Hyperprolactinemia

Overview

Definition

Hyperprolactinemia means abnormally high levels of prolactin (PRL) in the blood.

Normal PRL levels (may vary according to the lab):

• < 23.5–25 ng/mL or μg/L for non-pregnant women
• 80–400 ng/mL or μg/L for pregnant women
• < 20–21.5 ng/mL or μg/L for men

Epidemiology

• Occurs in < 1% of the general population 
• The most common form of pituitary hormone hypersecretion (hyperpituitarism) in both men and women
• Slightly more common in females

Etiology

• Physiologic causes:
  • Pregnancy (most common):
    • During pregnancy, PRL levels rise but are regulated by estrogen and progesterone.
    • After the birth, PRL levels will decrease without nipple stimulation.
  • Nipple stimulation (via breastfeeding/suckling)
  • Stress 
  • Sleep (levels return to normal within an hour of awakening)
• Pathologic causes:
  • Prolactinomas: 
    • PRL-secreting pituitary adenomas caused by a monoclonal expansion of the lactotrophs
    • Approximately 50% of cases are due to the overexpression of pituitary tumor transforming gene (PTTG1) and MEN1 syndrome.
    • Cause approximately 50% of non-pregnant cases
  • Primary hypothyroidism: Low levels of thyroid hormones cause a compensatory increase in thyrotropin-releasing hormone (TRH), a PRL‑releasing hormone.
  • Pharmacologic causes:
    • Any drug that inhibits dopamine secretion or blocks dopamine receptors, because dopamine inhibits PRL secretion
    • Most commonly, antidepressants and antipsychotics
  • Disorders of the hypothalamus or hypothalamic-pituitary region: such as tumors of the hypothalamus (craniopharyngioma), head trauma, surgery, or non–PRL-secreting pituitary adenomas
  • Chest-wall trauma: invokes the reflex suckling arc
  • Chronic renal failure:
    • Produces an increase in PRL levels through a decrease of urinary elimination of the hormone
    • The uremic state will also stimulate the release of PRL.

Pathophysiology

PRL functions and effects

• Growth and development of mammary glands during pregnancy
• Production of breast milk
• Lactational amenorrhea (lack of menstruation during breastfeeding)
• A decrease in sexual drive and reproductive function

PRL regulation

• Secreted by the anterior pituitary gland (lactotroph cells)
• Dopamine inhibits PRL secretion.
• TRH and estrogen stimulate PRL secretion.
• Also stimulated by sleep, exercise, pregnancy, and stress
• Increased levels of PRL inhibit gonadotropin-releasing hormone (GnRH) → decrease in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) → decreases estrogen → cessation of ovulation and menstruation

Pathophysiology

Excessive and prolonged increase in PRL levels →  suppression of GnRH → lower levels of LH, FSH → chronically low estrogen and testosterone → hypogonadotropic hypogonadism

Clinical Presentation

• Varies depending on the degree of increase and cause
• May be asymptomatic (especially in postmenopausal women)
• In men and premenopausal women, hyperprolactinemia presents as hypogonadism: 
  • Infertility due to the cessation of ovulation
  • Amenorrhea (lack of menstruation) or irregular menstrual bleeding
  • Galactorrhea (discharge of milk from nipples in men or non-breastfeeding women)  
  • Decrease in libido
  • Osteoporosis
  • Erectile dysfunction and gynecomastia in men
• Large tumors can present with headaches and visual problems.

Diagnosis and Management

Diagnostic algorithm

Laboratory tests

• Pregnancy testing to rule out pregnancy in premenopausal women
• Repeated measurements of PRL levels to confirm hyperprolactinemia (PRL level > 200 ng/ml in a man or non-pregnant woman → prolactinoma)
• TSH levels should be measured to rule out hypothyroidism (PRL < 100 ng/mL).
• Visual field testing to assess complications
• FSH, LH, testosterone, and estrogen levels will be decreased.

Imaging

• Magnetic resonance imaging (MRI) is the study of choice to identify or confirm pituitary masses.
• Particularly useful in cases with a history of head trauma, headaches, and visual problems

Management

• 1st-line: dopamine agonists to suppress PRL secretion
• The underlying cause should be addressed:
  • Discontinuation of medication in drug-induced cases
  • Surgery might be needed in the case of pituitary adenomas.
  • Medical treatment of primary hypothyroidism
  • Dialysis or renal transplant in the case of chronic renal failure
• If medical therapy fails, transsphenoidal surgery is needed with postoperative radiation.
• Small prolactinomas with minimal symptoms should be followed with serial PRL levels and computed tomography (CT)/MRI scans yearly.

Clinical Relevance

The following conditions should be ruled out in the case of hyperprolactinemia: 

• Hypothyroidism: deficiency of the T3 and T4 hormones. Will present with high levels of TSH and moderately increased PRL levels.
• Chronic renal failure: progressive loss of renal function. Will present with uremic syndrome in patients undergoing dialysis.
• Gigantism/acromegaly: excess production of growth hormone by the pituitary gland, due to a somatotroph adenoma. The tumor will produce an increase in PRL through the inhibition of regulation from the hypothalamus.
• Prolactinomas: tumors from the anterior pituitary that secrete PRL. Prolactinomas present with typical signs and symptoms of elevated PRL levels, with PRL usually over 200 ng/ml. An MRI identifies the location and size of the tumor.
• Pituitary adenomas: tumors that can secrete PRL or other pituitary hormones (growth hormone (GH) or adrenocorticotropic hormone (ACTH)). Pituitary adenomas can disrupt the hypothalamic-pituitary axis, affecting the inhibition of PRL release. An MRI will confirm the diagnosis.