Abdullah M. Kharbosh, B.Sc. PharmAbdullah M. Kharbosh, B.Sc. Pharm

HYPERPROLACTINEMIHYPERPROLACTINEMIA A

CAUSES, DIAGNOSIS, CAUSES, DIAGNOSIS, MANAGEMENT MANAGEMENT

OPTIONSOPTIONS

19281928 Discovered by Discovered by Sticker 1928 Sticker 1928 (Veterinarian) in (Veterinarian) in extract extract

of bovine pituitary.of bovine pituitary. 19701970 Sensitive bioassay.Sensitive bioassay. 19711971 RIA (Friesen, Fournier, Desjardians).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).

Prolactin (PRL)Prolactin (PRL)

Secretion:- In a pulsatile fashion:

- Highest in the early morning- Lowest in the afternoon

- No storage, no feedback

PRLPRL

Plasma T1/2: 50 min

Clearance pathway

Plasma level:♀:25 ng/ml♂:20 ng/ml

PRLPRL

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

PRLPRL

PRL Function (Action) In Male (Unclear)PRL Function (Action) In Male (Unclear)– Sperm production.– Prostate citrate production.

PRL 5α-Reductase .

PRLPRL

PRLPRL

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.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.

HyperprolactinemiaHyperprolactinemia

EtiologyEtiology

Physiologic Factors Cause PRL Persistent, marked elevation:

– Pregnancy (200-500 ng/ml).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).

EtiologyEtiology

Etiology vs. PRL serum levelStress of vein puncture (pain), stress or physical (breast, pelvic) examinationRepeat ( pulsatile secretion)∵

20-100 ng/ml

Prolactinoma, drug-induced100-150 ng/ml

Interference with dopamine action Modest elevation, rarely exceeding 150 ng/ml

Prolactinoma 150 ng/ml

Psychoactive drugs, oestrogen, or functional (idiopathic) causes, but can also be caused by Microprolactinemias

The upper normal limits> PRL level <100 ng/ml

Prolactinomas PRL level > 150 ng/ml (5 X normal value)

Macroadenomas Typically associated with levels > 250 ng/ml

Tumor extension into cavernous sinus> 1000 ng/ml

Pregnancy 200-500 ng/ml

PRL PRL

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 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 Diagnosis

Diagnostic Algorithm

Diagnosis Diagnosis

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

Before PRL sample collection: 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.

Diagnosis Diagnosis

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

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.

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 PitfallsDiagnostic Pitfalls

Diagnostic PitfallsDiagnostic 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.

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 Prolactinomas

Pituitary AdenomasPituitary 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 Prolactinomas

Women • Premenopausal 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.

Men • Macro “Most common”- mass effect.• Due to delayed recognition.

• Usually cause: impotence, infertility, & libido.

Children • Uncommon, but if occur, Macro - “mass effect”.• Delayed puberty in both sexes.• Primary amenorrhea & Galactorrhea in girls.

Prolactinomas Prolactinomas

Drug-InducedDrug-Induced

* Rarely reported

Drug-InducedDrug-Induced

Antipsychotics

Typical Atypical

Phenothiazines 3+Risperidone 3+

Butyrophenones 3+Molindone 2+

Clozapine 0

Quetiapine +

Ziprasidone 0

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-InducedDrug-Induced

Tricyclics MAOIsSSRIsOther

Amitryptyline +Aripiprazole 0Fluoxetine CRNefazodone 0

Desipramine +Olanzapine +Paroxetine Bupropion 0

Chlomipramine 3+Pargyline 3+Citalopram Venlaflaxine 0

Nortriptyline -Clorgyline 3+Fluvoxamine Trazodone 0

Imipramine CRTranylcypromine MAOIs: monoamine oxidase inhibitors SSRIs: selective serotonin re-uptake inhibitors. Maprotiline CR

Amoxapine CR

Antidepressants

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-InducedDrug-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?Who Should Be Treated?

Should be treatedShould 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 treatedShouldn’t be treated Premenopausal 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

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

Goals of TherapyGoals of Therapy

Hyperprolactinemia treatment depends on the underlying cause: If DIf Drug – induced… management options include:

1) Discontinue offending medication2) Initiate an appropriate alternative3)3) If no If no alternative: dopamine agonists

• Only after careful psychiatric counseling If PIf Prolactinomas… management options include:

1) Clinical observation2) Medical therapy (dopamine agonists)3) Transsphenoidal surgical removal4) Radiation therapy

Management OptionsManagement Options

Dopamine AgonistsDopamine 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 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 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 CabergolineBromocriptine 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 SurgeryTranssphenoidal Surgery(Neurosurgery)(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

Some effectiveness in reducing PRL Slow Less completely Alternative therapy (generally not recommended as primary therapy) Indication:

- Post-operation recurrence

RadiotherapyRadiotherapy

Management of hyperprolactinemia in women

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

Management 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

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

Management: Management: During pregnancyVisual 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)

Management Management

Safety of Dopamine AgonistsSafety 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

• 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

Summary Summary

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.

ReferencesReferences