PHY3181 Lecture Notes - Lecture 6: Sex Steroid, Gonadotropic Cell, Estrous Cycle
30 Jun 2018
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Lecture 7 the reproductive brain
The link between the brain and hormones is based on
closed loop negative feedback mechanisms. When
these homeostatic loops do not exist we see
dysfunction in physiology.
We look at sheep as they are representative of humans
Overview
• Neuroendocrinology – structure and function
of the hypothalamo-pituitary gonadal axis
• GnRH neurons – have to function in pulses, if
they do not secrete in a pulsatile function they
cannot regulate LH and therefore cannot
control the gonads and therefore cannot
control the gonads
• The GnRH pulse generator – note that we do
not know what the pulse generator is
• Negative versus positive feedback – note that
the same neurons regulate both positive and
negative feedback
Hypothalamus: where GnRH synthesis occurs. The
hypothalamus is the location of GnRH neurons have
to project down to the ME where GnRH is secreted to
enter the portal blood to the AP stimulate release
of LH and FSH
GnRH is synthesised and primarily stored in the
terminals in the ME area there ready to be secreted.
It is stored so that it can secreted in a pulsatile fashion.
Note that if GnRH is not pulsatile it cannot stimulate
the gonadotrophins.
The hypophyseal portal veins connect the pituitary to
the brain. Note that both of the pituitary and
hypothalamus are fundamental for life.
The ME has internal and external zones. The external
zone has the vascular system that links the brain the
pituitary.
The ME with the GnRH-IR terminals
• Project down to the external zone
• Typically see a nerve terminal
• Secretory vesicles are ready to stimulate
hormones
• GnRH neurons are located at the
hypothalamus they send long projections to
the external zone
• There are very few GnRH neurons they all
act together to make pulses
• GnRH is secreted into the ME at the external
zone
GnRH pulses are key
Every single pulse of LH is preceded by a GnRH pulse.
Note that small GnRH pulses may not correlate to an
LH pulse. You will never see an LH pulse that is not
preceded by a GnRH pulse.
This was discovered by the simultaneous sampling of
hypophyseal portal blood (GnRH) and peripheral blood
(LH and FSH)
We know that the hypothalamus regulates pituitary
function from portal sampling. This has been done in
sheep (larger animals). Have access through the nose
insert a cannula can insert a need to collect the
sample. This is the only model to study hypothalamic
and pituitary hormone secretion.
Continuous GnRH does not stimulate LH or FSH
secretion. Note that even though FSH is not pulsatile is
still depends on GnRH.
• Non pulsatile causes a rapid desensitisation
of the GnRH receptors
• Non-pulsitile GnRH = inhibition of LH secretion
• This is a form of contraception (a GnRH super
agonist)
• By blocking GnRH pulsative secretion shuts
down LH secretion
Novel characteristics of GnRH neurons
• Sparsely distributed throughout the pre-optic
area and anterior hypothalamus (primarily
located in the medial pre-optic area)
• Act in concert to create pulses
• They all have to be activated at the same time
to result in a pulse
• They are spiney
• Dendrites – receive information from adjacent
cells and relay it back to the neuronal cell body
• Communication occurs via dendrites
o Receive and transmit information
o They can give and receive info at the
same time
o Dendrites are dins at the cell body and
the cell terminal
o They wrap around each other
o This is fundamental to create pulses
• Cell dendrites are connected through synapses
(unique)
GnRH Dendrons
• Projections of GnRH neurons to the ME are not
typical axons
• The spiney processes exist the whole way
down the terminal – because of this we say
that they do not have an axon makes them
unique
• These projections are called dendrons
• They give and receive information – GnRH
terminals receive synaptic input from cell body
all along the axon (dendron)
• This is important with kissppetin (acts at GnRH
neurons it can stimulate GnRH secretion by
simply acting at the nerve terminals)
Dendrite/ dendron: any of the threadlike extensions of
the cytoplasm of a neuron; they typically branch into
tree like processes, and compose most of the receptive
surface of a neuron. They look like an axon by they have
the spiney processes where they can both transmit and
receive information.
GnRH neuron summary
• GnRH neurons are sparsely distributed
throughout the medial pre-optic nucleus
(different to many other neuron groups) – i.e
at the very front of the hypothalamus
• Must act in a co-ordinated manner ie pulses –
the pulses are needed for LH and therefore
reproduction
• Every pulse of LH is preceded by a pulse of
GnRH
• FSH is secreted in a passive (not pulsatile) but
is still dependent on GnRH
• Talk to each other using dendrites
• Pulses can be triggered via terminal on
terminal interaction – this means that GnRH
secretion is not necessarily regulated at the cell
body it is fundamentally regulated at these
terminals
GnRH is controlled by a closed feedback loop system
• Stimulus: GnRH
• Effector: LH/FSH
• Sensor: Sex steroids feedback to stimulus
Negative feedback hormones (at the brain)-
hormones do not all feedback the same way
1. Progesterone reduces GnRH pulse frequency in
the luteal phase (in combination with low-dose
estrogen) only acting at the brain, strong
negative feedback in females
2. Estrogen has a short-term negative feedback
effect in the early follicular phase to reduce
GnRH pulse amplitude acting at the brain
and pituitary
3. Testosterone reduces GnRH pulse frequency in
males only acts at the brain
Remember that the GnRH neurons are at the pre-optic
nucleus
4. Inhibin exerts negative feedback at the
pituitary gland
Positive feedback – estrogen only. This is essential for
ovulation. In the late follicular phase of the menstrual
cycle, positive feedback enhances the amount of GnRH
and enhances the ability of the pituitary to utilise it. i.e
this is acting at the brain and the pituitary.
