REGULATION OF LACTOGENIC HORMONES

BY

DEVI PRIYA SUGATHAN

MSC BIOCHEMISTRY AND

MOLOCULAR BIOLOGY

What are lactogenic hormones ?

• The hormones which stimulate growth of

mammary glands and lactation after parturition.

• From the 24th week of pregnancy, the women’s

body produces hormones that stimulate the

growth of the milk duct system in the breast.

• Lactogens – any agent [hormone] that enhances

milk production. Eg: prolactin, human chorionic

somatomammotropin.

Key Female Hormones

Gonadotropin releasing hormone

Follicle stimulating hormone

Luteinizing hormone

Estrogen

Progesterone

Prolactin

Milk Production

• Milk production potential is a function of the

number of mammary epithelial cells in the gland.

• Therefore, improved lactation performance can be

achieved under conditions that enhance mammary

cell proliferation (or decrease apoptosis),

biochemical and structural differentiation of

mammary epithelium, and synthesis and secretion

of milk components.

• There are various hormones that are involved in

these processes.

Lactation Hormones

MAMMOGENIC LACTOGENIC LACTOPOEITIC

• Estrogen

• Progesterone

• Prolactin

• Growth hormone

• Human Placental

Lactogen[HCS]

• Prolactin

• Insulin

• Glucocorticoids

• Growth hormone

• Glucocorticoids

• Thyroid hormone

• Prolactin

• Parathyroid hormone

• Insulin

• Oxytocin

Prolactin – Key Lactogenic Hormone

• Prolactin is a protein of 198 aminoacids secreted from the

anterior pituitary.

• Prolactin secretion is stimulated by PRH and repressed by

estrogen, progesterone and dopamine from

hypothalamus.

• The level of prolactin in serum increases during pregnancy

and causes enlargement of the mammary gland and

prepare it for milk production.

• Estrogen in pregnancy helps to increase prolactin.

PRL has a wide

variety of target

tissues, including

mammary gland,

prostate, ovary, cells

of the immune

system, adipocytes,

liver, and other

tissues.

PRL Receptors• The prolactin receptor interacts with prolactin as a transmembrane

receptor.

• It is a cytokine receptor and second messenger cascades include the

JAK-STAT pathway, JAK-RUSH pathway, Ras-Raf-MAPK pathway.

• It contains an extracellular region that binds prolactin, a transmembrane

region and a cytoplasmic region.

• The PRLR also binds and is activated by GH and hPL.

• As a result of the signal transduction pathways, prolactin stimulates

uptake of some aminoacids, the synthesis of milk proteins casein and α-

lactalbumin, uptake of glucose and synthesis of the milk sugar lactose

as well as milk fats.

Regulation through Jak - Stat Pathway

• Milk protein genes are regulated by lactogenic hormones,

through a cascade of events mediated by Jak/Stat5.

• This intracellular signaling pathway transfers information

from the cell membrane receptor to the nucleus.

• Once the lactogenic hormone binds to the membrane

receptor two Jak molecules become phosphorylated

which subsequently phosphorylates Stat5.

• The Stat5 factor transfers to the nucleus to bind a

conserved DNA sequence motif, GAS [ milk protein

genes].

• This mechanism is suppressed by SOCS3. The

activated Stats5 stimulate the transcription of gene

SOCS3 which inhibit Jak and as a result the

pathway is turned off [ negative feedback].

• Therefore progesterone inhibits lactation by

interfering with prolactin receptor/ Stat5 signalling

and blocks Stat5 from binding to GAS.

Prolactin level varies according to:

• Level of prolactin is higher at night.

• Prolactin levels are at the highest until two months postpartum..

• Prolactin levels increase if more milk is removed from the breast.

• Women who smoke have low prolactin levels.

• Stress and anxiety may increase prolactin levels.

• High prolactin levels are inclined to delay ovulation.

Insulin

• Insulin causes the nonsecretory epithelia to undergo

cell division in late pregnancy. This cell division seems

to be necessary for lactogenesis to occur.

• IGF-1 may be the primary mitogen involved in this cell

division leading up to lactogenesis.

