4 - Androgens/Antiandrogens

What is the stimulatory factor of LH, FSH, & hCG?

pulsatile GnRH

What is the result of continuous GnRH?

desensitization & down regulation of GnRH receptors

What is the inhibitory factor of LH, FSH, & hCG?

• feedback inhibition by sex steroids

• inhibin

What are the target hormones of LH, FSH, & hCG?

estrogen, progesterone, testosterone

Where is testosterone secreted in men vs. women?

• men: 95% in Leydig cells, 5% in adrenal cortex

• women: corpus luteum & adrenal cortex 50/50

What are the “weak androgens”?

androstenedione & dehydroepiandrosterone (DHEA) → can be converted to testosterone

What binds testosterone in the blood?

• albumin (weakly, ~60%)

• sex hormone-binding globulin (strongly, ~40%)

What enzyme converts testosterone to dihydrotestosterone & what is the difference?

• 5⍺-reductase

• much less abundant, much more potent

What enzyme converts testosterone to estradiol?

aromatase

What are the active metabolites of testosterone?

• dihydrotestosterone

• estradiol

What are the effects of testosterone via dihydrotestosterone?

• binds androgen receptor

• differentiates external genitalia (gestation), maturation (puberty), prostate disease (adulthood)

• increased hair growth (puberty)

What are the direct effects of testosterone?

• bind androgen receptors

• internal genitalia development (gestation)

• increased skeletal muscle mass (puberty)

• erythropoiesis

What are the effects of testosterone via estradiol?

• binds estrogen receptor

• epiphyseal closure of bone

• increased libido

What is the MOA of testosterone?

• binds intracellular androgen receptor

• transported to the nucleus

• alters gene transcription

How does 5⍺-reductase change the structure of testosterone & how does this affect it’s function?

• adds 2 H’s, removing a double bond to create dihydrotestosterone

• has a higher affinity for the androgen receptor

What is the result of testosterone deficiency during 1st trimester in utero?

• CYP17 deficiency or dysfunctional receptors

• degree determines extent of female characteristics

What is the result of testosterone deficiency in the 3rd trimester in utero?

incomplete genital development

What is the role of testosterone during puberty?

• reproductive capability

• sebum production (acne)

• hair, muscle, & bone growth

• ↑erythropoiesis

• behavior changes

What is the result of testosterone deficiency in puberty?

• decreased traits of puberty

• gynecomastia

What are the effects of testosterone in adulthood?

• maintenance of male characteristics

• male pattern baldness (DHT)

• prostate issues

  • benign prostatic hyperplasica (BPH), 5⍺-reductase II in prostatic cells (DHT)

  • prostate cancer (testosterone dependent)

What is the result of testosterone deficiency in adulthood?

• rapid: ↓ libido & energy

• gradual: ↓ muscle mass, Hgb, Hct, bone mineral density

What is the effect of testosterone decline in senescence?

• testosterone gradually decreases & SHBG gradually increases

• ↓ energy, libido, muscle mass, bone mineral density

How does aromatase change the structure of testosterone?

adds an aromatic ring, creating estradiol & allowing binding to estrogen receptor

• synthesis of 85% of estrogen in men

What is the result of estradiol deficiency during puberty?

epiphysis do not close, leading to long limbs compared to trunk

What are PK issues with therapeutic preparations of testosterone?

rapidly metabolized orally, most designed to bypass hepatic 1st pass

What dosage forms of testosterone are available?

• patch (androderm)

• gel (androgel, testim)

• injectables

• buccal tablet

• pellet implant

What is the structural difference between testosterone & testosterone esters?

ester substiuent on 17⍺-OH group

What agents are testosterone esters?

• testosterone enanthate

• testosterone cypionate

What is the difference in PK of testosterone esters?

• prodrug, ester hydrolyzed in the body

• more lipophilic, dissolved in oil

• admin q 2-4wk

• has a higher concentration initially → increased side effects

What are the toxicity characteristics of testosterone at endogenous doses?

• no ADE at endogenous doses (puberty-like effects can occur)

• can interact with concomitant illnes

  • erythrocytosis

  • congestive HF (mild aldosterone-like effect)

What are the toxicity characteristics of testosterone at high doses?

• ↓ testicular size and function

• gynecomastia

• erthrocytosis & sodium/water retention

• possible cardiovascular risk

What is testosterone undecanoate?

orally bioavailable, long-acting testosterone ester

How does testosterone undecanoate bypass 1st pass?

orally - uptake in the lymphatic system

What is notable about IM testosterone undecanoate?

produces stable concentrations for 2 months, restricted availability in the US

• not used in age related hypogonadism or patients <18

• can cause pulmonary embolism, anaphylaxis

What is the structural difference between testosterone vs. alkylated testosterone?

CH3 substitution on 17⍺ position

What agents are alkylated androgens?

• methyltestosterone

• oxandrolone

• stanozolol

• fluoxymesterone

• danazol

How do alkylated androgens PK differ from testosterone PK?

• orally bioavailable, but <androgenic

• additional toxicity to liver

• decreased HDL

What is the primary indication for testosterone preparations?

hypogonadism (males)

How should testosterone be monitored for efficacy in hypogonadism?

• serum concentrations

• hormone effects

What is the effect of testosterone therapies in male senescence?

• ↑ bone mineral density, muscle mass, libido, energy

• ↓ fat mass

• may worsen BPH or increase incidence of prostate cancer

When might testosterone be used in catabolic or wasting states?

effective in muscle wasting associated with AIDS

What is the goal plasma level of testosterone in female-to-male conversion?

300-500 mg/day

What agents are used as inhibitors of testosterone secretion?

• GnRH antagonist

• Ketoconazole (inhibits CYPs)

What agents act as androgen receptor antagonists?

• flutamide

• biclutamide

• nilutamide

• enzalutamide

What is the indication of androgen receptor antagonists?

• indicated for metastatic prostate cancer

• used in combination w/ GnRH analogue

What is the effect of spironolactone on testosterone action?

weakly inhibits as a side effect of intended aldosterone inhibition

What agents are 5⍺-reductase inhibitors?

• finasteride

• dutasteride

What is the MOA & indication of 5⍺-reductase inhibitors?

blocks conversion ot testosterone → DHT

• indicated for BPH & male pattern baldness

What are the ADE of 5⍺-reductase inhibitors?

• impotence

• gynecomastia