PHAR 300 Lecture Notes - Lecture 13: Gonadotropin, Adrenal Cortex, Immunocontraception
7 Jun 2018
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PHAR300
Male contraceptives
Male reproductive system
-sperm produced in the testes, migrate through the
efferent ducts to the epididymis, then go into the vas
and finally ejaculated
-sperm production : inside the testes are seminiferous
tubules, feed into the head of the epididymis and then
transit through the long tubule to the vas deferens
-spermatogenesis : long process, humans 64 days
from a germ stem cell into a mature spematozoa =>
contraceptive for males take time (a thousand sperm
developed in every heart beat)
-daily sperm production : 4.4 million sperms per
gram of testes (relatively poorly compared to other
mammals)
-regulation : in the hypothalamus, cells produce GnRH (= LHRH) -> impinge on cells in the
anterior pituitary -> stimulate LH and FSH -> will go and affect the testes ; end product :
increase steroidogenic capacity of cells in the testes
-LH interacts with receptors on Leydig cells
(steroidogenic cells in the testes, make
testosterone, released in the circulation ->
maintain male phenotype ; and testosterone can
also communicate with cells inside the
seminiferous tubules : Sertoli cells also called
mother cells or nurse cells -> help the germ cells
developing into mature spermatozoa)
-Sertoli cells are stimulated by FSH
-germ cells inside the tubules, imbedded in the
Sertoli cells
-Leydig cells between (outside) the semineferous
tubules
-adult men produce 5-7mg of testosterone daily
Testosterone biosynthesis
-into Leydig cells
-LH stimulates G protein coupled receptor, we
have cAMP which activates PKA-> increase
availability of cholesterol which will interact with
other enzymes to produce testosterone
-testosterone is not the only (and not the most
active) androgen in our body
-5alpha reductase converts it to
dihydrotestosterone (DHT) by removing one
double bond -> has high affinity for androgen
receptor
-testosterone can also be aromatised to make
estradiol (which is also important in males)
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-all biologically active -> go in the circulation and
may act as testosterone in certain tissues, or
aromatised and act as estrogen in certain tissues ; in
other tissues it can be reduced to DHT (some
people may have a deficiency in one of the enzymes
-> differences in the phenotype of the individual)
Steroid pyramid
-cholesterol in high concentrations (10^-3M) -> then
progestins (10^-8-9M) -> androgens (10^-9M) and
finally estrogens (10^-11M)
-we don’t need a lot of testosterone to interact with
the androgen receptor and have a response, even
less estrogen is needed
-testosterone has an action on muscles, bone
marrow, bone and brain ; DHT has activity on
external genitalia, prostate, skin and hair (including
potentially baldness) ; estradiol : bone, breast and
brain
Actions of androgens
-brain (libido, mood)
-skin (hair growth, acne, balding)
-muscle (strength and volume)
-liver (synthesis of serum proteins)
-kidney (stimulation of erythropoietin production)
-male sexual hormones and organs (spermatogenesis and steroidogenesis, prostate growth and
function, penile growth and erection)
-bone (accelerated bone loss, closure of epiphysis)
CNS aggressive behavior
-experiment : look at what happens if we remove source of testosterone -> do we have more or
less aggressive behvior
-castrated mice : not aggressive anymore
-if we give back testosterone -> biting attacks come back
Androgen metabolites and behavior
-estrogen in male is important for sex desire, copulation as well as activity => aromatase
blockers will decrease copulation and activity
-estrogen decreases eating ; DHT increases eating
Mechanism of androgen action
-testosterone and DHT can bind the androgen receptor
-bind androgen response elements in the nucleus -> transcription of specific genes leading
to maybe an increase in DHT…
-parallel to some of the structure of corticosteroid receptor
-DNA binding domain, N terminal and ligand binding domain where testosterone and DHT
will bind and the DNA binding domain will interact with various response elements
-they have many of the same complexities as other steroid receptors
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Document Summary
Sperm produced in the testes, migrate through the efferent ducts to the epididymis, then go into the vas and nally ejaculated. Sperm production : inside the testes are seminiferous tubules, feed into the head of the epididymis and then transit through the long tubule to the vas deferens. Spermatogenesis : long process, humans 64 days from a germ stem cell into a mature spematozoa => contraceptive for males take time (a thousand sperm developed in every heart beat) Daily sperm production : 4. 4 million sperms per gram of testes (relatively poorly compared to other mammals) Germ cells inside the tubules, imbedded in the. Leydig cells between (outside) the semineferous tubules. Adult men produce 5-7mg of testosterone daily. Lh stimulates g protein coupled receptor, we have camp which activates pka-> increase availability of cholesterol which will interact with other enzymes to produce testosterone. Testosterone is not the only (and not the most active) androgen in our body.
