Androgen Pharmacology and Testosterone Therapy

Androgen Pharmacology Learning Objectives

• Understand the use of testosterone replacement therapy for male primary and secondary hypogonadism.
• Know the drugs used in testosterone replacement therapy in forms for injection, pellets, patches, and gels.
• Know the clinical indications and drugs to inhibit endogenous androgens for prostate cancer and benign prostatic hyperplasia (BPH) treatments.

Hypogonadism and Testosterone Therapy

• Hypogonadism is a decrease in sperm or testosterone production.
• Male hypogonadism comes from disease of the testis or pituitary which is primary or secondary hypogonadism respectively.
• In male children and adolescents, failure to undergo or complete puberty is an indicator.
• Adult male symptoms of hypogonadism include decreased energy and libido, decreased muscle mass and body hair, hot flashes, gynecomastia, and infertility.
• Male hypogonadism is usually treated with testosterone replacement.

Testosterone Replacement Therapies

• Drugs and administration routes include:
  • IM depot testosterone esters
  • Oral methyltestosterone
  • Topical testosterone gels and creams
  • Transdermal testosterone patch
  • Buccal testosterone
  • Testosterone subcutaneous pellets

Intramuscular Depot Testosterone Esters

• Testosterone esters have increased solubility in fats, slowing their release from IM injection sites.
• After IM injection, testosterone ester is slowly absorbed into general circulation and rapidly hydrolyzed in plasma, with a half-life of 30-60 min.
• IM injections of long-acting testosterone esters are inexpensive, are administered at home every other week, and result in physiological and predictable serum testosterone levels.

Oral Methyltestosterone

• Methyltestosterone (17α-methyltestosterone) differs from testosterone by a methyl group at C17, increasing its oral bioavailability and metabolic stability.
• Methyltestosterone tablets and capsules are FDA-approved as replacement therapy for conditions associated with a deficiency or absence of endogenous testosterone.
• Pediatric dosage is 10 mg daily, and the adult dosage is 10-50 mg/day in androgen-deficient men.
• Cautions include risk for jaundice, cholestatic hepatitis, and abnormal liver function tests.

Testosterone Gels: AndroGel and Generics

• Applied topically once daily delivers continuous transdermal testosterone for 24 hours.
• Used for replacement therapy in adult males for conditions associated with deficiency or absence of endogenous testosterone (1º and 2º hypogonadism).
• Dose adjustment for AndroGel 1.62%: minimum of 20.25 mg of testosterone (1 pump actuation) and a maximum of 81 mg of testosterone (4 pump actuations).
• The FDA warns of secondary exposure, so avoid unintentional exposure of women or children, as it can produce signs of virilization.

Testosterone Topical Solution (Axiron and Generics)

• AXIRON ("axillary application," generic 2017) is a topical single-phase testosterone solution in replacement therapy for primary and secondary hypogonadism.
• Axiron contains 30 mg testosterone/one pump actuation, with a starting dose of 60 mg is applied to the axilla once daily, to deliver physiologic levels of circulating testosterone (300-1050 ng/dL).
• The FDA warns of secondary exposure.

Transdermal Testosterone Delivery: Androderm

• Two transdermal drug delivery systems (2.5mg/d) applied in hypogonadal men delivered 4-5 mg testosterone over 24 hours, achieving circulating testosterone of around 300 – 1050 mg/dL.
• The therapy shows continuous absorption within 24 hours and a Tmax of 4-12 hours.
• The patch has a self-contained central drug reservoir and reduces the risk of transference to partners or children.
• An ideal dosage is one patch (2 or 4mg)/day.

Other Parenteral Delivery of Testosterone

• Mucoadhesive buccal delivery (Striant) should be replaced twice a day.
• Subcutaneous pellet insertion (Testopel) delivers testosterone for 3 to 6 months.
• Buccal system is a bioadhesive progressive hydration sustained release tablet with 10% absorption.
• Subcutaneous testosterone pellets (75 mg testosterone per pellet) are inserted in subdermal fat in abdominal wall or lateral aspect of the gluteus.

Contraindications of Testosterone Therapy

• Avoid in men with breast cancer, known or suspected prostate cancer.
• Avoid in women who are pregnant, as testosterone can cause fetal harm.

Indications and Drugs to Inhibit Androgen Action

• Some drugs include GnRH receptor agonists (gonadotropin-releasing hormone), GnRH receptor antagonists, antiandrogens, and testosterone synthesis inhibitors.
• Prostate Cancer Drugs:
  • leuprolide- GnRH receptor agonist
  • degarilex- GnRH receptor antagonist
  • enzalutamide- antiandrogen
  • apalutamide- antiandrogen
  • abiraterone- testosterone synthesis inhibitor
• Benign Prostatic Hyperplasia Drugs:
  • tamsulosin- alpha-1 adrenergic receptor blocker
  • finasteride- 5α-reductase inhibitor
  • dutasteride -5α-reductase inhibitor

Prostate Cancer Statistics 2024

• National Cancer Institute Statistics
• Surveillance, Epidemiology, and End Results (SEER) Program
• Estimated 299,010 new cases and 35,250 estimated deaths in the United States in 2024.
• Diagnosis median age: 66 years old
• Death From Prostate Cancer median age: 80 years old (2013-2017)
• Five-Year Relative Survival: 97.5%
• Regional/Local cancers are close to 100%, distant/metastasized cancers are approximately 37%.
• Active surveillance, surgery, and radiation remain the main therapies.
• Androgen-deprivation therapy is the standard of care for newly diagnosed metastatic disease (8% of total).

