Transcript MILK - London Health Sciences Centre

MILK
Hala Mosli
PGY-5
November 4, 2009
Objectives:
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What is prolactin?
Where does it come from?
How is it regulated?
Disorders of prolactin production.
Prolactin
• 198-Amino acid polypeptide hormone.
• Contains three intra-molecular disulfide
bonds.
• Gene located on chromosome 6.
• Circulates in the blood in different sizes:
• Monomeric PRL (little PRL; 23 kd)
• Dimeric PRL (big PRL; 48-56 kd)
• Polymeric PRL (Big big PRL; >100 kd)
• Shares a common tertiary structure with a family of
polypeptide hormones, eg GH and HPL and are
structurally related to members of the cytokinehematopoietin family (EPO, GM-CSF, IL-2-IL-7).
• Biological effects produced by interacting with and
dimerizing specific single transmembrane-domain
receptors.
• The receptors belong to a superfamily of cytokine
receptors.
• Synthesized and secreted from the lactotrophs of the
anterior pituitary gland.
• A precursor molecule (MW 40,000-50,000) is also
secreted and may constitute 8-20% of prolactin
immunoreactivity.
Regulation
• Hypothalamic control of PRL secretion is mainly
inhibitory.
• Dopamine is the most important inhibitory factor.
• Many factors influence PRL secretion:
– Physiologic
– Pharmacologic
– Pathologic
Lactotroph cells
• Make up 15-25% of functioning anterior pituitary cells.
• Absolute number does not change with age.
• Hyperplasia occurs during pregnancy and lactation.
• Most PRL-expressing cells appear to arise
from GH-producing cells.
• Two cell forms express PRL gene:
• Large polyhedral cells throughout the gland
contain large secretory granules.
• Smaller, angulated or elongated cells clustered
mainly in the lateral wings and median wedge
sparse smaller granules.
• Occasional mammosomatotrophs cosecrete both
GH and PRL, often stored within the same
granules.
Functions
• Mammary gland development and
lactation:
• Puberty: PRL is not essential for pubertal
mammary gland development.
• Pregnancy: PRL increases to a mean of 207 μg/L.
Amniotic fluid PRL is 100 times that level.
– Plays a role in mammary gland maturation in the third
trimester of gestation.
• Lactation: active lactation is due in part to a fall in
estrogen and progesterone and an elevation of
PRL after delivery.
• Suckling is essential to maintain lactation.
• Without suckling, prolactin levels fall to normal
within 7 days post-partum.
• As nursing continues, PRL concentrations fall.
• Each suckling episode causes an episodic rise in
PRL.
• Milk yield does not closely correlate with serum
PRL level.
• Suckling also stimulates oxytocin release from the
posterior pituitary.
• Oxytocin induces milk ejection by stimulating the
contraction of myoepithelial cells, as well having
important effects on alveolar proliferation.
• Immune function:
• PRL is a lymphocyte growth factor.
• It also stimulates immune responsiveness.
• PRL levels change in patients with Lupus and
other immune disease.
• Exact role in immunomodulation is not clear.
• Reproductive/ gonadal function:
• PRL has no physiologic role in the regulation of
gonadal function.
• Hyperprolactinemia leads to hypogonadism.
• Exact mechanisms unknown but likely due to
alteration of the hypothalamic-pituitary control of
gonadotrophin secretion.
• In women:
– Shortened luteal phase.
– Normal basal LH and FSH normal but pulsatile secretion
is decreased.
– This interferes with the midcycle LH surge.
– Anovulation, oligomenorrhea, amenorrhea
– Infertility
• In men:
– Decreased testosterone synthesis and decreased
spermatogenesis.
– Decreased libido and impotence.
– Infertility.
PROLACTINOMA
• Definition:
– Prolactinomas are pituitary adenomas that express
and secrete prolactin to variable degrees
– They are almost invariably benign.
– Occasionally, these adenomas can be aggressive
or locally invasive and cause compression of vital
structures.
– Malignant prolactinomas that are resistant to
treatment and disseminate inside and outside the
central nervous system are very rare
Epidemiology
• Prolactinomas are the most frequent pituitary tumors, with an
estimated prevalence in the adult population of 100 per million
population.
• Beckers et al. found a much higher prevalence at 55 per 71,000 (775
per million) inhabitants in Belgium.
• Their frequency varies with age and sex, occurring most
frequently in females between 20 and 50 yr old, when
the ratio between the sexes is estimated to be 10:1.
• After the fifth decade of life, the frequency of
prolactinomas is similar in both sexes.
