HYPERPROLACTINEMI

A
CAUSES, DIAGNOSIS,
MANAGEMENT
Abdullah M. Kharbosh, B.Sc. Pharm
OPTIONS
Prolactin (PRL)

 1928 Discovered by Sticker 1928 (Veterinarian) in extract

of bovine pituitary.
 1970 Sensitive bioassay.
 1971 RIA (Friesen, Fournier, Desjardians).
 Source:
• Lactotrophs.
• Decidual cells.
- Small form (mol wt 22,000) - 80% of secreted PRL – Active.
- Big form (mol wt 50,000).
- Big-Big form (mol wt >100,000).
 PRL
 Secretion:
- In a pulsatile fashion:
- Highest in the early morning
- Lowest in the afternoon
- No storage, no feedback
 PRL

 Plasma T1/2: 50 min

 Clearance pathway

 Plasma level:
♀:25 ng/ml
♂:20 ng/ml
 PRL

PRL function (action) in Women:

 Breast:
- Stimulate breast development
- Initiate and maintain lactation
• Duct growth: Estrogen
• Lobuloalveolar development: PRL+ Progesterone
• Lactation: PRL + Oxytocin
 Gonad:
- Interrupts GRH pulsatile secretion   Gonadal Steroidogenesis
( LH/FSH)  Amenorrhoea, infertility
 PRL
 PRL Function (Action) In Male (Unclear)
– Sperm production.
– Prostate citrate production.
  PRL  5α-Reductase .
PRL
 Hyperprolactinemia
 Hyperprolactinemia is a state of persistent serum PRL elevation.
 PRL conc. > 20 mcg/L observed on multiple occasions.
 The most common hypothalamic-pituitary axis disorder.
 More commonly occurs in♀ during reproductive age, but it can occurs
in♂.
 Incidence:
- In general population < 1%.
 Prevalence:
- Unselected normal adult population: 0.4%.
- Women with reproductive disorders: 9-17%.
 Age prevalence varies widely
- Have been reported in patients from 2-80 years.
Etiology
 Etiology

Physiologic Factors Cause  PRL

 Persistent, marked elevation:
– Pregnancy (200-500 ng/ml).
 Transient elevation:
– Pain.
– Nipple stimulation (nursing).
– Fondling (women only).
– Pelvic examination.
– Exercise.
– Coitus.
– Eating.
– Sleep.
– Stress (including the stress of phlebotomy).
 PRL
Etiology vs. PRL serum level
20-100 ng/ml Stress of vein puncture (pain), stress
or physical (breast, pelvic) examination
Repeat (∵ pulsatile secretion)
100-150 ng/ml Prolactinoma, drug-induced
Modest elevation, rarely exceeding 150 ng/ml Interference with dopamine action
150 ng/ml Prolactinoma
The upper normal limits> PRL level <100 ng/ml Psychoactive drugs, oestrogen, or
functional (idiopathic) causes, but can
also be caused by Microprolactinemias
PRL level > 150 ng/ml (5 X normal value) Prolactinomas
Typically associated with levels > 250 ng/ml Macroadenomas
> 1000 ng/ml Tumor extension into cavernous sinus
200-500 ng/ml Pregnancy
 Diagnosis

Remember
 Hyperprolactinemia inhibits gonadotropin secretion.

 Hyperprolactinemia inhibits sex-steroid synthesis.

 Very large tumours (macro or giant adenomas) cause neurological

manifestations due to space-occupying & optic chiasm compression.
 Hyperprolactinemia-induced prolonged estrogen suppression  bone
mineral density (BMD) & significantly  the risk for osteoporosis.
 Untreated hyperprolactinemia may  IHD risk.
 Diagnosis
Clinical Presentation
 Signs & symptoms (When to check PRL?)
Female (PRL >60 mcg/L = Anovulation, typically present with):
• Menstrual irregularities 60-90% (oligo or amenorrhea) & infertility.
• Galactorrhea ≈ 30-80%.
• Estrogen deficiency: vaginal dryness  libido, hirsutism,
dyspareunia.
Male
• Headache (63%).
• Visual abnormality .…blindness (an exceptional event).
• Hypogonadism.
- libido↓ (83%). - Adiposity -  muscle mass (70%).
- Impotence. - Galactorrhea (14-33%).
- Erectile dysfunction. - Gynecomastia.
- Infertility.
 Diagnosis
Diagnostic Algorithm
 Before PRL sample collection: rest for 2hrs.

