Download General approach to hyperproolactinaemia

General approach to
management of
hyperprolactinaemia
Dr. But Wai Man
Prolactin
Polypeptide hormone consisted of 199
aminoacids with 3 intramolecular
disulfide bonds
Encoded by a single gene on
chromosome 6, 5 coding exons
Secreted by lactotrophic cells in anterior
pituitary gland
Prolactin receptor
Identified as a member of the cytokine
receptor superfamily
Single –chain transmembrane receptor
Functions by binding a single prolactin
molecule and then dimerizing with a
second receptor molecule
Functions of prolactin
Important role in a variety of reproductive
functions
Essential factor for normal production of
breast milk following child birth
Hyperprolactinaemia disrupts normal pulsatile
secretion of gonadotrophic-releasing hormone,
altered LH and FSH secretion and impaired
gonadal steroidogenesis, leads to infertility
and gonadal dysfunction
Control of prolactin secretion
Secretion is mainly under inhibitory
control by hypothalamic dopamine
Circadian variation. Levels rise after the
onset of sleep, nocturnal peak of 2x
daytime concentration
Hyperprolactinaemia
Clinical manifestations
Galactorrhoea 90%: affect mammary
gland development
Amenorrhoea/Oligomenorrhoea: In
women,
prolactin-secreting tumors is usually
small, headache and neurological
deficits are rare
In men, tend to be large, and may cause
cranial-nerve dysfunction, visual loss and
panhypopituitarism
loss of libido and erection dysfunction
Galactorrhea and gynaecomastia are
uncommon N Engl J Med 78; 299: 847-52
In both men and women
Low bone density
Weight gain
Mood and behaviour changes
Causes
Pregnancy 10X
Dopamine antagonist drug therapy ( phenothiazines
and metoclopramide,
TCA, monamine oxidase inhibitors, oestrogen,
verapamil, methyldopa
Stress eg venepuncture/ exercise
Polycystic ovarian syndrome
Pituitary-secreting microadenomas/macroadenomas
Pituitary stalk disruption by interfering with the
normal suppression of prolactin by hypothalamic
dopamine
Chronic renal failure
Evaluation
Biological evaluation of
related hormonal axes:
Careful drug history and physical
examination
TFT, RFT
PCO
and exclusion of pregnancy
Levels of prolactin
<1000 m U/L <5000 m U/L
stress
Micro-prolactinoma
hypothyroidism
Pituitary stalk
disconnection
PCOS
> 10,000 m U/L
Macroprolactinoma
Macroprolactinaemia
High molecular-weight prolactinimmunoglobulin complexes
Polyethylene glycol precipitation of
complexes allows the measurement of
free monmeric prolactin
Not thought to have pathological
significance
Evaluation for hypothalamicpituitary pathology
Clinical examination: assessment of
visual fields
Imaging : MRI /CT
Pituitary microadenoma < 10mm
Pituitary macroadenoma > 10 mm
Pituitary stalk lesions
Hypothalamic tumours, granulomas
Pituitary microadenoma
20% of the normal population at
autopsy
50% of MRI imaging
No lesion suggesting microadenoma <
2mm, lactotroph hyperplasia
Hypopituitarism in structural lesion
Prolactin secreting pituitary
tumors
Benign tumors
Commonest pituitary tumors, 40%
>90% are small, intrasellar tumors that
rarely increase in size JCEM 89; 68: 412-8
Treatment of prolactinsecreting pituitary adenoma
Medical
Surgical
Radiotherapy
Indication
To suppressive abnormal lactation
To restore ovarian function
Protection against development of
osteoporosis
Rx may not be required in a few women
with modest elevations of prolactin,
may retain normal ovarian function and
have few symptoms
Dopamine agonist
Primary treatment of choice
Normalise prolactin levels, restoration of
pituitary function and tumor shinkage in 8090% over several weeks JCEM 1997 82 996-1000
Tumour shinkage by at least 25% of volume
in 80% of patients with large macroadenoma
Improvement in pressure symptoms within 48
hrs
In men, 50% may require testosterone
replacement, withhold until prolactin levels
are normalised
Bromocriptine
Cabergoline Quinagolide
1st dopamine agonist since early New, high affinity
for lactotroph
1970
dopamine
receptors
2-3 x/day
5-30mg/day (7.5mg/d)
1-2x/week
0.5-2 mg/wk
Nausea, postural hypotension,
dizziness, headache, depression
Improved efficacy
and few side
effects NEJM 94;
331: 904-909
Start with low dose and increase Most effective
dosage gradually. Start 0.625
in reducing
mg Nocte
tumor size JCEM
2000 85 2247-2252
Duration 2-6 years?
