----start physio.lec.04.30.97----

Dr Sertich....LACTATION (everyone should have already gotten this 
handout; I noticed mine sitting under my coffee table last night :))

this is a quick, dirty overview of lactation...there's enough info for a 
whole separate course on lactation, but we just have a coupla hours to 
discuss it so, we'll give it the old college try...

SO:

LACTATION is the production of milk, and is that period of time following 
parturition when milk is secreted from the mammary glands of the dam. 

all mammals we work with require milk after birth. Guinea pigs are the 
only ones that do not. each species' milk has its own composition. if you 
need to make milk replacer, it's really best to try to give its own kind 
of milk, eg, not give cow milk to a dog, etc.

TYPES OF MAMMALS:
PROTHERIAN (monotremes): young hatched from eggs. not found naturally in 
US. mammary gland has no nipple. milk secreted onto the hair, and licked 
off by young. these animals include the duck-billed platypus. all 
naturally occuring protherians are in Australia

METATHERIAN (marsupial): short gestation; offspring poorly developed at 
birth, crawl from vagina into a pouch where they hook onto a nipple and 
stay attached there. they have delayed implantation. one species we have 
available to us that we may see is the oppossum - she's showing a slide 
from Ranger Rick magazine...the very tiny baby bushy tailed oppossum 
(that's just a few hours old) of australia is about the size of an index 
finger's fingernail. but he was able to crawl from vagina to nipple.  
note that it is possible to have infants of different developmental 
stages in the pouch at the same time, and can be pregnant during this 
time too. the intrauterine fetus can arrest development until older 
siblings are weaned. the composition of milk in diff portions of mammary 
glands is different depending on the needs of the infant on that part of 
the gland. by 115 days has hair, eyes open, and soon will be able to 
detach. and all these stages can be attached at the same time....pretty 
interesting animals!

EUTHERIAN (true placental mammals): humans, all domestic animals, 
dependent on mammary gland. 

mammary glands are modified apocrine sweat glands. in the developing 
embryo, there are two lines of stuff on either side of midline - "milk 
ridge" that becomes nipples. the mesenchyme beneath it induces the 
overlying ectoderm to become mamm gland. you start out with potential to 
have a whole line of glands from top of chest to caudal abdomen, but only 
a few develop in each species. in mare, only most caudal pair develops. 
in cattle, two inguinal pairs develop. in dog/cat/pig, the whole set 
develops. in sows, it's really important for them to have enough 
teats...in humans, only the pectoral glands develop, which is 
interesting...the other species that does that is the elephant.

mesenchyme under ectoderm induces teat development

mare/ewe only most caudal inguinal teats develop. sometimes you see 
"rudimentary teat" develop - esp in sheep, producers were excited about 
this, but usually they have no functional gland with it, so it's pretty 
useless. (my friend had one of these but she had it removed :)).

elephants...dr sertich wants a photo of elephant nursing (ooh, i can 
email stacey and get one!)

COW:
of all species we deal with lactation is most important in cow, from 
commercial standpoint. we refer to cow mamms as her UDDER. UDDER is 
divided into four quarters. each calf has two quarters (ooh. fractions!). 
Each half - L and R - has independent suspensory apparatus, blood supply, 
and innervation. that's typical in most species, btw. in humans, if you 
have to have one breast removed, it's totally separate from other side...


so realize left and right side are totally independent. can separate the 
udder down the midline. there's a big suspensory system...there's a 
medial and lateral component. medial system has yellow elastic tissue and 
it passes between two halves of udder and attachese to prepubic tendon. 
lateral is white CT, runs across laterally to prepubic tendon and pelvic 
symphysis. need good suspensory system...if udder hangs down, can get 
hurt, dirty, stepped on....

blood supply to udder: mostly from external pudendal and perineal 
arteries. there is a large vein in lactating cows running up abdominal 
wall - often called "milk vein" - subcutaneous abdominal vein. this is a 
very important vessel in draining the udder of blood. lymphatics draining 
udder go to superficial inguinal LNs, so may see enlargement of those 
nodes if udder inflamed.

innervation of udder comes from inguinal and perineal nerves.

so...mammary artery and vein == external pudendal a and v. 
there's also a supramammary LN.

