Ball sports skill centre

Hearing childrenin the middle

of the night area

Listening cell

Attention span segment

Crotch scratching area

Avoid all personalquestions area

Additionalsex

Toilet aim centre

TV & remote control addiction centre

Ability to drivecentre

Domestic skill area

Ironing centre

Lame excuse gland

Moresex

THE MALE BRAIN

SEX

Chat centre

SEX

Car parking skill

Sense of direction neuron

Unallocated segment

Telephone addictioncentre

Indecisioncentre

Shopping gland

Chocolatecravingsegment

Jealousy

Chat centre

SEX

Car parking skill

Sense of direction neuron

Unallocated segment

Telephone addictioncentre

Indecisioncentre

Shopping gland

Chocolatecravingsegment

Jealousy

THE FEMALE BRAIN

Need forcommitment

centre

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.'

Speakers

Prof Gerald Schatten; University of Pittsburgh School of Medicine, USADirector, Division of Developmental & Regenerative Medicine;

Eggs and sperm from stem cells: ensuring blessings and avoiding curses in human reproductive futures

Prof Alan Trounson Past-President; California Institute of Regenerative MedicineEmeritus Professor; Monash University

Stem Cells Entering Clinical Trials: Opportunities for Much Needed Therapies

Prof Gab Kovacs Monash IVF International Medical Director

Fertility preservation- is it realistic and is it cost-effective?

Prof Warwick Anderson Chief Executive Officer of the National Health and Medical Research Council

How good are we at translating discoveries into policy and practice?

Prof Moira O’Bryan School of Biomedical Sciences; Monash University

More than just babies

BIOL30001 Reproduction

Hypothalamo-pituitary-gonadal axis 1

Geoff Shaw

Hypothalamus

Pituitary

gonad

Reproductiveorgans

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-the-hypothalamus-and-pituitary/

http://www.endotext.org/chapter/gnrh-gonadotropin-physiology-and-pathology/

Reading and references

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 ….

figure from Turner & Bagnara (1971)

Anteriorpituitary

Posteriorpituitary

Structure of the hypothalamus(a)

(b)(c)

EssRep7 Figs 1.9, 1.11

• bilateral symmetry

• forms walls, floor of 3rd ventricle

• 3rd ventricle contains cerebrospinal fluid

• supraoptic, paraventricular, arcuate, ventromedial, suprachiasmatic, medial preoptic & medial anterior hypothalamic nuclei

The hypothalamus and pituitary interactions

Hypothalamic nuclei• 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)

EssRep7 Fig 1.10

Hypothalamo-pituitary axis

numerous interconnections with other brain areas

3rd ventricle(down midline)

Hypothalamic nuclei and pituitary

anterior commissure

paraventricular nucleus

preoptic area

supraoptic nucleus

suprachiasmatic nucleus

optic chiasm

anterior pituitary

dorsomedial nucleus

ventromedial nucleus

mamillary body

sphenoid bone intermediate lobe

posterior pituitary

median eminence

arcuate nucleus

HPA: nomenclature

HPA: hypothalamo-pituitary axis

HPG: hypothalamo-pituitary-gonadal axis

pituitary = hypophysis (pituitary ablation (removal) = hypophysectomy)

anterior pituitary = pars distalisposterior pituitary = pars nervosaintermediate lobe = pars intermediapituitary stalk = infundibulum

Anterior Pituitary cells• Gonadotroph secretes LH and/or FSH• Lactotroph secretes prolactin

Hypothalamic nuclei and pituitary

3rd ventricle(down midline)para-

ventricularnucleus

supraopticnucleus

anteriorpituitary

sphenoidbone

posterior pituitary

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

Oxytocin

• uterine contractions

• mammary milk ejection

• maternal behaviour

Hypothalamic nuclei and pituitary

3rd ventricle(down midline)

para-ventricular

nucleus

preopticarea

anteriorpituitary

ventromedialnucleus

sphenoidbone

posterior pituitary

medianeminence

arcuatenucleus

hypothalamo-pituitaryportal vessels

• make GnRH and other releasing factors

• small cell bodies in several nuclei

• 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

parvocellular neurons

GnRH secretion is pulsatile

(Johnson & Everitt Fig 6.6 after Clarke and Cummins 1982)