Once daily
0.05-0.25 mg
Duration of treatment
Early studies showed remission is rare
after interruption of therapy, life long
treatment Clin Endo 1991; 34: 173-174
Recent studies showed increase in
remission and therapeutic withdrawal is
recommended J Royal College of Physicians 1997; 31:
628-636
List of studies assessing dopamine agonist withdrawal
Authors
No
Agent
Duration
(month)
Type
Remission FU
(month)
Zarate 83
16
BRC
24
Micro
37.5%
24
Moriondo 84
36
BRC
12
Macro
11%
30
Wang 87
24
BRC
24
Micro
21%
12-48
Rasmussen
87
75
BRC
24
All
44%
>6
Ferari 92
127
CAB
14
All
31%
3-24
Muratori 97
26
CAB
12
Micro
19%
38-60
Colao 03
105
CAB
48
Micro
73%
24-60
Biswas 05
89
67- CAB
22- BRC
37
Micro
31%
>12
Remission
Long term follow up studies of
untreated patients have shown that
prolactinomas are very indolent
Short term therapy appears to induce
cytostatic effects including reduction in
organelle size and reduction in the
volume of prolactin cells JCEM 55, 117981183
Long-term therapy induces cytocidal
effects such as necrosis, fibrosis and
inflammatory cell infiltration JCEM 58,
1179-1183
Pregnancy
Warned that restoration of ovulatory menstral
cycle within weeks
Advised to use mechanical form of
contraception until 2 regular menstrual flow
Stop dopamine agonist as soon as pregnancy
is confirmed for microadenoma, risk of
pituitary enlargement is low <2%
Bromocriptine can cross placenta and
suppress pituitary prolactin secretion, but no
apparent risk of congenital abnormality or
misscarriage JCEM 97 82 996-1000
For macroadenoma, bromocriptine is advised
during pregnancy to avoid significant tumor
expansion as risk of enlargement is 15-30% (J
Reprod Med 99; 44: 1121-6)
Some recommend debulking for
macroadenoma which have extended beyond
the sella before pregnancy and bromocriptime
prescribed throughout pregnancy (Am J O&G 83;
146:935-8)
Cabergoline should not be used as a therapy
for infertility until more information is
available
Surgery
Not first line option as outcomes reported are
variable
Experienced center cure rate 85-90%,
recurrence and complication <10% and
hypopituitarism <1% JCEM 1995 81 1711-1719
Prolactin decrease to very low values
immediately after surgery and gradually to
low-normal over wks, recurrence rate is very
low Meta 1986 35 905-912
Success is less likely (<50%) in
macroadenoma which has extended beyond
the sella JCEM 1995 81 1711-1719
Indications for pituitary surgery
Resistance or intolerance to optimal medical
therapy
For patients with intrasellar tumor for whom
long-term drug treatment is not acceptable
Surgical decompression may be required for
tumors pressing on optic chiasm
Avoid in cases o f extrasellar expanding
tumors without optic chiasm compression
because of low success rate
Hormonal therapy
Fertility is not a concern
For hypogonadism
Prevent progressive bone loss
Macroadenomas
Tend to grow, absolute indication for
therapy
Managed with dopamine agonist
Confined to the sella should be
managed as micraoadenoma as unlikely
enlarged sufficiently to cause serious
complications
Higher doses
Decrease in prolactin levels within 2-3
wks and precedes a decrease in the size
of the tumor and restoration of anterior
pituitary function
Visual field assessment 1 month after
the initiation of therapy
MRI repeated 6 months later
Prolactin measured yearly
Hyperprolactinaemia and
antipsychotic drugs
Hyperprolactinaemia and
antipsychotic drugs
34% of men and 75% of women showed
hyperprolactinaemia (Curr Med Res Opin 2004;20:(2) 18997)
Hypogonadism is common. Mean levels were
in the hypogonadal range for women and
6.4% of men were hypogonadal (Br J Psy
2004;184:503-8)
Sexual dysfunction in 45% compared with
17% of GP clinic control (Br J Psy 2004;184:503-8)
Effects of long term prolactin raising
antipsychotic medication on bone
mineral density in patients with
schizophrenia
Male and post-menopausal female
patients with schizophrenia on longterm prolactin –raising antipsychotic
drugs (>10yr)
British J of Psychiatry 2004; 184; 503-508
Results
Hyperprolactinaemia was present in
62% of the overall group (60% in male
and 64% in female)
57% of the men and 32% of the
women had reduced bone mineral
density
Antipsychotic drugs
A new risk factor for osteoporosis
in young women with
schizophrenia
To study the effect of prolactin-raising
and prolactin-sparing antipsychotic
drugs (olanzapine) on bone density of
premenopausal females
J of clinical psychopharmacology 2005; 25 (1):26-31
Results
Low BMD in 65% of prolactin-raising
group, compared with 17% in prolactinsparing group
Hyperprolactinaemia was associated
with low BMD; 95% with low BMD had
hyperprolactinemia and only 11% of the
group with normal prolactin had
abnormal BMD
Relative percentage distribution of low
BMD in prolactin-sparing and prolactin –
raising groups
Relative percentage distribution of
bone loss in normal prolactin and
hyperprolactinemia
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