Pharmacology of Gonadal Hormones 3

Question 1

What is the structure and mechanism of action of androgens?

Answer 1

• Structure
  
  • steroids
  • synthesized and secreted by testes (testosterone)
  • made in lesser amounts by the adrenal (dehydroepiandrosterone)
  • also ovaries (testosterone)
• Mechanism of action
  
  • ​bind to intracellular receptors
  • receptors bind as homodimers to transcription factors that regulate target mRNA production

Question 2

What are the early actions of androgens?

Answer 2

• During fetal development:
  
  • development of internal ducts of male reproductive tract
  • development of male genitalia
• Changes at puberty:
  
  • Pituitary becomes less sensitive to feedback inhibition
  • GnRH increases – through GABA, NPY, kisspeptides
  • Androgen concentrations increase up to 50X
  • There are major changes in general growth
  • There are changes in:
    
    • testis
    • scrotum
    • penis
    • larynx
    • pubic
    • axillary and facial hair
    • sebaceous glands
    • possibly behavior

Question 3

What are the adult actions of androgens?

Answer 3

• Maintenance of secondary sex characteristics
  
  • hypogonadism leads to:
    
    • loss of libido and potency
    • some atrophy of prostate and seminal vesicles
  • testosterone production declines in 3rd decade along with clearance
    
    • so plasma levels may still be normal
  • further decline in 6th-7th decades that can result in menopause-like vascular symptoms
    
    • due to loss of negative feedback and consequent increased gonadotropins
• Spermatogenes
  
  • required for normal spermatogenesis in the seminiferous tubules
  • normal maturation of sperm in the epididymus

Question 4

What are the other actions of androgens aside from sexual development?

Answer 4

• Anabolic effects (muscle developement)
  
  • some sites such as shoulder girdle more sensitive
  • effects limited but most marked in prepubertal males and females
  • largely due to androgen-receptor mediated competition with glucocorticoids at their receptors
• Growth plate
  
  • accelerate maturation and epiphyseal closure
  • premature closure results in short stature
• Erythropoetin
  
  • androgens increase production
  • castraction decreases rbc mass and increases fragility
  • females given androgen can develop polycythemia
• Sebacious glands
  
  • stimulate proliferation
  • plugging in prepubertal male can result in acne

Question 5

Describe the pharmacokinetics of androgen

Answer 5

• Testosterone strongly bound to sex hormone binding globulin (SHBG)
  
  • weakly bound to albumin
• Rapidly metabolized by liver and converted to water-soluble metabolites and excreted
  
  • not orally effective in native form
  • analogs can be orally effective
• Parenteral routes include:
  
  • im
  • transdermal patch
  • gel
  • pump

Question 6

Describe the process of androgen activation at target tissues.

Answer 6

• Convereted to dihydrotestosterone through 5-alpha reductase
  
  • sex accessory tissues
  • hair follicles
• Converted to 17beta-estradiol by aromatase
  
  • ​hypothalamus
  • bone
  • liver
  • adipose tissue

Question 7

List the representative androgenic agents.

Answer 7

• Tesosterone
  
  • rapid first pass metabolism
  • im and transdermal
• Testosterone propionate
  
  • depot perparation
• Methyltestosterone
  
  • synthetic
  • orally effective
• Stanozolol
  
  • orally effective
  • anabolic/androgenic ratio ~3:1

Question 8

What is the mechanism of actio of estrogen and progestin?

Answer 8

• binds to nuclear receptors that interact with transcription factors, influencing mRNA production
• Recptors have typical domains similar to those for steroids, calcitriol, and thyroid hormone
  
  • A/B domain - activate transcription in absence of ligand
  • C domain - DNA binding domain
  • D domain - nuclear localization domain
  • E/F domain - ligand binding, dimerization, and ligand independent transactivation

Question 9

What are the different receptor isoforms of estrogen and progestin, and what functions do they serve?

Answer 9

• ERalpha mediates most of the effects of estrogen on sexual development and reproductive functions
• ERbeta roles are less well established
• PR also exists as two isoforms of A and B

Question 10

What are the actions of estrogens and progestins on the following? Uterine endometrium, uterine cervix, vaginal mucosa, mammary glands.

Answer 10

• Uterine endometrium
  
  • estrogens - proliferation
  • progestins - secretion
• Uterine cervix
  
  • estrogens - watery mucus
  • progestins - viscous mucus
• Vaginal mucosa
  
  • estrogens - thickening
  • progestins - none
  • excess estrogen can lead to vaginal adenocarcinoma and other cancers
• Mammary glands
  
  • estrogens - ductal growth
  • progestins - alveolar growth

Question 11

What are the actions of estrogens and progestins on non-reproductive tissues?

Answer 11

• Kidney
  
  • estrogens increase Na and water retention
• Liver
  
  • estrogens stimulate synthesis of:
    
    • clotting factors
    • corticosteroids
    • thyroxin-binding proteins
    • HDL
  • estrogens decreases LDL
  • progestin has various effects on lipoproteins
• Connective tissues
  
  • estrogens contribute to growth at puberty
    
    • promote epiphyseal closure
  • estrogens decrease aging-associated changes in skin and bones
• CNS
  
  • estrogens cause nausea at high doses
  • progestins increase body temperature
• Receptors
  
  • estrogens increase progestin receptors
  • progestins decrease estrogen receptors

Question 12

What are the pharmacokinetics of estrogen and progestin?

Answer 12

• 17beta-estradiol and progesterone are rapidly metabolized and excreted, resulting in limited oral effectiveness
• Micronized forms ofestrogen and progesterone are orally effective
• Estrogen is effective topically, with transdermal absorption
  
  • sunscreen can decrease absorption
  • transfer through skin contact is a concern (mother/child, female/male)
• Estrogen can also be administered by vaginal application, nasla mist
• Estrogen and progesterone associate in serum with binding proteins
  
  • estrogen - SHBG
  • progesterone - corticosteroid binding globulin

Question 13

What are the representative estrogenic agents?

Answer 13

• 17beta-estradiol
  
  • physiological estrogen
  • first-pass metabolism
  • orally effective when micronized
• Estradiol benzoate
  
  • semisynthetic
  • long-acting
• Ethinyl estradiol
  
  • orally effective synthetic analog
• Conjugated equine estrogens
  
  • orally effective mixture
• Diethylstilbesterol
  
  • nonsteroidal
  • orally effective
  • long acting
  • carcinogenic
  • early menopause and infertility in female offspring
  • low sperm counts and undescended testes in male offspring

Question 14

What are some drug interactions of estrogen?

Answer 14

• Estrogen can affect the binding and metabolism of other drugs
  
  • anticonvulsants
  • anticoagulants
  • antidepressants
  • antibiotics (can also decrease estrogens)
    
    • conjugated estrogen secreted in bile
    • intestinal bacteria hydrolyze conjugates
    • estrogen reabsorbed into enterhepatic circulation
    • broad spectrum antibiotics kill intestinal bacteria and prevents resorption of estrogen
• Agents affecting CYP450 can affect the bioavailability of estrogen