LH-R FSH-R

Production & Function of Pituitary Gonadotropins
Animal Physiology (Hill, Wise, Anderson):
Ch. 14 — 399-403
1
Pituitary Development
diencephalon
Rathke’s pouch
stomodeum
chorda
2
Pituitary Development
infundibulum
Rathke’s
pouch
3
Pituitary Development
hypothalamus
optic
chiasm
infundibulum
Pars
Intermedia
Pars Intermedia
neurohypophysis
adenohypophysis
4
Pituitary – Anatomy
hypothalamus
bone
hypophysis
5
Pituitary – Structure and Function
Diversity of
cell types?
6
Sets of Transcription Factors Determine Cell Fate
7
Gonadotroph Cell
Characteristics - I
• Production of gonadotropins
– LH: luteinizing hormone
– FSH: follicle-stimulating hormone
• most gonadotrophs produce both LH
& FSH
– composed of 2 subunits; ca. 35kD
• both glycosylated; common
glycoprotein (GP) α-subunit
• hormone-specific β-subunit
– (LH, FSH [CG, TSH])
receptor
LH-R
testis
Leydig
ovary
theca/interstitium
later: granulosa
function
steroid
production
FSH-R
Sertoli
granulosa
germ cell
maturation
8
Gonadotroph Cell Characteristics - II
• Cell specific expression
– LH: Egr-1 & SF-1
– FSH: SF-1? other?
• GnRHs stimulate
gonadotropin secretion and
expression
– molecular mechanism for
expression
• GnRH-stimulated
phosphorylation (ie. activation)
Egr-1 and SF-1
– concentration
– frequency
– desensitization
• acute <->long-term
9
Gonadotroph Cell Characteristics - III
– Regulation of GnRH-R
expression (long-term)
• Low/high Hz
inhibitory
• GnRH + & —
• Intermediate
• estrogen +
• Continuous
– in males after
conversion of T
– preparing ovulatory LH
surge or approaching
breeding season
stimulatory
inhibitory
LH
• High dose
inhibitory
– Steroids (DIRECT effects on
pituitary)
E2
• estrogen Ï LHβ & ER expression
• androgen Ï FSHβ synthesis BUT
Ð FSH release (via GnRH)
10
Gonadotroph Cell Characteristics - IV
βA
– Inhibin (TGFβ family)
βA
βB
βB
βA
• Specific for FSH
• inhibits FSH synthesis
and secretion by classic
feedback
βB
βB
inhibin
gonad
+
βA
—
pituitary
FSH
11
Gonadotroph Characteristics - V
– Activin (TGFβ)
• inhibin counterpart; stimulates FSH
• produced in pituitary, ie. autocrine
– Follistatin (FS)
cell membrane
• activin binding protein
• neutralizes activin activity
intracellular
breakdown
– Activin action
• ratio activin/FS at low GnRH frequency
allows activin action
• when more FS due to higher GnRH
frequency: neutralisation of activin Î
less FSH secretion while LH secretion
up-regulated (direct GnRH effect)
12
Summary Feedback Systems
• Positive effects of steroids (e.g. ovulation)
– Hypothalamus: PR (interneurones) and GnRH-R (GnRH neurones)
expression
– Pituitary: GnRH-R and gonadotropin subunit expression
• Negative steroid feedback on GnRH secretion dominates over
positive steroid feedback on gonadotrophs (see above)
– Net effect in vivo: inhibition of pituitary gonadotropin release due to
reduced GnRH
• FSH: Negative / positive feedback via inhibin / activin
• Autostimulation of GnRH secretion BUT rapid, homologous
GnRH-R down-regulation in GnRH neurons Î GnRH secretion
bursts
13
Gonadotropins Regulate
Gonadal Hormone Production
External cues
GnRH
GONADS
germ
cells
BRAIN
steroids &
growth factors
PITUITARY
LH/FSH
14
GTH-Receptor Localization and Function
LH-R
testis
ovary
Leydig
theca/interstitium
later: granulosa
function
steroid
production
FSH-R
Sertoli
granulosa
germ cell
maturation
LH
Pituitary
LH -R
Leydig
• However, also FSH stimulates
steroid production
FSH
FSH -R
androgens
Sertoli
Testis
– Direct
• Aromatase expression in Sertoli/granulosa cells
– Indirect
• Growth factors from Sertoli/granulosa cells
stimulate Leydig/theca cell functions
• LH-R expression by granulosa cells
15
Mammals versus Fish
LH
Pituitary
LH -R
Leydig
FSH
FSH -R
androgens
Sertoli
Testis
Both receptors
selective
LH
Pituitary
LH - R
Leydig
FSH
FSH - R
androgens
Sertoli
Testis
One receptor (often
FSH-R) promiscuous
16
Gonadotropin Receptors
LRR – ribonuclease
inhibitor
7 TM (GPCR) – rhodopsin
17
LH Receptors and Steroidogenesis
• LH-R
– required for germ
cell maturation
and fertility;
THE mediator of
steroidogenesis
limited
relevance
major
relevance
– Homologous downregulation
– Heterologous up- regulation
• FSH ´ Sertoli/granulosa ´ inhibin ´
stimulation of LH-R expression (Leydig or
autocrine in granulosa)
18
cAMP Acts in Two Ways to
Increase Steroid Production
• Activity of existing proteins by phosphorylation
– e.g. cholesterol transport to and into (StAR) mitochondria
• Gene expression via phosphorylation of
transcription factors (e.g. CREB or
CREM)
Phosphorylated CREB
recruits CBP to loosen
up chromatin
– StAR: steroidogenic
acute regulatory
protein (minutes)
– Steroidogenic enzymes
(longer-term
stimulation of hours or
days)
19