Androgens Flashcards
What are androgens?
What are their precursors?
Where are they synthesized?
Testosterone is the principal androgen secreted in men and women.
Androstenedione and DHEA are precursors with weak androgenic properties.
Testosterone is synthesized from cholesterol in the leydig cells, corpus luteum and adrenal glands.
When and what amount is testosterone secreted?
Secretion of testosterone begins in the fetal testes in the first trimester.
Beginning of second trimester 250ng/dl, thereafter falls.
At birth 250ng/dl and falls again.
2-3 months after birth, rises to 250ng/dl.
Falls to 50ng/dl at 6 months.
Early adulthood, 500 to 700ng/dl in men.
Women: 30-50ng/dl
Regulation of androgens
Principal stimulus for secretion is LH potentiated by FSH.
LH secretion is positively regulated by GnRH.
Testosterone directly inhibits LH secretion.
Secretion of testosterone is pulsatile and diurnal.
Maximal secretion at 8am and lowest secretion at 8pm
Pharmacokinetics of androgens
8mg produced dly in men
Plasma level of testosterone is 0.6mcg/dl after puberty in men and 0.03mcg/dl in women.
About 65% is bound with high affinity by SHBG.
33% is bound with low affinity by albumin.
2% is free to be active
Metabolism is to dihydrotestosterone and estradiol which are active.
Degradation of testosterone occurs mainly in the liver to androsterone and ethiocholanolone which are inactive metabolites.
Androsterone and ethiocholanolone conjugates are excreted in urine.
DHT is metabolised to androsterone, androstanedione and androstanediol.
Pharmacodynamics
Action is by interacting with androgen receptor (testosterone or DHT) or by interaction with estrogen receptor via aromatization to estradiol.
Androgen receptor (NR3A) is a transcription factor.
NR3A consist of amino-terminal, ligand binding and DNA binding domains.
Effects of androgens
In utero:
Stimulation of the differentiation of the Wolffian duct into male internal genitalia.
Development of the male external genitalia.
Puberty:
Development of seminiferous tubules.
Increased length and width of the penis.
Rugation of the scrotum.
Onset of secretion by the prostate gland.
Increased sebum production.
Onset of growth of axillary, pubic, body and facial hair.
Increased muscle mass and strength.
Reduction in subcutaneous fat.
Increased erythropoiesis.
Acceleration of epiphyseal bone growth
Thickening of the larynx.
Development of libido.
Development of male aggression.
Adulthood:
Development of male pattern baldness.
Prostatic hyperplasia.
Effects of androgen deficiency
During first trimester, incomplete sexual differentiation or dev. of female external genitalia, failure of differentiation of Wolffian ducts.
During 3rd trimester, microphallus, cryptorchidism.
Before completion of puberty: impairment of secondary sexual characteristics, eunuchoidism, gynecomastia.
After completion of puberty: decrease of libido and energy, gradual regression of the pubertal effects of testosterone
Androgen preparations
Testosterone esters e.g testosterone enanthate, testosterone cypionate, testosterone undecanoate.
17α-Alkylated androgens like stanozolol, danazol, methyltestosterone, oxandrolone, fluoxymesterone.
Transdermal delivery systems.
Others: 7α-methyl-19-nortestosterone, Tetrahydrogestrinone.
Uses of androgens
Male hypogonadism.
Treatment of endometriosis.
Management of breast engorgement.
Management of anemia.
Perfomance enhancer in sports.
Growth stimulant in boys with delayed puberty
Catabolic and wasting states.
Angioedema.
Male contraception.
Adverse effects
Masculinization.
Increased susceptibility to atherosclerosis.
Sodium retention and edema.
Hepatic dysfunction.
Prostatic hyperplasia.
Azoospermia .
Hepatic tumours.
Behavioural abnormalities.
Anti-androgens
Inhibitors of testosterone secretion.
GnRH analogues downregulate the GnRH receptors and inhibit testosterone secretion.
GnRH antagonists e.g abarelix for prostatic Ca.
Ketoconazole and similar antifungals block synthesis of steroid hormones.
Inhibitors of androgen action
Androgen receptor antagonists
These are flutamide, bicalutamide, nilutamide, cyproterone, cyproterone acetate and spironolactone.
Flutamide
Potent androgen receptor antagonist.
Substituted anilide.
Used in conjunction with a GnRH analog in treating metastatic prostate Ca.
Administered 3 times daily.
Side effects include gynecomastia and hepatotoxicity.
Very effective for treating hirsutism in women.
Bicalutamide
Administered once daily.
Causes less hepatotoxicity.
Also used in managing metastatic prostate cancer.
Spironolactone, Cyproterone and cyproterone acetate
Competitive inhibitor of aldosterone and DHT.
Also reduces 17α-hydroxylase activity.
Used in treatment of hirsutism in women.
Cyproterone and cyproterone acetate
They are used in treatment of hirsutism in women.
Also used for decreasing xcessive sexual drive in men.
