Aug28 M1,2-Male Reproductive System Flashcards
HPT (testicular) axis with hormones
- h: GnRH (gonadotropin releasing H)
- p: LH and FSH (gonadotropins)
- t: steroids and inhibin
- Feedback
what ntr controls pulsatile secretion of GnRH
kisspeptin, 10 aa peptide
GnRH charact
- susceptible to proteases
- analogs used for infertility tx, contraception, etc.
(imp?) main use of GnRH today
prostate cancer
how to use GnRH analog as an agonist
give in pulsatile fashion (every 60-90 min) (like phgy)
how to use GnRH analog as an antagonist
give constant long lived dose (inhibits the gonadotropes = cells in pit making LH, FSH)
2 parts of LH and FSH (gonadotropins)
- alpha subunit (same in LH and FSH). same gene
- beta subunit (makes the bio specif): two diff genes
half life of FSH vs LH
FSH very much longer half life than LH
why FSH half life long
need constant exposure to stim the dev of germ cells
why LH half life short
comes out in pulsatile fashion (resp to GnRH pulse).
FSH fct
stim dev of germ cells
LH fct
stim steroidogenesis
R of gonadotropins are what
GPCRs with 7 parts TM prot. (classic)
precursor to all sex steroids
cholesterol. 5 areas of substitutions to make the diff steroids (prog, androgens, CS, estrogen)
steroid binding Rs parts and are where
- nuclear. are TFs. turn on-off many genes
- steroid binding domain. area of dimerization. zinc finger (to bind DNA)
cells making testo
Leydig cells
how to make DHT (dihydrotesto)
5 alpha reductase reduces the double bond of testo
how to make estradiol
aromatase aromatizes double bond of testo
pro hormone concept in steroid action
testo pro hormone. depending on tissue, will find testo OR a derivative (DHT, estradiol)
is estrogen a pro hormone (like testo)
no
cell membrane steroid hormone Rs (SHRs) where and diff
allow faster response of transcription (1-5 min). nuclear SHRs = hours
*membrane SHRs in brain for sleep, etc
inhibin origin
testes Sertoli cells
inhibin fct
inhibit FSH release by gonadotropes of pit
inhibin structure
Inhibin A: alpha + betaA subunits
Inhibin B: alpha + betaB subunits
activin def
molecule made by combining 2x beta subunit of inhibin. either activin A, AB or B
activin origin
gonadotropes and Sertoli cells
activin fct
regulate FSH secretion
activin Rs are where
most of body tissues (just like androgens have Rs almost everywhere) effects not understood
activin’s family of proteins
TGFbeta superfamily
testo Rs where in body
almost all tissues
LH stim prod of hormones (like testo). testo (these hormones) effect in axis is what
feedback that is pulsatile (bc the LH release is pulsatile and therefore testo prod is pulsatile)
gonadal vs periphery conc of testo
100x more in gonads. important concept for contraception and infertility
what cells make estradiol in the male
Leydig cells (same that makes testo)
androgen (testo) and estradiol of Leydig cells fct in gonads
act on androgen Rs of Sertoli cells to promote germ cells dev
2 hormones of HPT axis secreted by Sertoli cells
inhibin and activin
1 feedback in HPT axis for LH
-testo of Leydig cells feedbacks on gonadotropes in pulsatile fashion
2 feedbacks in HPT axis for FSH
- inhibin and activin of Sertoli cells act on gonadotropes
* note: makes sense bc FSH acts on Sertoli cells. (whereas LH acts on Leydig cells)
inhibin feedbacks where in HPT axis
pituitary only (for FSH regul) (gonadotropes). not hypothalamus. bc doesn’t cross the BBB
testo feedbacks where in HPT axis
both pituitary and hypothalamus (for LH regul)
androgen disruptors def
chemicals that mimic androgens and disrupt the HPT axis
LH vs FSH time of release by gonadotropes
same time (bc pulsatile GnRH acts at same time). but each has diff conc bc of diff half life
interval of LH rise in the serum
60-90 min (same as GnRH pulsatility), bc after released, is degraded quickly (whereas FSH lasts long)
interstitium of testes composition (between STs)
60% Leydig cells
macrophages
factors in how much steroid a Sertoli cell produces
size because bigger = more SER = more enzyme = more steroid produced
LH R is where
cell membrane (Leydig)
steps of LH signal to get testo prod in Leydig cell
- cholesterol in mt
- cholesterol side chain cleaved off
- pregnenolone released (dnm)
- 3 steps to make it into testo
rate limiting step in testo prod
cleavage of cholesterol
how steroids (testo) are secreted out of the cell
via facilitated acid transport (bc are lipids)
it’s not like proteins and Ach, ntrs which use vesicles and packaging
how testo gets to seminiferous tubules and into the circulation
bind high affinity proteins.
