THE MALE BRAIN
Ball sports
skill centre
Hearing children
in the middle
of the night area
More
sex
Listening cell
Additional
sex
SEX
Attention span
segment
Crotch scratching area
Avoid all personal
questions area
Toilet aim
centre
Ability to drive
centre
TV &
remote control
addiction centre
Domestic skill
area
Ironing centre
Lame excuse gland
THE FEMALE BRAIN
Chat centre
Jealousy
Telephone addiction
centre
Indecision
centre
Need for
commitment
centre
SEX
Chocolate
craving
segment
Car parking skill
Sense of direction
neuron
Unallocated segment
Shopping gland
Alternative medical dictionary
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Artery - The study of paintings.
Barium - What Doctors do when patients die.
Cauterize - Made eye contact with her.
Colic - A sheep dog.
Dilate - To live long.
Enema - Not a friend.
Fibula - A small lie.
Genital - Not a Jew.
Impotent - Distinguished, well known.
Labour Pain - Getting hurt at work.
Morbid - A higher offer.
Nitrates - Cheaper than day rates.
Node - Was aware of.
Outpatient - A person who has fainted.
Post Operative - Letter carrier.
Recovery Room - Place to do upholstery.
Terminal Illness - Getting sick at the airport.
Urine - Opposite of 'you're out'.
Doctor Henderson spoke very seriously to Old
Terry, 'I'm afraid I have some bad news and some
worse news for you, Terry.'
'Tell me the worse news first, please, Doc,'
mumbled Old Terry.
'You've got cancer and have only 3 months to live,'
replied Doctor Henderson quietly.
'What's the bad news?' asked Terry after a short
while.
'You've also got Alzheimer's disease,' said Doctor
Henderson.
'Thank the Lord,' muttered Old Terry, 'For a moment
there I thought I had cancer.'
Hypothalamus
BIOL30001
Reproductive
Physiology
Pituitary
Hypothalamo-pituitarygonadal axis 1
gonad
Geoff Shaw
Reproductive
organs
Reading and references
Reading:
Johnson (2013) Essential Reproduction 7TH Ed, Chapter 1,7,9, esp pp
12-19, 158-170, 124-127
Johnson and Everitt: Essential Reproduction (6th), Chapter 6 (& 4, 5)
Austin and Short: Reproduction in Mammals, Book 3 (2nd edition)
Chapter 1
http://www.endotext.org/section/neuroendo/, especially
http://www.endotext.org/chapter/functional-anatomy-of-thehypothalamus-and-pituitary/
http://www.endotext.org/chapter/gnrh-gonadotropin-physiology-andpathology/
Outline
• Hypothalamus-pituitary axis
– Anatomy and development
– LH, FSH, Prolactin, Oxytocin
• Hypothalamic releasing factors
– GnRH
• The GnRH pulse generator and gonadotropin
secretion
• Feedback effects at hypothalamus and pituitary
– Steroids – T, E2, P4
– Inhibin
• Prolactin & dopamine
• Oxytocin
The pituitary development
• dual embryological origin
– roof of pharynx  anterior pituitary
– neural outgrowth  posterior pituitary
• “master endocrine gland”
regulates reproduction,
metabolism, growth, stress
response etc etc.
– LH, FSH, Oxytocin, Prolactin
– GH, TSH, ACTH, MSH ….
Posterior
pituitary
Anterior
pituitary
figure from Turner & Bagnara (1971)
Structure of the hypothalamus
(b)
(a) (c)
• bilateral symmetry
• forms walls, floor of 3rd
ventricle
• 3rd ventricle contains
cerebrospinal fluid
• supraoptic, paraventricular,
arcuate, ventromedial,
suprachiasmatic, medial preoptic
& medial anterior hypothalamic
nuclei
EssRep7 Figs 1.9, 1.11
The hypothalamus and pituitary interactions
Hypothalamic nuclei
numerous
interconnections with
other brain areas
• parvocellular neurons
(small cell bodies)
• magnocellular neurones
(large cell bodies)
Portal blood system
Pituitary gland
• neural and oral ectoderm origin
• Ectodermal  anterior pituitary
• Neural  posterior pituitary
(cell terminals)
Hypothalamo-pituitary axis
EssRep7 Fig 1.10
Hypothalamic nuclei and pituitary
anterior commissure
paraventricular nucleus
preoptic area
3rd ventricle
(down midline)
dorsomedial nucleus