• Both insulin and the IGFs may be involved in glucose

uptake by the mammary cells.

• This glucose uptake is of critical importance for lactose

synthesis.

• Insulin also may be directly involved in expression of

milk protein genes.

Glucocorticoids

• Glucocorticoids are required for full initiation of milk secretion.

• They seem to be involved in development of the RER and other

ultrastructural changes required for massive protein synthesis.

• They also may be directly involved in transcription of the casein

and α-lactalbumin genes.

• Increased uptake of glucocorticoid by the mammary tissue coincides

with lactogenesis.

• Glucocorticoid receptors in the mammary cells increase in numbers

in late pregnancy.

• It is also known as Human chorionic

somatomammotropin.

• It is a hormone produced from the placenta.

• It mimics the action of prolactin and binds to

the prolactin receptor.

• HPL gets released from the second month of

pregnancy and is involved in the growth and

development of breast, nipple and areola

before birth.

Human Placental lactogen

Estrogen

• All through pregnancy, the large quantities of

estrogens secreted by the placenta cause the

ductal system of the breasts to grow and

branch.

• Simultaneously, the stroma of the breasts

increases in quantity, and large quantities of fat

are laid down in the stroma.

• High levels of estrogen inhibit lactation.

Estrogen levels also drop at delivery and remain

low for the first several months of breastfeeding.

Progesterone

• Final development of the breasts into milk secreting organs

requires progesterone.

• Once the ductal system has developed , progesterone

causes additional growth of the breast lobules, with

budding of alveoli and development of secretory

characteristics in the cells of the alveoli.

• High levels of progesterone inhibit lactation before

birth.

• Progesterone levels drop after birth; this triggers the onset

of copious milk production.

• Prolactin and Human placental lactogen promotes the production of milk but

no more than a few milliliters of fluid are secreted each day until after the baby

is born.

• This is due to the suppressive action of estrogen and progesterone produced

during the pregnancy.

• Immediately after the baby is born, the sudden loss of both estrogen and

progesterone, allows the lactogenic effect of prolactin from the mother’s

pituitary gland to assume its natural milk promoting role, and over the next 1

to 7 days, the breasts begin to secrete copious quantities of milk .

• The fluid secreted during the last few days before and the first few days after parturition is

called colostrum; it contains essentially the same concentrations of proteins and lactose as milk,

and has no fat.

• Secretion of milk requires an adequate background secretion of most of the mother’s other

hormones as well, but most important are growth hormone, cortisol, parathyroid hormone, and

insulin. These hormones are necessary to provide the amino acids, fatty acids, glucose, and

calcium required for milk formation.

• If this prolactin surge is absent or blocked as a result of hypothalamic or pituitary damage or if

nursing does not continue, the breasts lose their ability to produce milk within 1 week or so.

• However, milk production can continue for several years if the child continues to suckle,

although the rate of milk formation normally decreases considerably after 7 to 9 months.

Oxytocin – Ejection or ‘let down’ process in milk secretion.

• A type of neurosecretory cells in the posterior pituitary gets

stimulated by suckling and would release oxytocin.

• When the baby suckles, it receives virtually no milk for the

first half minute.

• Sensory impulses must first be transmitted through somatic

nerves from the nipples to the mother’s spinal cord and then

to her hypothalamus, where they cause nerve signals that

promote oxytocin.

• Oxytocin is carried in the blood to the breasts, where it

causes myoepithelial cells to contract, thereby

expressing the milk from the alveoli into the ducts at a

pressure of +10 to 20 mm Hg.

• Then the baby’s suckling becomes

effective in removing the milk.

• Thus, within 30 seconds to 1 minute after a

baby begins to suckle, milk begins to flow.

• This process is called milk ejection or

milk let-down.

• The sucking action of a nursing infant

causes a reduction in hypothalamic

secretion of dopamine (PIH).

• This increases prolactin secretion and

stimulating milk production in the breast.Suckling on one breast causes milk flow not only in that

breast but also in the opposite breast.

Hearing the baby crying often gives enough of an emotional

signal to the hypothalamus to cause milk ejection.