Male Gonad Physiology Flashcards
Can you measure GnRH in the serum?
No. It’s really only present in the hypophyseal circulation from hypothal -> ant. pit.
What’s Kallman’s syndrome?
GnRH neuron precursors fail to migrate to hypothalamus (due to KAL gene mutation)
Results in congenital hypogonadism
In what cell type is GnRH produced?
Parvi-cellular hypothalmic neurons
What kind of receptor is the GnRH receptor?
GPCR using Gq (PLC, Ca2+ pathway)
Is a MEMBRANE receptor found on the Gonadatrope cell in anterior pituitary gland
What’s the circadian rhythm of GnRH?
GnRH (and thus LH and testosterone) are highest in the early morning
Levels vary throughout day
Controlled by melatonin output of pineal gland
What’s the pulsatile rhythm of GnRH: what rhythms favor which gonadotropins? What happens when you have excessive frequent pulses or continuous GnRH release?
Pulses that occur every 60-180 minutes during the day
High freq -> LH secretion
Lower freq -> FSH
Abnormal (severe stress, eg.) -> inhibition of gonadotropins
Controlled by sex steroid feedback–> Initially frequent pulses lead to increase in LH/FSH but eventually get GnRH receptor down-reg and get LOW LH and FSH
What’s a pharmacological GnRH receptor agonist?
Leuprolide
probs not important for this lecture. Used to treat hormone-dependent and for chemical castration
What cells does FSH stimulate in males? How about LH? What does each cell make in response to this stimulation?
FSH -> Sertoli -> Inhibin B
LH -> Leydig -> Testosterone
Are LH and FSH co-secreted?
No, they appear to be in different granules. (but high levels of one can have crossover effects)
What provides negative feedback to FSH and LH secretion?
FSH: inhibin B
LH: testosterone (acts on both hypothal and ant. pit.)
What kind of receptors are those for FSH and LH?
Both are GPCRs using Gs-alpha (increases cAMP)
Major effect of LH?
Increased testosterone production
Stimulates Leydig cells to produce testosterone
Major effect of FSH?
Spermatogenesis and spermiogenesis
(Acts on Sertoli Cells in the testes)
Also results in production on INHIBIN B
What cells in males have aromatase? What is the effect of estradiol on the HPT axis?
Sertoli and peripheral tissues make estradiol.
Decreases LH and FSH response to GnRH.
What’s the major difference in the HPT axis between pre and post-puberty?
Pre-puberty, GnRH secretion is very sensitive to negative feedback from steroid hormones.
Afterward, negative feedback is reset to allow larger FSH and LH pulses.
What induces Leydig cells to proliferate and produce T during early gestation?
hCG
Where do Leydig cells come from, embryologically?
Mesenchymal cells adjacent to renal system… the migrate into the intersitium around sex cords. (probably not important?)
6 intracellular features of Leydig cells?
1) Cholesterol droplets.
2) Lots of mitochondria.
3) Lots of smooth ER.
4) Lots of Golgi.
5) Lipofuscin granules.
6) Reinke’s crystals…. which are mysterious.
What’s the rate limiting step of steroid synthesis? What protein accomplishes this? THIS WILL BE ON EXAM***
Transport of cholesterol across inner mitochondrial membrane.
via Steroidogenic Acute Regulatory (StAR) protein .
(this IS probably important)
What does T do in the plasma?
It binds proteins (SHBG and albumin).
Free T has a short half-life.
Free amount is what can ACT on receptors
What’s more potent than T?
DHT
Must the Androgen Receptor dimerize to do its work?
Yes, it must.
How does proliferation of Sertoli cells change in infant vs. adults?
In children, Sertoli cells are very mitotic.
Sertoli proliferation stops afer the first meiotic division of germ cells (i.e. when puberty starts).
What is the effect of Androgen Binding Protein?
It allows T concentration in Sertoli cells to be 100x that in the circulation.
4 ways Sertoli cells support spermatogenesis?
1) Create specialize microenvironment.
2) Give lots of T to the GCs (though they don’t make it).
3) Gap junctions between Sertoli’s and GCs.
4) Transport GCs toward lumen.
2 reasons why it’s good to have a Blood-Testis-Barrier?
Isolation of haploid GCs (from toxins and immune system).
Allows separate microenvironment (so SC can nurse germ cells to maturity)
Which germ cells replicate to maintain a supply of stem cells?