 Role out drug-induced  careful Med. Hx.

 Evaluate the presence of preg, hypothy, RF,

hepatic dysfunction.
 Exclude potential 2ndry causes.

Guidelines of the pituitary society. Clinical Endocrinology (2006) 65, 265-273.

 Diagnosis
 Prolactinoma diagnosis (Confirmation)
- Lab evidence: Sustained (multiple)  PRL level measurements.
- Radiographic evidence: Effectiveness with large (macro) > small (micro).
 Effectiveness of CT-Scan < MRI in small adenomas detection.

 Normal MRI ≠ No microadenomas (Present in ≈10% normal population).

- Alternative (empirical confirmation of the diagnosis)

 Pharmacological (Dopamine agonists) treatment:

- For several months.

- With serial PRL level & adenoma size assessment.

Guidelines of the pituitary society. Clinical Endocrinology (2006) 65, 265-273.

 Diagnostic Pitfalls
 Macroprolactinemia = Pseudo-hyperprolactinemia

 Up to 20%.
 PEG ppt.
 Measure in patients with:
o Moderately elevated PRL (25-150 mcg/l) &
o Less typical symptoms: headaches or  libido + regular menses.
 Diagnostic Pitfalls
 The Hook Effect

 To overcome:
- Perform PRL assay at 1:100 serum dilution.

 Role out hook effect in:

- All new patients with macroadenomas.

with
- Normal or mildly elevated PRL levels.
 Prolactinomas
 Generally classified (according to size):
– Microadenomas (< 10 mm in diameter).
– Macroadenomas (> 10 mm in diameter).
 Over 90% of prolactinomas are:
– Small.
– Intrasellar.
– Rarely  size.
 Occasionally, can be:
– Aggressive, progressive.
– Locally invasive.
– Compress on vital structures “mass effect”.
 Very rarely, can be malignant:
– Resistant to therapy.
– Disseminates inside & outside the CNS.
 Familial prolactinomas also described (a genetic component?).
 Prolactinomas
Pituitary Adenomas
 About 40% of all pituitary adenomas are prolactinomas.

 Prolactinoma (PRL-Secreting) 40-50% (2/3 Micro, 1/3 Macro)

 Non-functioning adenoma 30%
 Gonadotroph cell adenoma 10-15%
 Acromegaly (GH-Secreting) 10%
 Prolactinomas
• Premenopausal women Women
• Micro “Most common”.
• Oligo/amenorrhea: 90%.
• Galactorrhea: up to 80%.
• Anovulatory infertility.
• Postmenopausal women
• No classical symptoms.
• Large adenoma - Macro “mass effect”.
• If taking HRT: Galactorrhea.
• Macro “Most common”- mass effect. Men
• Due to delayed recognition.
• Usually cause: impotence, infertility, &  libido.
• Uncommon, but if occur, Macro - “mass effect”. Children
• Delayed puberty in both sexes.
• Primary amenorrhea & Galactorrhea in girls.
 Drug-Induced

* Rarely reported
 Drug-Induced

Antipsychotics

Atypical Typical
3+ Risperidone 3+ Phenothiazines
2+ Molindone 3+ Butyrophenones
0 Clozapine
+ Quetiapine
0 Ziprasidone

0: No effect; +: Increase to abnormal levels in a small % of patients; 2+: Increase to abnormal levels in 25-
50% of patients; 3+: Increase to abnormal levels in > 50% of patients;

Adapted from: Molitch M.E. (2005) Medication induced hyperprolactinemia. Mayo Clinic Proceedings.
 Drug-Induced
Antidepressants
Other SSRIs MAOIs Tricyclics
0 Nefazodone CR Fluoxetine 0 Aripiprazole + Amitryptyline
0 Bupropion  Paroxetine + Olanzapine + Desipramine
0 Venlaflaxine  Citalopram 3+ Pargyline 3+ Chlomipramine
0 Trazodone  Fluvoxamine 3+ Clorgyline - Nortriptyline
MAOIs: monoamine oxidase inhibitors  Tranylcypromine CR Imipramine
SSRIs: selective serotonin re-uptake
inhibitors. CR Maprotiline
CR Amoxapine
0: No effect; : Minimal increase but not to abnormal level; +: Increase to abnormal levels in a small % of
patients; ++: Increase to abnormal levels in 25-50% of patients; 3+: Increase to abnormal levels in > 50%
of patients; CR: Isolated case reports of hyperprolactinemia but generally no increase in PRL levels.

