Androgen Pharmacology Flashcards
What are the basic functions of FSH, Testosterone, and LH in spermatogenesis?
FSH from pituitary controls spermatogenesis in seminiferous cells; testosterone produced in Leydig cells is also required for spermatogenesis. LH from pituitary stimulates androgen (testosterone) production in Leydig cells.
What causes the pulsatile release of GnRH, and what immediate consequence does this have?
Episodic firing of peptidergic neurons in arcuate nucleus results in pulsatile release of GnRH → pulsatile release of LH (lesser amounts of FSH) from the pituitary
What are the effects of testosterone on the external genitalia and hair follicles and how does it achieve these effects?
Effects on external genitalia: differentiation during gestation, maturation during puberty, adulthood prostatic diseases. Hair follicles: increased hair growth during puberty.
Testosterone is converted to dihydrotestosterone by 5a-Reductase. Dihydrotestosterone acts on the androgen receptors to induce the effects.
What are the direct effects of testosterone and what receptor does it trigger?
Internal genitalia: Wolffian development during gestation,
Skeletal Muscle: increased mass and strength during puberty
Erythropoiesis
Bone Growth
Testosterone activates the androgen receptor
What are testosterone’s effects on bone and how does it achieve these effects>
Effects on Bone: Epiphyseal closure, increased density
Testosterone is converted by CYP19 (Aromatase) into Estradiol, which then acts on estrogen receptors.
What are the pharmacokinetics of testosterone (including protein binding %, total daily secretion, and metabolism)?
98% bound to proteins (SHBG and albumin); only free hormone is active (2%), increasing proteins decreases free testosterone (therapeutic potential, esp in women)
Concentrations fluctuate during the day, but total daily secretion constant. [♂: 5-7 ng / ♀: 0.25 ng] – diurnal variation with highest levels at 8 AM (500-700 ng/dl) – hypogonadal if levels less than 200-300 ng/dl
Testosterone and metabolites rapidly degraded by liver
Where are each of the two forms of 5a-reductase found and what drugs target this enzyme?
• Two forms of 5α-reductase have been identified: type I is predominantly located in non-genital skin, liver and bone, and type II in urogenital tissue. DHT is the predominant androgen intracellular mediator in some tissues (prostate, penis-scrotum, hair, skin)
• Conversion to DHT blocked by the enzyme inhibitors
finasteride (type II) (Proscar® [prostate cancer], Propecia® [hair loss])
dutasteride (type I and II) (Avodart® [prostate cancer])
What is the specific MOA of testosterone, and what events does it initiate?
- Mechanism of testosterone action - binds to cytosolic receptor (as testosterone or DHT or estrogen)
- Genomic action involves diffusion of hormone across membrane → interaction with cytosolic receptor → dimerization and binding to DNA response elements with other co-regulators (co-activators or co-repressors) → alteration of target gene transcription
- Initiates series of events → growth, differentiation, synthesis of enzymes-functional proteins
What are the three processes of male development that are driven by testosterone?
- Responsible for PUBERTY ASSOCIATED CHANGES in male (development of secondary sex characteristics); also essential in utero.
- General GROWTH-PROMOTING properties. Increased muscle mass, skeletal growth, but closing of epiphysis (bone growth plate) via conversion to estrogen.
- PSYCHOLOGIC / BEHAVIORAL CHANGES also occur via direct effects on CNS (hypothalamus)
What are the accepted applications of androgen replacement therapy?
• Androgen replacement therapy in hypogonadal boys (larger parenteral doses required if deficiency occurs prior to sexual maturation) and men. Must titrate testosterone dose to attain normal concentration range.
• Only in men distinctly subnormal T (less than 200-300 ng/dl) on multiple occasions with symptoms
o Androgen deficiency related low libido, decreased morning erections, low bone mineral density, gynecomastia, small testes
o Less specificfatigue, depression, anemia, reduced muscle strength, increased fat
What are the symptoms and diagnostic criteria for testosterone replacement therapy?
Androgen deficiency related → low libido, decreased morning erections, low bone mineral density, gynecomastia, small testes
o Less specific → fatigue, depression, anemia, reduced muscle strength, increased fat
What are the significant side effects of anabolic hormones?
All anabolic hormones tested to date also have androgenic effects (block of LH-FSH release and promotion of prostate growth)
Which testosterone esters are administered intramuscularly, and what are the dosage frequency and side effects?
- Testosterone ethanate and testosterone cypionate are esters with increased lipophilicity - following IM administration esters are sequestered in tissues with gradual release from vehicle
- Can initiate and maintain normal virilization in hypogonadal men given every 1 to 3 weeks
- Trade-off between less frequent injections and greater fluctuations in serum T levels which can results in fluctuations in energy, mood, and libido
Which testosterone supplements are delivered transdermally and what are the dosage frequency and side effects?
- Four gel formulations available (AndroGel®, Testim®, Fortesta®, Axiron®) given every 24 hrs
- Major advantage of maintaining relatively stable T levels throughout the dosing period → maintenance of mood, energy, and libido
- Most expensive of T formulations
What are the adverse effects of physiologic levels of testosterone supplementation in hypogonadism.
Use in male hypogonadism - physiologic doses. Testosterone itself has no “side effects” when used for male hypogonadism but some undesirable effects can be seen in certain situations.
• Raising serum T from prepubertal to adult levels at any age could result in effects seen at puberty: acne, gynecomastia, aggressive sexual behavior
• Presence of concomitant illnesses
• Stimulation of erythropoiesis could raise hematocrit above normal if predisposed (e.g., chronic pulmonary disease)
• Mild Na+ and fluid retention could exacerbate heart failure