ventromedial nucleus
suprachiasmatic nucleus
supraoptic nucleus
optic chiasm
mamillary body
arcuate nucleus
median eminence
anterior pituitary
sphenoid bone
posterior pituitary
intermediate lobe
HPA: nomenclature
HPA: hypothalamo-pituitary axis
HPG: hypothalamo-pituitary-gonadal axis
pituitary = hypophysis
(pituitary ablation (removal) = hypophysectomy)
anterior pituitary = pars distalis
posterior pituitary = pars nervosa
intermediate lobe = pars intermedia
pituitary stalk = infundibulum
Anterior Pituitary cells
• Gonadotroph  secretes LH and/or FSH
• Lactotroph  secretes prolactin
Hypothalamic nuclei and pituitary
paraventricular
nucleus
supraoptic
nucleus
3rd ventricle
(down midline)
magnocellular neurons
• make oxytocin and vasopressin
• large cell bodies in
paraventricular and supraoptic
nuclei
• axons run down pituitary stalk
• terminate in posterior pituitary
• release oxytocin (OT) & VP
anterior
pituitary
Oxytocin
• uterine contractions
sphenoid
bone
• mammary milk ejection
posterior pituitary • maternal behaviour
Hypothalamic nuclei and pituitary
paraventricular
nucleus
3rd ventricle
(down midline)
• make GnRH and other
releasing factors
preoptic
area
• small cell bodies in several
nuclei
ventromedial
nucleus
arcuate
nucleus
median
eminence
anterior
pituitary
sphenoid
bone
hypothalamo-pituitary
portal vessels
parvocellular neurons
• axons terminate at capillary
beds in median eminence,
where they release factor
• capillaries coalesce to form
hypothalamo-pituitary portal
vessels that connect to capillary
beds in anterior pituitary
• in anterior pituitary GnRH
stimulates gonadotrophs to
release LH and FSH
posterior pituitary
GnRH secretion is pulsatile
GnRH decapeptide
GnRH secreted in pulses
― pulse generator in
hypothalamus sets
frequency of pulses
― GnRH in portal blood is
pulsatile
Portal
― 10 amino acids
― Rapidly broken down in
blood
LH secretion is pulsatile
― GnRH and LH pulses
coincide
Pulse frequency varies
with species / reprod
― ewe 1pulse /2hr
― Rhesus monkey 1 pulse / hr
(Johnson & Everitt Fig 6.6 after Clarke and Cummins 1982)
Experimental models
• Gonadectomy
+/- gonadal hormones  effects on LH/FSH
& feedback
• Hypophysectomy
+/- exogenous GnRH  effects on gonads
• Antibodies
GnRH, inhibin, steroids …
• Pituitary stalk lesion
+/- GnRH pulses
 role of portal vessels
 effects on LH/FSH
GnRH pulses needed for LH release
• pulsatile GnRH  LH &
FSH release
Experimental model: Rhesus Monkey
• ovariectomised,
• hypothalamus lesioned;
• given GnRH by infusion
• continuous GnRH 
basal LH & FSH release
– pituitary GnRH receptors
down regulated
– GnRH regulates its own
receptor
GnRH pulse generator is a central regulator of reproductive activity
neuroendocrine control of the testis
GnRH
GnRH
testosterone
inhibin
testosterone
inhibin
LH FSH
castrate – about 10ng/ml,
pulses every hour to 14
ng/ml
intact about 1 ng/mlpulses every 2 h to 4
ng/ml
LH
FSH
T but not DHT can be converted to oestrogens
OH
OH
AndrogensAR
O
O
testosterone
aromatase
H
DHT
OH
OestrogensER
HO
oestradiol
HPG axis in ram
castrated rams (wethers) + T, DHT, E2
compared to control
GnRH
T,DHT,E2 or oil
LH FSH
GnRH
infusion
T,DHT,E2 or oil
all treatments:  LH,  FSH
 pulse frequency
hypothalamo-pituitary (HPD) disconnected
wethers with GnRH pulses infused
every 2 h
LH FSH
all treatments: no effect on LH or FSH
wethers ± testosterone treatment
- portal blood samples for GnRH
GnRH
T or oil
LH FSH
effect of T:
 GnRH conc.,
 GnRH pulse frequency
 GnRH pulse amplitude
based on Tilbrook AJ, et al. (1991) Endocrinology 129:3080-92
LH & FSH secretion in women – changes in cycle
Feedback control
• oestradiol and inhibin
Early follicular
Post-menopausal
post menopausal
• release from oestradiol
feedback
• pulse frequency changed
• LH & FSH levels reversed
• inhibin effect ?
