Estrogen, Progesterone, Androgens

farmakologi fkub

Antiprogestins

Mifepristone (RU486)
Competitive inhibitor of the progesterone receptor. The drug can also bind to the glucocorticoid receptor. It is used as an abortifacient to terminate early pregnancy. Drug administration is usually followed by a prostaglandin.

Danazol
Partial or weak agonist at androgen, glucocorticoid, and progesterone receptors. Appears to act centrally to reduce ovarian production of steroids. Used in the treatment of endometriosis and fibrocystic disease of the breast. Adverse reactions are due to its weak androgenic properties.

Androgens & Anabolic steroids

Regulation of secretion
Testosterone is the principle androgen secreted by the testes (Leydig cells). Testosterone and other androgens are also secreted by the adrenal cortex and in small amounts by the ovaries. Once secreted, testosterone is 99% bound to plasma proteins, mostly to sex hormone-binding globulin.

Regulation of secretion
Secretion of testosterone is regulated by the hypothalamic-pituitary system. LH stimulates the Leydig cells to synthesize and secrete testosterone. Testosterone and FSH act to increase spermatogenesis. Testosterone provides negative feedback to the pituitary.

Mechanism of action
Similar to other steroid hormones. Binds to cytosolic receptors, which are translocated to the nucleus where they regulate gene expression. In some organs (e.g., prostate), testosterone is converted to dihydrotestosterone (via 5alpha-reductase activity), a more potent receptor agonist.

Physiologic effects
Necessary for the development of secondary male sex characteristics and male sexual behavior. Required for spermatogenesis. Promotes protein anabolism and growth. Enhances linear bone growth and muscular development.

Physiologic effects
Causes an increase in the size of the larynx and deepens the voice. Increases sebaceous gland activity, which may result in acne, and stimulates erythropoiesis.

Indications for Use

Used in replacement therapy for hypogonadism and hypopituitarism. Used to accelerate growth and to promote anabolism. In breast cancer, androgens are used as palliatives. Also used in the treatment of angioneurotic edema and endometriosis (danazol).

Specific agents
Compounds with androgenic and anabolic activity include testosterone and methyltestosterone. Synthetic analogs with greater anabolic than androgenic properties include fluoxymesterone, nandrolone, and oxandrolone. These "anabolic steroids" were first produced for treatment of patients with debilitating diseases or prolonged immobilization to prevent negative nitrogen balance.

Side Effects
Include masculinization in women. Prostatic hypertrophy, priapism, and feminization in men. Testicular atrophy and gynecomastia are problems in chronic users. The most common adverse reactions are edema, jaundice, local irritation, urinary obstruction, and steroid fever.

Side Effects
Other adverse effects include: Premature epiphyseal closure in children. Liver dysfunction. Hypercalcemia. Alteration of serum lipids.

Androgen Antagonist
Have been synthesized for the treatment of prostate cancer and benign prostatic hyperplasia.

Androgen Antagonist
GnRH analogs (e.g., leuprolide). Long-term therapy reduces the secretion of FSH and LH, thus reducing testosterone production. Used for advanced prostate cancer.

Androgen Antagonist
Flutamide Nonsteroid competitive antagonist at androgen receptors. Used in metastatic prostate cancer to block testosterone.

Androgen Antagonist
Cyproterone acetate. An androgen receptor antagonist with progestin-like activity. It is being tested for the treatment of hirsutism in women.

Androgen Antagonist
Finasteride. Inhibitor of 5a-reductase and, thus, inhibits the production of dihydrotestosterone. It is used in the treatment of benign prostatic hypertrophy and male pattern baldness.

Androgen Antagonist
Ketoconazole. Imidazole type antifungal agent. Inhibits steroid synthesis. Used in androgen receptor-positive cancer therapy.

Other Drugs
Anastrozole. An aromatase inhibitor used in breast cancer. Danazol. Inhibits ovarian steroid synthesis. Used in endometriosis and breast fibrocystic disease.

Figure 4. Control of androgen secretion and activity and some sites of action of antiandrogens. (1) competitive inhibition of GnRH receptors; (2) stimulation (+) or inhibition (-) by GnRH agonists; (3) inhibition of testosterone synthesis by ketoconazole; (4) inhibition of dihydrotestosterone production by finasteride; (5) inhibition of androgen binding at its receptor by flutamide and other drugs.

