Hyperprolactinemia
Hyperprolactinemia is a common clinical problem. Cases resulting from
inappropriate prolactin secretion by the pituitary gland are the third most
frequently diagnosed cause of chronic anovulation and secondary amenorrhea.
There are many etiologies for this condition; some result from serious
underlying pathology and others from reversible functional disorders.
Control of prolactin secretion is
dominated by tonic inhibition and there is no regulation by classic negative
feedback from its target organs. These characteristics are unique among
pituitary hormones. The major inhibitor of prolactin secretion is dopamine and
the two major stimuli are estrogen and thyrotropin-releasing hormone (TRH).
Numerous other neurohormonal regulators must also be considered when
elucidating the mechanisms by which hyperprolactinemia develops.
Regulation of prolactin secretion
Embryonic differentiation of the
lactotroph is under the control of the pituitary-specific transcriptional
factor Pit-1. While Pit-1 regulates prolactin gene transcription by binding
directly to the prolactin promoter, other regulators of prolactin gene
expression use alternative pathways (Fig. 32.1a). Dopamine released into the
pituitary portal system binds to a G1-protein-coupled receptor and
inhibits adenylate cyclase and phospholipase C. Acting as a neurohormone,
rather than a neurotransmitter, dopamine reduces prolactin synthesis and
prolactin release by the pituitary lactotrope. TRH acts through a second lactotroph
cell membrane receptor to activate phospholipase C. In contrast to dopamine,
TRH increases prolactin gene transcription and release of prolactin hormone
from its storage granules. The effect of TRH is modulated by thyroid hormone
such that decreases in T3 and T4 enhance prolactin
release and increased concentrations of T3 and T4
decrease prolactin secretion. Estradiol acts through a third mechanism, binding
not to a membrane receptor but to a nuclear receptor.
The hormone receptor complex then
interacts with estrogen response elements upstream of the prolactin gene.
Estradiol also interferes with dopaminergic activation of its receptor and
increases the concentration of TRH receptors on lactotrophs. Both actions
potentiate the stimulatory effects of the sex steroid.
Like dopamine, γ-aminobutyric
acid (GABA) and glucocorticoids inhibit prolactin secretion. The mechanism by
which GABA acts as a prolactin inhibitory factor is unknown. Like estrogen,
glucocorticoids act through nuclear receptors to inhibit prolactin gene
transcription. Vasoactive peptide (VIP), oxytocin, angiotensin II (AgII) and
serotonin all increase prolactin secretion. VIP employs two mechanisms: it
stimulates oxytocin release via the hypothalamus and it interferes with
dopamine inhibition of adenylate cyclase. AgII acts on a specific membrane
receptor on the lactotroph to provoke rapid release of pre- synthesized
prolactin. It is a more potent secretagogue for prolactin than TRH. Serotonin
released by the dorsal raphe nucleus also stimulates prolactin release but not
its synthesis. Here, serotonin activity occurs independent of dopamine
pathways.
In the physiologic state, fine
tuning of prolactin secretion is deter- mined by the balance between the
prolactin inhibitory factors (PIF) and the prolactin-releasing factors (PRF).
Any disorder that alters the balanced secretion of these regulatory compounds
will result in altered prolactin secretion. Regardless of its cause,
hyperprolactinemia can interfere with hypothalamic–pituitary function and
result in hypogonadism with or without galactorrhea. The fact that women with
prolactin-induced amenorrhea are hypo-estrogenic but do not experience hot
flashes suggests that one mechanism by which prolactin alters hypothalamic pituitary
function is via modulation of central neurotransmission. The hypothalamic
dopaminergic and opioid systems that regulate gonadotropin releasing hormone
(GnRH) pulsatility are likely to be involved in
this effect.
Most physiologic
hyperprolactinemia is transient and of no clinical consequence. High
physiologic concentrations of plasma prolactin occur at night and result from
both an intrinsic circadian rhythm and sleepentrained prolactin release. High
protein meals at midday, but not in the morning, induce prolactin release
through an unknown mechanism. Physical and emotional stress, including
exercise, hypoglycemia and anesthesia are associated with elevations in
prolactin secretion. Orgasm promotes prolactin secretion, but only in women.
