L10: Endocrine Control of Testis Function Flashcards
What are the hormones required for optimal spermatogenesis?
- Testosterone and FSH
- Testosterone is released from testicular Leydig cells, stimulated by LH released by the pituitary
- FSH is released by the pituitary act on Sertoli cells (doesn’t act directly on germ cells)
What is LHCGR? Where is it expressed?
Luteinising hormone/chorionic gonadotrophin receptor is expressed in Leydig cells
What is the predominant pathway of testosterone production in humans? in rodents?
In humans: delta-5 pathway
In rodents: delta-4 pathway
What and how stimulates steroidogenesis in Leydig cells?
LHCGR signalling:
- induces phosphorylation and activation of StAR (StAR moves cholesterol from cytoplasm of the cell into the mitochondria)
- upregulates transcription of steroidogenic enzymes
- binding of LH receptor produces large amounts of cAMP
- if not stimulated by LH, steroidogenesis will happen, just at the very low pace
What are the effects of inactivating LH-beta and LHCGR mutations in humans? (external genitalia, puberty, testosterone, LH) What does it suggest?
LH-beta -/-
external genitalia at birth: male
puberty: delayed
testosterone: low
LH: absent
LHCGR -/-
external genitalia at birth: female
puberty: absent
testosterone: low
LH: high
- Suggests LH is not required for male sexual differentiation (HCG can substitute) but its receptor is
- Postnatal testicular development and spermatogenesis is, however, dependent on pituitary LH signalling through LHCGR
What are the differences in levels of testicular testosterone and circulating testosterone?
Testicular testosterone levels are much higher than circulating, around 100X more concentrated, because essential for spermatogenesis.
Testosterone can be converted to DHT in peripheral tissues by action of the enzyme 5-alpha reductase, it has very strong action, that’s why lower conc is enough, DHT mostly acts on post-pubertal characteristics
Which receptors do androgens act through?
- Through nuclear steroid hormone receptors, they are unique because they have the ability to act as both a receptor and transcription factor
- Ligand (steroid hormone) diffuses into the cell, binds to the receptor protein, translocates to the nucleus and then it can actually bind to promoters in genes
- AR gene is on X chromosome, so inherited from mothers
Which phases is testosterone produced in humans?
In three phases:
- embryonic surge: development of male reproductive tract (epididymis, vas deferens and seminal vesicles) testicular descent
- neonatal surge: no info yet, doesn’t occur in rodents
- continuous post-puberty: spermatogenesis, male secondary sexual characteristics
What is Complete Androgen Insensitivity Syndrome (CAIS)? What is the phenotype of people with CAIS?
Humans with inactivating mutations in androgen receptors.
XY chromosomes but have:
- ‘female’ external phenotype but no ovaries
- small, abdominal testes with no spermatogenesis
- no Wolffian-duct derived structures (producing testosterone normally, however no spermatogenesis)
- but also a short vagina, and no uterus, due to continued AMH production by testicular Sertoli cells
- infertile
What is the animal model for CAIS?
Total androgen receptor knockout (ARKO) mice.
When no functional androgen receptor is present in all cells in the body:
- testes are undescended (cryptorchid)
- spermatogenesis is absent beyond spermatogonia
- Wolffian duct-derived structures do not develop
How does androgen signalling control spermatogenesis?
- Peritubular myoid (PTM) cells: contractile interface between tubules and interstitium
- Sertoli cells: intratubular nurse of spermatogenesis
- Developing sperm: no AR
- Leydig cells: produce testosterone
What is the conditional AR knockout mice animal model?
Gene knock-out only in one cell type not in every single cell
uses the Cre/loxP transgenic system to make a knockout of your gene of interest ONLY in one particular cell type
What is the Sertoli cell-specific ARKO (SCARKO) model? what are the results?
Conditional knock-out of sertoli cells androgen receptors
- normal testis descent, normal reproductive organs
- but infertile with a block in spermatogenesis at meiosis
- blood-testis barrier disruption
- De Gendt et al.
What is the PTM (Peritubular Myoid cells) cell-specific ARKO (PTM-ARKO) animal model? what are the results?
- Normal testis descent, normal reproductive organs
- infertile with a reduction of sperm at all stages of spermatogenesis (but not a block)
- later found that androgens act on PTM cells to stimulate GDNF production
- Welsh et al.
What is the Leydic cell-specific ARKO (LCARKO) animal model? what are the results?
- Knockout in approx. 80% of adult Leydig cells
- normal testis descent, normal reproductive organs
- NOT infertile, but Leydig cells do not develop properly: apoptosis as the mouse reaches adulthood
- had normal testosterone levels, maybe overcompensating from other Leydig cells
- O’Hara et al.