Type Ad (dark)
Which germ cells replicate to produce a clonal population that goes on to meiosis / differentiation?
Type Ap (pale) ...once they differentiate, they're called Type B.
Review: What does spermiogenesis refer to?
Morphological changes of spermatid into actual spermatozoan.
4 stages of spermiogenesis?
Golgi phase - polarity established.
Cap phase - nucleus condensation, acrosomal cap.
Acrosome - tail develops, acrosome matures
Maturation - extrusion of excess cytoplasm (residual bodies)
Can exogenous testosterone induce spermatogenesis in pre-pubertal males?
No, but T-producing Leydig tumors can. The T has to be local due to the whole Testosterone Binding Protein thing…
What is primary hypogonadism? Signs?
Testicular defect causing infertility.
Signs: Infertility precedes low T, FSH is often elevated (due to decreased Inhibin being made by SC’s)
What is secondary hypogonadism? Signs?
Not enough gonadotropins or GnRH. T often low.
Infertility and T occur simultaneously.
FSH and LH are low or inappropriately normal.
How do you diagnose hypogonadism?
Multiple morning measurements of T, “consistent signs and symptoms,” infertility…
- Oligo or azoospermia may also suggest infertility
Sequelae of hypogonadism?
It varies with time of onset… but predicable defects in internal and external sexual development.
1) 1st Trimester: Ambiguous genitalia, hypospadias
2) 2/3rd Trimester: Micropenis, undescended testes
3) Childhood: Delayed/abesent puberty, small penis, eunuchoid body proportions
4) Adult: Gynecomastia, infertility, low libido, loss of body hair, ED, hot flashes
What are FSH, LH, and T levels in isolated spermatogenic failure?
Only FSH is elvated. Others normal
What are FSH, LH, and T levels in isolated obstructive infertility?
All normal
What are FSH, LH, and T levels in testicular failure (primary hypogonadism)?
FSH and LH high, but T remains low.
What are FSH, LH, and T levels in secondary hypogonadism?
FSH and LH are low or normal, T is low.
What are 2 common causes of congenital primary hypogonadism?
Klinefelter syndrome (47 XXY) Cryptorchidism
3+ causes of acquired primary hypogonadism?
Torsion
Chemotherapy/medications/toxins
Mumps orchitis
Other: (trauma, radiation, cancer, etc. etc.)
Causes of secondary hypogonadism?
There are lots:
Kallman’s syndrome (no GnRH producing neurons)
Anything that damages pituitary/hypothalmus (masses, infection, metabolic)
Medications (esp. opiates)
What was mentioned as a genetic cause of infertility?
Y chromosome microdeletions
these mutations a probably hard to pass on…
3 treatments for hypogonadism?
1) T replacement (may help symptoms but worsen infertility).
2) Gonadotropin replacement (if secondary) for fertility.
3) Testicular sperm extraction (TESE).
What is a hormone?
Chemical messenger with specific action (i.e. causes conformational change in a receptor)
What 2 types of receptors do hormones act on (i.e. what 2 did he mention in lecture)?
1) Act on MEMBRANE receptors that go via 2nd messenger signaling (GPCR)
2) Nuclear receptors (such as steroids)
What is co-secreted with GnRH?
56AA GAP (GnRH Associated Protein)
WHERE is GnRH secreted into?
Hypothalamo- Hypophyseal Portal System
Is the connection between brain and pituitary gland (capillary systems that are connected at both ends but don’t go through heart)
What is the structure of LH and FSH? What are they structurally similar to? What is different?
- Glycoproteins made of Alpha and Beta subunits
- Common Alpha unit with hCG and TSH
- Beta unit is unique and confers activity (what is measured for hCG in pregnancy test)
4 Big Features of Sertoli Cells?
1) They are POLARIZED–> helps coordinate timeline of sperm maturation, can adapt shape
2) Secrete substances that support/nourish sperm (cytokine, prostaglandins)
3) Make Inhibin B, AMH, and contain aromatase so they make Estradiol (may have role in sperm maturation)
4) Determine Testes volume (dependent on # of Sertoli and germ cells )- make up 1/3rd of germinal epithelium
Causes of congenital primary hypogonadism?
- Klinefelter (XXY)- incomplete puberty, infertility, eunuchoid body, cyrptorchidism (at risk for testicular cancer)
