Medical Pharmacology

April 11, 2003

Doug Bayliss

PROLACTIN
1. OVERVIEW
Prolactin is a peptide hormone synthesized by lactotropes of the anterior pituitary. Lactotrope function is
primarily regulated by thyrotropin-releasing hormone (TRH) and dopamine, which enhance and inhibit,
respectively, the synthesis and secretion of prolactin. The most well recognized physiological effect of
prolactin is to initiate and support lactation. Bromocriptine, a dopamine agonist is used to inhibit prolactin
release in hyperprolactinemia, a major cause of infertility.

2. REVIEW OF BASIC PHYSIOLOGY

Human prolactin is a 199 amino acid (23 kDa) protein that is highly homologous to growth hormone. It is
released from pituitary lactotropes in an episodic fashion, with ~14 major pulses every day. A major
nocturnal peak occurs shortly after sleep onset. Regulation of prolactin secretion differs from most other
pituitary hormones as it is: [1] under primarily negative control from the hypothalamus (via dopamine); and
[2] not under long-loop feedback control as it produces no known target organ hormone.
Prolactin secretion is:
inhibited by dopamine from hypothalamic neurons, via D2 receptors and involving decreases in adenylyl
cyclase and cAMP. Inhibition of secretion is the predominant control mechanism for prolactin secretion.
Synthesis and secretion of dopamine is itself enhanced by prolactin, which in turn decreases
prolactin secretion, providing a short loop negative feedback.
enhanced by TRH from the hypothalamus. Other
hypothalamic factors may also be important in
stimulating prolactin release (e.g. vasoactive intestinal
peptide, among others).
stimulated immediately by suckling via a
neuroendocrine reflex arc. The lactational
hyperprolactinemia may contribute to postpartum
anovulation and infertility.
enhanced during pregnancy, probably by the actions
of estrogen. Estrogen increases the number of
lactotropes and stimulates prolactin expression. It
TRH (+)
also enhances secretion of prolactin by augmenting
TRH-stimulated secretion and blunting dopamine
inhibition of secretion. Finally, it increases
expression of prolactin receptors, so that target tissue
sensitivity is enhanced.
Prolactin secretion is enhanced by many factors that
also stimulate GH release (e.g. stress, exercise, sleep,
hypoglycemia)
Mechanism of Action
The prolactin receptor is a member of the hematopoeitin receptor family and is highly homologous to the GH
receptor. It has a single membrane spanning domain with an extracellular N-terminus that contains four
conserved cysteine residues and binds prolactin (and GH to some extent). The mechanism of action is incompletely understood but appears to involve agonist-induced dimerization followed by activation of a tyrosine
kinase cascade involving the JAK-Stat pathway as well as activation of MAP kinase pathways.
1

Prolactin

Physiological Effects
The breast is the principal target of prolactin. Together with progesterone, estradiol, growth hormone and
glucocorticoids, prolactin is required during pregnancy to prepare the breast for milk secretion. It stimulates
expression of milk protein genes. Lactation is inhibited by estrogen and progesterone during pregnancy and
initiated by prolactin after hormone levels decline post partum.

Prolactin decreases LH and FSH secretion. This accounts for the infertility of hyperprolactinemia.

Prolactin receptors are present in many other tissues where their physiological effects may be important, but
are currently not well understood.

IC. PROLACTIN PHARMACOLOGY

Prolactin itself has no known therapeutic value. However, dopamine agonists
(e.g. bromocriptine) are the treatment of choice for hyperprolactinemia.
Bromocriptine is an orally-available semi-synthetic ergot alkaloid with a halflife of ~3h. New dopamine agonist drugs that are longer-lasting and produce
fewer side effects (e.g. cabergoline, quinagolide) are under investigation and in
the future may be approved for use in hyperprolactinemia.
Bromocriptine
To treat hyperprolactinemia
Hyperprolactinemia is the most common hypothalamic-pituitary disorder. It is
associated with infertility secondary to hypogonadotropic hypogonadism in females and with sexual dysfunction
in both sexes (i.e., decreased libido, impotence in males). Bromocriptine causes a reduction in prolactin
secretion and can reduce the size
of prolactin secreting adenomas.
Fertility is restored with
bromocriptine and, if desired,
women should be able to have
uneventful pregnancies with no
increased risk to the fetus
(although bromocriptine
treatment should be stopped as
soon as pregnancy is detected).
Serum prolactin levels in women with hyperprolactinemia are reduced after a
Side Effects
single oral dose of bromocriptine (2.5 mg) and remain suppressed after 3 and
Common side effects of
6 months of bromocriptine treatment (2.5 mg three time daily).
bromocriptine therapy include
nausea, dizziness and orthostatic
hypotension. Less commonly, headaches, abdominal cramps and constipation have been reported. Psychosis
with symptoms such as auditory hallucinations, delusions and mood changes may develop in a small population
of patients.
The most common side effects are mitigated by starting with low doses (administered with food before
sleep) and building to higher doses. When present, symptoms of psychosis stop once treatment is
discontinued.