on p 2 of lactation handout...anatomical arrangement of udder: alveoli of 
mammary gland are the main secretory portion of the gland. just like 
alveoli in lungs, these alveoli hook up to ducts - ducts drain into 
lactiferous sinus which is divided into gland sinus - where milk 
collects, just above base of teat. then smaller part called teat cistern 
is separated from gland sinus by ring of smooth muscle. during lactation 
teat cistern is enlarged. otherwise it's just a potential space. at 
distal part of teat is the "streak canal" - a very narrow canal opening 
the teat cistern to the outside. it protects against ascending infxn, 
etc. the "rosette of furstenburg" is a ring of sm muscle, just at 
proximal end of streak canal, to prevent ascending infxn.

again...streak canal, teat cistern, udder/gland cistern, ducts, alveoli.
the alveoli are little blind end pouches at proximal ends of ducts, lined 
with secretory epithelium. in mamm gland you might think that only 
alveoli make milk, but actually the larger ducts and even the gland 
cistern can secrete milk. the milk flows into the ducts, small ducts 
drain into large ducts, eventually gets to gland cistern, then teat 
cistern, then out of cow.

there are groups of alveoli which form "intralobular groups" and 
intralobular groups group together into "interlobular groups"

supernumerary teats in heifers are often removed at early age to prevent 
problems with it, because they have no function. you don't want calf to 
nurse off it, either.

slide of a bull. bull should have teats...most species, both sexes have 
teats. not all, though.

EWE AND DOE:

in ewe and in doe, they have two inguinal mamm glands, each with own 
teat. in ewe, each teat has single orifice in each streak canal. from 
clinical aspect, if gland is infected or inflamed and you want to give 
abx, it's good to know there is only one opening to infuse. 

so ewe/doe each gland has one streak canal, one teat cistern, and one 
gland cistern. milking does have pretty large udder. again is in two 
halves, L and R - but just one on each side.

ram lamb - has teats, that's normal.

MARE: two teats, each with two to four orifices. each teat has two teat 
cisterns continuous with two separate gland cisterns. so if mare has 
mastitis, you have to infuse all openings, b/c you don't know which 
orifice communicates with which cistern. teats are small in nonpregnant 
mare. the stallion does not have teats. they are the only regularly 
handled domestic animals that do not have teats. we've seen a few 
stallions with teats, and they were infertile. note that DONKEY males do 
have teats. HORSE STALLIONS do not have teats. if you see a stallion with 
teats, may be intersex, may have other abnormalities...we saw one case 
here where a breeding stallion had very poor fertility but could 
impregnant mares, and he had teats.

SOW: 4-9 pairs of teats. each teat has 2-3 streak canals. each teat 
contains two teat cisterns. so some cisterns have more than one canal 
opening from it. each teat cistern continuous with gland cistern. it's 
very important for sow to have enough teats to nourish her offspring. 

old saying: (old wives' tale): when something isn't worth much, they say 
"it's as useless as tits on a boar hog." but in fact, now that we know 
more about pigs....there is a high correlation between the # of teats a 
boar has, and the # of teats his female offspring have. so it is valuable 
to breed boars that have a lot of teats. so teats on a boar hog are 
actually worth a LOT, not useless :)

BITCH: 4-9 pairs of teats, 8-20 ducts/teat. small breeds with small 
litters tend to have fewer teats, larger breeds that have large litters 
tend to have more. if you ever try to milk a bitch, milk sprays out due 
to multiple openings. wouldn't be practical to try to infuse these teats, 
too many openings.
Dr Sertich's aunt didn't get married til she was like 50 or so and she 
had this dog come to her house one day and she started feeding it and it 
started hanging out there, and she made friends with the dog and would 
brush it and stuff. they live in texas. one day she noticed that the dog 
had a tick stuck to his belly and she thought she'd pull it off with 
tweezers, and the dog got really upset. she took it to the vet and found 
out that it was a nipple. this aunt was surprised that the male dog would 
have a nipple. :)

QUEEN: 5 pairs of teats, each has 6-12 orifices. spike is the hoffman 
center cat. dr sertich clipped him up and they opened him up to spay him, 
then they noticed he had testicles. oops. so they neutered him.

back to the mammary gland in general.
INFECTION PREVENTED BY:
circular smooth muscle surrounding the streak canal
just proximal to the streak canal, the rosette of furstenberg
if there is trauma to the teat, or if you canulize the teat and injure 
these structures, animal may have chronic infexn problem in that gland.

