EAST 501 Lecture Notes - Lecture 8: Heat Shock Protein, Vas Deferens, Epidermal Growth Factor Receptor
21 Jun 2018
School
Department
Course
Professor
8- C. O’Flaherty
13- Role of androgens and estrogens in male reproduction and cancer
●Learning objectives
○Understand mechanism of action of androgen and estrogen and their action in tissue
targets
○Understand the actions of androgens and estrogens on the male reproductive system
○Understand the relationship of steroids with cancer in men
●Synthesis of androgens and estrogens
○Cholesterol is a lipid highly abundant in our cells, and is the core of steroid hormones.
■Androgens = male hormone
■Estrogen = female hormone
○The synthesis occurs in the mitochondria.
■Starts with cholesterol → series of reactions done by hydrogen reductases that
produce progesterone, testosterone, and estradiol.
■So from cholesterol: produce mostly testosterone and estrone.
■Aromatase (CYP19) will convert testosterone into estradiol.
■Estrone is converted to estradiol by 17beta-HSD.
○Estradiol is the active steroid for females (also present in males). And the most active
androgen is dihydrotestosterone (DHT).
■Converted by 5alpha reductase from testosterone.
●Source of estrogens and androgens
○Estrogens:
■Male: adipose tissues, skin, testis, brain
■Female: ovaries, placenta, adipose tissues, brain
○Androgens:
■Male: Leydig cells in testis, adrenal glands, brain
■Female: adrenal glands, ovaries, brain
○Table: locations of 5 alpha reductase (converts testosterone to DHT).
■Important for secondary attributes in the male (pubic and scalp skin, testis,
epididymis, vas deferens, seminal vesicles, prostate).
●Classical mechanisms of action of ER and AR: genomic effects
○Delayed response (hours to days).
○Hormone binds to receptor, and this produces a change in conformation of the complex
that then enters the nucleus, and stimulates the gene expression of target genes.
○When you increase transcription: takes a long time to have an effect.
○Steroid-hormone binding globulin → binds testosterone in the plasma.
■When it reaches the target tissue, testosterone enters the cell, is converted to
DHT, and binds to the AR.
■HSP is the heat shock protein which usually keeps the receptor silent to prevent it
form being degraded or entering the nucleus.
●Released
●Change in conformation → complex enters the nucleus.
●But before so, PKA or MAPKs will phosphorylate the receptor to allow
it to dimerize and allow the dimer to enter the nucleus, bind to the
8- C. O’Flaherty
androgen response elements ARE in the DNA → and recruit
co-activators (ARA70 → allows initiation of gene transcription).
●Non-classical mechanisms of action of estrogen/ androgen
○Short-term effects (sec to min).
○Takes minutes to lead to a response- doesn’t involve gene transcription.
○Involves only phosphorylation cascades and pathways that will allow a rapid delivery of
the signal.
○The estrogen is binding to a GPCR on the membrane, and therefore will activate G
protein pathway (like EGF receptor) → phosphorylation cascade like ERK pathway (Ras,
Rac, Mek, Erk).
○Similar situation for testosterone: non classical mechanism of action as well, particularly
for Sertoli cells.
■Will activate GPCRs that will activate PLC → IP3 and DAG secondary
messengers → membrane depolarization → increased intracellular calcium levels
and activation of subsequent phosphorylation pathways.
●Transcription factor complexes involved in genomic and nongenomic effects
○These hormones can activate many many genes.
●Roles of androgens and estrogens in the male
○Androgens: drive brain masculinization.
○Estrogens: also important to allow for male behaviors.
■Mating activity, ejaculation. Stimulation of certain neurons by estrogen is
responsible for this.
■Male fetus is surrounded by testosterone, which enters the brain, and in the brain
there is high expression of aromatase → local conversion of testosterone to
estradiol in the brain.
○If you expose female fetuses in the womb with estrogen, will have females with male
behavior.
○Other important action of both is cardioprotective actions and anti inflammatory actions.
■Estrogens decrease LDL-cholesterol.
○Both important for spermatogenesis.
○Increased estrogens → erectile dysfunction, and impairment of development of
epididymis and vas deferens.
■This is through their ability to inhibit FSH/LH secretion.
○Androgens are associated with increased muscle mass.
●Male reproductive system
○Site of spermatozoa production = testes (lowered temperature).
■If they don’t descend from the abdominal cavity to the scrotum → will produce
testicular cancer (even though can also occur in descended testes).
○Epididymis: transit through the epididymis is preparation to become competent to
recognize and fertilize the oocyte.
■Sperm: testes → epididymis → vas deferens → urethra → ejaculation.
○For sperm to swim, need to have a medium: seminal vesicle, prostate, cowper’s gland.
Document Summary
13- role of androgens and estrogens in male reproduction and cancer. Understand mechanism of action of androgen and estrogen and their action in tissue targets. Understand the actions of androgens and estrogens on the male reproductive system. Understand the relationship of steroids with cancer in men. Cholesterol is a lipid highly abundant in our cells, and is the core of steroid hormones. Starts with cholesterol series of reactions done by hydrogen reductases that produce progesterone, testosterone, and estradiol. So from cholesterol: produce mostly testosterone and estrone. Aromatase (cyp19) will convert testosterone into estradiol. Estrone is converted to estradiol by 17beta-hsd . Estradiol is the active steroid for females (also present in males). And the most active androgen is dihydrotestosterone (dht). Male: leydig cells in testis, adrenal glands, brain. Table: locations of 5 alpha reductase (converts testosterone to dht). Important for secondary attributes in the male (pubic and scalp skin, testis, epididymis, vas deferens, seminal vesicles, prostate).
