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Patients with Hyperprolactinemia
Dr WONG Lap Ming
21-9-06
Patient 1
History (1)
• Female, 14 year old
• Referred from Student Health Service for premature
adrenarche & delayed thelarche
• F2 student with average school performance
• Onset of pubarche since 12 year old, with gradual
increase in length, number and area of distribution
of pubic hair
• Axillary hair development since 12.5 year old
History (2)
• Slight breast development only in the past, but
cannot recall exact event
• No acne, no growth of beard
• No deepening of voice, no prominent ‘Adam apple’
• No regular drug or herbs
• On & off frontal headache for 2 years with several
attacks per month. Each episode lasted for 1-2
hours & mainly in afternoon, occasionally required
paracetamol for relief. Not associated with nausea,
dizziness or headache.
Past Health
• G1P1, Full term, normal spontaneous delivery, birth
weight 2.8kg
• Fever on Day 2 of life. Full sepsis work-up,
including lumbar puncture were performed with all
result unremarkable.
• Several hospital admissions for pneumonia but
recovered fully after treatment
• No regular medical follow-up now.
Family History
• Maternal uncle died at neonatal period of unknown
cause
• No family history of ambiguous genitalia or female
infertility
• Father height 168cm. Mother height 155.9cm
Physical Exam
• Body weight 42.6kg ( 25-50%)
• Height 146cm (3-10%)
• Neurological system: muscle tone & power normal.
No cerebellar sign.
• Visual field: normal by confrontation test
• Fundi-no papilloedema.
• Chest, cardiovascular, abdomen: normal
• Pubertal stage: B1P3A1 Mo, many curled pubic
hairs on both labia majora.
Investigation (1)
•
•
•
•
•
•
•
•
•
Full blood count: normal
ESR: 19 mm/1st hour
Renal/Liver function CaPo: normal
Anti-nuclear factor: negative
Morning cortisol: 323nmol/L
Estradiol: 67 pmol/L
Testosterone: 1.29 nmol/L
a feto-protein: 1.7 ng/ml ( ref <6.0)
B-HCG: <0.6 iu/L ( ref <5.3)
Investigation (2)
• Morning 17-OH progesterone: 0.7 nmol/L ( ref 0.64.0)
• X-ray left hand: RUS score 650 ie bone age of 12.7
yr at chronological age of 14.0
• Luteinising hormone-releasing hormone stimulation
test:
Time( min) 0
20
60
FSH(iu/L) 3.9
7.3
8.7
LH(iu/L) 0.1
13.1
11.8
Investigation (3)
• CT scan brain:
A large hyperdense mass at the left parasellar region.
It measured 4.6x4.6x4.4cm. No calcification or
cystic component found. It was extra-axial in
location & extended into the pituitary fossa, middle
& posterior cranial fossae. The left carotid artery
was encased. The optic chiasm was compressed.
There was mild hydrocephalus noted due to
compression at level of Foramen of Monro.
Investigation (4)
• MRI brain:
A contrast enhanced solid tumor , measuring
4.6x4.8x6.3cm , was occupying whole sella with
superior & inferior extension. Superiorly it extended
to suprasellar cistern compressing left hypothalamus
with the left cerebral peduncle being compressed &
elevated. The frontal horn of left lateral ventricle
was compressed from below. The left carotid artery
was encased by tumor. The optic chiasm could not
be identified but was likely to be compressed &
encased.
Investigation (5)
• MRI brain ( cont’d)
Laterally the mass was compressing left temporal
lobe & was occupying cavernous sinuses &
Meckel’s cave. The mass also occupied right
cavernous sinus & encasing right carotid artery.
Inferiorly, the mass eroded through sellar floor &
occupied sphenoid sinus with floor of sphenoid
sinus preserved.
Posteriorly the mass extended into left
cerebellopontine angle cistern and caused
compression of left of pons. Fourth ventricle not
distorted.
Investigation (6)
• Ophthalmologist consulted :
Formal perimetry revealed no visual defect.
Investigation (6)
• What is the next investigation ?
Investigation (7)
• Prolactin : 154350 miu/L
therefore, working diagnosis of
macroprolactinoma made.
Treatment
• Bromocriptine 2.5mg nocte with food started.
• Initially with mild nausea, but subsided few days
later, dose then increased to 2.5mg BD
• Patient’s condition stable with no CSF rhinorrhea or
visual filed impairment.
• Prolactin level 3300 miu/L one week after treatment
and was normalised 3 months later.
Discussion (1)
• Hyperprolactinemia caused by lesion of
hypothalamus or pituitary stalk is due to
disinhibition of the tonic Prolactin-inhibiting factor
( dopamine) acting at the level of lactotrophs.
• Level for such lesion is almost always < 3000miu/L
• Treatment for such lesion usually requires surgery
• When prolactin level is >4000miu/L, the chance of
finding a prolactinoma by CNS imaging is high
Discussion (2)
• At times, no apparent cause is found for
hyperprolactinemia, i.e. idiopathic.
