autocrine control of lactation
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AAutocrineutocrine Control of Control of Lactation Lactation
Illinois Module : Lactation
Autocrine Control of Lactation
Control of lactation is clearly regulated by hormones,
However local factors are also important
Evidences
Cows and goats, frequent milk removal increases milk yield
Requires actual removal of milk from the gland, as hourly massage of the gland without milk removal does not have the same effect (Linzell and Peaker, 1971)
Evidences
One side of udder milked more frequently than the other side – Rate of milk secretion increases in the
gland milked more frequently – milk yield decreased in the less
frequently milked gland
These unilateral effects cannot be hormonal control, as both sides of udder exposed to the same concentrations of galactopoietic hormones
Evidences
In addition, it is not the result of increased pressure of the stored milkGoats where one gland was milked 2X/day and the other gland milked 3X/day, and replaced inert sucrose solution so that intramammarypressure was the same in both sides
EvidencesThe result, – secretory rate increased by 3X/day
milking
Thus, hypothesis is that a milk constituent acts as an inhibitor of milk secretion and removal of this inhibitor at milking regulates the rate of milk secretion
Feedback Inhibitor of Lactation:
FIL
Feedback Inhibitor of Lactation:FIL
A milk whey protein, ~7 kDa (Wilde et al., 1995 Biochem J 305:51-58)
Secreted by mammary epithelial cells to inhibits further milk secretion as its own concentration increases in the alveolar lumen
The exact mechanism of how this feedback inhibitor works is unknown
Feedback Inhibitor of Lactation:FIL
In vitro, FIL– reduce secretory rate and key enzymes
in mammary cells– stimulates intracellular degradation of
newly synthesized casein– reduces prolactin receptor numbers on
the cells – inhibit differentiation of mammary cell
function
Balance between systemic (hormonal)
and local (FIL) control of milk secretion
Each time milk is removed:
Prolactin secretedIntra-mammary pressure relievedFIL removed from alveoli
If milk is not removed:
No stimulation of PRL secretionAcute accumulation of milk in the gland, resulting in:
• Increased intra-mammary pressure• Activation of sympathetic nerves• Decreased mammary blood flow• Decreased availability of hormones
and nutrients to the gland
– Rate of milk secretion declines
Systemic and Local Factors in control of galactopoiesis as a
seesaw
gland under influence of systemic factors shortly after milking and maximal secretion rate achievedThen, gradually slows as the role of the local factors becomes dominant
If milk is not removed, then secretion rate drop to zero (see figure)
under normal nursing or milking intervals secretion rate does not go to zero
Once milk is removed, cycle begins again
Wilde and Peaker 1990 J. Agric. Sci. 114:235)
Milk Secretion Rate
1) the amount of secretary tissue
2) the rate of milk secretion (per unit of time)
Milk yield depend on
Milk Secretion Rate
Secretion rate affected by accumulation of milk in alveolar lumen
Accumulation of milk in lumen increases intra-mammary pressure (see figure)
Milk Secretion Rate
Once the intra-mammary pressure reaches a certain level (8 to 10 hrs after last milking in dairy cow), secretion rate declines
If the pressure increases enough (in cow, about 70 mm Hg, 35 hrs after last milking), then secretion stops and milk starts to be resorbed
Milk Secretion Rate
Inhibition of milk secretion and increasing intra-mammary pressure caused by FIL rather than increased pressure
intra-mammary pressure measured in teat cistern using teat cannula reflect total gland pressure from accumulation of milk and not directly the intra-alveolar pressure
Adapted from Schmidt, G.H., 1971, Biology of Lactation, W.H. Freeman and Co., p. 150.]
Milking Interval andMilk Secretion Rate
For 2X/day milking, optimum interval is 12 hr – milk accumulation not significantly
lowered milk secretion rate, – but by ~14 hr secretion rate decline
Effect of long milking intervals on secretion rate greater in higher producing cows than lower producing cows
UI Dairy Research Facility (1996)
Milking Frequency
Nursing frequencymay be: Species
continuous kangaroo (joey)
or at intervals of:
.5 hr whale, dolphin
1 hr pig
4-6 hr cow
1X/day rabbit
1X/2 days tree shrew
1X/week Northern fur seal
Milking Frequency in Dairy Cattle
In most dairy cattle management schemes, cows are milked twice daily or three times dailyIn robotic milking systems, typically cows will enter 4 or less times per dayLittle additional benefit for milking more than 4 times per day
Summarized observations on milking frequency in dairy
cattle and effects on milk yield
A. 3 times/day vs. 2 times/day milking
3X/day milking increases milk production up to 25%
But, ~2/3 due to better feeding and management and ~1/3 due to decreased udder pressure
3X/day milking must be accompanied by a compensatory feeding program; if not, yield decline to that from 2X/d
3X/day milking more beneficial in late lactation,
Both first lactation and older cows increased yield in 3X/day vs. 2X/day
Mammary DNA , RNA and activities of key enzymes increased (Wilde et al., 1987, J. Anim. Sci. 64:533.)
