Hyperprolactinemia

충북의대 전현정

Regulation of prolactin secretion

Predominant inhibitory signalStimulatory signal

Renal clearance

Causes of hyperprolactinemia(1)

Causes of hyperprolactinemia(2)

Causes of hyperprolactinemia(3)

Incidence of hyperprolactinemia (1)

Unselected healthy adult : 0.4 % - 5.0 %

Among women with Amenorrhea : 9%

Among women with galactorrhea : 25%

Among women with amenorrhea and galactorrhea : 70%

Among men with impotence or infertility : 5%

Clinical presentation of hyperprolactinemia (1)

Premenopausal women

31 < PRL < 50 g/L 51 < PRL < 75 g/L 100 g/L < PRL

Hypogonadism Galactorrhea Amenorrhea Oligomenorrhea Short luteal phase

Decreased libido Infertility

Increased body weight – associated with prolactin-secreting tumor Osteopenia – patients with associated hypogonadism Degree of bone loss – related to duration and severity of hypogonadism

Clinical presentation of hyperprolactinemia (2)Men

Decreased libido Impotence – unresponsive to testosterone treatment Decreased sperm production Infertility Gynecomastia Rarely galactorrhea Decreased muscle mass Body hair Osteoporosis

Female Galactorrhea Amenorrhea Oligomenorrhea Infertility History of fracture

Male Low libido Impotence Infertility Gynecomastia Galactorrhea History of fracture or osteoporosis

We should check serum Prolactin level.

Nipple discharge

Rule out breast pathology (by history, physical examination, mammography)

Galactorrhea

Galactorrhea Unilateral Single duct Bloody or Serosanguineous Associated with breast mass

Evaluation for breast tumor

Step 1.

Galactorrhea Bilateral Multiductal Milky (can be yellow, green or brown)

Milk production is in doubt

Sudan IV staining for Fat droplet

Check prolactin

Galactorrhea

Step 2.

Elevated prolactinCheck physiologic or secondary cause 1. Pregnancy history 2. Medication 3. Recent breast / nipple manipulation4. Kidney / Liver disease 5. Check - Thyroid function test - BUN/Creatinine - hCG

Objectives of treatment of hyperprolactinemia

Restoration and maintenance of normal gonadal function Restoration of normal fertility Prevention of osteoporosis

Drug induced hyperprolactinemia

1. Discontinuation of the medication for 3 days or substitution of an alternative drug followed by recheck of serum prolactin 2. PRL Level : 25 to 100 μg/L - Metoclopramide, risperidone, phenothizines > 200 μg/L - associated with variants of the D2 receptor gene

3. If the drug cannot be discontinued and the onset of the hyperprolactinemia does not coincide with therapy initiation Check Sellar MRI

4. Start Estrogen or testosterone therapy - If the drug cannot be discontinued and the patients have hypogondal symptoms

Galactorrhea

Step 3.

Elevated prolactin

Sellar MRI

1. Exclude physiologic or secondary causes2. If, negative clinical symptoms : evaluate macroprolactinemia

To evaluate pituitary lesion

Prolactinoma Hypothalamic stalk interruption

Macroprolactinemia

Definition of macroprolactinemia : elevated Big-Big PRL, over 60%

Mechanism of Elevated prolactin

① Difficult to remove due to big size via kidney

② Difficult to absorption or break down in target tissue

③ Difficult to control H-P axis feedback

Asymptomatic

Type of PRL Size Distribution Monomeric- PRL 23 kDa 85- 95%Big-PRL 50 – 60 kDa 10% Big-Big PRL 150 kDa 5 %(Macro-PRL)

Galactorrhea

Step 3.

Elevated prolactinSellar MRI

Normal & Asymptomatic

Normal & Symptomatic

Microadenoma & Symptomatic

Macroadenoma

Dopamine agonist therapy

Measure other pituitary hormones to exclude associated deficiency or excess

Follow-up Measurement of ProlactinOnce yearly

Objectives of treatment of hyperprolactinemia

Restoration and maintenance of normal gonadal function Restoration of normal fertility Prevention of osteoporosis

If a pituitary tumor is present: Correction of visual or neurological abnormalities Reduction or removal of tumor mass Preservation of normal pituitary function Prevention of progression of pituitary or hypothalamic disease

Measure other pituitary hormones to exclude associated deficiency or excess

Macro-adenoma

Isolated Prolactin excessStalk effect (Prolactin level not high enough for size of tumor)

Pituitary surgery recommendedDopamine agonist therapy

Normal Prolactin level

ReducedProlactin levelAfter 6 months therapy

No effect on prolactin levelAfter 6 months therapy

AsymptomaticSymptomaticdespite prolactinreduction

Pituitary surgery

Measure prolactin levelEvery 4 – 6 months;MRI every 1 – 2 yrs

“Hook effect”

Hook phenomenon

Mildly elevated prolactin level A Very large pituitary tumor

To distinguish 1. Large prolactinoma2. NFPA

Dilution of sample and recheck prolactin

Resistance or intolerance to optimal medical therapy

Instra-sellar tumor for whom long-term drug therapy is not acceptable

Tumors pressing on the optic chiasm

Surgery should be avoided in cases of extrasellar (without optic chiasm compression)

because of the low success rate

Indications for pituitary surgery in patients with hyperprolactinemia

Normal & Sympto-matic

Micro & Sympto-matic

Dopamine agonist therapy

Micro-adenoma

1) Periodic PRL check starting 1 month after therapy2) Repeat MRI in 1 year - if new symptoms : galactorrhea, visual disturbance, headache other hormone disorders

Idiopathic hyperprolactinemia Prolactinoma

Dopamine agonist therapy (Outcomes)

Reduction in tumor size : 62% Resolution of visual field defect : 67% Resolution of amenorrhea : 78% Resolution of infertility : 53% Improvement of sexual function : 67% Resolution of galactorrhea : 86% Normalization of prolactin level : 68%

Normal & Sympto-matic

Micro & Sympto-matic

Dopamine agonist ther-apy

Micro-adenoma

Normal Prolactin level

Reduced prolactin levelAfter 6 months therapy

Prolactin level still elevatedAfter 6 months therapy*

Asymptomatic Symptomatic

Consider pituitary surgeryMeasure prolactin level

Every 4 – 6 months

Dopamine agonist resistance

① A failure to achieve a normal prolactin level on maximum dose ② A failure to achieve a 50 % reduction in tumor size ③ A failure to restore fertility in patients

1. Switch to cabergoline 2. TSA 1) cannot tolerate high doses of cabergoline (11mg/week) 2) who are not responsive to dopamine agonist therapy 3. Radiotherapy 1) who fail surgical treatment

Bromocriptine : 25 % Cabergoline : 10 %

of patients are resistant

Dopamine agonist therapy may be tapered

Undertaken after 2 years who no longer have elevated serum PRL who have no visible tumor remnant on MRI

May be possible to discontinue therapy when menopause occur