Male Reproductive Endocrinology

What cells are stimulated by LH in males?

leydig

What cells are stimulated by FSH in males?

sertoli

What hormone is released by Leydig cells?

testosterone

What hormone receptor is expressed on leydig cells?

LH receptor (LHCGR)

How is testosterone produced in humans (3)?

• leydig cells

• via alpha 5 pathway

• pregnenolone start NOT progesterone

How is the human testosterone production pathway different to the rat (2)?

• human - alpha5 pathway, pregnenolone

• rat - alpha4 pathway, progesterone

What is the result of LHCGR stimulation in leydig cells (2)?

• phosphorylation and activation of StAR

• upregulates transcription of steroidogenic enzymes

What is the role of StAR in leydig cells (2)?

• activated by LH

• moves cholesterol into mitochondria to be converted to pregnenolone (to make testosterone)

What stage of development is dependent on LH signalling via LHCGR on leydig cells?

postnatal testicular development and spermatogenesis

What stage of development is NOT dependent on LH and why (3)?

• male sexual differentiation

• LH substituted for by hCG in utero

• LHCGR still required (not present = develop female)

What is the consequence of having a LHCGR K/O (3)?

• no response to LH

• develop female even if XY

• no puberty

Why are testosterone levels much higher in the testis than in the circulation?

required to stimulate spermatogenesis

What are the approximate testosterone concentrations in the testis vs in the circulation?

• testis = 2500nM

• circulating = 20nM

Where does the conversion of testosterone into dihydrotestosterone take place?

peripheral tissues via 5-alpha reductase

What type of hormone are testosterone and dihydrotestosterone?

androgens

Why are nuclear steroid hormone receptors unique?

act as BOTH a receptor and transcription factor

Where is the androgen receptor gene located?

X chromosome

What receptor do androgens act via?

androgen receptor

What are the 3 phases of testosterone production by the testes (3 points of life with highest testosterone)?

• embryonic surge

• neonatal surge

• continuous post-puberty

Why is there an embryonic testosterone surge (2)?

• development of male reproductive tract

• testicular descent

Why is there a testosterone neonatal surge?

unknown (unique to humans = hard to research)

Why is there continuous testosterone release post-puberty (2)?

• spermatogenesis

• male secondary sexual characteristics

When does the embryonic testosterone surge occur?

~1/2 way through 2nd trimester

When does the neonatal testosterone surge occur?

~6 months old

What condition is caused by inactivating mutations in androgen receptors?

complete androgen insensitivity syndrome (CAIS)

What are some of the phenotypes associated with complete androgen insensitivity syndrome (CAIS) (6)?

• XY chromosomes with…

  • female external phenotype BUT no ovaries

  • small, abdominal testes BUT no sperm

  • no wolffian duct derived structures

• short vagina and no uterus

• infertile

Why do people with complete androgen insensitivity syndrome (CAIS) develop a short vagina but no uterus?

continued AMH production by testicular sertoli cells

How are mice models created for human complete androgen insensitivity syndrome (CAIS)?

total androgen receptor K/O (ARKO) mice

What is the fancy name for undescended testes (remain in abdomen)?

cryptorchid

What mouse experimental system can be used to K/O a specific gene in a specific cell type?

Cre / loxP transgenic system

What happens in mice when androgen receptors are specifically knocked out in sertoli cells (4)?

• normal testis descent

• normal reproductive organs

• infertile with block in spermatogenesis at meiosis

• blood-testis barrier disrupted

What happens in mice when androgen receptors are specifically knocked out in peritubular myoid cells (PTM) (4)?

• normal testis descent

• normal reproductive organs

• infertile - sperm reduced at all spermatogenesis stages (not just after meiosis)

• later found androgens act on PTM to stimulate GDNF production

What happens in mice when androgen receptors are specifically knocked out in leydig cells (4)?

• normal testis development

• normal reproductive organs

• NOT infertile

• leydig cells don’t develop properly - apoptosis as mouse reaches adulthood

Why are mice with K/O androgen receptors in leydig cells not infertile?

only K/O 80% leydig cells - remaining 20% compensate

How much higher is the affinity of dihydrotestosterone for the androgen receptor compared to testosterone?

3x higher affinity

What is dihydrotestosterone needed for?

masculinisation of organs distal to testes (due to decreased testosterone concentration outside of testes)

What causes ‘eggs at 12’ syndrome (2)?

• 5alpha-reductase type II deficiency

• XY genotype with Srd5a2 mutation

What are the clinical phenotypes of ‘eggs at 12’ syndrome (5alpha reductase type II deficiency) (4)?

• babies identified female at birth

• testes and repro tract develop normally BUT cryptorchid

• Srd5a1 can compensate at puberty - masculinisation

• penis often not properly developed but sperm can be used for artificial insemination

What 2 hormones are required for optimal spermatogenesis?

• testosterone

• FSH

What are the actions of FSH on sertoli cells (4)?

• foetal / neonatal sertoli mitosis

• stimulates sertoli to signal to and support germ cell development

• production of androgen binding protein

• inhibin production

What is the negative feedback signal onto FSH production?

inhibin from sertoli cells

What is the role of androgen binding protein produced by sertoli cells?

concentrates testosterone in seminiferous tubule fluid

Where are LH and FSH produced?

anterior pituitary

When do sertoli cells produce AMH (2)?

• ONLY during embryogenesis

• has no impact on spermatogenesis or postnatal development

What is the effect of inactivating FSH (4)?

• no mature spermatozoa

• smaller testes, less sertoli

• fewer spermatogonia

• INFERTILE

What is the effect of inactivating FSH receptor (4)?

• smaller testes, less sertoli

• fewer spermatogonia and mature spermatozoa

• VARIABLE PHENOTYPE

• suggests FSH may be able to act through another pathway

Where does steroid negative feedback occur in the brain?

kisspeptin neurones in hypothalamus

What is the structure of inhibin B (3)?

• heterodimer:

  • alpha subunit

  • beta_B subunit

Where is the alpha subunit of inhibin B produced?

sertoli cells in response to FSH

Where is the beta_B subunit of inhibin B produced?

maturing sperm cells

Where does inhibin B negatively feedback onto (2)?

• pituitary gonadotrophs

• represses ONLY FSH

What hormones does testosterone negatively feedback onto?

FSH and LH

What is the result of injecting extra testosterone (i.e. steroid injections) (4)?

• suppresses LH production (negative feedback)

• less T production by leydig cells

• T concentrations not high enough for spermatogenesis

• spermatogenesis stops, testicular shrinkage