17.1 Estrogens
The naturally occurring estrogens are the C18 steroids: 17 estradiol, estrone, and estriol, which are secreted by granulosa (follicular) cells within the ovary. 17-estradiol is the major estrogen in premenopausal women, and it maintains reproductive tissues and processes, along with progesterone. Estrogens also have important effects on metabolism, e.g., on transport proteins, clotting factors, electrolyte balance, and serum lipids.
Like other steroids, estrogen binds to receptors in the cytosol and alters DNA transcription.
Effects. See Table 17.1.
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Table 17.1 |
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Category |
Effects |
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Ovulation and reproduction |
Supports the growth and maturation of ovarian follicles and endometrium (along with progesterone) and stimulates ovulation ↑ the growth and the motility of the smooth muscle of the uterus and increases uterine blood flow ↓ the viscosity of cervical mucus and makes it more alkaline to support the survival of sperm |
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Puberty |
Initiates ductal development in the breasts Controls the female body configuration (e.g., narrow shoulders and broad hips) and the distribution of fat in the breasts and buttocks |
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Bone |
↑ osteoblast activity ↓ apoptosis of osteoblasts ↓ the number and activity of osteoclasts The net result is an increased formation of bone in the presence of estrogen. |
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Brain |
Estrogen may have a neuroprotective effect to increase neuronal survival and levels of neuronal growth factors and improve cognition. |
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Cholesterol levels |
↓ LDL levels ↑ HDL levels |
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Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein. |
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Estrogens: Estradiol, Premarin, Ethinyl Estradiol, Mestranol, and Diethylstilbestrol
Several types of estrogen preparations are available, and their effectiveness orally when taken depends on the extent of metabolism by the liver.
– Estradiol esters are administered intramuscularly and by a transdermal patch (Fig. 17.1).
– Premarin™ is a conjugated estrogen that contains estrone and equilin. It is administered orally.
– Ethinyl estradiol and mestranol are synthetic steroid estrogens that are administered orally.
– Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that is administered orally or parenterally.
Note: Estrogens are usually administered in cyclic fashion with a progestin (a natural or synthetic steroid hormone that has progesterone-like activity unless the uterus has been removed).
Uses
– Contraception
– To supplement inadequate production in conditions such as constitutional delay of puberty, ovariectomy, menopause, and osteoporosis
– To correct hormonal imbalance (e.g., dysfunctional uterine bleeding)
– To reverse an abnormal process (e.g., hirsutism or endometriosis) (see page 141)
Fig. 17.1 
Estradiol, progesterone, and derivatives.
Exogenous estrogen and progesterone mimic the natural hormones at their receptors. Depot preparations are absorbed slowly and thus have a longer duration of action than the natural hormones. Oral preparations undergo a higher degree of first-pass metabolism in the liver. All three estrogen metabolites are water soluble and are excreted by the kidneys. The main metabolite of progesterone is pregnanediol, which is also excreted by the kidneys. (FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.)
Note: Estrogens are not indicated for treatment or prevention of cardiovascular or neurodegenerative diseases because of possible untoward side effects including breast cancer, stroke, and adverse coronary events.
Side effects
– Nausea and vomiting, breast tenderness, and weight gain due to Na+ and water retention (usually disappear with continued administration)
– Increased risk of endometrial cancer. This is prevented by the addition of a progestin.
– Reproductive tissue abnormalities and cancers are seen in daughters and sons of women prescribed DES
– Gallstones (due to increased cholesterol caused by estrogen)
Gallstones
The majority of gallstones (75%) are formed when the amount of cholesterol in bile exceeds the ability of bile salts and phospholipids to emulsify it, causing cholesterol to precipitate out of solution. Gallstones may also be caused by an increased amount of unconjugated bilirubin (often in the form of calcium bilirubinate) in the bile (“pigment stones”). Gallstones may be aymptomatic or they can cause obstruction of a duct causing severe pain, vomiting, and fever. Non-drug treatment includes lithotripsy (shock wave obliteration of gallstones that allow the stone fragments to be excreted) or surgical removal of the gallbladder (cholecystectomy).
Hormone replacement therapy
The Women's Health Initiative (WHI) is a long-term study by the National Heart, Lung, and Blood Institute that has focused on the health of postmenopausal women. Prior to this study, perimenopausal women were routinely prescribed hormone replacement therapy to alleviate the symptoms of menopause. The WHI found that, compared with the placebo group, women taking estrogen plus progestin had slight increases in breast cancer, heart attacks, strokes, and thromboembolism in the lungs and legs. The benefits were fewer hip fractures and lower occurrences of colon cancer. Women taking estrogen alone had more strokes, more blood clots in the legs, and fewer hip fractures. Estrogen alone had no effect on breast cancer, heart attacks, or colorectal cancer.