• In the pediatric/adolescent age, prolactinomas are rare,
but represent about half of all pituitary adenomas, which,
overall, account for less than 2% of intracranial tumors
Classification
• Classified according to size into:
• Microadenomas: less than 10 mm in diameter
• Macroadenomas: more than 10 mm in diameter
• Over 90% of prolactinomas are small, intrasellar
tumours that rarely increase in size.
Pathogenesis
• Multi-step process that involves dysregulation of cell
growth or proliferation, differentiation, and hormone
production.
• It may be initiated as a result of activation of oncogene
function or after inactivation of a tumor suppressor gene,
or both.
• Studies have demonstrated that pituitary tumors are
monoclonal in origin thus tumors arise from a single cell
mutation followed by clonal expansion.
Manifestations
• Related to excess hormone production:
hyperprolactinemia.
• Mechanical symptoms.
• Symptoms of impaired pituitary function.
Excess hormone production:
• Galactorrhea-amenorrhea
• Infertility
• Decreased libido/ impotence.
• Galactorrhea-amenorrhea syndromes:
• Three distinct clinical syndromes described:
1) the Chiari-Frommel Syndrome—amenorrhea,
galactorrhea, and low urinary gonadotropins occurring
postpartum
2) Ahumada-Argonz-del Castillo syndrome—nonpuerperal
amenorrhea, galactorrhea, and low urinary gonadotropins
with no evidence of a pituitary tumor on standard skull x-rays
3) Forbes-Henneman-Griswold-Albright syndrome—
nonpuerperal amenorrhea, galactorrhea, and low urinary
gonadotropins in association with a chromophobe adenoma
• Other symptoms:
– Weight gain, fluid retention.
– Hirsutism
– Irritibality, anxiety and depression,
Mechanical symptoms:
• Headaches:
– A study was conducted by Strebel et al, to determine
whether headaches in women with non-puerperal
hyperprolactinemia were associated with
hyperprolactinemia or the presence of a prolactinoma.
– Headaches were found to be four times more
common in the presence of a prolactinoma than in its
absence.
Visual field defects:
• Disorders of the visual fields have been documented in
the literature in association with pituitary gland tumors
since the early 1900’s.
• Types of bitemporal defects are stages in a progressive
restriction of the visual fields. The field defect usually
begins in the upper temporal quadrant and progresses
into a bitemporal hemianopia. This may advance to
involve the nasal aspects of the visual fields as well.
Cranial Nerve Palsies:
• Not a frequent manifestation.
• Pituitary adenomata tend to displace or encircle the
cranial nerves rather than invade them.
• Seen in more aggressive, invasive tumors that extend
into the cavernous sinus.
Cavernous Sinus Invasion by Pituitary Adenomas, Ahmadi
et al AJR 146:257-262, February 1986
Impairment of Pituitary Function:
• Due to compression of normal pituitary tissue.
• Manifests as partial or panhypopituitarism.
• Almost always seen in macroadenomas.
Lab Evaluation
• Normal prolactin levels in women and men are below 25
μg/l and 20 μg/l, respectively, with the more commonly
used assays (1μg/l is equivalent to 21.2 mIU/l)
• PRL values between the upper limits of normal and 100
μg/l (∼2000 mIU/l) may be due to psychoactive drugs,
estrogen, or functional (idiopathic) causes, but can also
be caused by microprolactinomas.
• Most patients with PRL levels over 150 μg/l (∼3000
mIU/l) (five times higher than the normal values) will
have a prolactinoma.
• Macroadenomas are typically associated with levels of
over 250μg/l (∼5000 mIU/l),and in some cases over
1000μg/l (∼20000 mIU/l)
• Such values are not absolute; prolactinomas can present
with variable elevations in PRL, and there may be
dissociation between tumour mass and hormonal
secretion.
• There are two potential pitfalls in the diagnosis
of a prolactinoma:
– Macroprolactin
– Hook effect
• Macroprolactin is a complex of PRL and an IgG
antibody.
• Serum PRL concentrations are elevated secondary to a
reduced rate of clearance of this complex.
• Macroprolactin has reduced bioactivity and is present in
significant amounts in up to 20% of hyperprolactinemic
sera, resulting in pseudo-hyperprolactinaemia and
potential misdiagnosis.
• Macroprolactin is detected by most but not all PRL
assays; therefore each centre must know the specific
characteristics of the prolactin immunoassay they use.
• The ‘hook effect’ may be observed when the serum
PRL concentration is extremely high, as in some cases
of giant prolactinomas.
• The high amount of circulating PRL causes antibody
saturation in the immunoradiometric assay, leading to
artifactually low results.
