Flashcards in Androgen Pharmacology Deck (31):
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
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
What are the adverse effects of supra physiologic levels of testosterone taken to enhance athletic performance?
• Decreased spermatogenesis – testicular atrophy via decreased LH/FSH and conversion of androgens to estrogens. Generally return to normal function within a few months of discontinuation.
• Cardiovascular risks – data is conflicting and inconclusive. FDA has recently required changes in labeling to clarify approved uses and info about increased risk of stroke, MI or mortality
• Increased susceptibility to arterial thrombosis, and increased platelet aggregation)
• Psychiatric symptoms - major mood disorders and aggressive behaviors (“roid rage”)
• Hepatotoxicity, esp. with oral agents (17α-alkylated androgens): reversible cholestatic jaundice, prothrombotic changes in serum lipid levels (↓ HDL, ↑ LDL)
• Gynecomastia due to aromatization of testosterone to estrogens
What are the four primary physiologic targets of androgen therapy?
What are the mechanisms by which the GnRH receptor can be manipulated and what drugs can be used to accomplish each?
(1) Inhibition of GnRH receptor → competitive inhibition of GnRH receptors with GnRH antagonists (Degarelix - Ganirelix)
(2) Inhibition of GnRH receptor → inhibition (-) with continuous administration of GnRH agonists (Leuprolide)
(3) Stimulation GnRH receptor** → stimulation (+) with pulsatile administration of GnRH agonists (Leuprolide)
What are the mechanisms by which CYP17 (17a-hydroxylase) can be manipulated and what drugs can be used to accomplish this?
CYP17 (17α-hydroxylase) → inhibition of testosterone synthesis by ketoconazole
What are the mechanisms by which 5a-reductase can be manipulated and what drugs can be used to accomplish this?
5α-reductase → inhibition of dihydrotestosterone synthesis by Finasteride (5aR type II) Dutasteride (5aR type I and II)
What are the mechanisms by which the androgen receptor can be manipulated and what drugs can be used to accomplish this?
Androgen receptor → inhibition of androgen binding at its receptor by flutamide, Bicalutamide, and Spironolactone
What is the appropriate pharmacologic treatment for prostate cancer?
• GnRH agonists (continuous) plus androgen receptor antagonists to prevent disease flare due to transient increase in testosterone levels
• GnRH antagonists are option in advanced prostate cancer - will not see disease flare BUT requirement for monthly injection of antagonist and long experience with GnRH agonists make them preferred treatment
What is the appropriate pharmacologic treatment for benign prostate hyperplasia?
• Alpha-1 adrenergic antagonists: recommended initial medical therapy
• 5α-reductase inhibitors: recommended if larger prostate or intolerance of alpha-1 blockers
• PDE-5 inhibitors: if mild to moderate symptoms with erectile dysfunction
What is the appropriate pharmacologic treatment for male pattern baldness (androgenetic alopecia)?
• 5α-reductase inhibitors: finasteride (Propecia®) in lower dose than use for BPH
What is the appropriate pharmacologic treatment for precocious puberty in boys?
• GnRH agonists (continuous)
What is the appropriate pharmacologic treatment for hirsutism or polycystic ovarian syndrome?
• Estrogen - progestin contraceptive (COC) - first choice
• Androgen receptor antagonists: spironolactone (at higher doses than used in heart failure) added if suboptimal response to COC
What are the pharmacokinetics and side effects of leuprolide?
• Given SC or IM - depot implants with durations of 1-3-4-6 months
• ADRs: headache, nausea, injection site rxn, hypogonadism with prolonged treatment
What are the pharmacokinetics and side effects of finasteride?
• Given orally once a day - reduces DHT levels within 8 hrs
• ADRs: decreased libido, ejaculatory or erectile dysfunction (5-19%); weakness (5%)
What are the pharmacokinetics and side effects of dutasteride?
• Given orally once a day - slower onset of action with much longer half-life
• ADRs: similar to finasteride
What are the pharmacokinetics and side effects of bicalutamide?
Bicalutamide - preferred androgen receptor antagonist
• Given orally once daily (vs tid for flutamide)
• ADRs: androgen deprivation effects (loss of libido, gynecomastia), nausea (10%), transient abnormal LFTs (vs potential for serious hepatotoxicity with flutamide)