Endocrine

Prolactinoma: Early Detection, Evaluation and Management

CLINICAL ACTIONS:

Prolactinomas are generally benign prolactin-secreting tumors and account for 40-66% of all pituitary adenomas. The vast majority are microadenomas (diameter < 1cm) and suppress the hypothalamic-pituitary gonadal hormonal axis, while 10% are macroadenomas (≥ 1cm) and may cause additional mass effects due to size. Age prevalence varies widely, but they are commonly found in women during childbearing years, in part due to development of menstrual irregularities. Despite their benign nature, if diagnosis is delayed bone loss and vertebral fractures can occur, and the loss of bone density can be permanent.

Clinical signs and symptoms:

Oligo or amenorrhea
Galactorrhea and gynecomastia
Loss of libido and erectile dysfunction
Infertility
Decreased bone density
Mass effect:
- Headache
- Visual field abnormalities

Evaluation:

Endocrine Society practice guideline
- “To establish the diagnosis of hyperprolactinemia, we recommend a single measurement of serum prolactin; a level above the upper limit of normal confirms the diagnosis as long as the serum sample was obtained without excessive venipuncture stress”
History should be obtained to rule out obvious causes of elevated prolactin such as medications
MRI pituitary with and without contrast to assess size and type of tumor
Prolactin levels
- Prolactin levels above 200 µg/L is usually a prolactinoma
- Prolactin levels above 500 µg/L likely indicates a macroprolactinoma
- Prolactin macroadenomas can present with a falsely normal prolactin level due to the “hook effect” (false negative levels if excessive amount of analyte is present)
- When prolactin values are lower than expected in a patient, consider discussion with endocrinologist or clinical pathologist for further guidance
Non-prolactin secreting pituitary adenomas can cause pituitary stalk or hypothalamus compression and consequent prolactinemia
TSH, free thyroxine (FT4), and creatinine levels to exclude secondary causes

Treatment:

Minimal symptoms (mild galactorrhea and normal menses): observation and monitor q6-12 months may be acceptable
Oligo or amenorrhea (pregnancy not desired): oral contraceptives or other estrogen/progesterone combinations
Most patients placed on dopamine agonists
- Cabergoline > bromocriptine in reducing prolactin levels
- Nearly 80% of patients treated with dopamine agonists will normalize prolactin level and reduce the size of their adenoma
Transsphenoidal surgery
- Can result in normal prolactin levels in majority of microadenomas and up to 40% in macroadenomas
- Recommended: When dopamine agonists not tolerated/desired | Acute tumor complications |Visual deficits not corrected with medical therapy
- Recurrence is possible (20% over 10 years)
Radiotherapy
- Rarely used for those cases that do not respond to the above
Chemotherapy
- Temozolamide rarely used with limited success
Follow Up
- Once prolactin levels have improved monitoring is recommended with repeat prolactin levels every 3 to 6 months for the first year and then every 6 to 12 months thereafter
- MRI should be repeated in 1 year for microadenomas or 3 months for macroadenomas after medical therapy is initiated
- Therapy may be tapered after 2 years of treatment for patients with normal prolactin levels and no visible tumor on MRI
- Recurrence rates after stopping dopamine agonists is between 26 to 69% and most likely to occur in the first year, and should be monitored with serial prolactin measurements every 3 months for the first year and annually thereafter

SYNOPSIS:

The prevalence of prolactinomas is reported to be between 35 to 50 per 100,000. They are most commonly seen in women (10:1 ratio female/male) and the usual age range is between 20 to 50 years of age. Dopamine originating in hypothalamic neurons is a principal inhibitory regulator of prolactin release by pituitary lactotrophs and this pathway is the basis of medical treatments. Fortunately, only a minority of microadenomas will continue to grow (< 10%) but early detection, monitoring and a management plan, which may be multidisciplinary, is required for good outcomes. Consider accessing expertise in endocrinology and radiology to ensure correct differential between prolactinoma and non-secreting pituitary adenoma as treatment for the latter is usually surgical, not medical.

KEY POINTS:

Severe adverse effects of dopamine inhibitors are unusual but cabergoline may include compulsive behavior (e.g. excessive gambling) as well as cardiac valvular abnormalities at high doses

Other causes of hyperprolactinemia include
- Pituitary disorders (e.g. Cushing disease)
- Hypothalamic disorders (e.g. non-secreting pituitary adenoma)
- Neurogenic (e.g. chest wall or spinal cord lesions)
- Medical
  - Hypothyroidism
  - Chronic kidney disease
  - Cirrhosis
- Medications
  - Antipsychotics (e.g. phenothiazines)
  - Antidepressants (e.g. tricyclics, MAOIs, SSRIs)
  - Antihypertensives (e.g. verapamil, labetolol)
  - Anticonvulsants (e.g. phenytoin)
  - Prokinetics (e.g. metoclopramide)
  - Hormones (e.g. estrogen)
  - H2 blockers (e.g. cimetidine, ranitidine)
  - Controlled substances (e.g. opiates, cocaine, marijuana)
  - Other (e.g. alcohol)