17.2 Progestins
Progesterone is a C21 steroid secreted by the corpus luteum, placenta, and ovarian follicle that supports female reproductive tissues and processes (in conjunction with estrogen). It is also an important intermediate in steroid biosynthesis in tissues that secrete steroid hormones. Like other steroids, progesterone binds to intracellular receptors that act in the nucleus to regulate gene transcription.
Effects. See Table 17.2.
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Table 17.2 |
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Tissue |
Effects |
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Uterus |
During the menstrual cycle, progesterone decreases endometrial proliferation and leads to changes that promote implantation of a fertilized ovum. If implantation does not occur, the decline in progesterone at the end of the cycle is the main signal for the onset of menstruation. Maintenance of pregnancy |
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Breasts |
Stimulates lobular-alveolar development Induces differentiation of ductal tissue that has been stimulated by estrogen |
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Brain |
↑ body temperature and is probably responsible for the rise in basal body temperature at the time of ovulation |
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Progestins: Progesterone, Norethindrone, Ethynodiol, Norgestrel, an Medroxyprogesterone
– Progesterone, the natural hormone, is available in an oily solution for injection (Fig. 17.1).
– Norethindrone, ethynodiol, norgestrel (oral), and medroxyprogesterone (oral, parenteral) are synthetic steroids. Some have slight androgenic activity. Synthetic steroids are the most common progesterone preparations.
Uses
– Contraception
– Dysfunctional uterine bleeding
– Dysmenorrhea
– Endometriosis (see page 141)
Side effects
– Decreased high-density lipoprotein (androgenic preparations)
17.3 Hormonal Contraception
Estrogen and progesterone are primarily used for hormonal contraception. There are several preparations and modes of administration, which vary in effectiveness. Contraceptive choice largely depends on medical and lifestyle factors.
Combination Oral Contraceptives
A combination of a synthetic estrogen and a progestin is used (e.g., ethinyl estradiol or mestranol combined with norethindrone, ethynodiol, or norgestrel). Monophasic, biphasic, and triphasic preparations are available. In monophasic preparations, each active pill contains the same amount of estrogen and progestin. In biphasic preparations, the estrogen content is the same in each active pill but the level of progestin is increased about halfway through the cycle. In triphasic preparations, the hormone combination changes three times throughout the cycle (approximately every 7 days) (Fig. 17.2).
Mechanism of action. Combined oral contraceptive agents act by inhibiting ovulation through feedback inhibition of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary, by thickening cervical mucus, and by inhibition of endometrial proliferation necessary for implantation (Fig. 17.2).
Side effects. Most side effects are related to the estrogen component, but cardiovascular changes may be caused by either component. Adverse reactions other than those associated with estrogen therapy include
– Breakthrough bleeding with low-estrogen preparations
– Abnormal glucose tolerance
– Alterations in serum lipids
– Thromboembolic disease (minimal in low-estrogen preparations)
– Increased risk of myocardial infarction (MI) or stroke, particularly in women 35 years of age or older who smoke
Progestin-only Oral Contraceptives
Progestin-only “minipills” contain lower doses of progestin than combination oral contraceptives and are taken daily on a continuous regimen.
Mechanism of action. The contraceptive actions of these agents are due to the formation of impenetrable cervical mucus and to prevention of endometrial implantation. Because these preparations do not inhibit ovulation consistently (Fig. 17.2), they are not as effective as combination contraceptives.
Side effects. Unpredictable bleeding is common.
Note: Oral contraception has a 0.3% failure rate with perfect use and 8% with typical use during the first year.
Fig. 17.2 Oral contraceptives.
Oral contraceptives prevent ovulation by feedback inhibition of FSH and LH. The progestin-only minipill primarily acts to increase thick cervical mucus, which is impenetrable to sperm cells. It also inhibits the formation of the endometrial lining, and inconsistently prevents ovulation. Monophasic preparations contain equal amounts of estrogen and progestin. Biphasic preparations have the same estrogen content in each active pill but the level of progestin is increased about halfway through the cycle. Triphasic preparations have three changes to the estrogen and progestin combination throughout the cycle.
Emergency Contraception
Regimen for emergency contraception
– One progestin-only pill (i.e., levonorgestrel) immediately plus one more after 12 hours (e.g., Plan B™ which is approved by the U.S. Food and Drug Administration.)
– Two combination oral contraceptives immediately plus two more after 12 hours is also effective.
Effectiveness. Emergency contraceptive regimens provide a 75% reduction in pregnancy.
