Lecture 5: Androgens and Anti- Androgens

What two primary substances do the testes produce?

Sperm and testosterone.

What pituitary hormone controls sperm production, and what hormone is required for sperm maturation?

FSH controls production, but testosterone is required for maturation.

What pituitary hormone stimulates testosterone production from the testis?

LH (Luteinizing Hormone).

What specific cells in the testis produce 95% of testosterone?

Interstitial cells of Leydig.

Name two other hormones produced by Leydig cells besides testosterone.

DHT, DHEA, and androstenedione.

What percentage of circulating testosterone is derived from the adrenal glands?

5%.

What is the average plasma testosterone level in men?

0.6 µg/dL.

What percentage of testosterone is bound to SHBG (Sex Hormone Binding Globulin)?

60%.

What percentage of testosterone is unbound (free)?

2%.

What enzyme converts testosterone (T) into dihydrotestosterone (DHT)?

5-alpha reductase.

Which hormone, T or DHT, is generally considered more active?

DHT.

What enzyme converts some testosterone into estradiol?

Aromatase.

Name two tissues where the conversion of T to estradiol via aromatase occurs.

Adipose tissue, liver, and hypothalamus.

How is testosterone primarily degraded by the liver?

By inactivation through conjugation.

How are testosterone conjugates excreted?

In the urine.

Why does orally taken testosterone have low bioavailability?

Due to high first-pass metabolism.

What chemical modification improves the oral activity and duration of synthetic androgens?

Alkylation at the 17 position.

Name a synthetic androgen that is alkylated at the 17 position.

Methyltestosterone or fluoxymesterone.

Name three alternate dosage forms used to bypass the first-pass effect of testosterone.

IM injection (Delatestryl), transdermal patch (Androderm), gels (AndroGel), subcutaneous pellet (Testopel), buccal tablet (Striant), or auto-injector (Xyosted).

Name two synthetic androgens listed in the sources.

Methyltestosterone, fluoxymesterone, oxymetholone, oxandrolone, or nandrolone.

Through what mechanism are the actions of testosterone primarily mediated?

Via the androgen receptor (AR).

Where are androgen receptors typically located before ligand binding?

Intracellular/nuclear receptors (similar to other steroid receptors).

Besides genomic actions (affecting transcription), what other actions does the AR have?

Nongenomic actions.

For anabolic agents, what specific ratio of androgenic to anabolic effect is desired?

A low androgenic to high anabolic action.

Name two preparations of testosterone given by IM injection.

Testosterone cypionate (Depo-Testosterone) or testosterone enanthate (Delatestryl).

Name two pubertal changes stimulated by testosterone.

Penile/scrotal growth, increased libido, thickening of vocal cords, or prostate growth.

What effect does T have on physical growth concerning bones?

Stimulates skeletal growth and closure of epiphyseal plates.

What two components of the blood system are stimulated by T synthesis?

RBC and Hb synthesis.

What is the effect of T on muscle and subcutaneous fat?

Stimulates muscle growth and reduces subcutaneous fat.

How does testosterone affect the release of gonadotropins?

Causes inhibition via negative feedback.

How does T affect HDL and clotting factors?

Decreases HDL and increases clotting factor synthesis.

After age 50, what happens to plasma testosterone levels in men?

Levels decline.

What specific effect of T is utilized when treating anemias?

Increase in hematocrit.

What must be monitored frequently with x-rays when dosing T for growth stimulation in boys with delayed puberty?

Closure of epiphyseal plates.

What specific condition is T used to treat in older males (andropause)?

To offset muscle mass, strength, and libido loss.

What is a major indication for androgen replacement therapy in males?

Hypogonadism (due to pituitary deficiency, primary Leydig cell dysfunction, or secondary lack of FSH/LH).

If spermatogenesis is required in hypopituitarism, why is T alone not sufficient?

FSH is required for spermatogenesis.

Androgens are used in conjunction with estrogen to reduce what gynecological condition postpartum?

Postpartum breast engorgement.

What weak androgen is used to treat endometriosis?

Danazol.

How is T used in hormone replacement therapy (HRT) for postmenopausal females?

Low-dose testosterone is used in conjunction with estrogen.