Estrogens
Act at estrogen receptors Actions at many tissue in the body.

Clinical Uses
Oral contraceptives. Hormone replacement therapy. Female hypogonadism (congenital, acquire) Dysmenorrhea. Abdnormal uterine bleeding.

Estrogens
17 B-estradiol most potent natural strogen. Synthetic estrogen objective.

Increase oral bioavailability. Increase therapeutic half-life. Conjugated means sulfate esters. Used for hormone replacement therapy, Component of the oral contraceptives.

Conjugated equine estrogens

Ethinyl estradiol.

Side Effects
Nausea, Bloating. Headache, Mastalgia. Thromboembolism

Synthetic estrogens more thrombogenic.

Breast cancer. Endometrial cancer. Hepatic adenomas.

Diethylstilbestrol
Synthetic estrogen used long time ago for the prevention of threatened abortions. Removed from the market due to deleterious effect on fetuses. Clear cell adenocarcinoma of the vagina.

Diethylstilbestrol
Urogenital tract abnormalities.

Persistance of Mullerian glands on upper vagina. Male genital tract defects.

Selective estrogen receptor modulators (SERMs)

Compounds with tissue especific activity. Agonist activity in some tissues. No activity or antagonist in other tissues.

SERMs
The Goal is to Produce beneficial effects in target tissues.

Bone, Brain, Liver.

Avoid deleterious effects in other tissues.

Breast, Endometrium.

Tamoxifen
Antagonist activity at breast ERs. Partial agonist activity at endometrial ERs. Agonist activity at bone ERs. Used in breast cancer

Estrogen receptor expressing tumors.

Tamoxifen
Side Effects Result from estrogen antagonism.

Hot flashes. Vaginal discharge or bleeding. Menstrual irregularities. Impotence.

Raloxifene
Selective estrogen agonist in bone. Used to treat osteoporosis. Does not increase the risk of estrogen dependent cancers. Lowers LDL

Clomiphene
Estrogen receptor antagonist at all tissues. Fertility drug. Blocks anterior pituitary estrogen receptors. Decreases feedback inhibition of FSH by estradiol. Increases ovulation. Increases the incidence of multiple conceptions.

Progesterone
Progesterone (natural). 17 a-acetoxyprogesterone. 19-norgestel derivatives. Norgestrel.

Clinical Uses
Combination with estrogen hormone replacement.

Decrease risk of estrogen-sensitive cancers. Alone Combination with estrogens.

Oral contraception.

Progesterone
Agents Medroxyprogesterone. Norethindrone Norgestrel.

Progesterone
Adverse effects. Weight Gain Hirsutism. Acne Tiredness Depression.

Figure 5. Autonomic control of erection. The use of drugs to produce cavernosal smooth muscle relaxation. Smooth muscle tone is the prime determinant of the degree of erection (NO, nitric oxide; NE, norepinephrine; ACh, acetylcholine; PGE1, prostaglandin E1; VIP, vasoactive intestinal peptide).

Proposed mechanism underlying the antioxidant effect of sildenafil in relation to ED. (1) Risk factors promote the endogenous expression of NADPH oxidase which generates superoxide (O2 -) in pudendal arterial and cavernosal tissue (as well as associated neural and microvascular support tissues. (2) The increased formation of O2 - negates the protective effects and proerectile activity of NO through direct chemical reactions. (3) As Sildenafil inhibits type 5 phosphodiesterase (PDE5), the hydrolysis of cGMP is blocked. Increased cGMP levels promote erection through augmentation of smooth muscle cell relaxation, despite reduced NO formation. (4) However, since the NO-cGMP axis also inhibits NADPH oxidase expression/activity, it follows that augmentation of cGMP levels would also promote the inhibition of this enzyme. Reduced O2 - would further augment NO bioavailability, which would feed back into the loop to enhance the inhibition of NAPDH oxidase expression and activity. (5) NO donating sildenafil (NCX 911) would promote even greater relaxation since the drug intrinsically provides NO drive.