Male Reproductive Physiology
what is produced at the end of meiosis II
early spermatids are the result of meiosis II
what is the effect of estradiol on HPG axis
estradiol has a profound negative feedback effect on the hypothalamus and pituitary
where is estradiol produced in men
estradiol is produced in the testicle and in the adrenal gland
what is the role of exogenous testosterone
exogenous testosterone prevents the body from making its own testosterone -- means that you dont get sufficient spermatogenesis
what does exogenous testosterone do
exogenous testosterone suppresses both endogenous testosterone (decreased LH) and sperm production
what are DHT functions
external masculinization and sexual maturation at puberty
what are the symptoms of hypogonadism
fatigue, irritability, depression, lacking endurance, unable to build muscle, trouble sleeping, and low libido
what is the adluminal compartment of the blood-testis barrier
germ cells undergoing differentiation and maturation
how do you treat kallmann syndrome
give supplemental FSH and LH when trying to conceive. give supplemental testosterone eventually after done conceiving
what are testosterone functions
gonadotropin regulation, spermatogenesis, sexual differentiation (wolffian stimulation)
why do spermatazoa need protection from immune system
haploid cells have unique antigens that are not recognized as self. also there are anti-sperm antibodies that can give you autoimmune orchitis
isolated spermatogenic failure
have normal testosterone and function, but have another issue with sperm production - ex. from prior chemo/radiation
biopsy protocol for non-obstructive azoospermia
have to do more than one biopsy because there could be focal areas with complete spermatogenesis amidst a majority of abnormal tubules -- want to look for the functioning pockets if they're there
what pulse favors LH?
high pulse frequency of GnRH favors LH secretion
what happens with LH and FSH in infancy and early childhood
hypothalamus is very sensitive to steroid negative feedback -- very low GnRH and FSH/LH secretion prior to puberty
what is the basal compartment of the blood-testis barrier
immature germ cells and stem cells make up the basal component
what is the role of estrogen in the male system?
in males, estrogen has a profoundly negative effect on the HPG axis
how is seminiferous tubule structure related to spermatogenesis?
in most people, sperm production in the testicle is homogenous and the sperm migrate to the lumen as they are developing
What is the bound:unbound ratio of testosterone in the plasma
in the plasma, ~60% of testosterone is tightly bound to SHBG
what is the effect of inhibin on the HPG axis
inhibin has a negative feedback effect on the pituitary and directly affects FSH secretion
which cells produce inhibin
inhibin is produced by sertoli cells which reduces pituitary FSG output
what is in the testis interstitium
interstitium between tubules contains blood vessles, lymphatics, and leydig cells
what is the importance of the blood-testis barrier
it crease an immunologically privileged site for mature spermatazoa
how long does it take for sperm to travel to the epididymis
it takes 12 days and is governed by slow contractions of the muscular wall
is azoospermia common?
its in <2% of men overall, but 15% of men presenting with infertility
what are the genetics of kallmann syndrome
kallmann syndrome is x-linked
what do leydig cells produce and secrete
leydig cells are steroid producing and secrete testosterone
what do leydig cells arise from embryonically
leydig cells arise from mesenchymal cells next to the renal system
how do leydig cells make testosterone
leydig cells have membraine receptors that bind LH, resulting in an increase in intracellular cAMP and protein synthesis
how do leydig cells get to the testis interstitium
leydig cells migrate to the interstitium around early spermatic cords during fetal development
what is in the peritubular compartment of the testis
leydig cells, basement membrane, extracellular matrix, and myofibroblasts
what pulse favors FSH?
low frequency GnRH pulses favor FSH secretion
what is the proliferative phase of spermatogenesis
mitosis is the proliferative phase
what happens with LH and FSH during puberty
nocturnal FSH and LH pulses begin during puberty and the HPG axis resets its sensitivity threshold to steroid feedback
what are the two categories of azoospermia
obstructive and non obstructive -- with non-obstructive being a little more common
where are the testes located
outside the abdominal cavity
what happens with LH and FSH in early fetal development
placental hCG controls the development of the testes and wolffian ducts and pituitary LH takes over as fetal HPG axis matures
pulsatile GnRH rhythm
pulses every 60-180 minutes sending out LH or FSH and is controlled by sex steroid feedback
what is produced at the end of meiosis I
secondary spermatocytes are created in meiosis I
how is GnRH secreted
secreted into the hypophyseal portal system where it has a short half life -- serum levels are too low to detect
where does LH act and what does it do?
