Hyperprolactinemia

Dr. Mohammed R. Zughbur Endocrinologist, PhD, MD Al-Shifaa Hospital 2011

Prolactin

Is a polypeptide hormone containing 198 amino acids and having a molecular weight of 22,000 daltons

It circulates in different molecular sizesa (small) form (mol wt 22,000), a (big) form (mol wt 50,000), and an even larger (big-big) form (mol wt >100,000) The small form is biologically active, and about 80% of the hormone secreted is in this form

Dr. Mohammed R. Zughbur

Prolactin

Discovered by Sticker 1928 (Veterinarian) It is one of the stress hormones It has a short half-life (20 min) Sleep-related circadian rhythm , highest in the
early morning & lower in the afternoon

Dr. Mohammed R. Zughbur

Prolactin

Secreted in a pulsatile fashion

Its primary function is to enhance breast development during pregnancy and to induce lactation

However, prolactin also binds to specific receptors in the

gonads, lymphoid cells, and liver

Dr. Mohammed R. Zughbur

Neuroendocrine Regulation of Prolactin Secretion

PIF:
Dopamine Gonadotropin-associated peptide (GAP) Gamma aminobutyric acid (GABA)

PRF
TRH VIP Peptide histidine methionine (PHM)

Dr. Mohammed R. Zughbur

Etiology of Hyperprolactinemia

Pituitary disease Hypothalamic disease Medications TCA Neurogenic Other Idiopathic

Dr. Mohammed R. Zughbur

Pituitary disease

Prolactinomas Acromegaly Empty sella syndrome Lymphocytic hypophysitis Cushings disease

Dr. Mohammed R. Zughbur

Hypothalamic disease

Craniopharyngiomas Meningiomas Dysgerminomas Non-secretory pituitary adenomas Other tumors Sarcoidosis Eosinophilic graniuloma Neuraxis irradiation Vascular Pituitary stalk section

Dr. Mohammed R. Zughbur

Medications

Phenothiazines Haloperidol Monoamine oxidase inhibitorss

Dr. Mohammed R. Zughbur

Tricyclic antidepressants

Reserpine Methldopa Metoclopramide Amoxepin Cocaine Verapamil Fluoxetine Protease inhibitors

Dr. Mohammed R. Zughbur

Neurogenic

Chest wall lesions Spinal cord lesions Breast stimulation

Dr. Mohammed R. Zughbur

Other

Pregnancy Hypothyroidism Chronic renal failure Cirrhosis Pseudocyesis Adrenal insufficiency

Dr. Mohammed R. Zughbur

Idiopathic hyperprolactinemia

One third, prolactin levels return to normal 10-15% of patients, rise in prolactin levels to more than 50% over baseline Over 2-6 yr follow up, evidence of microadenomas developed in 10% of patients

Dr. Mohammed R. Zughbur

Pathogenesis and Natural History of Prolactinomas

Clonal proliferation of a single mutated cell Pituitary tumor transforming gene (PTTG), localized to chromosome 5q33 Correlate with tumor invasiveness in hormone-secreting adenomas Prolactinomas occur in 20% of patients with MEN type 1 More aggressive than sporadic prolactinomas Risk of progression from microadenoma to macroadenoma is only 7% One third return to normal levels

Dr. Mohammed R. Zughbur

Manifestation of hyperprolactinemia
In Females :

Dr. Mohammed R. Zughbur

Galactorrhea (Non-puerperal lactation) Unilateral or bilateral Free floating or expressive Continuous or intermittent Ovulatory dysfunction Oligo-ovulation LPD Anovulation Menstrual troubles Oligomenorrhea Hypomenorrhea Amenorrhea

Osteoporosis Nervous manifestations ( headache ) Visual field defects ( Bitemporal Hemianopia ) Hirsutism

Osteoporosis Nervous manifestations ( headache ) Visual field defects ( Bitemporal Hemianopia ) Hirsutism In men: Impotence Oligospermia Gynecomastia Headache Osteoporosis Visual field defects

Dr. Mohammed R. Zughbur

Diagnosis of Prolactinomas

Prolactin is secreted episodically Nonsecreting tumor causing modest prolactin elevations (usually < 150 ng/ml) Prolactin-secreting macroadenoma (prolactin levels usually > 250 ng/ml) Although modern high-speed helical CT scanners produce very detailed images
MRI is the imaging study of choice

MRI with gadolinium enhancement

MRI can detect adenomas that are as small as 3-5 mm.

Dr. Mohammed R. Zughbur

A "giant" prolactinoma

Dr. Mohammed R. Zughbur

Treatment of Prolactinomas

Observation Surgery Radiotherapy Medical Therapy

Dr. Mohammed R. Zughbur

Observation

Effects of tumor size or effects of hyperprolactinemia 93% microprolaactinomas do not enlarge over 4-6 yr period of observation If prolactin levels rise significantly, repeat scanning 7% will grow to be a macroadenoma Other indications for therapy: decreased libido, sexual dysfunction, menstrual dysfunction, galactorrhea, infertility, hirsutism, premature osteoporosis Without therapy, prolactin levels may return to normal in about one third of patients

Dr. Mohammed R. Zughbur

Management
Remember that there are four main known causes of hyperprolactinemia
1. 2. 3. 4. Pregnancy Drug use Hypothyroidism Pituitary tumors

Remember that it is not essential to treat asymptomatic hyperprolactinemic women but followup is a must
Dr. Mohammed R. Zughbur

Medical treatment goals

1.

Suppressing prolactin secretion and its clinical and biochemical consequences

Reducing the size of the prolactinoma Preventing its progression or recurrence

2. 3.

Dr. Mohammed R. Zughbur

Medical Therapy

Bromocriptine Pergolide Quinagolide Cabergoline

Dr. Mohammed R. Zughbur

Dopamine agonists
Agonist Bromocriptine (Parlodel) Lisuride (Dopergine) Quinagolide (Norprolac) Cabergoline (Dostinex)
Dr. Mohammed R. Zughbur

Nature Ergot Ergot

Dose 2.5-10 mg/day 0.1-0.2 mg/day

Maintenance 7.5 mg/d 0.1 mg/day

Ergot
Ergot

25-300 g/day
0.25-1 mg/TWW

75 g/day
1 mg/week

Side Effects of Bromocriptine Treatment

Most common side effects: nausea and vomiting 3-5% Usually transient but may recur with each dose increase Orthostatic hypotension Digital vasospasm, nasal congestion and depression Minimized by starting with 1.25 mg/d with snack at bedtime Gradually increased to 2.5 mg bid with meals over 7-10 days Higher than 7.5 mg/d usually does not necessary Psychotic reaction 8 of 600 patients, resolve within 72 h of discontinuing the medication

Dr. Mohammed R. Zughbur

Pituitary Surgery

Transsphenoidal approach:
used for 95% of pituitary tumors

Endonasal submucosal transseptal approach Septal Pushover/Direct Sphenoidotomy

Dr. Mohammed R. Zughbur

Dr. Mohammed R. Zughbur

Surgery

Transpheoidal surgery mainly, craniotomy rarely Recurreeence of hyperprolactinemia often occurs within first yr Recurrence rates for microadenomas (21%) and macroadenomas (20%) Long-term surgical cure rate is about 50-60% for microadenomas and 25% for macroadenomas

Dr. Mohammed R. Zughbur

Radiation Therapy

Reserved for patients with larger tumors and/or persistent hormonal hyperfunction despite surgical intervention
Conventional radiotherapy Gamma knife radiosurgery

Dr. Mohammed R. Zughbur

Thank you for your attention