1. Patients with Hyperprolactinemia Dr WONG Lap Ming

2. Patient 1

3. 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

4. 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.

5. 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.

6. 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

7. 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.

8. 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)

9. Investigation (2)
Morning 17-OH progesterone: 0.7 nmol/L ( ref )
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)
FSH(iu/L)
LH(iu/L)

10. 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.

11. 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.

12. 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.

16. Investigation (6) Ophthalmologist consulted :
Formal perimetry revealed no visual defect.

17. Investigation (6)
What is the next investigation ?

18. Investigation (7) Prolactin : 154350 miu/L
therefore, working diagnosis of macroprolactinoma made.

19. 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.

20. 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

21. 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.

22. 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

23. Discussion (4) Evaluation
History , physical exam, screening blood test, thyroid function test & pregnancy test will virtually exclude all causes except for hypothalamic-pituitary disease.

24. 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

25. 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.

26. 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.

27. 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

28. 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.

29. 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

30. Treatment (1) 1. Observation with careful follow-up ( only for
microprolactinoma)
2. Drug
3. Surgery
4. Irradiation

31. 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.

32. 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.

33. 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.

34. 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.

35. 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.

36. Treatment(7)
In general, surgery in indicated for dopamine-resistant 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.

37. 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 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.

38. 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.

39. Bromocriptine (3)
Analysis of 112 patients with macroprolactinomas revealed that
>50% reduction in size: %
25-50% reduction in size: %
<25% reduction in size: %
no reduction: %
Time course of regression is variable. Some patients had improvement in visual filed in hours with significant change on scan in 2 weeks. Others started to have clinical improvement in 6 weeks.

40. 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.

41. 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.

42. 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.

43. 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.

44. Suggested reading
Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas.
FF Casanueva et al.
Clinical Endocrinology; 2006;65:
Advances in the Treatment of Prolactinomas
MP Gillam et al
Endocrine Review 2006;27:

45. Patient 2

46. 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

47. Physical examination Body weight 29kg ( 50-75%)
Height cm ( 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

48. 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 )
Prolactin miu/L

49. Investigation
MRI brain including hypothalamo-pituitary region: normal ( at 9.4 years old and at 10.7 years old)

50. Progress Breast development since 9.4 years old No symptoms all along
Serial prolactin level showed persistent increase.

51. Serial prolactin level
Age
Prolactin
Age
Prolactin
At 11.7 years old, laboratory applied precipitation for macroprolactin & result corrected.