• To overcome the hook effect, an immunoradiometric PRL
assay should be performed at a serum dilution at 1 : 100,
or alternatively should include a washout between the
binding to the first antigen and the second step in order
to eliminate excess unbound PRL.
• It has been recommended that the hook effect be
excluded in all new patients with large pituitary
macroadenomas who have normal or mildly elevated
PRL levels.
Dynamic tests of prolactin secretion:
– Several dynamic tests of PRL secretion have been
proposed as diagnostic tools in the evaluation of
hyperprolactinaemia,
– These include the administration of TRH,L-dopa,
nomifensine, domperidone, and insulin-induced
hypoglycaemia.
– Despite the fact that some of these methods are
useful in particular hands it is now widely accepted
that the diagnosis of a prolactinoma should be
confirmed by analysing basal PRL values, imaging
the pituitary, and excluding other causes.
IMAGING:
– Gadolinium-enhanced MRI is the study of choice.
– Computed tomography (CT) with intravenous contrast
enhancement is less effective than MRI in diagnosing
small adenomas and in defining the extension of large
tumours, but may be used if MRI is unavailable or
contraindicated.
– However, microadenomas are present in about 10% of the
normal population.
– Normal MRI examination does not necessarily exclude a
microadenoma.
• Patients with macroadenomas that abut the optic chiasm
should undergo formal visual-field examination.
• Hyperprolactinaemia in the presence of an MRI-detected
pituitary adenoma is consistent with but not
unequivocally diagnostic of a prolactinoma, because any
pituitary mass that compresses the pituitary stalk may
cause hyperprolactinaemia.
• Unequivocal diagnosis requires pathological analysis,
but prolactinomas are rarely surgically removed.
Therapy
• Medical
• Surgical
• Radiation
Medical Management
• Mainstay of management are dopamine agonists.
• Dopamine inhibition of PRL secretion is mediated by the
D2 dopamine receptors expressed by normal and
tumorous lactotrophs
• The inhibition of cAMP levels is a key step in the
inhibition of PRL release by dopamine and it is likely that
all dopaminergic ergot derivative share similar
mechanisms of action.
• Dopamine agonists reduce the size of prolactinomas by
inducing a reduction in cell volume
• This is via an early inhibition of secretory mechanism,
and a late inhibition of gene transcription and PRL
synthesis
• They also cause perivascular fibrosis and partial cell
necrosis.
• There may also be a true antimitotic effect of these
drugs.
• Histologically, there is a reduction in secretory activity
and cell size, an increase in immunoreactive PRL
cellular content and inhibition of exocytosis
• Bromocriptine, pergolide, and cabergoline are all ergot
derivatives.
• The only nonergot derivative that is used in clinical
practice is quinagolide.
1. Bromocriptine.
– The first medical treatment for prolactinomas;
available for over 25 yrs.
– Bromocriptine-mesylate is a semisynthetic ergot
derivative that has D2 receptor agonist and D1
antagonist properties. It has a relatively short
elimination half-life; usually taken two or three times
daily.
– Therapeutic doses are in the range of 2.5–15 mg/d,
and most patients are successfully treated with 7.5
mg or less. However, doses as high as 20–30 mg/d
can be used in “resistant” patients.
– For microprolactinomas bromocriptine is successful in
80 to 90% of patients in normalizing serum PRL
levels, restoring gonadal function, and shrinking
tumor mass.
– For macroprolactinomas, normalization of serum PRL
levels and tumor mass shrinkage occur in about 70%
of patients treated with bromocriptine even at low
doses; visual field defects improve in the majority of
patients.
– Although prolactinomas usually remain sensitive to
bromocriptine, it usually does not “cure” these
pituitary adenomas, and the withdrawal of therapy
often results in recurrence; tumor regrowth may occur
later, with the consequent risk for compromised vision
– Prolonged bromocriptine treatment has been
associated with increased fibrosis of prolactinomas
and with increasing tumor consistency.
– In most patients, headache and visual field defects
improve dramatically within days after the first
administration of bromocriptine, with gonadal and
sexual function improving even before complete
normalization of serum PRL levels.
– PRL normalization with bromocriptine is also
associated with an increase in bone density both in
women and in men and with improvement of semen
quality in men.
– Other formulations of bromocriptine, long-acting and
the long-acting repeatable forms for IM injections, an
intranasal powder, and an intravaginal tablet, were
developed to overcome side effects such as nausea,
vomiting, postural hypotension, and headache.
– Despite promising data none of these formulations
were ever introduced in the pharmaceutical market for
hyperprolactinemia.