Pregnancy is associated with a marked elevation of prolactin secretion that
persists into the immediate postpartum period (Chapter 23). Of all the
physiologic hyperprolactinemic states, only lactation is associated with
amenorrhea.
Pharmacologic hyperprolactinemia Medications that interfere with dopaminergic inhibition of the pituitary
lactotroph can cause hyperprolactinemia. Any drug that decreases the synthesis
of dopamine, enhances its metabolism, increases its reuptake or interferes with
its binding to its receptor will reduce the action of dopamine. When the
inhibitory activity of dopamine on the pituitary lactotroph is blocked,
prolactin secretion increases. All of the medications listed in Table 32.1 can
inhibit dopamine action and cause hyperprolactinemia. Clinical manifestations
of pharmacologic hyperprolactinemia include galactorrhea and menstrual
irregularities. Menstrual dysfunction may be severe enough to result in
amenorrhea.
Pathologic hyperprolactinemia
Lesions in the hypothalamus or in
the pituitary gland can cause hyperprolactinemia. Those in the hypothalamus
typically do so by interfering with dopamine delivery to the pituitary gland.
Tumors are the most frequent of the pituitary causes of hyperprolactinemia; the
prolactin-secreting adenoma is the most common of these (Fig. 32.1b).
Prolactin-secreting adenomas (prolactinomas) are classified by size:
microadenomas are less than 1 cm in size and macroadenomas are greater than 1
cm. These tumors can occur in both men and women, but are more common in women.
In women they cause galactorrhea, amenorrhea, headache and visual field
defects. In men they cause headache, visual field changes and impotence. They
are often larger at diagnosis in men than in women because symptom onset is
typically late in men. Prolactinomas are usually benign. Pituitary adenomas
that produce adrenocorticotropic hormone (Cushing
disease) and growth hormone (acromegaly) may also cause hyperprolactinemia.
Primary hypothyroidism can also
cause hyperprolactinemia. The decrease in circulating thyroid hormone that
accompanies thyroid gland dysfunction diminishes negative feedback on the
hypothalamus and
pituitarygland.ThisresultsinanincreaseinTRHandthyroid-stimulating hormone
secretion. Excessive TRH can override the normal dopamine dominated inhibition
of prolactin secretion through direct, receptor- mediated effects on the
pituitary lactotroph. A significant proportion of patients with chronic renal
failure will have hyperprolactinemia. While the etiology of this effect remains
incompletely described, patients with chronic renal failure appear to have
circulating serum factors that interfere with dopaminergic inhibition of
prolactin synthesis and secretion. Treatment of hyperprolactinemia is directed
toward correction of the underlying cause. A notable exception to this rule
involves the management of the prolactin-secreting pituitary adenoma. Resection
of these tumors is associated with a high frequency of recurrence of the
hyperprolactinemia. Medical management is typically safer and more effective
and involves use of oral dopamine agonists (e.g., bromocriptine, cabergoline).
It is important to remember that men and women with hyperprolactinemia are
hypogonadal due to the associated abnormalities in the
hypothalamic–pituitary–gonadal axis. This hypogonadal state places them at
significant risk for osteoporosis (Chapter 24) and requires continuation of
therapy for as long as the hyperprolactinemia
persists.
Galactorrhea
Galactorrhea describes the secretion of breast milk in states unassociated
with nursing. Galactorrhea can
result from hyperprolactinemia or from excessive sensitivity of the breast to
normal circulating levels of prolactin. If galactorrhea is associated with
amenorrhea, then hyperprolactinemia is likely the cause. If galactorrhea occurs
in the presence of normal ovulatory cycles, then excessive sensitivity of the
breast to normal circulating amounts of prolactin is more likely. The three
most common causes of hyperprolactinemia resulting in galactorrhea are: (i) a
pituitary adenoma, (ii) medications interfering with dopamine action and (iii)
hypothyroidism. Galactorrhea can be suppressed by the use of dopamine agonists.