3x/day requires 50% more labor than
Incidence of mastitis and reproductive performance not altered by 3X/d milking
Stage Time Mechanism Response
1Immediate(hours to days)
removal of chemical feedback inhibitor
increased milk secretion
2 Short Term (days to weeks)
stimulation of cell differentiation
increased milk secretion
3 Long Term (weeks to months)
stimulation of cell proliferation
increased milk secretion
Sequential Response to Thrice-Daily Milking
B. Milking udder halves
Milking one udder half 3X/day gives 16-32% more milk than udder half milked 2X/day, even though the halves are exposed to the same systemic stimulation
C. 4x/day milking
Milking 4X/day results in 5-10% more yield than 3x/day
But labor costs are doubled compared with 2X/day
D. bST to goats milked 3X/day
Greater milk yield than goats + BST and milked 2X/day or in goats (no BST) and milked 3X/day
So, the effects of 3X/day milking and bST apparently are additive
E. Massaging udders between milkings
increase of 1-1.5% in milk yield, although not statistically significant
F. Milking less than 2X/day
Milking 3X in 2 days (skipping 1 out of every 4 milkings)
– decreased milk yields of 18% (started in week 4 of lactation
– decrease of 11% started in week 20
(Eldridge and Clark, 1978, J. Dairy Res. 45:509)
1X/day milking at late lactation results in 12% less milk for the entire lactation
Length of lactation reduced by 12 days
1X/day milking for a complete lactation reduces milk yield by 50% in first calf heifers and by 40% in older cows
Milk Ejection
Milk Ejection
Milk in alveolar lumen out of glandMilk ejection can occur – under water – as whales,
porpoises, sea-cows, sea otters, hippopotamus
– While in flight as bat
Milk Ejection
Streak canal must be opened to remove milkOccur by: – negative pressure - such as with
the milking machine – positive pressure - such as with
hand milking – positive and negative pressure -
both occur during suckling
Milk Ejection Reflex
To get milk from the alveoli requires an active process called the milk ejection reflex
Milk Ejection Reflex
a neuroendocrine reflex with
• afferent pathway : neural • efferent pathway : hormonal, blood-borne
Afferent Pathway: neural
greatest amount innervation in mammary gland is in teatsStimulate teats activates pressure sensitive receptors in dermisnerve impulses via spinothalamic nerve to paraventricular nucleus and supraoptic nucleus in hypothalamus where oxytocin-containing neurons stimulated The efferent pathway starts at this point
Efferent Pathway: hormoneBegins with release of oxytocin and neurophysin
Oxytocin binds to receptors and cause myoepithelial cells to contract
Intramammary pressure increase and ejection of milk from the alveolar lumen
The biological mechanisms involved are complex[See J. Dairy Sci. 1983 66:2251]
Biological mechanisms of oxytocin on milk ejection
Manual stimulation of the teat or nipple is not required for oxytocinrelease or milk ejectionOxytocin can be released by sights and sounds of the milking parlorOxytocin is not always measurably elevated in blood during milk letdown
Oxytocin and Milk Ejection
Oxytocin
Peptide hormone, 9 amino acid longCys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Glymolecular weight 1007 daltonsa disulfide bond between the two cysteinesReduction of the disulfide bond inactivates oxytocin
Hypothalamic Nuclei and Oxytocin Synthesis
Oxytocin syntheized in paraventricularand supraoptic nuclei in hypothalamusInitially synthesized as a large MW precursor, consists of the oxytocin-carrier peptide neurophysinThen, cleaved in neuron to yield oxytocinbound to neurophysinOxytocin-neurophysin complex is the intracellular storage form of oxytocin
The oxytocin-containing vesicles transported down hypothalamo-neurohypophysial tract to store at posterior pituitary
The synthesis of oxytocin in the cell bodies and its transport to the axon endings occur separately from the milk ejection reflex
Oxytocin Surge
oxytocin increased within 1 to 2 min. after udder stimulation, but declining during milking
Why pre-stimulation of the cow needed before milking?
