Male Reproductive Endocrinology Flashcards
How does the HPG axis work in males (Simple)?
Hypothalamus releases GnRH which tells pituitary to release LH and FSH
What does optimal spermatogenesis require and where are these released from?
Testosterone is released from leydig cells after LH stimulates them
FSH is released from the pituitary
Where is the LH receptors expressed?
Leydig cells
What is the major product of the leydig cells?
Testosterone produced by the delta 5 pathway in humans of the delta 4 pathway in rodents
How does leydig signalling stimulate leydig cell steroidogenesis?
The receptor signals and induced phosphorylation and activation of StAR which upregulates transcription of steroidogenic enzymes.
What would happen if you inactivate LH or the LH receptors on key components (External genitalia at birth, puberty, testosterone, LH)?
External genitalia at birth = Male if LH is inactivated, female if LH receptors inactivated
Puberty - delayed in LH inactivation and absent in receptor inactivation.
Testosterone - low in LH inactivation and low in receptor inactivation
LH - absent in LH inactivation and high in receptor inactivation
What is dependant on the LH receptor and what is dependant on LH itself?
Male sexual differentiation = receptor
Postnatal testicular development and spermatogenesis = LH
Are testosterone levels higher in the testes than in the circulating blood?
Testes
Why is testosterone converted to DHT in the blood and what does this?
Testosterone is concentrated enough in the testes to work but not in the blood and so its changed to the highly concentrated DHT.
5 alpha-reductase does this
How do androgens work?
Testosterone and DHT bind to AR’s better than the other androgens which is why they are the only active androgens. The other androgens can be used as intermediates.
These receptors can act as both a receptor and a transcription factor
What are the 3 surges of testosterone and what do they do?
Embryonic stage - helps the fetus develop male reproductive tract
Neonatal stage - no one knows
Continous post-puberty - spermatogenesis, male secondary sexual characteristics.
What happens in humans with inactive AR?
Complete androgen insensitivity syndrome (CAIS)
These individuals are assigned female at birth but have no ovaries, uterus and a short vagina. They have abdominal testes.
They do not know they are XY until puberty as they do not menstruate and will be told by the doctors.
Most chose to get testes removed and stay female.
What are ARKO mice?
Androgen receptor knockout mice which are a model for cais which show undescended testes, absent spermatogonia and no wolffian duct-derived structures developed.
How do you make conditional AR knockout mice?
Cre/loP transgenic system to make knockout of gene of interest in one cell type
What would happen in a sertoli-specific androgen receptor knockout (SCARKO)?
Normal testes descent and repro organs. Infertile due to a block of spermatogenesis at meiosis and blood testes disruption
What would happen in a PTM cell-specific androgen knockout mouse (PTM-ARKO)?
Normal testis descent and normal repro organs. Infertile with reduce sperm at all spermatogenesis stages (but no block). Androgens work on PTM to stimulate GDNF
What would happen in a leydig cell androgen receptor knockout (LCARKO)?
Normal testes and repro organs not infertile however the leydig cells dont develop properly and apoptose in adulthood.
What are the different types of DHT and where are they found?
Type 1 DHT - organs not associated with reproduction e.g chest and back skin
Type 2 DHT - organs more associated with reproduction e.g testes and helps grow beard
Both share liver
What is 5 alpha reductase type 2 deficiency?
When someone has an XY genotype with a mutation in the Srd5a2 gene they appear female at birth as their male repro organs are inside the body until puberty hits. The when it does their phenotype changes and they become male. They however have short penises and therefore cant reproduce naturally but everything else works fine and they can do IVF etc.
Where is the FSH receptor expressed?
Sertoli cells
What does FSH do to sertoli cells?
FSH released during fetal and neonatal development stimulating mitosis. Also stimulates them signalling to support developing germ cerlls, production of androgen binding protein and stimulate inhibin production.
What happens to testes size, sertoli, spermatogonia, mature spermatozoa and fertility when inactivating FSH receptor and FSH?
Testes size = smaller when both FSH and its receptor inhibited
Sertoli - are fewer when both FSH and receptor are inactive
Mature spermatozoa are none when FSH inactive and few when receptor is inactive.
Fertility - infertile when no FSH, variable when the FSH receptor is inactive
What two hormones are part of the gonadal feedback of the hypothalamus and what do they do?
Testosterone inhibits pituitary and hypothalamus
Inhibin B inhibits pituitary secretion of FSH
Where is steroid negative feedback in the hypothalamus at?
The Kisspeptin neurons
Where is inhibin produced and what does it do?
Inhibibin A produced by sertoli cells in response to FSH and inhibin Betab is produced mainly by maturing sperm cells
How does inhibin B repress FSH release?
Acts on pituitary gonadotrophin repressing their gene expression including Fshb.
How do testosterone injection male contraceptives work?
Injecting slow release testosterone results in the hyp/pit supression of endogenous LH production (this happens as ny testosterone in the blood and not the testes it directly inhibits). This causes testes shrinkage
