Lecture 7: Male Gonadal Physiology Flashcards
What is the significance of GnRH in males?
Decapeptide
Derived from pre-pro-GnRH (protein hormone)
24AA signal
Produced in parvi-cellular hypothalamic neurons
Secreted in hypothalamo-hypophyseal portal system
What is halflife of GnRH? Significance?
Less than 10 minutes
So serum levels are TOO LOW to detect
What is Kallman’s syndrome?
KAL gene mutation
Failure of GnRH neuron precursors to migrate to hypothalamus
Hypogonadotrophic hypogonadism
What is the structure of GnRH receptor on gonadotrophs/LH and FSH receptors?
Membrane receptor
GPCR
What are the characteristics GnRH output in men?
- There is a circadian (diurnal) rhythm
- 24 hour cycle
- controlled by melatonin output by the pineal gland
- greater GnRH action in the early morning
- highest levels of LH and testosterone
- Also a Pulsatile (ultradian) Rhythm
- pulses every 60-180 minutes
- higher frequency favors LH secretion
- lower frequency favors FSH secretion
- non-physiologic patterns inhibit gonadotropins
- controlled by sex steroid feedback
At a higher frequency GnRH pulse, what is secreted in men?
LH
Same in females
At a lower frequency GnRH pulse, what is secreted in men?
FSH
When are the greatest amount of GnRH produced in men?
In the early morning
What is the phenomenon of self-priming?
When GnRH binding sites increase during troughs of GnRH pulses
What is the flare effect?
When excessively frequent of pulsation or continuous GnRH INITIALLY leads to an increase in LH and FSH secretion
After the flare effect, LH and FSH levels become lower
What are the characteristics of LH and FSH?
Glycoprotein hormones
Consists of alpha and beta-subunitsgranules
Alpha unit is common but Beta unit confers unique characteristic
What are the characteristics of LH in men?
20 minute half=life -liver enzymes recognize sulfur residues of LH Pulsatile secretion Acts on LH receptor on the Leydig Cell Stimulates synthesis of testosterone Is inhibited by testosterone
What negatively inhibits LH?
‘Testosterone
What are the characteristics of FSH in men?
2 hour half-life -sialic acid residues inhibt metabolism Acts on FSH receptor in Sertoli cell Stimulates spermatogenesis Inhibited by Inhibin B
What is the purpose of inhibin B in men?
Inhibits FSH production in men
What is the purpose of LH? FSH? IN MEN
To promote testosterone production
To promote spermatogenesis
What does estradiol do in men?
Modifies GnRH response and decreases LH and FSH pulse amplitude
What is the significance of Inhibin B, Activin and Follistatin system in men?
Controls secretion of FSH
Inhibin and follistatin are inhibitory
Activin is stimulatory
What structure in testis is responsible for ENDOcrine function?
Leydig cell
Steroidogenesis
What structure in testis is responsible for EXOcrine function?
Sertoli cell
Gametogenesis
Dependent on endocrine function
Where do the seminiferous tubules terminate?
At the rete testis which anastomose with seminiferous tubules
Where are spermatozoa stored?
Epididymis
In early pregnancy, what do Leydig cells respond to?
They respond to hCG to produce testosterone
What is the relationship between hCG and Testosterone?
In early pregnancy, hCG, rather than LH, is used to bind to Leydig cells to produce testosterone
What is the rate limiting step of steroid synthesis?
Steroidogenic Acute Regulatory protein Transports Cholesterol (initial precursor) across inner mitrochondrial membrane 9which is where pregnenolone is made
What are steps of testosterone formation?
- Steroidogenic Acute Regulatory protein
- Cytochrome p450 cc
- 3beta hydroxyl steroid dehydrogenase
- CYP17 (17 hydroxylase)
- 17 beta hydroxyl steroid dehydrogenase
What is the mechanism of androgen action?
2 zinc-finger DNA binding domains
1st is involved in DNA binding
2nd is involved in dimerization of androgen receptor
Difference between Testosterone and LH/FSH?
Testosterone = cholesterol/steroid receptor
LH/FSH are peptide hormones so they bind GPCR
Where is testosterone in circulation?
2% free
44% bound to SHBG (sex hormone binding globulin)
54% bound to albumin
What is the difference between spermatogenesis and spermiogenesis?
Seprmatogenesis is characterized by Proliferative phase -meiotic phse (spermatids) Spermiogenesiss is characterized by -maturation of spermatids to spermatozoa (last part of step)
How does sertoli cells support spermatogenesis?
- create a specialized microenvironment
- Expose germ cells (GC) to high levels of testosterone
- Coordinate maturation via gap junctions
- Transport differentiating GCs towards lumen
When do meiosis I and II occur in sperm?
Primary spermatocytes = meiosis I
Secondary spermatocytes = meiosis II
What are the two types of hypogonadism?
- primary = testicular failure
2. secondary = dysfunction of hypothalamus or pituitary
What are the characteristics of primary hypogonadism?
- infertility precedes androgen deficiency
- FSH often disproportionately elevated
- decreasd inhibin B production by Sertoli cell
What are the characteristics of hypogonadism?
-central defect
-simultaneous infertility and androgen deficiency
Low or normal LH and FSH levels
If you have HIGH FSH levels, what kind of hypogonadism do you have?
Primary (because gonads are fucked)
If you have low/normal FSH levels, what type of hypogonadism is it?
Secondary (central defect)
How do you diagnose hypogonadism?
Infertility
Unequivocally low testosterone
What is oligozoospermia?
Semen with a low concentration of sperm
What is azoospermia?
No sperm in semen
What are causes of primary hypogonadism?
- Klinefelter
- Cryptorchidism (absence of one or more testes)
- testicular torsion
- chemotherapy (ketoconazole, cyclophosphamide)
- trauma
What are causes of secondary hypogonadism?
Hypogonadotropic HYPOgonadism
(Kallman’s syndrome)
Suprasellar masses, HIV, pituitary disorders
What is TESE?
Testicular sperm extraction
