BIOL30001 Reproductive Physiology

Lactation: The final phase of mammalian reproduction

Geoff Shaw

EssRep7 Chapter 18J&E6: Chapter 14.Hormonal control of lactation, A.Cowie in Hormonal Control of Reproduction:

Austin & Short. Book 3, Chapter 8:

Physiology of Reproduction 1994 4th Ed. Knobil & Neill:

Chapter 56, p.1099:Control of Mammary Gland Growth and Differentiation. W. Imagawa, J. Yang, R. Guzman & S. Nandi

Chapter 57, p.1065 :Lactation and Its Hormonal Control. H. Allen Tucker

Chapter 59, p.1131:Milk Ejection and Its Control. JB. Wakerley, G. Clarke & A.J.S. Summerlee

Lactational control of Reproduction, A.S. McNeilly, in Reproduction Fertility and Development (2001) 13: 583-590

Margaret C. Neville. (1998) Milk Secretion: an overview. http://mammary.nih.gov/reviews/lactation/Neville001/index.html

References

Lactation• Primary source of nutrition and energy

for newborn mammal• Immune protection• Mammary glands change – hormones

and development • Variation between species: eg

– number of glands: human 2; wallaby 4; pig 18; cow 4 (apposed in single udder)

Milk composition varies with species

Component (g / 100 mL)

Human Elephant Seal

Water 90 35

Protein 1.1 10

Carbohydrate 7.5 2

Lipid 4.2 55

Energy (MJ / L) 3.3 23

From Austin and Short 1984

Structure of a mammary lobuleeg. cluster of alveoli in the goat

milk

Alveolus

alveolar epithelial cells

myoepithelial cells

capillaries

milk duct

venule

arteriole

J and E, Fig 14.3

Note vascular supply aroundalveolus

myoepithelialcells surroundingalveolus contract, increasing intra-mammary pressure at milk let-down

Structure of mammary lobules and alveoli

J and E Fig14.2

15-20 mammary lobesDilating as a lactiferous sinus emerging at nipple

duct systems in different species

Ovariectomisedfemale

Castrated maleNormal male

Normal female

From Austin and Short 1984

Development of mammary gland in fetal mouse

androgens cause regression of the mammary primordia

From Austin and Short 1984

Oestrogen, progesterone, cortisol, growth hormone, placental lactogen and prolactin needed for mammary growth during first pregnancy

Postnatal mammary growth in ratpre-pubertal

pubertal

post-pubertal

late-pregnancy lactation

cyclic changes through oestrous / menstrual cycles

Mammary gland cycle

http://mammary.nih.gov/atlas/wholemounts/normal/index.html

Summary: structure and development

Mammary gland: • Structure of mammary gland – variations on a theme

– ducts and cisterns – alveoli open into milk ducts– ducts join and empty via nipple or teats.– galactophores are common ducts leading to teat:

rabbits 6-8; man 15-20; agile wallaby approx. 20.– supernumerary teats

• Fetal development

– present in both sexes but poorly developed in men– Regress in male mice and rats as a result of androgens

• Development after birth – full growth not achieved until end of puberty or in early

lactation

To maintain high milk production after removal of the pituitary gland:

Rats need:

Prolactin

Adrenocorticotrophin

Sheep & goats need:

Growth hormone

Prolactin

Adrenocorticotrophin*

Thyrotrophin†

Rabbits need:

Prolactin

ACTH maintains cortisol secretion from the adrenal gland

† TSH maintains thyroid hormone secretion from the thyroid gland

Milk secretion requires hormonal support but species’ needs vary

Hormonal regulation of milk secretion differs between species

Mammary gland transplanted to the neck of a goat (Jim Linzell’s experiment)- separated from nerve supply- continued milk secretion

However milk removal necessary for continued lactation(Malcolm Peaker)

Control is hormonal, not neural

Milk secretion: hormonal control

J & E 14.5

Onset of lactation in women

Pregnancy, hormones and milk secretion

Colostrum• high protein• rich in immunoglobulins

Mature milk• 7% lactose• 4% fat• 1% protein• +minerals, vitamins etc

Two 25 mL samples of human breast milk. The left hand sample is foremilk, the watery milk coming from a full breast. The right hand sample is hindmilk, the creamy milk coming from a nearly empty breast

http://en.wikipedia.org/wiki/Human_milk

• pregnancy mammary gland development– high progesterone and oestrogens– hPL (hCS)– prolactin

• peripartum transition to lactogenesis– fall in progesterone and oestrogens– no hPL– slow fall in PRL needs nipple stimulation

(suckling) to maintain PRL and milk production

Local regulation

• FIL – Feedback inhibitor of lactation– Small protein secreted in alveolus– If not removed by emptying alveolus, it acts

to suppress further milk secretion.

