HORMONAL CONTROL

OF MAMMOGENESIS,

LACTOGENESIS, AND

GALACTOPOIESIS

MAMMOGENESIS• MAMMOGENIC COMPLEX OF HORMONES

• Growth hormone (anterior pituitary)• Estrogen (ovary)

• Progesterone (ovary)• Prolactin ( anterior pituitary)

• Glucocorticoids (adrenal glands)• Placental lactogen ( placenta)

• Local mammary factors (IGF, TGF, EGF)• SPECIES DIFFERENCES!

GROWTH HORMONE

• Produced in the anterior pituitary• Been shown to influence mammary

development even in the fetal stages• Mammary parenchyma: + correlated to GH• Receptors on epithelial / stromal tissue• MOST EFFECTS MEDIATED THROUGH

LOCAL STROMAL FACTORS (IGF)

GLUCOCORTICOIDS (C)

• Produced in the adrenal glands• Involved in nutrient metabolism• Shown to be involved in both:

- ductal development: with GH and E2

- lobulo/alveolar growth: GH, PRL, E2, P4

• DIRECT vs. INDIRECT EFFECTS?

ESTROGEN (E2)• Produced in the ovary (placenta)• SPECIES SPECIFICITY!!!!!

• Parenchymal development even very early

- rodents, bovine : essential

- sheep: ovex and still get development• Parenchymal development: species specific

- rodents: duct / stroma bovine: duct• Mediated through local factors: IGF

Rodent

4 weeks old

PUBERTY TO CONCEPTION

PROGESTERONE (P4)

• Produced in the ovary ( placenta)• Lobulo-alveolar dev:Lactogenesis-stage 1• Function of high E2 and P4 ( GH, PL, C)

- luteal phase: some dev./ milk synthesis?

- pregnancy: massive development P4/E2

** especially late pregnancy• Inhibitory to lactogenesis (Stage 2)?

PUBERTY TO CONCEPTION

PREGNANCY

RodentDay 9

PREGNANCY

RodentDay 16

PROLACTIN

• Produced in the anterior pituitary• SPECIES SPECIFIC!!

• Bovine: Permissive effect for steroids• Rodents: ESSENTIAL for mammo.

* Regression of elongated terminal end buds

* Promotes ductular side branches

* Direct effect on lobulo- alveolar development

Rodent

4 weeks old

PLACENTAL LACTOGEN• Produced by the placenta (fetal origin• Growth hormone and prolactin-like

activities• Linkage to calf size / future milk

production?• Mediated by local factors (IGF)?

MAMMOGENIC HORMONE ACTIONS

• Related to hormone concentrations• Related to tissue sensitivity

- increase in receptors / late pregnancy• Hormone biological availability

- Steroid hormones bound to transport proteins : glucocorticoids

LOCAL TISSUE MEDIATORS

• Growth factors• Transforming growth factors (TGF)

- down regulate development• Epidermal growth factors (EGF)?• Fibroblast growth factors (FGF)?• Insulin-like growth factors (IGF)!!!

INSULIN-LIKE GROWTH FACTORS

• Widely expressed peptides

- cell growth - cell differentiation

- maintenance of cell function

- Prevention of apoptosis• Without IGF, E2 and GH don’t develop

mammary gland!!• Mediated through IGF binding proteins

* prolong life * transport * localize

INSULIN-LIKE GROWTH FACTORS

PARTURITION - LACTOGENESIS

PARTURITION - LACTOGENESIS

• Lactogenic complex of hormones• - Insulin / IGF?

•** Glucocorticoids•** Prolactin

• - estrogen• - growth hormone• thyroid hormones

PARTURITION - LACTOGENESIS

PARTURITION - LACTOGENESIS

PARTURITION - LACTOGENESIS

P4

PARTURITION - LACTOGENESIS

• Insulin / IGF 1- cell division

- carbohydrate metabolism

• Growth hormone / IGF?- nutrient uptake

- mammary blood flow

• Thyroid hormones- increased metabolism

PARTURITION - LACTOGENESIS

• GLUCOCORTICOIDS* development of RER

* casein* - lactalbumin

*P4 drop decreases binding tocorticoid binding globulin

• PROGESTERONE- Can get milk w/ out

PARTURITION - LACTOGENESIS

• PROLACTIN- casein / - lactalbumin transcription

- milk protein mRNA translation

- fatty acid synthesis

- swelling of golgi apparatus

- lactose synthesis

PARTURITION - LACTOGENESIS

GALACTOPOIESIS• Prolactin!

• Growth hormone!• Glucocorticoids

• Thyroid hormones• SPECIES SPECIFIC!

Prolactin - rodents GH - ruminants• IGF!

* MUST REMOVE MILK FROM GLAND*

Milk Letdown

Stimulus (pleasurable)

Afferent nervesInguinal Nerve

Spinal Cord

Hypothalamus

Anterior Pituitary

Prolactin

Alveoli secrete milk

Posterior Pituitary

Oxytocin & Neurophysin

Alveoli contract

Mmmm…MILK!!!

PROLACTIN

SECRETION

OXYTOCIN

What prevents milk letdown?

STRESS!!!• Sympathetic innervation: vasoconstriction• Central Inhibition

– Failure of oxytocin to be released

• Peripheral Inhibition– Failure of oxytocin to reach myoepithelial cells

- Failure of oxytocin receptors

• Oxytocin-short 1/2 life – ~5 minutes

Constriction of blood vessels

ARTIFICIAL INDUCTION OF LACTATION

WHAT HORMONES

ARE

INVOLVED?

ARTIFICIAL INDUCTION OF LACTATION

• Estrogen: .1 mg/kg/day in oil 2X/12 hr.• Progesterone: .25 mg/kg/day “ “ “

*** E2 and P4 given for 7 days ( days 1-7)• Dexamethasone: 20 mg/d (day 18, 19-20?)• Milk on day 21 or when engorged w/milk• Reserpine: tranquilizer that prolactin

(days 8, 10, 12, 14)

• AS 337 LACTATION BIOLOGY

EXTRA CREDIT # 2 QUESTION (10 PTS)

• How can lactation be induced (how was Tom Cruise going to nurse his baby or an animal who is not

pregnant initiate a new lactation)? Look for strategies, products, organizations, or interesting information about induction of lactation in any

species and/or male lactation. Share what you find and where you found it.

• DUE ON/ BEFORE CLASS Th 2/5 (Th before exam)• Can give to Sarah, Erin, Kevin or me in class or send

via email .• HAVE A FANTASTIC WEEKEND!!!