LH acts on LH receptors on leydig cells to stimulate synthesis of testosterone
what regulates LH in men
LH is controlled by negative feedback from testosterone and estradiol
how is LH affected by inhbin and activin
LH is not affected by inhibin
why are the testes located outside the abdominal cavity
because the temperature is 35 celsius -- need lower temp for sperm production
how is the blood-testis barrier created
blood-testis barrier is a physiologic barrier created by active transport processes
when are sertoli cells mitotically active
sertoli cells are mitotically active during puberty, but mitotically inactive in adulthood (because of surges of FSH in puberty)
what is the structure of sertoli cells
sertoli cells are polarized cells that extend from the basemement membrane to the lumen
how much of the testis do sertoli cells make up?
sertoli cells comprise 1/3 of the bulk of the germinal epithelium
what kinds of receptors to sertoli cells have
sertoli cells contain membrane receptors that bind FSH, leading to increased intracellular cAMP and protein synthesis
what do sertoli cells do for developing germ cells
sertoli cells engulf and nurture developing germ cells
how do sertoli cells regulate the tubule microenvironment?
sertoli cells govern fluid secretions, phagocytosis, steroid metabolism, sperm production, and sperm movement/development
what cells make up the blood-testis barrier
sertoli cells make up the blood testis barrier
what do sertoli cells secrete
sertoli cells secrete AMH (fetus), androgen binding protein, and inhibin (adults)
what is the half life of LH
short half life - metabolized by the liver with wide variation throughout the day
how do sperm mature in the epididymis
sperm become progressively more motile they traverse the epididymis (this is important for harvesting sperm with IVF/ICSI) and they also gain capacity (necessary for fertilization)
what is the timeline of sperm production
sperm production is a constant process with constantly renewing cycles in different areas -- kind of patchwork pattern rather than wave like. takes ~60 days
what is spermiogeneisis
spermiogenesis is the maturation of spermatids to spermatozoa
what is the pathway of development for sperm through meiosis II
stem cells --> primary spermatocytes --> secondary spermatocytes --> spermatids
what does testis atrophy suggest
testis atrophy suggests low sperm count
what is the main regulator of spermatogenesis
testoserone is the main regulator of spermatogeneis
what is the ratio of testosterone in the testicle vs. in the blood
testosterone concentration in the testis is 100x peripheral concentration
what is the endocrine function of testosterone?
testosterone diffuses into the plasma where 2% is free, and the remained is bound weakly to albumin or tightly to SHBG
what is the paracrine function of testosterone
testosterone diffuses into the seminiferious tubule lumen bound to androgen binding protein (ABP)
what is the effect of testosterone on the HPG axis?
testosterone has a negative feedback effect on the hypothalamus and pituitary - this affects LH and FSH
what protein is testosterone bound to in the blood
testosterone is bound to androgen binding protein (ABP) when traveling in the body
where is testosterone produced
testosterone is produced in the leydig cells and then enters sertoli cells
interplay of LH and FSH with testosertone
testosterone is released in response to LH, but the effect is facilitated by FSH
what is testosterone made from
testosterone is synthesized from cholesterol
how is testosterone converted to estradiol
testosterone undergoes aromatization in adipose tissue to estradiol
how is the blood-testis barrier maintained?
the blood-testis barrier is maintained by dissolution and reassembly of tight junctions
what is the tunica albuginia
the capsule surrounding the functional units of the testis - connective tissue
what is the name of the connective tissue in the testis
the connective tissue capsule is called the tunica albuginea
what else is in the scrotum other than the testes?
the cremaster muscle is also in the scrotum -- descends with the testicle during development
what are the efferent ducts
the efferent ducts drain into the epididymus
what is the endocrine function of the testis
the endocrine function of the testis is to make steroids in leydig cells
what is the exocrine function of the testis
the exocrine function of the testis is to make sperm -- made in the sertoli cells and dependent on the exocrine function
what are the fibrous septa
the fibrous septa are the connective tissue that separate the lobules of the testes
which testosterone is functionally available
the functionally available testosterone is only what is free and what is bound to albumin
where are the leydig cells located
the leydig cells are located in the testicular interstitium
what is the meiotic phase of spermatogenesis
the meiotic phase is the production of haploid gametes (spermatids)
what is klinefelter syndrome
the most frequent sex-chromosome disorder seen in 1/600 boys, 3% infertile men, and 11% of men with azoospermia
what determines the testosterone set point?