Positive and negative feedback across the menstrual
cycle
Luteal phase:
• GnRH: low pulse frequency
• Both E and P negative feedback (E and P are
high)
• E: reduces pulse amplitude
• P: reduced pulse frequency
• Inhibition of KNDy cells (the effect of negative
feedback is only at the KnDY cells)
• Increase in GnIH
• E negative feedback at the pituitary is
modulating LH pulse amplitude
• P infrequent GnRH pulses
Early Follicular phase:
• Increase in GnRH pulse frequency
• Only due to the decrease in P
• Reduced P negative feedback and activation of
KnDY cells – this is a tonic activation (note that
the KnDY are also responsive to P) small
increase in GnRH pulse frequency
• Note that GnIH is under negative feedback –
with a reduction in negative feedbcak we may
start to see a small decrease in GnIH (note that
here we may see not much of a change)
• There are no major changes to the POA kiss
cells
Late follicular phase:
• Estrogen switches to elicit positive feedback
• There is no longer an inverse relationship
between gnRH pulse frequency and LH pulse
amplitude (this is seen at all other phases)
• Rapid increase in GnRH
• P is low
Note that estrogen can only ever stimulate GnRH
neurons when P is low.
P has a massive effect for increasing core body
temperature in women.
The effects of E on core body temp are only seen when
progesterone is low.
Estrogen feedback in the ovariectomised female
Ovariectomised = removal of endogenous hormones. If
you treat this patient with estrogen:
• Very acute sense – you will see negative
feedback: inhibit LH and FSh secretion
• Once maintained – E will switch to positive
feedback
• This is from the same E treatment at different
time points
• In this case we have no P, E will switch between
positive and negative feedback
• Note that long term E will cause negative
feedback
********************************************
Positive and negative feedback summary
• There is no direct action of sex steroids on
GnRH neurons
• Steroid feedback occurs via ERalpha, PR and AR
• Progesterone elicits negative feedback only
• The positive feedback effect of estrogen occurs
during the late follicular phase
• For estrogen to cause positive feedback
progesterone levels must be low or negligible
• Steroids DO NOT act directly at GnR neurons to
cause positive or negative feedback
Lecture 8. The reproductive brain 2
• Kisspeptin and GnIH are neuropeptides
• Kisspeptin stimulated GnRH secretion
• GnIH = inhibitory hormone responsible for
relaying negative feedback in the brain
• These both relay steroid feedback to GnRH
• Kisspeptin cells in the POA (activated prior to
LH surge) and KnDY cells in the arcuate nucleus
are activated
• Have to have high amplitude LH pulses from
rapid GnRH pulses the surge is cumulative
• We get priming of the vesicles all of the LH
vesicles will dock to the cell membrane ready
for secretion (increase in LH production – see
an increase in FOS)
• Note that we have to increase LH production
so that LH does not plateau
• E pos at the pituitary: increase in GnRH R
prevents desensitisation of the system
Note that GnRH is regulated by convergent pathways
GnRH neurons do not typically express the relevant
receptors for direct action at the neurons. This is a
gating system. Information regarding steroid/
nutrition/ stress are processed in other brain regions
and then relayed to GnRH neurons. Prevents
information overload at a single neuron. This allows
neurons to act in concert.
• GnRH neurons do not contain Era, PR or AR
(these are the receptors responsible for steroid
feedback)
• They do express ER-beta (do not know the
function) – it is not involved in steroid feedback
however
Kisspeptin – a feedback system in the arcuate nucleus
and the POA
• This is the major regulatory of puberty and
hormone production
• Kiss1 (gene) Kiss1 (mRNA) Kisspeptin
(protein) binds to the GPR54 (receptor)
(Kiss1R)
• Mutations can occur in the gene – the patient
will not enter puberty because without it – it
will shut down GnRH secretion and therefore
reproductive function
• Mutations can occur in the GPR54 (receptor)
patients will again not enter puberty
There are species differences in kisspeptin expression
Document Summary
Lecture 7 the reproductive brain: gnrh is secreted into the me at the external. The link between the brain and hormones is based on closed loop negative feedback mechanisms. When these homeostatic loops do not exist we see dysfunction in physiology. We look at sheep as they are representative of humans. The hypothalamus is the location of gnrh neurons have to project down to the me where gnrh is secreted to enter the portal blood to the ap stimulate release of lh and fsh. Gnrh is synthesised and primarily stored in the terminals in the me area there ready to be secreted. It is stored so that it can secreted in a pulsatile fashion. Note that if gnrh is not pulsatile it cannot stimulate the gonadotrophins. The hypophyseal portal veins connect the pituitary to the brain. Note that both of the pituitary and hypothalamus are fundamental for life.