• Such cases might be due to small prolatcinomas that
is too small to be detected by current radiological
techniques or presumed hypothalamic dysfunction.
• Over 2-6 years follow-up, only about 10%
developed evidence of microadenomas and none
developed macroadenomas.
Discussion (3)
• Etiologies of hyperprolactinemia
Hypothalamic: craniopharyngioma, LCH, pituitary
stalk lesion, other tumors
Pituitary disease: prolactinoma, acromegaly
Drugs: neuroleptics, methyldopa etc
Neurogenic: chest wall lesion, breast stimulation,
Others: pregnancy, hypothyroidism, chronic renal
failure, ectopic prolactin production
Idiopathic
Discussion (4)
• Evaluation
History , physical exam, screening blood test,
thyroid function test & pregnancy test will virtually
exclude all causes except for hypothalamic-pituitary
disease.
Discussion (5)
• Pituitary adenomas contribute <3% of supratentorial
tumors in children, and 2.3-6% of all intracranial
tumors.
• The average annual incidence of pituitary adenomas
in children has been estimated to be 0.1 per million
children.
• According to tumor size, prolactinoma can be
divided into microprolactinoma when < 10mm or
macroprolactinoma when >10mm in greatest
diameter respectively
Discussion (6)
• Microprolactinoma is usually confined to sella
turcica.
• Macroprolactinoma can be totally intrasellar, but is
usually extrasellar, extending inferiorly to the
sphenoid sinus but more often superiorly to the
suprasellar space owing to lower resistance. During
the process of extension, optic chiasm may be
compressed or the cavernous sinuses can be
involved.
Discussion (7)
• Prolactinoma can exert effect by:
1. Effect of excessive hormonal production. In
female, primary or secondary amenorrhea,
galactorrhea, menstrual disturbance can occur. In
male, gynecomastia, galactorrhea, decreased libido
or impotence can occur.
Discussion (8)
2. Pressure effect: eg visual field disturbance,
headache, cranial nerve palsy, hydrocephalus etc,
notably in macroprolactinoma
3. Other pituitary hormone insufficiency: more
common in macroprolactinoma e.g growth hormone
deficiency, hypogonadism
Discussion (9)
• In one large series with detailed description of 26
patients under 18 of age at diagnosis, several
importance observation made.
1. All except one boy ( at 7 yr old) were >10 yr old
2. Macroprolactinoma & microprolactinoma were in
15 & 11 patients respectively.
3. For boys , 8 out of 9 had macroprolactinomas. The
one with microprolactinoma presented with
galactorrhea while others presented with headache
or visual field defect.
Discussion (10)
4. For girls: all presented with menstrual disturbance
ie primary amenorrhea, secondary amenorrhea or
oligomenorrhea. All girls with headache were found
to have macroprolactinomas.
5. Overall, pituitary hormone insufficiency at
presentation were found in 2 out of 26 patients.
6. For microprolactinomas, serum prolactin ranged
from 1400 to 10,000miu/L, with median of 2100
miu/L. For macroprolactinomas, serum prolactin
ranged from 2900 to 66,000 miu/L, median at
14400miu/L
Treatment (1)
1. Observation with careful follow-up ( only for
microprolactinoma)
2. Drug
3. Surgery
4. Irradiation
Treatment (2)
• For microprolactinomas, more than 90% do not
enlarge over 4-6 years period with only 7 % will
grow into macroprolactinomas.
• It is unlikely for a prolactinoma to grow
significantly with no increase in serum prolactin
level. Therefore , most patients with
microprolactinomas can just be followed with serial
prolactin levels and only one or two repeat scan is
indicated.
Treatment (3)
• Macroprolactinomas have already indicated a
propensity for growth & virtually all should be
treated. Local or diffuse invasion or compression of
adjacent structure, such as the stalk or optic chiasm,
are additional indication for therapy.
• Other indication for treatment are relative e.g.
menstrual disturbance, premature osteoporosis,
infertility, sexual dysfunction, galactorrhea.
Treatment (4)
• Microprolactinoma:
Most suggest drug therapy as about 80-90% will
have normalisation of serum prolactin level over
several weeks & regression of tumor in about 70%
within 3-6 months.
No consensus for duration of drug treatment. In
general, 2 to 6 years of continuous treatment are
recommended before considering tapering off
treatment.
Treatment (5)
• Microprolactinoma:
For transphenoidal surgery, about 75% of patients
had normalisation of serum prolactin level, followed
by clinical improvement few weeks later, with
recurrence rate about 20% at 10 years later.
Treatment(6)
• Macroprolactinoma:
Primary treatment is drug which is effective in
normalising prolactin level in about 85% & reduce
tumor size in 70%. Also no consensus for duration
of treatment but at least 4-6 years of therapy is
recommended.
Surgery is indicated for failed drug therapy after 3-4
months of treatment or compression on optic chiasm.