Side effects. Nausea, vomiting, and irregular bleeding are common; however, there is less nausea than seen with a progestin-only regimen.
Transdermal Patch Contraceptives
Progestin, Norelgestromin, and Ethinyl Estradiol
Transdermal patches deliver the progestin, norelgestromin, and ethinyl estradiol daily. The patch is applied to the buttocks, upper outer arm, lower abdomen, or upper torso and left on for 3 weeks, followed by a patch-free week to allow for withdrawal bleeding.
Mechanism of action. The mechanism of action is the same as that for combination oral contraceptives.
Effectiveness. Generally, transdermal patches are comparable in effectiveness to oral contraceptives; however, women weighing > 90 kg (~198 lb) may experience increased contraceptive failure.
Side effects. Dysmenorrhea and breast tenderness were more frequent with the patch. Otherwise, the side effects are the same as low-dose oral contraceptives.
Subdermal Implant Contraceptives
Etonogestrel
Etonogestrel (a progestin) is available in a 4-cm–long rod for implantation under the skin of the upper arm. This time-release rod is effective for up to 3 years.
Mechanism of action. As a progestin, this agent thickens the cervical mucus and produces an atrophic endometrium. Ovulation is suppressed in 97% of cycles.
Effectiveness. Effectiveness approaches 100%, but it has not been studied in women weighing more than 130% of their ideal body weight.
Side effects. The major side effect is irregular menstrual bleeding. Others include headache, vaginitis, weight gain, acne, and breast and abdominal pain.
Intravaginal Ring Contraceptives
Etonogestrel and Ethinyl Estradiol
These agents are contained within a flexible polymer ring with an outer diameter of 54 mm and an inner diameter of 50 mm. It is inserted into the vagina for 3 weeks and then removed to allow bleeding.
Mechanism of action. The mechanism of action is the same as that for combination oral contraceptives.
Effectiveness. Effectiveness approaches 100%.
Side effects. Serum levels of hormones are lower, which minimizes side effects. Both women and men have reported feeling the ring during intercourse.
Intrauterine Contraceptive Devices
Levonorgestrel
Levonorgestrel is a progestin.
Mechanism of action. The mechanism of action is the same as that for progestin-only contraceptives.
Effectiveness. Intrauterine devices (IUDs) are very efficacious and provide 5 to 10 years of continuous contraception.
Side effects. Fewer systemic effects are seen because serum concentrations of hormone are low, but there may still be the following side effects:
– Increased risk of pelvic inflammatory disease related to introduction of bacteria into the genital tract during insertion
– Increased menstrual blood flow and dysmenorrhea
Pelvic inflammatory disease
Pelvic inflammatory disease (PID) is an infection of the fallopian tubes (salpingitis) or ovaries, usually due to sexually transmitted bacteria, e.g., chlamydia. Symptoms include pelvic pain, pain during intercourse or urination, irregular menstrual bleeding, heavy vaginal discharge with an unpleasant odor, fever, fatigue, diarrhea, and vomiting. Untreated PID may cause fibrosis and abscesses in the fallopian tubes. This may lead to ectopic pregnancy, infertility, and chronic pelvic pain. Treatment involves the administration of antibiotics and the avoidance of intercourse until both partners are infection free.
Depot Contraceptive Injections
Medroxyprogesterone Acetate
Medroxyprogesterone acetate is a progestin administered by deep intramuscular injection in the gluteal or deltoid muscle or subcutaneously into the abdomen or thigh. It inhibits ovulation for > 3 months.
Mechanism of action. The mechanism of action is the same as that for progestin-only contraceptives.
Effectiveness. With typical use, 3% of women experience unintended pregnancy.
Side effects. The side effects are the same as those for oral progestin-only contraceptives.
17.4 Estrogen Antagonists
Selective Estrogen Receptor Modulators (SERMs)
Tamoxifen, Toremifene, and Raloxifene
Mechanism of action. Tamoxifen and the related compounds toremifene and raloxifene are partial agonists that inhibit the actions of full agonists such as estradiol at the estrogen receptor (Fig. 17.3).
Uses. SERMs are used to treat all stages of breast cancer in both pre- and postmenopausal women, as a palliative treatment for those with advanced disease, and as adjuvant treatment following surgery.
Side effects. Hot flashes, nausea, and vomiting are common.
Antiestrogen
Clomiphene
Mechanism of action. Clomiphene is an antiestrogen with weak estrogenic activity. It acts by binding estrogen receptors and preventing the normal feedback inhibition by estrogen of gonadotropin-releasing hormone and gonadotropin secretion (Fig. 17.3). Ovarian stimulation and ovulation result.