Mammary secretory processes

I. exocytosis: proteins made via RER and Golgi; Lactose

II. apocrine secretion of lipids; vesicle membranes phospholipids

III. trans-membrane: water; small molecules; drugs

IV. trans-cytosis: immunoglobulins; some hormones & growth factors

V. paracellular: immune cells; leakiness may be high in disease states increasing transfer of interstitial fluids.

http://mammary.nih.gov/reviews/lactation/Neville001/index.html

Milk Fat Globule

lactation

Milk secretion• Initiation of milk secretion begins in pregnancy• Prolactin and other hormones• Synthesis of milk constituents within alveolar cells• Intracellular transport of milk components• Discharge of constituents into alveolar lumen• Local control - FIL

Milk removal• Passive removal of milk from

cisterns and large ducts• Stimuli

– Sucking– Sights, smells, sounds, tactile

stimuli associated with suckling• Reflex ejection of milk from

alveoli (‘let down’ or ‘draught’)• Oxytocin

ProlactinVIP = Vasoactive intestinal peptide , - VIP a potent Prl releasing factor

Dopamine from TIDA nerves, - DA a Prl release inhibitory factor

EssRep7 18.6

Sucking induced release of prolactin.

Milk secretion: The importance of sucking

EssRep7: 18.7

Sucking-inducedrelease of oxytocin.

The milk ejection reflex

PM preparation for milking; MA application of teat cups; S stripping; C control level.From Austin and Short 1984

Milk ejection: Anticipation of milking on oxytocin concentrations in dairy cows

Hottentot method of inducing milk let down (Ferguson Reflex)

Milk ejection: the role of oxytocin

Oxytocin receptors during pregnancy and lactation in rat mammary gland from Soloff and Weider 1983

Milk ejection: Oxytocin receptors regulate response

Hormonal control of lactation:

• consists of milk secretion and milk removal stages. • Maintenance of lactation usually requires several anterior

pituitary hormones • prolactin is critical in non-ruminants, and growth hormone

in ruminants. • Oxytocin essential for milk ejection. Milk removal essential

for continued lactation• responses mediated by receptors.

Milk compositionin women pre- and post-partum.

0 indicates time of birth

From Kulski and Hartmann,1981

Milk composition: Changes in peripartum periodcolostrum

Milk Composition:• Colostrum: post-partum secretion high in protein, sodium

and chloride.– also antibodies (IgG and IgA).

• Milk: large species differences in concentrations of milk fat, lactose, protein and water.

• Milk fat mixture of lipids: triglycerides, diglycerides, monoglycerides, free fatty acids, phospholipids and sterols.

• Arctic, aquatic, desert mammals produce milk with 75% energy in lipid fraction

• Frequent nursing species produce milk with lower nutrient density

Milk composition changes in marsupialsFrom Green 1984

Lipids

Proteins

Carbohydrates

Lactation in marsupials

from Lincoln and Renfree 1981

difference in response to OT allows milk ejection in gland with PY continuously attached

sucking by young at foot causes ME in both glands

Milk ejection in the agile wallaby -concurrent asynchronous lactation

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• Dopamine and agonists (bromocriptine) inhibit prolactin synthesis.

• High levels of Prolactin in lactation inhibits GnRH.

• pituitary LH response to GnRH reduced, failure of positive feedback

• ovarian response to LH same.

• naloxone (opiate inhibitor) also inhibits prolactin release (alternate pathway)

Prolactin related suppression of reproductive cyclesuckingstimulus

nipple

spinal cord

hypothalamus

β-endorphin release

milkejection

oxytocin

lactationalinfertility

GnRH pulse generator

milk production

prolactin

dopamine release

- -

-

Non lactating, no contraception

Lactating, no contraception

Post partum, lactating + post menstrual contraception

Contraceptive effects of breastfeeding

Short RV, Lewis PR, Renfree MB, Shaw G (1991) The contraceptive effects of extended periods of lactational amenorrhoea. The Lancet 337, 715-717.

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Mo

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Months postpartum Months of lactational amenorrhoea

% w

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-▽-

Lactational control of hormonal cycles:

Lactational control of reproduction:

• Prolactin release important in suppressing cyclic release of gonadotrophins.

• Endogenous opiates (beta endorphins) are also involved.

• Frequency of suckling very important in lactational amenorrhoea

Summary• nutrition, energy, water, immune protection for newborn• mammary gland has multiple lobules–alveoli secretory epithelium–myoepithelial cells OT & milk ejection–well vascularized

• development induced by hormones – prolactin, Prog, E2 etc• placental lactogens in pregnancy• initially colostrum (immunoglobulins) mature milk• oxytocin & Fergusson reflex + CNS• lactational control of reproductive cycles - role of endorphins

–anoestrus–diapause