Normalisation of prolactin level can be achieved in
up to 60-70% for intra-sellar macroprolactinomas.
However, recurrence rate of 20-50% are likely over
10 years.
Treatment(7)
• In general, surgery in indicated for dopamineresistant prolactinomas, poor tolerance to long term
dopaminergic treatment or rare complication to drug
therapy eg CSF rhinorrhea.
• Radiation therapy is indicated for failed drug or
surgical treatment.
Bromocriptine(1)
• Bromocriptine is an ergot derivative that binds to &
stimulate dopamine(D2) receptors on normal &
adenomatous lactotroph cells.
• Single dose study showed that serum level peaked at
3 hours with undetectable level 11-14 hours later.
• Bromocriptine decrease prolactin synthesis, cell
multiplication & tumor growth.
• When bromocriptine is stopped for 1 week after 2
weeks of therapy, there is rapid re-growth of tumor
cells.
Bromocriptine(2)
• With longer duration of treatment, stopping
bromocriptine may not result in a reversal of cell
atrophy & tumor re-growth does not always occur.
• Bromocriptine results in normal prolactin level or
return of ovulatory cycles in 80-90% of patients.
Bromocriptine (3)
Analysis of 112 patients with macroprolactinomas
revealed that
>50% reduction in size: 40.2%
25-50% reduction in size: 28.6%
<25% reduction in size: 12.5%
no reduction:
18.7%
Time course of regression is variable. Some patients
had improvement in visual filed in 24-72 hours with
significant change on scan in 2 weeks. Others
started to have clinical improvement in 6 weeks.
Bromocriptine (4)
• Reduction in tumor size often accompanied by
visual filed improvement and restoration of other
pituitary hormonal axes.
• After prolonged therapy of 3-4 years, bromocriptine
withdrawal results in resumption of
hyperprolactinemia in about 80-90% of patients but
tumor growth in 10-20%.
• In patients with very large tumor having excellent
tumor regression, stopping therapy must be done
very carefully, if at all.
Bromocriptine (5)
• The best approach is to reduce the dose gradually
over several months, following prolactin level, and
only discontinue the drug if no more increase in
prolactin level or tumor size while on just 2.5mg or
less per day.
• Overall, about 20% of patients can stop
bromocriptine and maintain normal prolactin level.
Bromocriptine (6)
• Common side effects are nausea and vomiting.
• Can be minimised by starting with 1.25mg daily
with snack at bedtime. Then gradually increase to
2.5mg BD with meals over 7-10 days and prolactin
level checked after 1-2 months.
• Most patients respond within 1-2 months if they are
going to respond.
• Dose higher than 7.5 mg per day are usually not
necessary except for very large tumor.
Bromocriptine (7)
• The incidence of abortions, ectopic pregnancies or
congenital malformations is no higher in infants
born to mothers who conceived while taking
bromocriptine than that in the general population.
• However, it is best to limit the exposure of the
embryo to such drugs as much as possible.
• It is recommended that bromocriptine be stopped
once the first menstrual period has been missed and
a positive pregnancy test is obtained.
Suggested reading
• Guidelines of the Pituitary Society for the diagnosis
and management of prolactinomas.
FF Casanueva et al.
Clinical Endocrinology; 2006;65:265-273.
• Advances in the Treatment of Prolactinomas
MP Gillam et al
Endocrine Review 2006;27:485-534
Patient 2
History
• Presented at 9.0 years old for pubic hair
development since 8.1 years old.
• No breast development, no axillary hair
• Growth spurt since 8.5 years old
• No headache, no visual field problem
• No regular drugs or herbs
• No family history of neonatal death
Physical examination
•
•
•
•
•
•
•
•
•
Body weight 29kg ( 50-75%)
Height 138.4cm ( 75-90%)
Pubertal stage: B1P2A1 Mo
External genitalia: no clitoromegaly
No hirsutism
Visual field: normal by confrontation test
Fundi: normal
Other systems: normal
BP 104/62mmHg
Investigation
•
•
•
•
•
•
•
TSH 1.66 miu/L, fT4 13.5 pmol/L
Estradiol <37pmol/L
Testosterone 0.34 nmol/L
a-feto protein 1.8 ng/ml B-HCG <2.0 iu/L
Basal FSH 4.3 IU/L basal LH 0.4 IU/L
Cortisol 530 nmol/L
Morning 17-OHprogesterone 9.4 nmol/L ( ref 0.314.4)
• Prolactin 1022 miu/L
Investigation
• MRI brain including hypothalamo-pituitary region:
normal ( at 9.4 years old and at 10.7 years old)
Progress
• Breast development since 9.4 years old
• No symptoms all along
• Serial prolactin level showed persistent increase.
Serial prolactin level
• Age
9.0 9.1 10.1 10.6 10.7 11.1
Prolactin 1022 1333 1558 3125 3248 3016
• Age
11.4
Prolactin 2679
11.7 12.3
204 300
At 11.7 years old, laboratory applied precipitation for
macroprolactin & result corrected.