Side effects. They include mild menopausal symptoms, ovarian cyst formation, and multiple births.
Fig. 17.3 Selective estrogen receptor modulators.
Clomifene is an antagonist at estrogen receptors in the anterior pituitary; because of this, feedback inhibition of gonadotropins by estradiol is suppressed. Raloxifene uses the bone protective effects of estrogen in the prophylaxis and treatment of osteoporosis. Tamoxifen blocks the estrogen stimulus for tumor growth in breast cancer. The relative effects of these agents on cancer and thromboembolism risk, as well as climacteric symptoms (e.g., hot flashes and sweating) and bone mass, are shown.
17.5 Progesterone Antagonists
Mifepristone
Mechanism of action. Mifepristone (RU 486) is a potent competitive antagonist of progesterone. When administered in the follicular phase of the menstrual cycle, the drug prevents ovulation by inhibiting the effects of progesterone on the pituitary or hypothalamus. When given later, the drug terminates pregnancy by blocking the actions of progesterone on the uterus (Fig. 17.4). Mifepristone is also a glucocorticoid antagonist.
Uses
– Contraception
– Medical termination of pregnancy
Fig. 17.4 Progesterone receptor antagonist.
Implantation of the embryo causes the secretion of human chorionic gonadotropin (hCG), which acts on the corpus luteum to secrete progesterone. Progesterone is responsible for maintaining the endometrial lining. Mifepristone is an antagonist of progesterone at its receptors. This agent causes abortion of the embryo due to shedding of the endometrial lining.
17.6 Ovulatory Agents
Antiestrogen
Clomiphene
See page 164 for a discussion of this agent.
Gonadotropins
Human Chorionic Gonadotropin, Human Menopausal Gonadotropin, Urofollitropin, and Follitropin
Mechanisms of action
– Human chorionic gonadotropin (hCG), which is isolated from the urine of pregnant women, mimics the actions of LH.
– Human menopausal gonadotropin (hMG), or menotropin, which is isolated from the urine of postmenopausal women, contains equal amounts of FSH and LH, as well as other urinary proteins.
– Urofollitropin is highly purified FSH.
– Follitropin is recombinant FSH (rFSH).
Uses
– To induce ovulation
– Cryptorchidism (undescended testicle) to cause the testicle to move to the scrotum, and hypogonadotropic hypogonadism in men (absent or decreased function of the testes) to encourage maturation of leydig cells
Side effects
– Multiple births
– Ovarian enlargement with possible pain and ascites (excess fluid in the peritoneal cavity).
This is known as ovarian hyperstimulation syndrome (see page 141).
Prolactin-inhibiting Hormone Agonists
See page 142 for a further discussion of these agents.
Cabergoline and Bromocriptine
Uses
– Infertility (male and female) secondary to hyperprolactinemic states
17.7 Androgens, Anabolic Steroids, and Antiandrogens
The hormone testosterone is produced by the testis, adrenal glands, and ovaries (in small amounts). It has androgenic effects that are important in the development and maintenance of male sex characteristics and anabolic effects to increase muscle size and strength. In cells that contain the 5α-reductase enzyme (skin, prostate, seminal vesicles, and epididymis), testosterone is converted to 5-dihydrotestosterone (DHT), which is the more active form. Like other steroids, testosterone and 5-DHT bind to intracellular receptors that alter gene transcription.
Effects. See Table 17.3.
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Table 17.3 |
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Androgenic effects |
Stimulates the growth of the penis, testes, and scrotum Induces pubic, axillary, and facial hair Thickens the vocal cords and growth of the larynx, producing a lower-pitched voice ↑ libido ↑ activity of sebaceous glands |
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Anabolic effects |
↑ muscle growth and bone mass ↑ production of red blood cells |
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Synthetic Testosterone Esters
Synthetic agents vary in the ratio of anabolic to androgenic effects. Unaltered testosterone is not suitable for oral or parenteral administration because of its rapid absorption and hepatic metabolism.
Testosterone Cypionate and Testosterone Enanthate
Pharmacokinetics. These agents are given intramuscularly in oily solutions.
Uses
– Replacement therapy in hypogonadism (primary, secondary, or tertiary)
Synthetic Androgens
Fluoxymesterone, Methyltestosterone, and Danazol
These agents contain 17α-alkyl substitutions to retard hepatic degradation.
Pharmacokinetics
– Orally effective
Uses
– Replacement therapy in hypogonadism (primary, secondary, or tertiary)
– Endometriosis (page 141), fibrocystic breast disease, and hereditary angioneurotic edema (danazol)
Side effects. The substituted androgens produce liver dysfunction.