If oestradiol increased
(200% or more)
• +ve feedback occurs leading
to LH, FSH surge
Johnson & Everitt Fig 6.8
Steroids can directly affect pituitary
• Rhesus monkey with
lesions in MBH that
blocked GnRH secretion,
given exogenous GnRH
pulses
• large dose of oestradiol
benzoate
• initial suppression of FSH
and LH
• if E2 remains high enough
for long enough  LH
surge
Johnson & Everitt Fig 6.9
Based on Nakai et al (1978) Endocrinology 102:52
LH secretion pattern in
menstrual cycle
• LH pulsatility varies during
the ovulatory cycle
• Pre-ovulation LH pulse
frequency steady but LH
levels rise
Johnson & Everitt Fig 6.14
Inhibin regulates FSH
• rabbit infused with either normal rabbit serum
(NRS) or an inhibin antiserum in the late follicular
phase
• Note the large rise in FSH when inhibin is
inactivated
Johnson & Everitt Fig 6.11
Sexual dimorphism in the Hypothalamo-Pituitary-Gonadal Axis
Johnson & Everitt Fig 6.20
Oestradiol challenge in male and
female rats
Neonatal androgen exposure
prevents response to E2 in adult
Johnson & Everitt Fig 6.21
Oestradiol challenge in male monkey
Neonatal androgen does not
masculinise hypothalamus
Prolactin in
reproduction
In rats prolactin surges with
GnRH before ovulation
In human no clear cycle
Prolactin
• protein hormone
• secreted by lactotrophs of anterior
pituitary gland
• circadian pattern of release
• promotes lactation
• luteotrophin in some species (eg rat
and mouse  pseudopregnancy
after infertile mating)
Johnson & Everitt Fig 6.24,25
Johnson & Everitt Fig 6.24
Control of Prolactin secretion
Pituitary disconnection increases Prl
• prolactin inhibitory factor (PIF)
• Dopamine (DA)
• GABA
• GnRH-associated peptide (GAP)
• prolactin releasing factors
• vasoactive intestinal polypeptide
(VIP)
• thyrotrophin releasing hormone
(TRH)
• oestrogen
Prl short loop feedback
• Prl-R on tuberoinfundibular
dopamine associated neurons
(TIDA)
• Prl inhibits its own release
Oestrogen
• stimulates Prl synthesis and
release by lactotrophs
E2
+
Short-loop feedback
EssRep7 Fig 1.12
Dopamine is the prolactin inhibitory
factor (PIF)
• Dopamine and D2 receptor
agonists (eg bromocriptine)
inhibit Prl
• D2 receptor antagonists
(haloperidol, domperidone)
increase Prl
Johnson & Everitt Fig 6.22
Hyperprolactinaemia
In women
• amenorrhoea and decreased libido
• no pulsatile release of LH
• reduced response to GnRH
• no +tive feedback
In men
• no pulsatile release LH
• decreased testosterone and libido
• erectile dysfunction
• infertility
Treatment
• drugs like bromocriptine
• surgery (tumours)
hyperprolactinaemic man
Posterior pituitary hormones
oxytocin (OT) & anginine vasopressin (AVP)
• related nonapeptides
Oxytocin
Cys-Tyr-Ile - Gln-Asp-Cys-Pro-Leu-Gly
AVP
Cys-Tyr-Phe-Gln-Asp-Cys-Pro-Arg-Gly
Oxytocin
• stimulates uterine contractions during labour
• acts on smooth muscle (myometrium) of uterus
• milk ejection during lactation
• initiates nursing behaviour in mothers
• stimulates contractions of seminiferous tubules and epididymis
EssRep7 Fig 1.12
How important is oxytocin in reproduction?
Targeted gene inactivation - OT gene knock out mice (OTKO -/-)
• deliver litters of normal size
• no delay in onset of labour
• no prolongation of labour
• fail to lactate, no milk let-down, pup mortality
OT not essential for normal birth in mice; role in lactation important
OT receptor antagonist - block OT receptor function
• deliver normal size litters
• no prolongation of duration of labour
• delay in onset of labour in some species ( guinea pig, tammar wallaby)
OT may be important for normal birth in some species
Summary
• Parvocellular neurons synthesize GnRH & release it into the hypothalamopituitary portal blood vessels
• Hypothalamic GnRH secretion pulsatile so LH, FSH secretion pulsatile
• GnRH pulse generator in the anterior hypothalamus
In females
• Ovarian oestrogen, progesterone control GnRH, LH & FSH via –ve feedback
• Oestrogen acts on pituitary & hypothalamus to induce LH surge via +ve feedback
• Ovarian inhibin controls FSH secretion by –ve feedback at anterior pituitary
In males
• Testosterone controls GnRH, LH & FSH via –ve feedback on pituitary &
hypothalamus
• Testosterone acts via AR or is aromatised to oestrogen in pituitary &
hypothalamus, binds ER
• Testicular inhibin controls FSH secretion via –ve feedback at anterior pituitary
• LH surge mechanism present in male primates, absent most species
• Prolactin controlled by dopamine  lactation; luteotroph in some species;
hyperprolactinaemia causes infertility
• oxytocin from posterior pituitary  milk let-down; uterine contractions; maternal
behaviour