What condition in premenopausal women is T used to treat as chemotherapy?

Breast tumors.

Name two conditions where androgens are used as anabolic agents to reduce protein loss.

After surgery, trauma, immobilization, or debilitating diseases.

Anabolic agents are used to reverse catabolic effects following long-term therapy with which drug class?

Glucocorticoids.

What specific synthetic androgen is used to increase hematocrit in anemias?

Oxymetholone (Anadrol-50).

Name two conditions besides hypogonadism that T is used for replacement therapy in older males.

Andropause and osteoporosis.

What condition in young boys requires careful monitoring of dosing when using T for growth stimulation?

Delayed puberty.

What specific risk makes the use of anabolic steroids for athletic purposes undesirable?

Side effects (systemic and behavioral).

Name two synthetic androgens used as anabolic agents.

Oxandrolone (Anavar, Oxandrin) or Oxymetholone (Anadrol 50).

Name three adverse effects of T due to masculinizing effects.

Voice deepening, hair growth, amenorrhea, or acne.

How does the lowering of HDL by androgenic steroids affect women?

May increase atherosclerotic risk.

T administration during pregnancy should be avoided because it can profoundly affect the CNS maturation of centers governing what development?

Sexual development.

Name two teratogenic effects of T on fetal external genitalia during pregnancy.

Masculinization of female fetal genitalia or undermasculinization of male fetal external genitalia.

T should be used with caution in the presence of heart and kidney disease due to the potential for what rare adverse effect?

Sodium and water retention (edema).

Most synthetic alkylated androgens are associated with what dose-dependent dysfunction?

Hepatic dysfunction.

Hepatic dysfunction associated with alkylated androgens may manifest as what specific signs?

Increased bilirubin and jaundice.

Name two adverse effects of T replacement therapy in older males related to the prostate or breathing.

Prostatic hyperplasia and urinary retention or sleep apnea.

Supraphysiological doses of T (abuse) can lead to what two male fertility issues?

Azoospermia and decreased testicular size.

What severe liver conditions have been reported due to high doses of alkylated androgens?

Cholestatic jaundice, hepatic failure, hepatic adenoma, and carcinoma.

What two behavioral effects are associated with anabolic steroid abuse?

Aggression, psychosis, and psychological dependence.

Name two absolute contraindications for testosterone use in male patients.

Prostate or breast cancer.

What is a primary use for androgen suppression therapy?

Advanced prostate cancer.

Name two GnRH analogs used for androgen suppression.

Goserelin (Zoladex), leuprolide (Lupron Depot), nafarelin (Synarel), histrelin (Vantas), or triptorelin (Trelstar).

How do continuous GnRH analogs achieve gonadal suppression?

By inhibiting FSH and LH release, thereby reducing testosterone synthesis.

What is the mechanism of action of the 17-alpha hydroxylase inhibitor Abiraterone (Zytiga)?

Inhibits conversion of pregnenolone to progesterone, preventing synthesis of active androgens.

Abiraterone is approved for use in combination with what steroid?

Prednisone.

What is the mechanism of action of 5-alpha reductase inhibitors?

They stop the conversion of T to DHT.

DHT is essential to the growth and development of what male organ?

The prostate.

Name the 5-alpha reductase inhibitor approved for BPH and early onset male pattern baldness.

Finasteride (Proscar, Propecia).

What condition besides BPH is Dutasteride (Avodart) approved for?

It is approved for BPH (no additional indication listed).

What is the major use for androgen receptor (AR) blockers?

Metastatic castration-resistant prostate cancer (CRPC).

AR blockers are typically used in combination with what other type of agent for prostate cancer?

A GnRH agonist.

Name two non-steroidal AR antagonists used to treat prostate cancer.

Flutamide, bicalutamide (Casodex), nilutamide (Nilandron), or enzalutamide (Xtandi).

What specific adverse effect is often associated with AR blockers like Flutamide?

Gynecomastia.

What is the dual mechanism of action of Enzalutamide (Xtandi)?

Blocks the androgen receptor and inhibits its nuclear translocation.

What are the two mechanisms by which Spironolactone acts as an anti-androgen?

Competes with DHT for receptor binding and reduces 17-alpha hydroxylase activity.