Anabolic Steroids
Oxymetholone and Oxandrolone
These agents also have 17α-alkyl substitutions. They are weak androgens designed to provide anabolic activity. It is impossible to completely separate androgenic and anabolic effects.
Uses. Anabolic steroids are used in the treatment of constitutional delay of growth.
Side effects
– Androgenic effects: acne, facial hair, and deepening of the voice are the earliest effects, followed by priapism (a persistent, usually painful, erection of the penis) and prostatic hyperplasia.
– Gynecomastia
– Cholestatic hepatitis (with 17α-alkylated compounds)
– Atherogenic changes in blood lipids (when taken in large doses, e.g., by athletes)
– Na+ retention and edema
– Benign and malignant tumors of the liver (rare)
Antiandrogens
Flutamide and Finasteride
Mechanisms of action
– Flutamide is a competitive antagonist of testosterone.
– Finasteride blocks the conversion of testosterone to DHT by inhibiting the enzyme 5α-reductase (Fig. 17.5).
Uses
– Finasteride is used in benign prostatic hyperplasia and male pattern baldness.
– Flutamide, in combination with a luteinizing hormone–releasing hormone agonist, is used to treat prostate cancer.
Fig. 17.5 Testosterone.
Natural testosterone (or its synthetic derivatives) is reduced in target cells to dihydrotestosterone (DHT) by 5α-reductase. DHT has a higher affinity than testosterone for androgen receptors. The liver rapidly metabolizes testosterone to androsterone, which undergoes renal elimination. 5α-reductase inhibitors inhibit the production of DHT and the androgenic activity in tissues where this is active (e.g., the prostate). They have little or no effect on testosterone-dependent tissues (e.g., skeletal muscle). Androgen receptor antagonists inhibit all androgen effects.
17.8 Drugs Acting on the Uterus
Anatomy and innervation of the uterus
The uterus is composed of a thick layer of smooth muscle with a central cavity that is lined by glandular epithelium. This cavity is continuous laterally with the fallopian tubes and inferiorly with the lumen of the vagina. The uterus is completely under autonomic control. It is innervated by the inferior hypogastric plexus (sympathetic) and the pelvic splanchnic nerves (parasympathetic from S2 to S4). Afferent signals from the uterus travel with the sympathetic efferents to T10-T12 and L1 spinal cord segments.
Oxytocin
Oxytocin is a posterior pituitary hormone that can now be synthetically produced for pharmacological use. The uterus is more sensitive to vasopressin than oxytocin except in the third trimester of pregnancy. During the third trimester, uterine oxytocin receptors increase in number, with sensitivity to oxytocin being maximal at term (vasopressin sensitivity decreases in parallel).
Effects
– Stimulates uterine smooth muscle contraction to facilitate parturition (birth)
– Causes myoepithelial cells of the mammary gland to contract and stimulates milk “let-down”
– Oxytocin-containing parvocellular neurons of the hypothalamus send axonal projections throughout the brain to regulate memory and maternal behaviors.
Pharmacokinetics
– Oxytocin is ineffective orally (destroyed by stomach enzymes) and is usually given intravenously or intramuscularly.
– Uterine contractions occur within seconds after intravenous injection and last ~20 minutes.
Uses
– Induction of labor
– Control of postpartum hemorrhage
Side effects
– Transient fall in blood pressure when injected intravenously
– Na+ and water retention
Note: Do not use oxytocin in patients with uterine abnormalities.
Ergot Alkaloids
Ergot (Claviceps purpurea) is a fungus that grows on rye. Extracts of ergot contain a variety of pharmacologically active substances (histamine, tyramine, etc.). Ergot alkaloids per se are derivatives of lysergic acid. Ergot alkaloids have varied actions as agonists or antagonists on tryptaminergic, dopaminergic, and adrenergic receptors.
See Chapter 32 for a discussion of ergot alkaloids in relation to migraine.
Ergonovine
Mechanism of action. Ergonovine is the most potent ergot compound for oxytocic effect with a relatively selective action on the uterus. It is also a partial α-adrenergic receptor agonist.
Pharmacokinetics. Rapid absorption after oral administration provides prompt onset of action.
Effects. Ergonovine can cause forceful, prolonged, or sustained contractions.
Uses
– Prevention and treatment of postpartum hemorrhage (after delivery of the placenta)
– Hastens involution of the uterus (the process where the uterus returns to its normal pre-pregnant size and state after childbirth)
Methylergonovine
Methylergonovine is a semisynthetic derivative with similar properties as ergonovine.
Effects of Estrogen