the normal set point of testosterone is determined by low levels of circulating T, not intratesticular T
what are the structural compartments of the testis
the peritubular and intratubular compartments and the blood-testis barrier
how long is the process of maturation and transport in the epididymis
the process takes about 78 days
what promotes the production of androgen binding protein
the production of ABP is mediated by FSH
what is the pulsatile secretion of LH
the pulsatile secretion of LH mirrors GnRH -- released about every 2 hours
what is the structure of the seminiferous tubules
the seminiferous tubules are arranged into lobules with 2-4 loops per lobule. they are about 300 m in total length
what comprises the bulk of the testis
the seminiferous tubules comprise the bulk of the testis and are responsible for sperm production
what is in the intratubular compartment of the testis
the sertoli cells and germ cells
what is the primary target for LH and FSH in men
the testis
what happens with GnRH neurons with kallmann syndrome
there is a failure of GnRH neuron precursors to migrate from the nose to the hypothalamus (often also have a diminisehd sense of smell)
what happens during puberty for those with kallmann syndrome
there is a failure to start puberty
what is obstructive azoospermia
this is someone who has blocked the path somewhere between production and ejaculation (ex. vasectomy)
what is non-obstructive azoospermia
this is when you have an issue with the actual production of sperm -- where some bigger process is involved
what do you get after the first meiotic division
two secondary spermatocytes after meiosis II (these cells are genetically different)
what are rete testis
when the seminiferious tubules anastomose
what do you get after meiosis II
you get 4 haploid spermatids
what regulates FSH
FSH regulated by negative feedback by inhibin b, testosterone, and estradiol
what stimualtes sertoli cell function
FSH timulates sertoli cell function
where is GnRH produced
GnRH is produced in the pre-optic anterior hypothalamus
how is GnRH released in men
GnRH is released in a circadian rhythm and in a pulsatile rhythm
how do GnRH neurons get to the hypothalamus
GnRH neurons migrate from the nose to the hypothalamus during development
what is azoospermia
absence of sperm in the ejaculatory fluid
what has a stimulatory effect on FSH
activin has a stimulatory effect on FSH from the pituitary
where does FHS act and what does it do
acts on the FSH receptor in sertoli cells and stimulates spermatogenesis
GnRH and circadian rhythms
24 hour cycle that is controlled by melatonin output from the pineal gland. you have greater GnRH action in the early morning -- this is therefore when you have the highest levels of LH and testosterone
what percent of couples become pregnant after one month of trying
25% pregnant after 1 month
what is the most common genotype in klinefelters
47, XXY in 80-90% of klinefelter's -- small percent are mosaic
how is testosterone converted to DHT
5-alpha-reductase is the enzyme that converts testosterone to DHT
where are the sperm stored in the epididymis
60% of the sperm are stored within the tail (Cauda) of the epididymis
how many sperm are stored in the epididymis
700 million sperm are stored
what precent of couples will become preganant after 1 year
85% pregnant after 1 year
what percent of couples have difficulty conceiving
15% have trouble getting pregnant
how do you diagnose klinefelter's
1. amniocentesis 2. learning difficulties and behavioral problems in childhood - possibility for cognitive deficits 3. lack of masculinization and small testes (atrophic) during puberty 4. infertility in adulthood
what happens to primary spermatocytes in meiosis I
1. chromosome reduplication 2. synapsis 3. crossing over 4. homologous recombination
what are the 4 ways sertoli cells support spermatogenesis
1. create specialized microenvironment 2. expose germ cells to high levels of testosterone 3. coordinate maturation via gap junctions between SC and GC 4. transport differentiating GC towards the lumen
how do sperm get from the testis to the epididymis?
1. fluid pressure in the seminiferous tubule 2. myoepithelial contractions of the tubules or the tunica albuginea 3. cilia within efferent tubules
what happens during spermiogenesis?
1. nuclear condensation and repackaging of DNA from histones to protamines 2. acrosome formation 3. residual body separation from the sperm 4. tail formation (Develops from centriole)
what does androgen binding protein do
ABP binds testosterone in the tubules and keeps the testosterone in the testicles
What receptors does DHT bind to
DHT binds to the same receptors as testosterone but with higher affinity
what is the half life of FSH
FHS has a longer serum half life -- these levels remain relatively steady
what iskallmann syndrome
a syndrome of hypothalamic disfunction - congential hypogonadotropic hypogonadism