Adapted from: Molitch M.E. (2005) Medication induced hyperprolactinemia. Mayo Clinic Proceedings.
 Drug-Induced

 PRL levels do NOT typically rise to >150 mcg/L (modest elevation).

 Measurement PRL level prior to the initiation of a known cause of
PRL elevation (may):
– Obviate the need for extensive pituitary function examination.
– Aid with the appropriate diagnosis.
 Who Should Be Treated?
Should be treated
 All macro, most micro req treatment. 
 Indications for treatment include:
– Infertility
– A pituitary tumour with neurological
effects (particularly visual defects)
– Bothersome galactorrhea
– Long-standing hypogonadism
– Alterations in pubertal development
– Prevention of bone loss in ♀
because of hypogonadism
 Mild hyperprolactinemia with regular
menses if pregnancy is desired
Shouldn’t be treated
Premenopausal ♀ with normal menstrual
cycles & tolerable galactorrhea
 Postmenopausal ♀ with tolerable
galactorrhea who have idiopathic
hyperprolactinemia or microprolactinoma
 Should be reassured & not actively
treated
 Must carefully followed with periodic
PRL check to detect potential
enlarging tumors
 Goals of Therapy
 If Asymptomatic:
Observe & closely follow-up
 If Symptomatic:
PRL- Secreting Microadenomas (alleviate symptoms):
- Normalizing PRL level
- Restoring menstruation
- Re-establish gonadotropin secretion to:
- Restoring fertility
- Osteoporosis risk reduction
PRL- Secreting Macroadenomas (be aggressive):
- Normalizing PRL level
- Tumor shrinkage
- Visual defects correction
 Management Options
 Hyperprolactinemia treatment depends on the underlying cause:
 If Drug
D – induced… management options include:
1) Discontinue offending medication
2) Initiate an appropriate alternative
3) If no alternative: dopamine agonists
• Only after careful psychiatric counseling
 If Prolactinomas…
P management options include:
1) Clinical observation
2) Medical therapy (dopamine agonists)
3) Transsphenoidal surgical removal
4) Radiation therapy
 Dopamine Agonists
 Proven to be very effective in:
- Normalizing PRL level
- Restoring menstruation
- Significantly  Tumor size
 Approx. 80-90% of patients achieve goals  3 to 6 months
 Recommended as primary therapy (bromocriptine & cabergoline) for:
- Hyperprolactinemia
- Prolactinomas (all sizes)
 Indication: amenorrhea, infertility or bothersome galactorrhea
 Bromocriptine
 The first DA, the mainstay of therapy for over 20 yrs (1970s)
 Short acting, less expensive
  PRL within 2 hrs, max. supp. after 8 hrs, lasts x 24 hrs
 Initial dose: 0.625-2.5 mg HS,  by 1.25 mg at weekly intervals
 Therapeutic dose: 2.5-15 mg/d; doses up to 40 mg/d may be required
- Given in BID or TID, but OD shown to be effective
 Normalizes PRL, restores gonadotropin production, shrinks tumor size
in ≈ 90% of patients with prolactinomas
 The most common ADRs: (intolerance rate:12% of patients)…
- CNS: headache, lightheadedness, dizziness, nervousness, fatigue
- GIT: nausea, abdominal pain, diarrhea (give with food)
 Vaginal preparations: an effort to  ARDs incidence
 Cabergoline
 long-acting DA, high selectivity & affinity for D2-receptors.
 Short acting, less expensive.
 Effectively  PRL in 80-90%,  tumor size (both micro/macro)
  PRL within 2 hrs, max. supp. after 8 hrs, lasts x 24 hrs.
 Initial dose: 0.625-2.5 mg HS,  by 1.25 mg at weekly intervals.
 Therapeutic dose: 2.5-15 mg/d; doses up to 40 mg/d may be required.
- Given in BID or TID, but OD shown to be effective.
 Normalizes PRL, restores gonadotropin production, shrinks tumor size in ≈ 90%
of patients with prolactinomas.
 The most common ADRs: (intolerance rate:12% of patients)…
- CNS: headache, lightheadedness, dizziness, nervousness, fatigue.
- GIT: nausea, abdominal pain, diarrhea (give with food).
 Vaginal preparations: an effort to  ARDs incidence.
Bromocriptine or Cabergoline
 Large comparative studies of BC & CAB demonstrated:
 Superiority of CAB in terms of:

