Androgens and Testosterone Production

• Testosterone is the primary androgen, produced in the interstitial (Leydig) cells of the testes.
• Its secretion increases sharply at puberty and is responsible for the development of secondary sexual characteristics in men.

Testosterone Physiological Effects

• Androgenic effects include maturation of sex organs, stimulated spermatogenesis, voice deepening, hair growth, libido, and negative feedback on LH and FSH.
• Anabolic effects include muscle growth, bone density increase, stimulation of linear growth and bone maturation, and increased erythropoiesis via increased EPO and reduced ferritin and hepcidin.

Testosterone Metabolism

• Testosterone is converted into dihydrotestosterone and estradiol, explaining its diverse effects in different tissues.
• Dihydrotestosterone has a higher affinity for the androgen receptor than testosterone.
• Testosterone is rapidly metabolized in the liver, leading to a low oral bioavailability with only 1/6 available after oral administration due to first pass effect.
• Androsterone and Etiocholanolone are inactive metabolites excreted in the urine.

Mechanism of Action

• Testosterone and its metabolites (dihydrotestosterone and estradiol) bind to intracellular receptors, affecting gene transcription.

Therapeutic Androgen Preparations

• Poor bioavailability of oral testosterone due to first-pass effect of the liver, thus oral testosterone has been associated with liver tumors.
• Administration routes include transdermal (scrotum and skin patches, gel), buccal, IM, and SC implant.
• Chemical modifications to improve bioavailability include 17-β esterification to increase lipophilicity, enabling IM injection and slow release, also allowing oral administration as it can be absorbed via lymphatic circulation.
• Alkylation decreases hepatic catabolism, improving oral administration.

Testosterone Derivatives

• 17-β testosterone esters are hydrolyzed slowly after absorption to release testosterone.
• Alkylated testosterone is less androgenic than testosterone, resistant to hepatic catabolism, and hepatotoxic.

Common Testosterone Preparations

• Oral preparations include testosterone undecanoate (80-200 mg per day) and 17a-methyltestosterone (10-30 mg per day).
• Intramuscular preparations include testosterone enanthate, cypionate, and propionate.
• Transdermal preparations include nonscrotal and scrotal skin patches, and transdermal gel.

Advantages and Disadvantages of Delivery Methods

• Key factors include efficacy, physiological levels, duration, self-administration, cost, local problems, and pain.

Uses of Androgens

• In men, androgens compensate for low testosterone (hypogonadism, aging) and induce puberty.
• In women, they treat breast carcinoma with metastasis (enanthate only), vasomotor symptoms of menopause, and endometriosis.
• Unapproved use includes athletic performance enhancement.

Side Effects of Androgens

• In females, side effects include facial hair growth, voice deepening, and menstrual irregularities.
• Pregnancy can cause virilization of the fetus.
• In males, side effects include acne, gynecomastia, decreased spermatogenesis, hair loss, aggressive behavior, hypertension, edema (heart failure), prostate pathologies, and premature growth cessation.
• Hepatotoxicity is a risk with 17-a alkyl compounds, potentially causing cholestasis, peliosis hepatis, and hepatocarcinoma.

Chemical Modifications

• Modifications to testosterone affect androgenic and anabolic activity.
• 17-OH group modifications favor androgenic activity, oxidation reduces it, and esterification favors anabolic activity.

Androgenic:Anabolic Activity Ratios

• Testosterone, testosterone cypionate, testosterone enanthate, and methyltestosterone have a 1:1 ratio.
• Fluoxymesterone has a 1:2 ratio, and oxymetholone has a 1:3 ratio.

17-β Esterified Androgens

• Include testosterone enanthate and cypionate, which are long-acting IM injections given every 2-4 weeks.
• Testosterone undecanoate can be administered via IM injection, and is also available orally.
• They treat hypogonadism, delayed puberty, and metastatic breast cancer.

17-β Esterified Anabolic Androgens

• Nandrolone decanoate or Phenylpropionate ester which has been discontinued is an anabolic steroid metabolized into dihydronandrolone (not DHT) or estrogen used to treat stimulating the production of erythropoietin.
• Side effects included gynecomastia, reduced, libido, erectile dysfunction and cardiovascular damage.

Alkylated Testosterone

• Includes Methyltestosterone and Fluoxymesterone (now discontinued).
• Used to treat hypogonadism, inoperable breast cancer in premenopausal women, as well as prevention of postpartum breast pain and engorgement.

17-α Substituted Anabolic Compounds

• Oxymetholone used to treat anemia by increasing the kidney production of erythropoietin has been discontinued.
• Oxandrolone which is a 17-α substituted anabolic compound is discontinued, used to promote weight gain after surgery, illness, trauma or glucocorticoid treatment and treats bone pain caused by osteoporosis.
• Specific side effects include hepatic toxicity and jaundice.

Enhancement of Athletic Performance

• Androgens are used by athletes, classified as Schedule III controlled substances.
• Modern compounds include testosterone esters, hCG, and terahydrogestrinone (THG) which is rapidly metabolized and not easily detected.
• Side effects of taking for athletic purposes in males is suppression of LH levels and virilization.
• Doses for athletic purposes can cause erythrocytosis and gynecomastia-except DHT: which cannot be converted into estrogens.
• 17-a alkylated androgens are hepatotoxic, and risks include psychological disorders, change in lipid profile, and coagulation activation. Cardiovascular isides effects include MI, myocarditis, cardiomegaly, CVAs, pulmonary embolisms, sudden death, hepatomegaly and avulsions (tears).

Anti-Androgens: Leuprolide

• Leuprolide is a synthetic GnRH analog administered via subcutaneous injection and depot, or intramuscular depot.
• It acts as an antagonist in continuous fashion, down-regulating GnRH receptors in the pituitary, decreasing LH and testosterone production.
• Used to treat prostate cancer.
• Side effects include hot flashes, decreased bone density, and erectile dysfunction.

Anti-Androgens: Degarelix, Abarelix

• These are GnRH antagonists.
• They inhibit the GnRH receptor in the pituitary, decreasing FSH and LH, which causes a decrease in testosterone production.
• Primarily have been used to treat symptomatic advanced cases of prostates cancer.
• Side effects include nausea, headache, hot flashes, lower bone density, erectile dysfunction, and weigh gain.

Anti-Androgens: Finasteride, Dutasteride

• Finasteride and Dutasteride are inhibitors of 5-alpha reductase.
• They inhibit the conversion of testosterone to DHT.
• Therapeutically used for benign prostatic hyperplasia and male pattern baldness.
• Side effects include impotence, gynecomastia, and a low risk of high-grade prostate cancer.

Anti-Androgens: Flutamide, Bicalutamide, Nilutamide

• These are androgen receptor antagonists (non-steroidal).
• When used alone is known to increase production of LH and stimulates higher serum testosterone concentration.
• Used in combination with a GnRH analog to inhibit adrenal androgens (combined androgen blockade).
• Used terapeutically in men for metastatic prostate cancer
• Therapeutically used in women who have hirsutism.
• Common side effects includes hepatotoxcity, gynecomastia, hot flashes and gastrointestinal disorders like diarrhea and nausea.

Explore the effects of Leuprolide on testosterone, side effects of androgen treatments like gynecomastia, and cardiovascular risks associated with androgen abuse. Understand the role of DHT and the varied effects of testosterone across different tissues. Learn about testosterone production and its impact on LH and FSH.