LH secretion is pulsatile ― GnRH and LH pulses

coincide

Pulse frequency varies with species / reprod

― ewe 1pulse /2hr― Rhesus monkey 1 pulse / hr

GnRH secreted in pulses― pulse generator in

hypothalamus sets frequency of pulses

― GnRH in portal blood is pulsatile

GnRH decapeptide― 10 amino acids― Rapidly broken down in

blood

Po

rtal

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

• continuous GnRH basal LH & FSH release– pituitary GnRH receptors

down regulated– GnRH regulates its own

receptor

Experimental model: Rhesus Monkey• ovariectomised, • hypothalamus lesioned;• given GnRH by infusion

GnRH pulse generator is a central regulator of reproductive activity

castrate – about 10ng/ml, pulses every hour to 14 ng/ml

intact about 1 ng/ml-pulses every 2 h to 4 ng/ml

neuroendocrine control of the testis

LH FSH

GnRH

testosteroneinhibin

LHFSH

GnRH

testosteroneinhibin

T but not DHT can be converted to oestrogens

aromatase

5-re

ducta

se

AndrogensAR

OestrogensER

OH

HO

O

OH

testosteroneO

OH

HDHT

oestradiol

HPG axis in ram

LH FSH

GnRH castrated rams (wethers) + T, DHT, E2 or control

all treatments: LH, FSH pulse frequency

hypothalamo-pituitary (HPD) disconnected wethers with GnRH pulses infused

every 2 h

all treatments: no effect on LH or FSH

wethers - portal blood samples for GnRH ± testosterone

effect of T: GnRH conc., GnRH pulse frequency GnRH pulse amplitude

T,DHT,E2 or oil

LH FSH

GnRHinfusion

T,DHT,E2 or oil

LH FSHT or oil

GnRH

based on Tilbrook AJ, et al. (1991) Endocrinology 129:3080-92

LH & FSH secretion in women – changes in cycleFeedback control • oestradiol and inhibin

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

Early follicular Post-menopausal

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 6.9Based 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

Oestradiol challenge in male and female rats

Oestradiol challenge in male monkey

Neonatal androgen exposure prevents response to E2 in adult

Neonatal androgen does not masculinise hypothalamus

Johnson & Everitt Fig 6.20 Johnson & Everitt Fig 6.21

Sexual dimorphism in the Hypothalamo-Pituitary-Gonadal Axis

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)

Prolactin in reproduction

Johnson & Everitt Fig 6.24

In rats prolactin surges with GnRH before ovulation

In human no clear cycle

Johnson & Everitt Fig 6.24,25

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

Short-loop feedback

Control of Prolactin secretion

EssRep7 Fig 1.12

E2+

• Dopamine and D2 receptor agonists (bromocriptine) inhibit Prl

• D2 receptor antagonists (haloperidol, domperidone) increase Prl

Dopamine is the prolactin inhibitory factor (PIF)

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

oxytocin (OT) & anginine vasopressin (AVP)• related nonapeptides

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

Oxytocin Cys-Tyr-Ile - Gln-Asp-Cys-Pro-Leu-Gly

AVP Cys-Tyr-Phe-Gln-Asp-Cys-Pro-Arg-Gly

Posterior pituitary hormones

EssRep7 Fig 1.12

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

How important is oxytocin in reproduction?

• Parvocellular neurons synthesize GnRH & release it into the hypothalamo- pituitary portal blood vessels

• Hypothalamic GnRH secretion pulsatile so LH, FSH secretion pulsatile • GnRH pulse generator in the anterior hypothalamusIn 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 pituitaryIn 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

Summary