1. General approach to management of hyperprolactinaemia
Dr. But Wai Man

2. 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

3. 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
Like a pair of hands holding the hormone

4. 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

5. 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

7. 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

8. loss of libido and erection dysfunction
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:
In both men and women
Low bone density
Weight gain
Mood and behaviour changes
Related to low testosterone level in men

9. 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

10. Evaluation Biological evaluation of related hormonal axes:
Careful drug history and physical examination
TFT, RFT
PCO
and exclusion of pregnancy

11. Levels of prolactin <1000 m U/L <5000 m U/L > 10,000 m U/L
stress
Micro-prolactinoma
Macroprolactinoma
hypothyroidism
Pituitary stalk disconnection
PCOS

12. Macroprolactinaemia
High molecular-weight prolactin-immunoglobulin complexes
Polyethylene glycol precipitation of complexes allows the measurement of free monmeric prolactin
Not thought to have pathological significance

13. Evaluation for hypothalamic-pituitary pathology
Clinical examination: assessment of visual fields
Imaging : MRI /CT
Pituitary microadenoma < 10mm
Pituitary macroadenoma > 10 mm
Pituitary stalk lesions
Hypothalamic tumours, granulomas

14. Pituitary microadenoma
20% of the normal population at autopsy
50% of MRI imaging
No lesion suggesting microadenoma < 2mm, lactotroph hyperplasia
Hypopituitarism in structural lesion

15. 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

16. Treatment of prolactin-secreting pituitary adenoma
Medical
Surgical
Radiotherapy

17. 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

18. Dopamine agonist Primary treatment of choice
Normalise prolactin levels, restoration of pituitary function and tumor shinkage in 80-90% over several weeks JCEM
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

19. Bromocriptine Cabergoline Quinagolide
1st dopamine agonist since early 1970
New, high affinity for lactotroph dopamine receptors
2-3 x/day
5-30mg/day (7.5mg/d)
1-2x/week
0.5-2 mg/wk
Once daily mg
Nausea, postural hypotension, dizziness, headache, depression
Improved efficacy and few side effects NEJM 94; 331:
Start with low dose and increase dosage gradually. Start mg Nocte
Duration 2-6 years?
Most effective in reducing tumor size JCEM

20. Duration of treatment
Early studies showed remission is rare after interruption of therapy, life long treatment Clin Endo 1991; 34:
Recent studies showed increase in remission and therapeutic withdrawal is recommended J Royal College of Physicians 1997; 31:

21. List of studies assessing dopamine agonist withdrawal
Authors No
Agent
Duration
(month)
Type
Remission FU
Zarate 83 16
BRC 24
Micro
37.5%
Moriondo 84 36 12
Macro
11% 30
Wang 87
21%
12-48
Rasmussen 87 75
All
44%
>6
Ferari 92
127
CAB 14
31%
3-24
Muratori 97 26
19%
38-60
Colao 03
105 48
73%
24-60
Biswas 05 89
67- CAB
22- BRC 37
>12

22. 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,
Long-term therapy induces cytocidal effects such as necrosis, fibrosis and inflammatory cell infiltration JCEM 58,

23. 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

24. For macroadenoma, bromocriptine is advised during pregnancy to avoid significant tumor expansion as risk of enlargement is 15-30% (J Reprod Med 99; 44: )
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

25. Surgery Not first line option as outcomes reported are variable
Experienced center cure rate 85-90%, recurrence and complication <10% and hypopituitarism <1% JCEM
Prolactin decrease to very low values immediately after surgery and gradually to low-normal over wks, recurrence rate is very low Meta
Success is less likely (<50%) in macroadenoma which has extended beyond the sella JCEM

26. 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

27. Hormonal therapy Fertility is not a concern For hypogonadism
Prevent progressive bone loss

28. 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

29. 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

30. Hyperprolactinaemia and antipsychotic drugs

31. Hyperprolactinaemia and antipsychotic drugs
34% of men and 75% of women showed hyperprolactinaemia (Curr Med Res Opin 2004;20:(2) )
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)

33. 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 long-term prolactin –raising antipsychotic drugs (>10yr)
British J of Psychiatry 2004; 184;

34. 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

37. 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

38. Results
Low BMD in 65% of prolactin-raising group, compared with 17% in prolactin-sparing 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

39. Relative percentage distribution of low BMD in prolactin-sparing and prolactin –raising groups

40. Relative percentage distribution of bone loss in normal prolactin and hyperprolactinemia

44. Thanks you