the secretory epi of mammary gland includes NOT ONLY the ALVEOLI, but 
also the larger ducts and even the gland cistern. so at peak lactation, 
most of the gland can participate in making milk.

alveoli and ducts are surrounded by MYOEPITHELIAL CELLS (remember dr 
weiss talked about these :)) that contract to allow milk letdown to 
occur. remember the alveoli are most proximal part, blind pouches of 
gland system. the myeopi cells encase these alveoli and large ducts, and 
can contract. in lactating animals, milk letdown must occur - milk 
letdown occurs when milk is being ejected from animal. these myoepi cells 
squeeze down, and force milk out otf the gland. without this response 
during nursing, the baby would be able to suck out only the milk sitting 
in the teat cistern.

p 7 of handout: MILK LETDOWN
in most species we deal with (not rats, not rabbits) there is milk 
present in cistern and largest ducts, and it accumulates there as milk is 
being produced. offspring that are nursing can't get milk out of deeper 
ducts by vacuum pressure alone. there is a neurological response due to 
stimulation of teat by nursing, nerve sends message to brain, brain tells 
hypothalamus, hormones go to pituitary, pit releases oxytocin from 
posterior pituitary. oxytocin causes smooth muscle contraction throughout 
body, esp the myoepi cells of mammary gland (oxytocin also causes uterine 
contractions; important in delivery). so oxytocin is needed for this 
reflex that causes milk letdown. we understand how this works. nerve from 
gland to brain. different studies were done to prove how it works. if you 
sever the nerves of the gland so that animal can't percieve suckling 
occuring, milk letdown won't occur. but if you take blood from a cow that 
has been stimulated and is having milk letdown, and inject it into 
nonstimulated cow, that second cow will have milk letdown (due to 
oxytocin in first cow's blood). can use exogenous oxytocin. if you take 
nursing female and put under general anesth, she won't have milk letdown 
secondary to suckling, but if you give oxytocin, she will have milk 
letdown. this makes sense...anesth animal won't feel suckling.

in addition to suckling stimulus, there is a learned stimulus associated 
with nursing or with milking of cows. eg, in women - women nursing their 
kids, if they are away from kid, and hear someone else's kid cry, they 
may have milk letdown. looking at photos of other kids can do this too. 
this is a neural response. from management standpoint, this is important. 
dairy cows who are milked by machine - need to have positive and 
consistent events occuring every time they are milked. so they can learn 
that clanging on a bucket, having udder washed, moving into milking shed, 
whatever, will stimulate milk letdown. from industry standpoint, it's 
important that milk letdown occur adequately. as you empty the gland, one 
thing that needs to happen to maintain production is to get all the milk 
out of the gland. if gland isn't emptied each time, cow will start making 
less milk. if you always totally empty the gland, will have enhanced milk 
production. so in dairy cows/doews/whatever, really wanna empty the whole 
gland of milk.

----break----

there is little difference in mammary glands of males and females before 
birth. remember, the underlying mesenchyme induces the overlying ectoderm 
to differentiate. ovarian hormones influence further development at 
puberty.

ISOMETRIC GROWTH

increase in adipose tissue and supporting tissues. this is independent of 
reproductive hormones, and occurs between birth and puberty. there is 
enlargement, but not of functional glandular tissue.

ALLOMETRIC GROWTH:

an increase in glandular tissue. this is dependent on steroid hormones. 
some differences between species, but in general, estrogen stimulates 
ductal development, and through pregnancy, the embryo/conceptus/membranes 
all make a lot of estrogen, and there is much ductal proliferation 
associated w/pregnancy because of this. progesterone acts with estrogens 
to cause development and maturation of alveoli, increased # of alveoli, 
maturation of alveolar epithelium, etc. this occurs during pregnancy as 
well.

right before parturition in most species, estrogen rises and progesterone 
falls. this change in hormone levels makes sense w/what we see in the 
mammary gland. 

high concentrations of progesterone inhibit the final differentiation of 
alveoli needed for milk production to occur. this is why there is no 
lactation DURING pregnancy. but with delivery, there is plummeting 
concentration of progesterone, and alveoli can mature. 

producers tried to enhance gland development in cows by giving hormones, 
trying to make some cocktail to enhance milk production...but if you 
don't get balance right, you get cysts, abnormal development, etc...and 
no good technique has been found.

again, ESTROGENS stimulate DUCT system all through pregnancy
PROGESTERONE w/estrogen is responsible for full alveolar growth during 
preg; at parturition the DECREASE in progesterone allows final alveolar 
differentiation so milk production can begin.

at puberty, animal has reproductive cycles, during which there are 
increases in estrogen, which cause some duct growth, etc. but when 
pregnancy occurs, there are more major changes in the glands. 

at end of lactation, there is involution of the lobules.

to make things more simple...it's a complex set of events that occur to 
allow lactation, and many hormones involved.

