Four major classes of steroids are derived from cholesterol: the progestogens, the androgens, the estrogens and the corticosteroids. The ovary is involved in the synthesis and secretion of the first three.
Natural progestogens are characterized by possessing 21 carbons (C-21 steroids), androgens by being comprised of 19 carbons (C-19 steroids), and natural estrogens have 18 carbons (C-18 steroids) in their structure. Ovarian steroids can exert feedback on both the hypothalamus and the pituitary. Whether estrogens and progestogens stimulate or inhibit gonadotropin release depends upon the plasma level and the duration of exposure. The plasma concentrations, production rates and secretion rates of the main ovarian steroids are given in Table Concentration, production rates and ovarian secretion rates of steroids in blood:
|Compound||Menstrual cycle phase||Representative concentration in plasma (nmol/1)||PR*(mg/day)||SR** by both ovaries (mg/ day)|
|Estradiol||Early follicular||0.2 (200 pmol/1)||0.08||0.07|
|Midluteal||0.7 (700 pmol/ 1)||0.270||0.250|
|Menopause||< 0.11 (110pmol/1)|
*PR, production rate, consisting of the sum of secretion rate and amount contributed by interconversion of precursor steroids; **SR, secretion rate, being the secretion of ovarian steroids in units per day
Over 97-98% of the steroids secreted by the ovary are bound to plasma proteins. Testosterone is mainly bound to sex hormone-binding globulin (SHBG). Estradiol is bound to albumin (60%) and SHBG (38%). SHBG is a β-globulin formed in the liver with a molecular weight of about 95 000. The level of SHBG, and thus the level of free hormone, can be affected by a number of conditions. Levels are increased by estradiol, combined oral contraceptives (COCs) and thyroid hormones, and are decreased by androgens, hypothyroidism and obesity.
There are number of naturally occurringgonadal steroids, all of them with different potency. The ones that are most important for clinical practice and their principal actions on the reproductive system are outlined in Table Relative potency and principal actions of some naturally occurring sex steroid in females. In our discussion we are going to use the terms progesterone and estrogen or estradiol to denote all naturally occurring progestogens and estrogens.
Table Relative potency and principal actions of some naturally occurring sex steroid in females
|Type of steroid and relative potency*||Properties|
|17β-Estradiol (100%)Estrone (10%)
|Stimulate secondary sexual characteristicsPrepare the genital tract for spermatozoal transport
Stimulate growth and the activity of mammary glands
Stimulate the growth of the endometrium and prepare the endometrium for progesterone action
Associated with sexual behavior
Regulate secretion of gonadotropins
|Progesterone (100%)17a-Hydroxyprogesterone (40-70%)||Prepare uterus to receive embryoMaintain uterus during early pregnancy
Stimulate growth of mammary glands but suppress the secretion of milk
Regulate secretion of gonadotropins
|Induce growth of androgen-dependent body hairInfluence sexual and aggressive behavior ? Regulate secretion of gonadotropins|
*The relative potencies are approximations only. They vary with (1) the assay used; (2) the affinity of the steroid for the steroid receptor in different tissues; (3) the local enzymatic conversion of the steroids in the target tissues; and (4) the differences in systemic metabolism
Mechanism of action of steroid hormones
All ovarian steroids have the same basic mechanism of action. For clarity and because the estrogen activity has been widely studied, the mode of action described here uses estrogen as the example. Free steroids are thought to diffuse passively to all cells because there is no evidence as yet of an active transport mechanism. Steroids are preferentially retained in target cells as stable complexes bound to intracellular receptor proteins (i.e., estrogen receptor — ER), which are steroid- and tissue specific. The receptor is thought to be a hormone- or ligand-activated transcription factor. The terms are used interchangeably.
The ER has six structural domains (protein regions having some distinct feature or role), A to F, but the important ones are the steroid-binding domain and the DNA-binding domain. The receptor binds the hormone, i.e., estrogen, through its steroid-binding domain. The binding of the steroid by the receptor results in the activation of the receptor molecules, which leads to conformational changes in the hormone-receptor complex, including its DNA-binding domain. This activation allows the hormone-receptor complex to bind to specific sites in the DNA, termed nuclear acceptor sites. Once bound to the DNA, the activated steroid-receptor complex acts as a transcription factor, which ‘switches on’genes, coding for the production of new proteins. The newly synthesized proteins change the metabolism of the target cell in a steroid-specific manner. The transfer of the steroid in the cell and nuclear binding of the steroid-receptor complex is rapid, occurring within minutes. Nuclear binding affects messenger RNA levels and synthesis within several hours, and finally protein synthesis and turnover happens within 12-24 h. The major physiologic effects of steroids in cells are seen in 12-36 h.
There are two estrogen receptors so far described: ERα (classic ER) and ERβ (recently described). Classic ER was cloned and sequenced from human breast cancer cells in 1986. The ERα consists of 595 aminoacids with a molecular weight of 66 kDa. The ERβ was cloned in 1996 from rat prostate and ovary. It consists of 485 amino acids and has a molecular weight of 54.2 kDa. ERβ is 95% homologous with ERα in the DNA-binding domain and 55% in the hormone-binding domain. ERα resides no chromosome 6 and ERβ on chromosome 14. ERα has a higher affinity for short-acting estrogens such as 17a-estradiol. Tissue distribution of ERα and ERβ varies and is under intense scientific investigation. Most of the work has been done on rodents, so-called estrogen receptor knockout (ERKO) mice. A knockout mouse is a genetically engineered animal in which the genome has been altered by site-directed recombination so that a particular gene is deleted. The reported findings may not be directly applicable to humans. The results depend on the sensitivity of the assays and are sometimes conflicting. Recent reports describe ERα predominance in the vagina, uterus, ovarian stroma, breast, cardiovascular system, liver, skeletal muscle, pituitary and epididymis; in contrast, ERβ is predominantly found in ovarian granulosa cells and the prostate. Both receptors are well represented in the brain and bone, but in different structural and functional parts. The levels of ERα and ERβ may vary depending on the age of the animal. The physiologic role of the different receptors is currently being studied. For example, ERα knockout mice develop to maturity, but are infertile, do not exhibit female sexual behavior and do not respond to estradiol.
