Module 1: The endocrine system

Prolactin (PRL) stimulates development of the mammary glands and milk production
during lactation. It also has many non-reproductive roles. Circulating PRL concentrations
are normally low in non-pregnant, non-lactating women, and in men. This is due to the
inhibition of PRL by the prolactin release-inhibitory neurohormone dopamine, which
tonically inhibits the lactotrophs from secreting PRL. In breastfeeding, the feedback
regulation is altered by the sucking stimulus, and high plasma concentrations of PRL
occurs. This change ensures ongoing milk production.

By the end of this unit, you should be able to:

Explain why prolactin concentrations are normally low.

Describe the key roles of prolactin in lactation.

Explain why prolactin concentrations are high in lactation.

Prolactin

Prolactin (PRL) is an anterior

pituitary hormone, secreted
from the lactotroph cells. In
humans it is a 199 amino acid
single chain polypeptide, folded
into a globular small protein
(see figure). It is the key
hormone that stimulates milk
production in mammals. It's old
name was lactotropin.
However, PRL is also important
in many other body functions,
including regulation of the
immune system, osmotic balance, and angiogenesis.

Image source: 'The structure of human prolactin'. By petarg, Adobe Stock.

Hypothalamic Releasing (and Release Inhibiting) Factors

For Prolactin -

the releasing inhibitory factor is Dopamine

and the releasing factor is unknown

Dopamine is a catecholamine, related to noradrenaline and adrenaline. Unlike the

other hypothalamic releasing factors, it is not a small polypeptide; but rather, a
derivative of tyrosine. The dopamine neurons that regulate PRL are found in the
arcuate nucleus of the hypothalamus. Dopamine is secreted from these neurons
into the capillary plexus at the median eminence. Since the identity of the prolactin
releasing factor is unknown, it is unclear where in the hypothalamus the PRL
releasing factor neurons are located. Nevertheless, there is good evidence that a
PRL releasing factor exists. There are a few candidates for the PRL releasing
factor, including the "Prolactin releasing peptide (PrRP), Thyrotrophin Releasing
Hormone (TRH), and Vasoactive Intestinal Peptide (VIP) - although none has been
firmly established as the PRL releasing factor.

PRL concentrations are normally low

In non-lactating non-pregnant women, and in men circulating, PRL concentrations

are low. This is due to the dominance of dopamine as the PRL inhibitory factor. In
normal healthy individuals, dopamine secretion constantly inhibits PRL secretion
from the lactotrophs in the anterior pituitary gland (see figure below). Dopamine acts
on dopamine D2 receptors on lactotrophs to inhibit PRL synthesis and secretion.

Recall that in hypothalamus-pituitary disconnection, circulating PRL

concentrations will increase, as it is predominantly under inhibitory control.
In the absence of dopamine, the lactotrophs will spontaneously secrete PRL.

Image source: PRL secretion from lactotrophs is low in a non-pregnant, non-lactating individuals.
Stephen Anderson, UQ.

PRL concentrations in lactation are high

In lactation, particularly early to mid lactation, the sucking stimulus by the baby
increases circulating PRL concentrations. Mechanoreceptors are activated by the
baby sucking and afferent neuronal signals provide input into the hypothalamic
dopamine neurons, inhibiting dopamine synthesis and secretion into hypophyseal
portal blood. With reduced dopamine there is less inhibition of the lactotrophs and
therefore an increase in PRL secretion.

Image source: 1) PRL secretion from lactotrophs is high in lactating individuals, as a result of the
suckling. Stephen Anderson, UQ.
2) Breastfeeding baby. By taramara78, Adobe Stock.

It is also important to acknowledge that in lactation, the PRL releasing factor is

probably stimulated at the same time as dopamine, as the release inhibitory factor, is
reduced. Overall, reciprocal changes in releasing and release inhibitory factors is
required for hyperprolactinemia.

Negative Feedback Loops

PRL is normally regulated by short loop negative feedback, where PRL acts on the
dopamine neurons in the hypothalamic arcuate nucleus to stimulate dopamine
production and secretion, and thereby inhibit further PRL release. In the non-
lactating state (as shown above), this feedback loop is operative. However, in
lactation PRL short loop negative feedback is diminished. The dopamine neurons
exhibit a resistance to PRL negative feedback, despite quite elevated plasma PRL
concentrations. PRL simply does not signal appropriately within the dopamine
neurons and as a consequence dopamine is not released (as normally in PRL
negative feedback).

PRL is not under any long loop negative feedback as the mammary gland does not
produce a hormone to signal back to the hypothalamus and anterior pituitary gland.

PRL - Physiological actions

PRL and the mammary gland

Prolactin has two major effects: the development of mammary glands and milk
production. During pregnancy PRL promotes growth of mammary gland in
conjunction with other hormones, including oestrogen, GH, cortisol and
progesterone. Whilst oestrogens promote proliferation and extensive ductal
branching during pregnancy, progesterone together with PRL (and a PRL-like
molecule, placental lactogen) promotes the development of the lobules and alveoli
containing the mammary epithelial cells that produce milk.

However, PRL receptors are down-regulated on mammary epithelial cells throughout

pregnancy due elevated progesterone levels. After delivery, the plasma
progesterone levels decline allowiing an up-regulation of PRL receptors on the
mammary alveolar cells, therefore enabling milk production - lactogenesis. Prolactin
stimulates the breast alveolar epithelial cells to synthesise milk components,
including milk sugar (lactose), proteins (e.g. casein), and lipids. These components
are secreted into the lumen of the alveoli. As noted above, circulating PRL
concentrations are only increased by the sucking stimulus. When the mother is not
breastfeeding, prolactin levels will decline and milk production is reduced. Regular
breast feeding is required to maintain milk synthesis and secretion.

Recall that the sucking stimulus is important for oxytocin release from the
posterior pituitary gland and contraction of the myoepithelial cells around
the epithelial cells. Both oxytocin and PRL are together important in milk
production and milk ejection respectively during breastfeeding.