AP has a role in lactation in that it stimulates the ovaries with 
gonadotropin. the AP also has direct effect on prolactin and GH both of 
which are involved w/lactation. commonly milk prod is enhanced by giving 
GH to cows. it can be very effective in increasing production in dairy 
cows. it is important that if you do this, you make sure to give extra 
food and water!! if they have no substrate to work with, they can't make 
more milk.

prolactin, ACTH, GH, TSH, all affect lactation in some way, directly or 
indirectly play role in mamm growth and lactation. but don't need to 
memorize specifics of that

LACTOGENESIS: milk secretion

is inhibited by estrogen and progesterone
drop in progesterone and estrogen at parturition allows release of 
prolactin
oxytocin released at parturition (associated w/uterine contractions etc)  
stimulates release of prolactin
premature lactation during pregnancy is often indicative of a problem eg 
death of one or more fetuses, early termination of pregnancy. precocious 
lactation in mare can indicate death of one fetus of a set of twins.

after delivery, there is a huge shift in blood flow. during preg, lots of 
blood went to uterus/placenta. after delivery, blood goes to mams to 
support lactation. in some species, milk secretion starts a couple of 
days prior to parturition...in humans, it is quite normal not to see any 
milk secretion til about a day after parturition. usually, human infants 
are supplemented with water or glucose water during that first day while 
waiting for milk to come in. 

near time of parturition, there's an increase in mitosis in 
alveoli...animals should reach peak lactation after parturition takes 
place.

GALACTOPOIESIS: maintenance of lactation

prolactin is necessary and important
GH, insulin, ACTH, TSH play a role
regular suckling/stimulation of gland/emptying of gland will maintain 
prolactin secretion in the animal, which is necessary for galactopoiesis. 
this is why complete emptying of the gland is important...increases amt 
of prolactin made, and also increases blood flow to gland - pressure of 
milk within gland decreases blood flow to gland. if you increase interval 
between emptying or decrease degree of emptying, will decrease milk 
production.

MILK LETDOWN:
necessary to fully, efficiently empty gland
systemic reflex that occurs
sensory nerves of teats carry impulses to hypothalamic/pituitary axis to 
cause release of oxytocin.
oxytocin causes contraction of the myoepithelial cells
increase in pressure within gland occurs, milk much more readily ejected.

will occur w/in one minute of administration of exogenous oxytocin.


MILK COMPOSITION:

COLOSTRUM is first milk produced after/prior to parturition. it contains 
Ab that have been sequestered from the dam's blood by selective and 
active transport to the mammary gland during the last few weeks of 
pregnancy. so these will be Ab to things in dam's environment. when 
offspring nurses, will get passive immunity. if we enhance immune status 
by vaccination in late gestation, will increase Ab in colostrum. this is 
important in cattle and mares. we vaccinate mares 30 days before due date 
to improve quality of colostrum. 

once animal is born, colostrum is most important in mares cows and sows 
who have no Ab that cross placenta. the neonate's GI tract is such that 
they can only absorb the Ig during the first day after delivery. after 
about 36 hrs the GI tract no longer allows such large proteins to be 
absorbed. now, in dogs/cats, there is a very small amt of transfer of Ab 
across placenta, so when offspring are born, they have some Ab in own 
blood...then they get more from colostrum but less critical. but in 
primates/humans, there is good passage of Ig across placenta, so they 
don't rely much on colostrum. MDs say colostrum isn't necessary. La Leche 
League says it is. If human baby gets NO mother's milk at all, it will 
still do ok though, immune-wise. cats/dogs get some Ab from colostrum and 
some via placenta. colostrum has lymphocytes, monocytes, histiocytes, 
proteins, etc. shouldn't see PMNs in colostrum or milk. that would 
indicate infxn or inflammation.

mare with beads at ends of teats - she is "waxed" - has little waxy drops 
of colostrum there, she's near parturition. (usually).