– Bromocriptine has been largely superseded by more
potent compounds with longer lasting effects and
improved side effect profiles. Nevertheless, it is still
widely used to treat prolactinomas, primarily in young
women desiring pregnancy
2. Cabergoline.
– D2 selective agonist widely used to treat
prolactinomas.
– Strongly suppresses PRL secretion both in vivo and in
vitro
– First line therapy for prolactinomas.
– Fewer side effects than other dopamine agonists
therefore better patient compliance.
3. Pergolide.
– A synthetic ergoline derivative with long-acting D2
and D1 agonist properties.
– Approximately 100 times more potent than
bromocriptine
– Suppresses PRL secretion for up to 24 h after a
single dose, allowing effective control of
hyperprolactinemia with once daily dosing.
– Approved in the United States only for the therapy of
Parkinson’s disease, where it has been used at doses
more than 10 times those used for PRL-secreting
tumors.
– Pergolide has advantages over bromocriptine in that it
only requires once a- day dosing and is approximately
one fifth of the cost.
– In short-term studies, pergolide has been shown to
effectively lower PRL levels.
– In an open-label, randomized, controlled, multicenter
study, Lamberts and Quik reported that bromocriptine
and pergolide were equally effective in lowering
serum PRL levels and in inducing tumor shrinkage; a
high incidence of adverse events, such as nausea,
dizziness, vomiting, asthenia, headache, and
decrease in blood pressure, was reported with both
drugs.
– Data concerning the reduction of macroprolactinoma
size by pergolide are limited
4. Quinagolide:
– An octahydrobenzyl(g)-quinoline nonergot oral
dopamine agonist with specific D2 receptor activity.
– Several studies demonstrated that once-daily
quinagolide treatment in women with
hyperprolactinemia reduced PRL levels and tumor
size and relieved gonadal dysfunction, thereby
restoring fertility
Other dopamine agonist
compounds
• Lisuride hydrogen maleate is another synthetic ergot
derivative, with PRL inhibitory activity in experimental
models of hyperprolactinemia
• Terguride, an analog of lisuride, binds to D2 receptors.
• Neither lisuride nor terguride is currently used in the
treatment of prolactinomas.
Serotonin receptor antagonists
• Metergoline is a nonselective antagonist for 5hydroxytryptamine-1B and 5-hydroxytryptamine-1D
receptors that has been used to treat hyperprolactinemia
in the past.
• Found to be effective in normalizing gonadal function
and in restoring fertility in women, no data are available
in patients with macroprolactinomas or in men with
hyperprolactinemia.
• Metergoline is seldom, if ever, used today in the
treatment of prolactinomas.
Oral contraceptives for
hypogonadism
• Hypogondal women with microprolactinomas may be
treated for their hypogonadism with oral contraceptives,
provided that their PRL levels do not increase
substantially and there is no evidence of tumor
enlargement.
• Series of patients with prolactinomas who are treated
with oral contraceptives for hypogonadism have not
shown substantial risk for tumor enlargement.
• It is advisable to monitor patients who use oral
contraceptives carefully with periodic measurement of
PRL and imaging.
What to expect with medical
management?
• Tumour shrinkage can often be observed within
a week or two after starting therapy, but may not
start for several months.
• Continued tumour shrinkage may occur for
many months or even years.
• Repeat the MRI 2–3 months after starting
therapy then at longer intervals.
• Several studies have demonstrated recovery of impaired
anterior pituitary function in association with tumour
shrinkage and ovulatory menses return in over 90% of
premenopausal women.
• Dopamine agonists usually restore visual function to an
extent similar to that produced by surgical
decompression of the chiasm in macroprolactinoma
patients.
• Patients with macroprolactinomas who have visual field
defects are no longer considered to be neurosurgical
emergencies.
When/how to stop medication
• When the PRL level has been normal for at least 2 years
AND the size of the tumour decreased by more than
50%, the dose of the dopamine agonist can be gradually
decreased, because at this stage low doses are likely to
maintain stable PRL levels and tumour size.
• In patients with macroadenomas suspension of therapy
may lead to tumour expansion and recurrence of
hyperprolactinaemia.
• Close follow-up is necessary when the drug is tapered or
withdrawn in patients with macroprolactinomas.
Special situations
• Malignant prolactinomas:
– Initially present as resistant prolactinomas or with
dissociation between serum PRL levels and tumour
mass.
– there is no typical clinical presentation of these
tumours except as a failure of dopamine agonist
therapy or recurrence after surgery.
– Usually, pathological information is unremarkable,
– Surgery and radiotherapy are the only treatments
available but are only palliative.
