L19: Hormonal control

Hormonal changes in females

(watch lecture recording)

GnRH(s) characteristics and how it works

• Decapeptides present in all vertebrates

• 3 major types of GnRH (1 in mammals)

• Released in a pulsatile manner in the median eminence (hypothalamus into portal system)

• Travels via the portal blood system to the anterior pituitary

• In the hypothalamus, GnRH neurons receive information about internal and external status; received feedback from testosterone in the male and estretdial7 in the female

GnRH receptor characteristics

• G-protein coupled receptors

• most species (primates? rodents?, mostly 1 receptor) posses at least 2 types of receptors

GnRH receptor actions and where they’re found

• Upon binding, can stimulate both Gαq and Gαs

• In the pituitary, leads to the synthesis and release of gonadotropins (LH and FSH)

• GnRHRs are also present in other tissues such as ovary, prostate and placenta. GNHR likely not from hypothalamus, but from local source.

LH and FSH composition

Glycoprotein hormones composed of 2 subunits bound by disulfide bonds:

common αSU + specific βSU (LHβ and FSHβ)

LH and FSH in mammal production

produced by the same pituitary cells (gonadotropes). In avian: different cell types

How are LH and FSH regulated

• Differential regulation based on GnRH pulse frequency.

• βSU is the limiting factor

• Control at the gene transcription level

• Secreted = stored in vesicles until signal (GnRH) is received

LH receptor characteristics and how it acts

• G-protein coupled receptor

• Activates Gαs = increase in cAMP

• Binds both LH and hCG (placental source of gonadotropin to be covered in lecture on implantation)

FSH receptors and how it acts

G-protein coupled receptor signalling via Gαs (trigger cAMP)

Inhibin and Activin characteristics and how it acts

• Glycoproteins composed of 2 subunits

• Inhibin produced by Sertoli cells in males and granulosa cells in females

• Inhibin inhibits FSH

• Activin stimulates FSH

• Mainly act in conjunction with GnRH

Gonadal (sex) steroids are derived from

• Derived from stepwise conversion of cholesterol

• Lipophylic with nuclear (intracellular) receptor

• Type of steroid depends on the presence of specific enzyme substrate in the cell

Conversion of pregneolone diagram

• Estradiol-17β contains a phenolic A ring (aromatization) which gives its potency (most potent of the natural steroids)

Estradiol-17β characteristics

• is a potent steroid

• Note that the phenolic “A” ring distinguishes a very potent estrogen from a moderate androgen (testosterone)

• Estradiol-17β produces physiologic effect at 1000-fold less amounts than either progesterone or testosterone

Sex steroid receptors characteristic and how they act

• NHR = effect on gene transcription (stimulate or inhibit); main action

• Recently: non-genomic rapid effects discovered

• Since steroids diffuse in virtually any cell of the body and receptors are widely distributed: multiple target organs

What receptor does testosterone use

Androgen receptor

What receptor do estrogens use

• Estrogens have 2 receptor types, ERα and ERβ

• Receptors require coactivators/regulatory molecule to mediate their actions on target gene promoters; regulate transcription

Differences between ERα and ERβ

• Location/presence (cell type)

• ERα stimulates transcription while ERβ inhibits it

• Effect of drugs will depend on ability to bind and activate ERα or ERβ

Kisspeptin history and what they discovered

• Discovered in early 1999/2000. Originally cloned as an anti-metastasis agent

• Over the last 25 years kisspeptins have been intensively studied in their role in regulating puberty and modulating the negative feed back of steroid in males and females.

• kisspeptin regulates GnRH, pulse frequency, seasonality

• important in regulating tonic vs surge centre

Kisspeptin receptor

GPR54

• has been localized in the hypothalamus on GnRH neurons

Why is Kisspeptin the missing link/key link

GnRH neurons do not express ERs but kisspeptine neurons do = missing link