- TEBG (testosterone estradiole binding globulin) also called SHBG (sex hormone binding globulin)
- albumin
- ABP (androgen binding protein), in STs
albumin binding capacity of steroids
- low affinity
- huge capacity (bc lot of albumin)
cells making ABP
Sertoli cells
ABP gene
same as SHBG AND same protein backbone
how ABP becomes diff from SHBG
difference in their liposilation
2 peaks of testo before puberty
- fetal (to become male)
- neo-natal (after birth, mini puberty): to mark tissues as male. affects their protein and enzyme expression via epigenetics (methylation)
testo constant or pulsatile secretion in the adult
pulsatile bc of pulsatile LH. + circadian rhythm with peaks in the morning
testo variations in life after puberty
peak at 20, decreases after
bound vs free testo
- 2% free
- 98% bound (50% to SHBG, 50% to albumin)
what testo is metabolically active
2% free + 49% bound to albumin bc easily picked up by tissues
(49% bound to SHBG is not bio active)
liver disease consequence on free testo
increases. bc less SHBG (bc SHBG prod by liver)
free vs bound DHT
highly bound (like testo)
testo in males vs females
much higher in males
estradiol in males vs females
same amount
testo works where (androgen Rs are where)
all tissues. so androgen deficiency or excess = consequences everywhere
steroid R affinity from lowest to highest
- cholesterol (milliM)
- progestins (nM)
- androgens (nM)
- estrogens (picoM)
bisphinol A and AF def
chemicals working like estrogens bc stim the estrogen R
2 estrogen Rs in male and female
alpha and beta
alpha R of estrogen location
most tissues
beta R of estrogen location
different from alpha R
alpha vs beta R of estrogen
diff in their domains but same estrogen binding domain
alpha vs beta R of estrogen difference
- have the same affinity for certain substances but diff affinity for other substances
- therefore, agonist + antagonist effect in diff parts of the body always diff (bc diff alpha to beta R affinity)
effect of estrogen R alpha knockout in females
infertility
effect of estrogen R alpha (ESR1) knockout in males
- have spermatogonia and spermatocytes but no spermatids (DECREASED fertility)
- back pressure atrophy (as if ligated the ductuli efferentes). estrogen in ED allows fluid resorption
location of estrogen R alpha in males (ESR1)
efferent ducts (ductili efferentes)
function of ESR1
- regulates a gene in the efferent duct called CFTR (cystic fibrosis transporter receptor)
- fluid absorption in ED
mutation of CFTR consequence
infertility (no the CF mutation, don’t necessarily have CF)
estrogen R alpha deficiency or aromatase deficiency in man consequence (aromatase makes testo into estradiol)
- no closure of bone growth plate (very tall)
- lower sperm motility
- osteoporosis
- normal sexual diff and pubertal maturation
right word to describe the reduction in production of androgens in men with aging
Partial androgen deficiency in aging men (PADAM) (also called andropause)
charact of andropause
- decrease in testo and DHT as of 40+
- increase in serum SHBG (less free testo)
- decrease in testicular fct (spermatogenesis and steroidogenesis) with age. sperm quality decreases but count remains the same
- decreased libido
- decreased muscle strength
- increasing risk of BPH (benign prostatic hyperplasia) and PC (prostate cancer)
side effects of androgen deprivation (drop with age) (on tissues with androgen Rs)
- bone loss (osteoporosis, fractures)
- muscle weakness
- hot flashes
- loss of libido
- erectile dysfunction
- liver, skin, behavior effects
drugs studied as hormone replacement therapy in men
- testo
- human growth hormone
- DHEA
- melatonin
consequences of HRT in men
- higher conc of RBCs (polycythemia)
- CV effects
- gynecomastia possible
benefits of HRT in men
- improved bone mass, muscle mass, strength
- better physical fct
- increased libido
why can’t give testo as a pill
metabolized rapidly
ways of administering testo
- injection (male contraception)
- patch
- solution
- roll-on
when to give HRT in men (testo)
androgen deficiency (only**). only give to men with very low serum testo to bring them back to the lower end of normal range
