcription.
The adrenal glands are made up of the adrenal medulla and the adrenal cortex. The adrenal cortex is divided into three main anatomic zones: the zona glomerulosa, which produces aldosterone; and the zona fasciculata and reticularis, which together produce cortisol and adrenal androgens. The medulla synthesizes catecholamines. More than 30 steroids are produced in the adrenal cortex; they can be divided into three functional categories: mineralocorticoids, glucocorticoids, and androgens. Steroids that are produced almost exclusively by the adrenal glands are cortisol, 11-deoxycortisol, aldosterone, corticosterone, and 11-deoxycorticosterone. Most other steroid hormones, including estrogens, are produced by the adrenal glands and gonads.
Mineralocorticoids are formed in the zona glomerulosa. The main function of mineralocorticoids is to promote tubular reabsorption of sodium and secretion of potassium and hydrogen ions in the collecting tubule, distal tubule, and collecting ducts. When sodium is reabsorbed, water is simultaneously absorbed. Sodium and water absorption increase fluid volume and blood pressure. Aldosterone is the most potent mineralocorticoid, accounting for about 90% of the total mineralocorticoid activity. Mineralocorticoid potency in descending order is aldosterone, 11-deoxycorticosterone, 18-oxocortisol, corticosterone, and cortisol.
Although cortisol has primarily glucocorticoid activity, it also has some mineralocorticoid activity. Cortisol has 1/400 the potency of aldosterone, but its concentration is about 80 times that of aldosterone. Adrenal production of cortisol is approximately 25 mg/day and that of aldosterone is 100 μg/day. Corticosterone has mainly glucocorticoid activity and some mineralocorticoid activity. Aldosterone secretion is regulated primarily by the renin-angiotensin system; it is also stimulated by increased serum potassium concentrations. Hyperkalemia and angiotensin II cause an increase in aldosterone. To a lesser extent, elevated sodium concentration suppresses aldosterone secretion, and corticotropin allows aldosterone secretion.
Glucocorticoids are produced primarily in the zona fasciculata. Glucocorticoids affect metabolism in several ways. Glucocorticoids stimulate gluconeogenesis and decrease the use of glucose by cells. Cortisol reduces protein stores in all cells of the body except the liver and increases protein synthesis in the liver. Cortisol also increases amino acids in the blood, decreases amino acid transport to extrahepatic cells, and increases amino acid transport to liver cells. Cortisol mobilizes fatty acids from adipose tissue, increases plasma free fatty acids, and increases the use of free fatty acids for energy. Cortisol, the most clinically important glucocorticoid, accounts for approximately 95% of all glucocorticoid activity.
Corticosterone accounts for a small but significant amount of the total glucocorticoid activity. Cortisol secretion is regulated almost entirely by corticotropin, which is secreted by the anterior pituitary gland in response to corticotropin-releasing hormone (CRH) from the hypothalamus. Serum cortisol inhibits CRH and corticotropin secretion, thus preventing excessive cortisol secretion from the adrenal glands. Corticotropin stimulates cortisol secretion and promotes the growth of the adrenal cortex in conjunction with growth factors such as insulin-like growth factor (IGF)-1 and IGF-2. There is a circadian rhythm in cortisol secretion; the highest cortisol levels occur about 1 hour before waking up. Stress, pain, and inflammation cause increased cortisol production.
The term “androgen” refers to any steroid hormone that has masculinizing effects. In men, androgens are responsible for the development of secondary sexual characteristics. Androgens play a less important role in women; however, adrenal androgens are responsible for much of the growth of pubic and axillary hair. Testosterone is the main androgen. Androgens are produced in the adrenal glands and the gonads. In men, the adrenal glands produce about 100 μg/day of testosterone and the testes produce about 7,000 μg/day. In women, 50% to 60% of testosterone is derived from androstenedione conversion in peripheral tissues, 30% is produced directly by the adrenal glands and 20% by the ovary.
Adrenal androgens are formed primarily in the zona reticularis. Dehydroepiandrosterone (DHEA) is the main steroid produced by the adrenal glands. The sulfation of DHEA produces DHEA sulfate (DHEA-S). Adrenal androgens are moderately active male sex hormones. Some of the adrenal androgens are converted to testosterone. The mechanism of stimulation of androgen secretion from the adrenal glands is not well understood. Adrenarche is the maturation of the adrenals, which causes an increase in these androgens and occurs between the ages of 5 and 20.
Adrenarche, therefore, begins well before puberty. Adrenal androgen secretion is partially regulated by corticotropin but also by other unknown factors. The testes secrete testosterone, dihydrotestosterone (DHT), and androstenedione. Gonadal androgen production is controlled by the hypothalamic secretion of GnRH, which causes the anterior pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Testosterone is secreted by the Leydig cells of the testes in response to LH stimulation. Most of the testosterone is converted to the more active DHT in target tissues.
Estrogens and progestins
In women, the main function of estrogen is to promote the proliferation and growth of specific cells in the body that is responsible for the development of most secondary sexual characteristics. Progestins are responsible for preparing the uterus for pregnancy and the breasts for lactation. In men, estrogens and progestins generally do not play a clinically significant role in the development of sexual characteristics. In women, estrogens and progestins are derived from the adrenal gland or the gonads. In women with intact ovaries, the adrenal contribution to circulating estrogen is negligible. Estrogens and progestins are secreted at different rates during different parts of the female menstrual cycle.
Estradiol is the prominent ovarian estrogen; estrone and estriol are two other estrogens. Estradiol is 12 times more potent than estrone and 80 times more potent than estriol. The ovaries produce estrone in small amounts, but most of it is formed by peripheral conversion from androgens. Estriol is primarily a metabolite of estrone and estradiol in non-pregnant women. In pregnancy, however, estriol is the main placental estrogen. DHEA-S from the fetal adrenal glands is converted to estriol by the placenta.
The main progestin is progesterone; a minor progestin is 17-hydroxy-progesterone. In the first half of the menstrual cycle, small amounts of progesterone are produced, about half by the ovaries and half by the adrenal cortex. Larger amounts of progesterone are secreted in the last half of the menstrual cycle by the corpus luteum. Men produce a small amount of estrogen (about 1/5 of the production of a non-pregnant woman). Sertoli cells convert a small amount of testosterone to estrogen. Also, estrogens are formed from testosterone and androstenediol in the periphery of the liver.