- Tolerability
- Convenience
  PRL secretion

- Gonadal function restoration

  Tumor size
 Transsphenoidal Surgery
(Neurosurgery)
 Effective in in removing prolactinoma
 Immediate removal of the tumor
 An option of choice if therapy failed
 Indication
• Failure of therapy
• Evidence of mass effect despite therapy
 Complications
• Infection
• CSF leakage
 Radiotherapy

 Some effectiveness in reducing PRL

 Slow
 Less completely
 Alternative therapy (generally not recommended as primary therapy)
 Indication:
- Post-operation recurrence
 Management
 Management of hyperprolactinemia in women

.N Engl J Med 2003;349:2035-41

 Management
 Recommended Treatment Algorithm For Prolactinomas

Felipe F. Casanueva, Mark E. Molitch, et al. Guidelines of the pituitary society for the diagnosis &
management of prolactinomas. Clinical Endocrinology (2006) 65, 265-273.
 Management

 Management: If pregnancy is desired

 If macro, shrink size before pregnancy with bromocriptine
(36% will develop neurologic symptoms)
 If causing major visual defect and unresponsive, consider
transspenoidal surgery before pregnancy
 Bromocriptine until pregnancy occurs, then stop
 Management
 Management: During pregnancy
Visual field check q2-3 mos. and MRI PRN
 If neurologic symptoms occur during pregnancy, usually
about 14wga, restart treatment.
 If severe (large tumor, neurological S/S), unresponsive
to treatment ( in size):
- 2nd trimester: consider surgery
- 3rd trimester: wait till delivery (close monitoring)
 Safety of Dopamine Agonists
 Bromocriptine & Cabergoline use prior or during pregnancy
 Not associated with increased problems

 Best to limit embryo exposure to DA as much as possible

 Stop once 1st menstrual period missed & +Ve preg. test obtained

 Cabergoline has very prolonged action: PRL  up to 120 days

 In patients with macro undergoing rapid tumor expansion

• Continue BC throughout pregnancy

 Summary

• Unlike other pituitary hormones PRL secretion is  by hypothalamus

• Hyperprolactinemia has several etiologies, but most common causes
are PRL-secreting adenomas, known as prolactinomas, & various
medications
• In patient with mild hyperprolactinemia taking a psychoactive drug,
Verapamil, or oestrogen, the drug is probably responsible
• Dopamine agonists therapy is more effective than neurosurgery for both
types of prolactinomas
• Because most patients are women wit a principal complaint of infertility,
the safety of bromocriptine in pregnancy must be considered
• Radiation therapy may require several years for effective tumor
shrinkage & reduction in PRL level, & is usually used only in conjunction
with surgery
 References
1. Molitch ME. Disorders of prolactin secretion. Endocrinol Metab Clin North Am
2001;30:585–610.
2. Mah PM, Webster J. Hyperprolactinemia: etiology, diagnosis and
management. Semin Reprod Med 2002;20:365–373.
3. Molitch ME. Medical treatment of prolactinomas. Endocrinol Metab Clin North
Am 1999;28:143–169.
4. Davies PH. Drug-related hyperprolactinaemia. Adverse Drug React Toxicol
Rev 1997;16:83–94.
5. Marken PA, Haykal RF, Fisher JN. Management of psychotropic-induced
hyperprolactinemia. Clin Pharm 1992;11:851–856.
6. Molitch M.E. (2005) Medication induced hyperprolactinemia. Mayo Clinic
Proceedings, 80, 10501057.