– Chemotherapy provides little or no benefit.
– Experience managing malignant prolactinomas is
very limited.
– These cancers are uniformly fatal, but fortunately are
very rare.
• Pregnancy and prolactinoma
– Women with prolactinomas who are pregnant or who
wish to become pregnant should be guided through
the process by an endocrinologist for a number of
reasons.
– During pregnancy, there can be a substantial increase
in the volume of the prolactinoma that may in turn
compromise visual fields.
– Serum PRL levels do not reliably reflect an increase
in the size of prolactinomas.
– Dopaminergic drugs cross the placental barrier; their
effects on the fetus should be carefully considered.
– There are four main issues with respect to
pregnancy and prolactinomas:
• hyperprolactinaemia and fertility,
• safety of dopamine agonists,
• tumour growth
• lactation.
• Long-term follow-up
– The minimal length of dopamine agonist therapy
should be 1 year.
– Long-term remission can occur after a period of
several years of dopamine agonist treatment.
– There are no signs to predict whether drug
discontinuation will be successful
– A recent report indicates that dopamine agonists can
be safely withdrawn in patients with long-term
normalization of prolactin levels and no evidence of
tumour on MRI.
– If a patient has normal PRL levels after therapy with
dopamine agonists for at least 3 years and the tumour
volume is markedly reduced, a trial of tapering and
discontinuation of these drugs may be initiated.
– Such patients need to be carefully followed to detect
recurrence of hyperprolactinaemia and tumour
enlargement so that treatment can be resumed.
Other therapies
• Trans-sphenoidal surgery
– Does not reliably lead to a long-term cure,
– Recurrence of hyperprolactinaemia is frequent.
– Up to 10% of patients may require surgery if they do
not respond to dopamine agonists or if visual field
deficits do not improve.
– Other indications for surgery include
• apoplexy with neurological signs in macroadenomas;
• cystic macroprolactinomas (which generally do not shrink in
response to dopamine agonist treatment) causing
neurological symptoms
• intolerance to dopaminergic agonists.
– The possibility of cure by surgery versus long-term
dopamine agonist therapy should be discussed with
the patient
– Patient preference is also an indication for surgery.
• Radiotherapy
– External radiation is rarely required to treat
prolactinomas and is associated with a significant
incidence of major side-effects:
•
•
•
•
•
Hypopituitarism,
Damage to the optic nerve
Neurological dysfunction
Increased risks of stroke
Secondary brain tumours.
– Radiotherapy is not an acceptable primary therapy for
prolactinomas
– Reserved for patients who do not respond to
dopamine agonists, those who are not cured by
surgery, or for those very rare cases of malignant
prolactinoma.
THANK YOU
References
• Williams textbook of Endocrinology 11th Edition.
• Journal of Mammary Gland Biology and Neoplasia, Vol. 7, No. 3,
July 2002 ( C° 2002)Growth Hormone and Prolactin—Molecular and
Functional Evolution. Isabel A. Forsyth and Michael Wallis.
• Greenspan’s Basic and Clinical Endocrinology.
• Medication-Induced Hyperprolactinemia, Mayo Clin Proc. • August
2005;80(8):1050-1057, Mark Molitch.
• PROLACTIN AND ITS DISORDERS,Laurence Katznelson,Anne
Klibanski
• Pediatric Endocrinology: Mechanisms, Manifestations, and
Management (1st Edition)
• Clinical Endocrinology (2006) 65, 265–273 doi: 10.1111/j.13652265.2006.02562.x, Guidelines of the Pituitary Society for the
diagnosis and management of prolactinomas
• Strebel et al, Headache, Hyperprolactinemia and Prolactinomas,
Obstetrics and Gynecology, August 1986
• A STUDY OF THE: VISUAL FIELDS \VITH WHITE AND
COLOURED OBJECTS IN CASES OF PITUITARY TUMOUR WITH
ESPECIAL REFERENCE TO EARLY DIAGNOSIS By Paul
Enoksson
• Cavernous Sinus Invasion by Pituitary Adenomas, Ahmadi et al
AJR 146:257-262, February 1986
• Gillam et al. Treatment of Prolactinomas Endocrine Reviews, August
2006, 27(5):485–534 525
• Endocrine-Related Cancer (2001) 8 287–305 Pituitary tumors:
pathophysiology, clinical manifestations and management B M
Arafah and M P Nasrallah
• Guidelines of the Pituitary Society for the diagnosis and
management of prolactinomas Felipe F. Casanueva*, Mark E.
Molitch†, Janet A. Schlechte, Clinical Endocrinology (2006) 65, 265–
273