delay for male contraception to work and why
3 months. because fixed time of spermatogenesis in species. 64 days in man. have to wait for full cycle of spermatogenesis
hormones essential to start spermatogenesis
- testo (high conc needed)
2. FSH (at puberty and re-initiation)
hormones essential to maintain spermatogenesis
testo only
most androgen sensitive step in spermatogenesis
the release of spermatids from the STs for spermiation (needs testo the most)
effect of giving inhibin to an adult male on spermatogenesis
none because blocks FSH release but FSH not needed to maintain spermatogenesis
knockout of FSH beta and FSH-R in animals consequence
fertile but smaller testes and less sperm
minimal testo required to maintain spermatogenesis
third of normal gonadal amount
spermatozoon charact
- sheds all cytoplasm
- haploid
- repackages its chromatin
- engine with mts
what happens to sperm nuclei in spermatogenesis
- histones removed (nucleosomes) (1. hyperacetylated to have less DNA affinity 2. transition prot pushes them out 3. RNA pushes transition prot).
- replaced with small very basic protein (protamine). these cross-link during passage in the EDD***
- methylation at same time. + maintain non coding RNAs, RNAs, acetyl and methyl sites
- DNA more condensed
info from sperm other than DNA delivered to the oocyte that is essential
- RNAs (coding and non coding)
- methylation sites
- histones
blood testis barrier formed by what
projections of Sertoli cells in ST epith
proteins above vs below BTB
above: different and unknown to immune system
note: smart barrier that lets certain things through (active transport) but not Abs
vasectomy effect on BTB
sperm leaks and get immune consequences on epith above BTB
research being made for spermatogonial stem cell loss after chemo
- in vitro spermatogenesis
- spermatogonial SC therapy
where sperm matures
EDD
something special of EDD
doesn’t divide and shed. never gets primary cancer
cells in EDD
- principal cc (abso and secrete)
- halo cc (immune)
- basal cc (protective, NOT stem cc)
- apical (unknown fct)
- clear cc (control pH in lumen)
- myoid cc
- interstitial SM cells and caps
what takes up the cytoplasm of sperm in the seminiferous tubules + what is left
Sertoli cells
a cytoplasmic droplet remains
what happens to the cytoplasmic droplet of spermatids
absorbed by clear cells of EDD + has many functions
3 parts of EDD + ions variations
- initial segment
- caput
- cauda
- ions composition diff in all*
why ion conc vary along the EDD
to maintain sperm in quiescent state
what varies along the EDD other than ions conc
protein composition. so electrophoretic pattern changes. potential target for infertility or contraception
what are exosomes (epididymosomes)
non coding RNAs secreted by principal cells of the EDD.
-enter nucleus of sperm and affect diabetic phenotype of the progeny
how is paternal obesity reflected in the progeny
-through EPIGENETIC marks transferred in the sperm in epididymosomes
(NOT through the genome)
how to properly dx infertility and why
3 semen samples taken at least 6 weeks apart
not 1 bc some people fluctuate and some constant values
some sperm parameters
- volume
- total number
- conc of sperm
- motility
- progressive motility
- vitality
- sperm morphology
why the decrease in sperm prod in males in dev countries over last 50 years
because meiosis can’t take place at body temp (and we wear underwear, clothes, etc.)
early erectile dysfunction linked with what
CV problems later in life
other parameters for sperm quality
chromatin biomarkers
- FISH for epigenetics, methylation, histones
- non coding RNA
- telomeres
problem of lack of secretions in sperm, problem of sperm secretion indicates what
possible CF
how sperm gets to the egg
-PGs produced by seminal vesicles + contraction of female reprod tract
motility is only useful to sperm for what
drilling through proteins around the egg (fusion and adhesion to egg PM, ZP interaction, cumulus interaction)
what happens to sperm mtDNA in the oocyte after fertilization
diluted
