Androgen

ANDROGENS & ANABOLIC STEROIDS

In humans, the most important androgen secreted by the testis is testosterone.
Androstenedione, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS) are also produced in significant amounts in humans, although largely in the adrenal gland rather than in the testes.
In men, approximately 8 mg of testosterone is produced daily
Plasma levels of testosterone in males are about 0.6 mcg/dL after puberty and appear to decline after age 50.
Testosterone is also present in the plasma of women in concentrations of approximately 0.03 mcg/dL
In many target tissues, testosterone is converted to dihydrotestosterone by 5α-reductase. In these tissues, dihydrotestosterone is the major active androgen
About 65% of circulating testosterone is bound to sex hormone-binding globulin. SHBG is increased in plasma by estrogen, by thyroid hormone, and in patients with cirrhosis of the liver.
The major pathway for the degradation of testosterone in humans occurs in the liver

Physiologic Effects

In the normal male, testosterone or its active metabolite 5α-dihydrotestosterone have a wide range of activities, the most important of which include actions on:
development of male secondary sex characteristics (including male distribution of body hair, lower-pitched voice, enlargement of the penis, sebum secretion and male-pattern balding);
protein anabolic effects influencing growth, maturation of bone and muscle development;
spermatogenesis and seminal fluid formation.
Synthetic Steroids with Androgenic & Anabolic Action
Testosterone, when administered by mouth, is rapidly absorbed. However, it is largely converted to inactive metabolites, and only about one sixth of the dose administered is available in active form.
Testosterone can be administered parenterally, but it has a more prolonged absorption time and greater activity in the propionate, enanthate, undecanoate, or cypionate ester forms.
Testosterone derivatives alkylated at the 17 position, eg, methyltestosterone and fluoxymesterone, are active when given by mouth.
Testosterone and its derivatives have been used for their anabolic effects as well as in the treatment of testosterone deficiency.


Clinical Uses
Androgen Replacement Therapy in Men: Androgens are used to replace or augment endogenous androgen secretion in hypogonadal men. Even in the presence of pituitary deficiency, androgens are used rather than gonadotropin except when normal spermatogenesis is to be achieved. In patients with hypopituitarism, androgens are not added to the treatment regimen until puberty, at which time they are instituted in gradually increasing doses to achieve the growth spurt and the development of secondary sex characteristics. In these patients, therapy should be started with long-acting agents such as testosterone enanthate or cypionate in doses of 50 mg intramuscularly, initially every 4, then every 3, and finally every 2 weeks, with each change taking place at 3-month intervals. The dose is then doubled to 100 mg every 2 weeks until maturation is complete. Finally, it is changed to the adult replacement dose of 200 mg at 2-week intervals
Gynecologic Disorders
Androgens are used occasionally in the treatment of certain gynecologic disorders, but the undesirable effects in women are such that they must be used with great caution.
Androgens have been used to reduce breast engorgement during the postpartum period, usually in conjunction with estrogens.
Given in combination with estrogens for replacement therapy in the postmenopausal period in an attempt to eliminate the endometrial bleeding that may occur when only estrogens are used and to enhance libido.
They have been used for chemotherapy of breast tumors in premenopausal women.
Use as Protein Anabolic Agents: Androgens and anabolic steroids have been used in conjunction with dietary measures and exercises in an attempt to reverse protein loss after trauma, surgery, or prolonged immobilization and in patients with debilitating diseases.
Anemia: In the past, large doses of androgens were employed in the treatment of refractory anemia, Recombinant erythropoietin has largely replaced androgens for this purpose.
Osteoporosis. With the exception of substitution therapy in hypogonadism, bisphosphonates have largely replaced androgen use for this purpose.
Use as Growth Stimulators: These agents have been used to stimulate growth in boys with delayed puberty.
Anabolic Steroid and Androgen Abuse in Sports
Aging: Androgen production falls with age in men and may contribute to the decline in muscle mass, strength, and libido. Preliminary studies of androgen replacement in aging males with low androgen levels show an increase in lean body mass and hematocrit and a decrease in bone turnover.

Adverse effects

Virilization in women and increased libido in men are predictable effects.
In women, acne, growth of facial hair and deepening of the voice are common undesirable features produced by androgens. Other masculinizing effects and menstrual irregularities can also develop.
In the male, excessive masculinization can result in frequent erections or priapism and aggressive behaviour.
Children may undergo premature fusion of epiphyses.
Other adverse effects include jaundice, particularly of the cholestatic type, and because of this complication methyltestosterone is no longer prescribed.
Azospermia occurs due to inhibition of gonadotrophin secretion.
In patients treated for malignant disease with androgens, hypercalcaemia (which may be severe) is produced by an unknown mechanism.
Oral testosterone preparations in oil cause various gastro-intestinal symptoms including anorexia, vomiting, flatus, diarrhoea and oily stools.


Danazol
Danazol, an isoxazole derivative of ethisterone (17α-ethinyltestosterone) with weak progestational, androgenic, and glucocorticoid activities, is used to suppress ovarian function.
It inhibits the midcycle surge of LH and FSH but it does not significantly lower or suppress basal LH or FSH levels in normal women.
Danazol binds to androgen, progesterone, and glucocorticoid receptors and can translocate the androgen receptor into the nucleus to initiate androgen-specific RNA synthesis.
Uses
Use in the treatment of endometriosis. For this purpose, it can be given in a dosage of 600 mg/d. The dosage is reduced to 400 mg/d after 1 month and to 200 mg/d in 2 months.
Danazol has also been used in the treatment of fibrocystic disease of the breast
Hematologic or allergic disorders, including hemophilia, Christmas disease, idiopathic thrombocytopenic purpura,
Angioneurotic edema.
Adverse effect
Weight gain, edema, decreased breast size, acne and oily skin, increased hair growth, deepening of the voice, headache, hot flushes, changes in libido, and muscle cramps.
Anti-Androgens
Reduction of androgen effects is an important mode of therapy for
Both benign and malignant prostate disease.
Precocious puberty.
Hair loss.
hirsutism
Receptor Inhibitors
Cyproterone and cyproterone acetate are effective antiandrogens that inhibit the action of androgens at the target organ. These compounds have been used in women to treat hirsutism and in men to decrease excessive sexual drive
Flutamide and related drugs (Bicalutamide and nilutamide) are nonsteroidal competitive antagonists of androgen receptors. These drugs are used to decrease the action of endogenous androgens in patients with prostate carcinoma.
Spironolactone, a drug used principally as a potassium-sparing diuretic also inhibits androgen receptors and is used in the treatment of hirsutism in women
5-αReductase Inhibitors
Testosterone is converted to DHT by the enzyme 5-α reductase. Some tissues, most notably prostate cells and hair follicles, depend on DHT rather than testosterone for androgenic stimulation. This enzyme is inhibited by finasteride, a drug used to treat benign prostatic hyperplasia and, at a lower dose, to prevent hair loss in men. Because the drug does not interfere with the action of testosterone, it is less likely than other antiandrogens to cause impotence, infertility, and loss of libido. Dutasteride is a newer 5-reductase inhibitor with a much longer half-life than that of finasteride.