Physiologic functions of steroid hormones
The main function of the ovarian steroids is related to reproduction. They are instrumental in developing the secondary sexual characteristics, establishing the menstrual cycle and in maintaining pregnancy. However, as our methods for studying the steroid hormones have developed, so has our understanding of their wider functions.
Female maturation Estrogen stimulates the growth of the vagina, uterus and fallopian tubes and the secondary sexual characteristics during puberty. It stimulates fat deposition, stromal development and ductal growth of the breast and is responsible for the accelerated growth phase and the closing of the epiphyses of the long bones that occurs at puberty. Estrogen contributes to the growth of axillary and pubic hair and alters the distribution of the body fat so as to produce the typical female body habitus. It stimulates the pigmentation of the skin, most prominent in the region of the nipples and areolae and in the genital region.
Other biological effects of estrogen Estrogen exerts effects on the cardiovascular system, connective tissue and numerous aspects of the metabolism such as lipids and carbohydrate metabolism. Some of those effects are well established and important and some are less well studied and/or less significant. Some estrogenic effects are summarized in Table Biological effects of estrogen:
- Gonadotropin regulation
- Stimulation of secondary sexual characteristics
- Increasing cervical mucus production
- Breast development (stromal and ductal tissue)
- Modulation of sexual behavior
- Endometrial stimulation
- Increased cardiac output Vasodilatation
- Endothelial effects
- Suppression of appetite
- Stimulates skin growth and wound healing
- Reduces motility of the bowel
- Mild anabolic effect
- Higher levels of corticosteroid-binding globulin, thyroxin-binding globulin, sex hormone-binding globulin, renin
- Reduction of cholesterol
- Reduction of bone resorption
- Reduction of capillary fragility
- Promotion of coagulation
The main sources of estrogen in women are the granulosa cells and the luteinied granulosa and theca cells of the ovaries. Estrogen is also produced by fat tissue and, in smaller amounts, by muscle and nervous tissue. Estrone and estriol are mostly formed from estradiol in the liver.
The chief function of progesterone is to prepare the endometrium for acceptance and maintenance of pregnancy, and the stimulation of alveolar growth of the mammary glands. Some of the effects of progesterone are listed in Table Biological effects of progesterone:
- Reproductive system
- gonadotropin regulation
- endometrial decidualization
- maintenance of early pregnancy
- breast development (alveolar tissue)
- Increase of appetite
- Mild catabolic effect
- Increase of basal body temperature via thermoregulatory centre of the hypothalamus
- Binding to the aldosterone receptor in the kidney and promoting natriuresis
- Contributes to premenstrual symptoms such as bloatedness, heavy tender breasts
- Slows peristalsis in the gastrointestinal tract, which may cause constipation
- Depressant and hypnotic effects on the brain
- Alters the function of the respiratory centre (increases respiratory drive)
- Progesterone is produced by theca and granulosa lutein cells and the corpus luteum.
Androgen production in the female is greater than is widely appreciated. The role of androgens in the female includes acting as precursors for estrogen production, anabolic effects, stimulation of axillary and pubic hair growth, sebum production, stimulation of bone formation, and stimulation of production of erythropoietin (EPO) from the kidneys in Table Biological effects of androgens:
- Reproductive system
- libido, sexual behavior
- growth of androgen-dependent body hair
- ? regulation of gonadotropins
- Anabolic effect
- nitrogen retention
- muscle growth
- Stimulate bone formation
- Increase serum production
- Increase erythropoietin production
- Decrease high-density lipoprotein cholesterol
- Contribute to general well-being
Androgens are produced from the ovaries, the adrenal glands and from peripheral conversion in adipose tissue. During reproductive life, the relative contribution from these sources varies. The ovaries and adrenals produce androstenedione, testosterone and dehydroepiandrosterone (DHEA), and the adrenals also produce DHEA sulfate (DHEAS). Androstenedione, DHEA and DHEAS are converted peripherally to testosterone, dihydrotestosterone (DHT) and estrogen. Only 1-2% of the total circulating testosterone is free or biologically active, the rest being bound to SHBG and albumin. In women, there are alterations in the level because SHBG has a dramatic effect on the free levels in plasma, binding 66% of total circulating testosterone. SHBG is increased by increased levels of estradiol and thyroxine, and suppressed by testosterone, glucocorticoids, excessive growth hormone, high insulin levels and obesity. The daily androstenedione and testosterone production in premenopausal women is thought to be about 3.2 mg and 0.26 mg, respectively.
In premenopausal women, 25% of testosterone is produced by the ovaries, 25% by the adrenals and 50% by peripheral conversion. In postmenopausal women, 50% of testosterone is produced by the ovaries, 10% by the adrenals and 40% by peripheral conversion, and the overall androgen production decreases with age. The age-related decrease in androgen production starts premenopausally and testosterone levels fall by approximately 50% between the ages of 20 and 40, and then level off. After the menopause, the process continues and the age-related decline is particularly noticeable for DHEA and DHEAS. Following natural menopause, the level of androstenedione is 50% of the premenopausal value. After oophorectomy, the levels of testosterone and androstenedione fall by 50% in previously premenopausal women and by 50% and 21% respectively in previously post-menopausal women. Some androgenic effects are listed in Table Biological effects of androgens.