Hygiene – for prevention of mastitis and for
maximizing milk quality
Milk ejection - [see J. Dairy Sci. 1980 63:800]
Manual stimulation resulted in higher milking efficiency and higher peak and average milk flow ratesMean peak oxytocin was not different, but pre-stimulated cows' oxytocin peaked at 2 min. after stimulation, compared with 5 min. after machine-on time for the unstimulated cows
Why pre-stimulation of the cow needed before milking?
Milk flow rate - [see J. Dairy Sci. 1985 68:1813] average milk flow rate increased with increasing duration of udder stimulation
However, oxytocin concentration was not different
Timing of oxytocinrelease relative to milk removal is an important
factor affecting milk ejection
A) Stimulate teats for 1 min prior to attaching the milking machine, or
B) Put milking machine on immediately without any prior manual stimulation
Machine-on-time is shorter for the pre-stimulated cow and the peak flow rate is higher for the pre-stimulated cowInitial rise and fall of flow rate during the first min of milking in B. In this case, the milking machine is initially removing the milk present in the cisterns (does not require milk ejection) and is providing the tactile stimulation necessary to elicit the normal release of oxytocin, which causes the second increase in milk flow rate
Results
Oxytocin & Milk ejection reflex
Sensitivity of the neuroendocrinereflex decline as lactation progressesPeak oxytocin come later after mammary stimulation as lactation progressesMaximum oxytocin concentration during milking also declines as lactation progresses
dry or nonlactating period may serve to restore the sensitivity of the neuroendocrinereflexNonlactating cows will release oxytocin in response to udder stimulation, but virgin heifers do not respond Maximum oxytocin in response to udder stimulation occurs only if the mammary gland is lactating or has lactatedMaximal prolactin release from the pituitary in response to tactile stimulation of the udder depends on the presence of a fully developed mammary gland
How much oxytocin is needed to elicit milk ejection?
Peak oxytocin is about 11to 65 microunits/ml serum; 40 liters of blood in a cow = about 0.4 to 2.6 IU. Normally inject 10 IU cause milk letdown, but as little as 0.02 IU into the jugular can result in milk ejection
(see Sagi et al. J. Dairy Sci. 1980 63:2006).
Oxytocin has a short half-life in the blood = 0.55 to 3.6 min
Thus, removal of milk by machine or by nursing must be closely timed with stimulation of the teats
Other Roles of Oxytocinin rats, induces maternal behaviorOxytocin has insulin-like activity and may be lipogenic (mother rapidly losing lipid when milk is removed)Both oxytocin and prolactin involve in osmoregulation (mother rapidly losing water when milk is removed)oxytocin acting as neurotransmitter
Other Roles of Oxytocin
interaction between oxytocin and prolactin release from the pituitary remains an area of investigation
(see also Mori et al., 1990, Endocrinology 125:1009)
Involvement of Autonomic Nervous System and Stress
Autonomic nervous system :ANS
Central nervous system
controls visceral function
ANS made up of parasympathetic and sympathetic nerves
Parasympathetic nerves
neurotransmitter is acetylcholine
There is no parasympathetic innervation in the mammary gland
Sympathetic nerves
epinephrine and norepinephrineEpinephrine (adrenaline) is primarily from adrenal medullaNorepinephrine is a neurotransmitter from peripheral nerves and nerves in the brain, and adrenal medulla
Effect of sympathetic nerves on milk ejection
depends upon the type of neurotransmitter receptor: alpha-receptors are vasoconstrictive- norepinephrine can stimulate milk ejection via brain alpha-receptorsbeta-receptors - norepinephrine can inhibit milk ejection via brain beta-receptors
Most sensory receptors (neurons) located in the teatpressure-sensitive neurons around the cisterns and the large ductsno direct innervation of alveoli or myoepithelial cellsNorepinephrine and epinephrine can inhibit oxytocin-induced contraction of myoepithelial cells
Stressful stimuli inhibit milk ejection
occurs via norepinephrine by the following mechanisms : reduces myoepithelial cell response to oxytocin;decreases mammary blood flow thus decrease oxytocin to the glandreduces oxytocin release from the pituitary
In bovine speciesnorepinephrine is the primary catecholamine
Injections of norepinephrine decrease milk yield, but Oxytocin is not altered
Emotional disturbances inhibit CNS in milk ejection reflex– especially in the first-calf heifer– oxytocin may be needed to remove milk to
prevent reduced yield through lactation
Other Mechanisms of Milk Ejection
Myoepithelial cells contract in response to vasopressin (ADH) though not of physiological significance in milk ejection Visual or auditory stimuli cause milk ejection as Milk ejection is a condition response
Stimulate genital tract, vaginal distention, release large amounts of oxytocin