MILK COMPONENTS FROM BLOOD:
everything in milk comes from blood. after parturition, blood flow to 
mamms dramatically increases...70x amt of milk to be made is amt of blood 
that must flow through gland. stuff gets into milk by:

direct transfer- immunoglobulins are just taken out of blood
modified transfer- glucose and FAs
synthesis w/in gland- proteins and fats

each species milk composition is different. animals in cold marine 
environments have very fatty milk, warmer climate == lower fat in milk, 
usually.

when animal is milked after hasn't been milked in a bit the milk coming 
out first will be lower in fat than the milk at the end of the session. 
dairy farmers get paid more for milk with higher % fat. so it behooves 
you to regularly milk the animals and fully empty the glands.

LIPIDS:

milk: contains triglycerides that are synthesized in smooth ER from long 
chain FAs in blood or from other substances. the triglycerides accumulate 
in droplets and are pinched off from the secretory cells. in 
non-ruminants, we can use glucose for fat production, but ruminants use 
acetate. 

blood: contains phospholipids and cholesterol. not the same fat found in 
milk. so mamm gland must make the lipids, very important.

LACTOSE: a disaccharide found only in mamm gland/milk. formed from 
glucose, lactic acid, pyruvate and hexose. high glucose concentration in 
blood of female will increase lactose content of milk. hypoglycemia 
reduces lactose  in milk. lactose is formed in golgi apparatus...in mamm 
gland, milk protein presence increases action of enzyme responsible for 
lactose production.

PROTEIN: main proteins in blood are globulins
in milk: casein is main protein. also some lactoglobulin and lactalbumin. 
made in rough ER, packaged in golgi, golgi vacuoles are pinched off and 
secreted. (exopinocytosis)

CALCIUM: most important mineral in milk
found in concentration 12 times higher than blood level in milk.
lactation drains dam's calcium reserves, so she needs high dietary Ca++ 
intake or must have really really big reserves!

hypocalcemia in dairy cows == milk fever == periparturient paresis 
==>neuro signs.

MISC TIDBITS:
important to remember...b/c animal is putting so much stuff into milk, 
need to think about what animal is being exposed to, and what might get 
into the milk. animals grazed on early pastures, there's onion grass out 
there. cows grazing on onion grass make smelly oniony milk, which people 
don't want to drink! you might not want to turn dairy cows out during 
that time.
another issue...it's sad to consider that - when the chernobyl accident 
occurred, there was contamination of pastures in many countries. dr 
sertich went to poland a few years ago, and were told that they couldn't 
give local milk to her daughter, had to give austrian milk, b/c the local 
cows were radioactive. same thing w/pesticides, toxic metals in water, 
etc etc...these things can all be concentrated in milk. infectious 
agents: TB, brucellosis - under control in this country, but used to be 
big risk of drinking unpasteurized milk...

INVOLUTION: drying off

lactation length is variable and dependent on how efficiently and 
frequently glands are emptied, nutritional status of dam, substrate 
available, etc.

females that have gone through peak of lactation curve and are out at 
tail end of it, milk production starting to decline: involution is 
easier. harder to do during peak lactation!
with involution, there is gradual decrease in # of active alveoli. epi 
tissue will involute. loss of secretory activity, increase in amt of CT. 
involution is hastened by decreased gland emptying, estrogen, and 
bromocriptine. most important factor is to stop regularly emptying the 
gland! stop milking/nursing. by not removing  milk, there is increased 
pressure and decreased blood flow, less substrate to make new milk, 
decreased prolactin release since no suckling will negatively affect milk 
prod. need to be careful with glands at this time. if there is no flow of 
fluid going through ducts, animal may be more prone to infxn. if you 
wanna dry her off, do it cold turkey w/o manipulation of mamms, don't 
want organisms getting in there. need to be very clean.

high concentrations of estrogen inhibit prolactin binding to prolactin 
receptors. in animals with inappropriate lactation (aren't even pregnant) 
best thing to do is probably to ignore it and will stop on its own. 
manipulation, massage, etc contraindicated - glands get swollen, hot, etc 
but stimulation of gland increases milk production. 

bromocriptine is a hormone used to stop lactation. not used commonly, has 
many side effects, but might use in filly at racetrack with inappropriate 
lactation or something.


----end----