9. Male endocrinology Flashcards
Explain the components and players in the HPG axis
Hypothalamus
Pituitary
Gonad
Explain the sources of testosterone and FSH role in spermatogenesis
- FSH from pituitary - releasede in response to GnRH from hypothalamus (H+P)
-
Testosterone - from steroidogenic Leydig cells (G)
–> HPG axis (GnRH -> FSH/LH -> testosterone)
Which cell expresses LHCGR?
Leydig cells
What is the more potent form of testosterone?
Dihydrotestosterone (DHT)
What pathway is used to produce testosterone in humans?
delta5 pathway
What signal stimulates steroidogenesis in Leydig cells?
LH - LHCGR signalling - cAMP levels - activation of StAR - moves cholesterol into Leydig mitochondria - pregnenolone production - conversion into testosterone in sER
What are the conclusions from inactivating LH production vs LH receptor activity?
LH is not needed for embryonic male development but LH receptor is (maybe other molecule substitutes for LH induce same response activation of LHCGR receptor)
LH is crucial for postnatal male development - puberty and spermatogenesis - dependent on LH signalling + LHCGR receptor
How are testicular testosterone levels compared to other organs?
Testicular testosterone levels are x10 higher than circulating levels in the rest of the body
What receptors do androgens bind?
Androgen receptors (AR) - nuclear steroid hormone receptors - can act both as receptor and TF - bind to gene promoters - activate transcription
What are the phases when testosterone is produced by the testis?
3 distinct phases:
1. Fetal - for SD - male reproductive tract development + testicular descent
2. Neonatal surge - not known for what
3. Continuous post-pubertal production - for spermatogenesis + male secondary characteristics
Explain what is CAIS
Complete androgen insensitivity syndrome (CAIS) - XY individual but no ARs - have external female phenotype but no ovaries/uterus - abdominal testes -> infertile
What experiment was done to model for CAIS?
Mice androgen receptor knock outs (ARKO) created to study CAIS - cryptorchid testes - spermatogenesis absent - only immature spermatogonia - Wolffian duct-derived structures don’t develop
Define what are cryptorchid testes?
Cryptorchid testes - cryptorchidism - a condition in which one/both of a baby boy’s testes have not descended into their proper place in the scrotum
Why are conditional KO mice lines more beneficial?
In conditional KO mice lines can KO genes in particular cell types - not all body cells
What cells express AR in male reproductive tract?
AR expressed by:
- peritubular myoid cells (PTM)
-Sertoli cells
- Leydig cells
How does androgen signalling control Sertoli cell function?
AR necessary in Sertoli cells for spermatogenesis - SCARKO normal reproductive organs but block of spermatogenesis at meiosis
How does androgen signalling control peritubular myoid cell function?
PTM cells - contractile interface between seminiferous tubules and interstitium - AR necessary for spermatogenesis - PTM-ARKO infertile with reduction of sperm - some reach maturation but little
??? PTM secrete GDNF for SSC self-renewal - testosterone might signal to decrease - to induce differentiation - sperm maturation + PTM contract and push sperm out of seminiferous tubule epithelium into the lumen
How does androgen signalling control Leydig cell function?
Testosterone -> AR necessary for Leydig cell development - LCARKO 20% Leydig KO - still fertile even with 80% missing Leydig ARs
Explain what is DHT
Dihydrotestosterone (DHT) - more potent testosterone form - has x3 greater affinity for AR than testosterone - DHT needed for masculinisation of organs that are more distal - where testosterone conc is low
5α reductase converts testosterone -> DHT
Explain 5α reductase type II deficiency
5α reductase type II deficiency - “eggs at 12” syndrome - XT genotype Srd5a2 mutation - necessary for external masculinisation - cryptorchid testes - females at birth - at puberty androgen levels rise - pubertal masculinisation and testis descent - penis underdeveloped for intercourse - sperm produced
Which cell types in male reproductive tract express FSH receptors (FSHR)?
FSHR expressed by Sertoli cells
What’s the action of FSH on Sertoli cells?
FSH in Sertoli cells:
- stimulates Sertoli cell mitosis in fetal development
- stimulates Sertoli cells to support developing germ cells
- Stimulates ABP production - concentrates testosterone in seminiferous tubules
- stimulates inhibin production - neg feedback on FSH in pituitary
What is ABP and what is its role?
Androgen binding protein (ABP) - concentrates testosterone in seminiferous tubules
What is inhibin and what is its role?
Inhibin - protein heterodimer - α subunit produced by Sertoli + βB subunit by maturing sperm cells - inhibins signal negative feedback to HPG axis - negative feedback for FSH release from pituitary
Which male cells produce AMH?
Sertoli cells produce AMH - only in embryogenesis - not postnatally
What are the effects of inactivating FSH production vs FSHR?
FSH signalling necessary for spermatogenesis but only partially mediated by FSHR (maybe FSH can be detected by other receptor too)
What controls LH and FSH release from pituitary?
FSH - neg feedback from inhibin B
LH - neg feedback from testosterone
In castrated FSH + LH rise
How do steroids induce negative feedback in hypothalamus?
Steroids (testosterone) induce neg feedback (stop release of GnRH) at Kisspeptin neurons in hypothalamus - AVPV + ARC neurons have steroid receptors - in males mainly ARC regulates neg feedback on GnRH release from hypothalamus
How can negative feedback of HPG axis be used as male contraceptive?
Injections of slow release testosterone -> hypothalamus / pituitary supression of LH production - Leydig cells produce less testosterone - but peripheral testosterone injection not sufficient enough to support spermatogenesis => spermatogenesis stops + testicular shrinkage
Lecture summary
