A. Types of Tumors

1. Usually benign tumors derived from secretory cells
2. Prolactinoma - most common [2]
3. Growth Hormone Secreting Tumors (Acromegaly) [5]
4. Thyrotrophin Secreting Tumors
5. Corticotropin Secreting Tumors (Cushing's Disease)
6. Tumors Divided By Size as well:
   1. Microadenoma: <10mm diameter
   2. Macroadenoma: >10mm diameter
   3. Most macroadenomas secrete prolactin

B. Symptoms

1. Symptoms are related to hormone production and/or mass effects
2. Symptoms due to Pituitary Mass Lesion
   1. Headache - may be severe [3]
   2. Photophobia
   3. Cranial Nerve III problems - double vision
   4. May mimic aseptic meningitis
   5. Pituitary rupture and hemorrhage ("apoplexy") have similar symptoms
3. Symptoms due to hormone excess are specific to type of hormone
4. About 10% of asymptomatic adults have pituitary masses by magnetic resonance (MRI)

C. Diagnosis

1. Hormone radioimmunoassay
2. MRI with gadolinium contrast is best for visualization of lesion

D. Therapeutic Overview

1. Multimodality therapy is usually required for best results
2. Transphenoidal (sterotactic) surgery
3. Radiation therapy [4]
   1. Usually for recurrent tumors
   2. Also for patients who do not undergo surgery
   3. Leads to 80-100% regression when used in conjunction with surgery
4. Hormone suppression therapy
   1. Somatostatin Analogs
   2. Dopamine Agonists
   3. Specific receptor blocking drugs - experimental

E. Prolactinoma [1,2]

1. Most common type of pituitary tumor
2. Increased prolactin (PRL) secretion leads to hyperprolactinemia including:
   1. Amenorrhea
   2. Galactorrhea
   3. Infertility
   4. Osteoporosis ensues due to suppression of estrogen production
3. Causes of Hyperprolactinemia
   1. Non-Pituitary Brain Tumors
   2. Pituitary Macroadenomas and some microadenomas
   3. Infiltrative disease: sarcoidosis, tuberculosis, histiocytosis, giant cell granuloma
   4. Pseudotumor cerebri
   5. Cranial irradiation
   6. Acromegaly
   7. Cushing's Disease
   8. Empty Sella Syndrome
   9. Drugs (see below)
   10. Primary hypothyroidism
   11. Chronic renal failure
   12. Cirrhosis
   13. Neurogenic - chest wall, spinal cord lesions, or breast stimulation
   14. Idiopathic
4. Drug Induced Hyperprolactinemia
   1. Usually associated with inhibition of dopamine D2 receptors in pituitary
   2. Typical neuroleptics: phenothiazines, butyrphenones, metaclopramide
   3. Respiridone (an atypical neuroleptic)
   4. Tricyclic antidepressants
   5. Verapamil
   6. Uncommon: a-methyldopa, reserpine
5. Diagnosis
   1. Prolactin (PRL) secretion is pulsatile
   2. Normal PRL levels are <25ng/mL women, <20ng/mL men
   3. Normal 10X increase in PRL levels in pregnancy
   4. Single PRL level >40ng/mL usually diagnostic
   5. Repeat PRL level if 25-40ng/mL prior to making diagnosis
   6. Neuroradiological studies, usually MRI, are indicated as well
6. Objectives of Therapy [1]
   1. Suppression of excessive hormone secretion
   2. Tumor removal to reverse mass effects
   3. Preservation of residual pituitary function
   4. Prevention of disease recurrence
7. Medical Therapy [4]
   1. Plays a central role in treatment of prolactinomas
   2. Use of dopamine agonists is first line therapy for macroadenomas
   3. Agents reduce size and PRL production from micro- and macroadenomas
   4. Macroademonas should always be treated
   5. Dopamine agonists bromocriptine or cabergoline are used
   6. Quinagolide (Norprolac®), another D2 agonist, is awaiting approval in USA
   7. Duration of therapy recommended >18 months
   8. Contraception should be used until two normal menstrual cycles have occurred
   9. PRL normal for 2 years and tumor <50% of original, begin medical therapy taper [2,7]
   10. Macroadenomas usually recur after cessation of dopamine agonists [7]
   11. Careful followup with imaging and PRL levels after cessation of therapy is critical
8. Bromocriptine (Parlodel®)
   1. Bromocriptine is a D1 and D2 dopamine agonist (ergot derivative)
   2. 2.5mg po bid restores menses in >50% of women and shrinks macroadenomas
   3. Used in pregnancy or if pregnancy desired due to long term safety studies
   4. Initial dose is 0.625mg po qhs with a snack
   5. After one week, add 1.25mg po qam
   6. Dose increased by 1.25mg po qd after 1 week to dose of 5mg po daily divided
   7. Maximum dose 7.5mg po daily divided
   8. Check serum PRL levels after 1 month on full dose
   9. Side effects: nausea, orthostatic hypotension, depression (minimized by nightly dosing)
9. Cabergoline (Dostinex®) [7]
   1. D2 dopamine selective agonist
   2. More effective and better tolerated than bromocriptine
   3. Usual starting dose of cabergoline is 0.25mg twice weekly at night
   4. Increase dose to 0.5-1.0 mg twice weekly if needed
   5. Cabergoline also shows shrinkage of macroadenomas resistant to bromocriptine
   6. Reduced incidence of side effects compared with bromocriptine
   7. Also effective in non-tumoral hyperprolactinemia
   8. Drug may be withdrawn slowly after 2 years of normalized PRL (and tumor shrinkage)
10. Surgery
    1. Excellent results for microadenomas (>70% complete responses)
    2. Restores normal menses and eliminates galactorrhea in 85-90% of patients
    3. Macroadenomas have 32% initial cure and 19% recurrence rate
    4. Surgery is still used for debulking macroadenomas
    5. However, medications are very effective for shrinking tumors
11. Radiotherapy
    1. For large invasive macroadenomas which fail medical shrinkage
    2. Gradually decreases PRL concentrations, reaching normal levels over 10 (ten) years
    3. Prevents further growth of tumors
    4. Rarely applied to PRL secreting tumors (more common for other types)

References

1. Colao A and Lombardi G. 1998. Lancet. 352(9138):1455
2. Schlechte JA. 2003. NEJM. 349(21):2035
3. Embil JM, Kramer M, Kinnear S, Light RB. 1997. Lancet. 350:182
4. Estrada J, Boronat M, Mielgo M, et al. 1997. NEJM. 336(3):172
5. Melmed S. 2006. NEJM. 355(24):2558
6. Cabergoline. 1997. Med Let. 39(1003):58
7. Colao A, Di Sarno A, Cappabianca P, et al. 2003. NEJM. 349(21):2023