Hormonal Therapies for Metastatic Disease

• Prostate cancers depend on testosterone for growth.
• Medical or hormone therapies lower testosterone levels in newly-diagnosed metastatic disease.
• Androgen deprivation therapy (ADT) uses medical castration via gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists to lower serum testosterone to castrate levels.
• Therapies used with ADT for metastatic disease therapy have powerful anti-androgen medications and testosterone synthesis inhibitors.

ADT using GnRH Receptor Agonists or Antagonists

• Androgen Deprivation Therapy can be achieved with GnRH receptor agonists or GnRH receptor antagonists.
• With an agonist drug (leuprolide), continuous GnRH receptor stimulation desensitizes pituitary cells, reducing LH/FSH secretion and ultimately reducing testosterone production by the testes.
• With antagonist drug (degarelix), there is immediate and direct inhibition of GnRH receptors, reducing LH/FSH secretion, and testosterone production by the testes.

Leuprolide – GnRH Receptor Agonist

• Leuprolide is a GnRH receptor agonist.
• Used in prostate cancer therapy, sustained pituitary GnRH receptor stimulation causes desensitization within weeks, decreasing LH and FSH hormone levels.
• Testosterone levels fall below castration threshold (50 ng/dL).
• Prostate cancers that depend on testosterone for growth stop growing, and PSA (prostate-specific antigen) levels fall to near zero.
• The medication is administered in 1, 3, 4, and 6-month formulations via depot administration (Lupron depot suspension).

Degarelix – GnRH Receptor Antagonist

• Degarelix received FDA Approval in 2008 for advanced prostate cancer.
• Degarelix promotes an immediate fall in serum testosterone while leuprolide requires a period of GnRH receptor desensitization before testosterone levels fall.
• Due to its earlier introduction as therapy, lower cost, and less frequent administration schedule (every 6 months vs. monthly for degarelix) leuprolide had been preferred for many years.

Enzalutamide and Apalutamide

• Both Enzalutamide and Apalutamide are anti-androgens for prostate cancer.
• They act as AR inhibitors by binding to the androgen receptor and competitively inhibiting androgen binding, AR nuclear translocation, and AR-mediated transcription.
• Both agents are FDA-approved with ADT and treat patients either with metastatic castration-sensitive prostate cancer or non-metastatic castration-resistant prostate cancer.
• Both agents are orally active and taken once daily.

Abiraterone – Inhibits Testosterone Biosynthesis

• Abiraterone is a specific CYP17 inhibitor, an enzyme expressed in testicular, adrenal, and prostatic tumor tissues required for testosterone biosynthesis.
• Abiraterone is FDA-approved with ADT to treat patients with metastatic prostate cancer.
• This drug is orally active and should be taken once or twice daily along with a GnRH analog and prednisone.

Drugs used in the treatment of Benign Prostatic Hyperplasia

• Alpha-1 adrenergic receptor blockers are:
  • tamsulosin (#24, 2021 top prescriptions filled)
  • alfuzosin
  • doxazosin
  • silodosin
  • terazosin
• 5α-reductase inhibitors (5-ARIs) are: finasteride (#88, 2021 top prescriptions filled) dutasteride

Benign Prostatic Hyperplasia (BPH)

• BPH is the enlargement of the prostate, pressing on the urethra and causes urination difficulty and bladder problems.
• Prostatic enlargement or hyperplasia is androgen-dependent but stimulated more by dihydrotestosterone (DHT) than by testosterone.
• Treatments include:
  • Watchful waiting, surgery
  • Medical (pharmacologic) therapies:
  • Alpha-blockers
  • 5-alpha-reductase inhibitors

Benign Prostatic Hyperplasia (BPH) Therapies

• Alpha-blockers and 5α-Reductase Inhibitors are treatments for BPH
• Alpha-blockers (tamsulosin, Flomax) are first-line therapies to relieve BPH symptoms by relaxing the smooth muscles of the bladder neck and allowing easier urination, and provides rapid onset of action in 1-2 weeks.
• Finasteride and Dutasteride lower DHT levels, reducing prostate gland size, increasing urine flow, and decreasing BPH symptoms.
• Both drugs are orally active, taken once daily, effectively reducing prostate volume and improving urinary symptoms with symptom improvement at 6 months.