Hyperprolactinemia

Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. Many factors contribute to the development of hyperprolactinemia. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Diagnosis is achieved through hormonal testing to rule out other endocrine conditions and confirmatory imaging tests. Dopamine agonists are the 1st-line drugs for treatment. Refractory cases require surgery and possibly radiation therapy.

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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.
Causes of hyperprolactinemia and feedback loop

The causes of hyperprolactinemia in relation to the regulatory feedback loop of prolactin hormone secretion

Image by Lecturio.

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
Prolactin diagram

The regulatory feedback loop of PRL: Note that TRH has a stimulatory effect on PRL; however, dopamine is the main regulator of PRL secretion.

Image by Lecturio.

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

Diagnostic algorithm for diagnosing hyperprolactinemia

Diagnostic algorithm to follow for a patient presenting with secondary amenorrhea

Image by Lecturio.

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
Prolactinoma

Axial (left) and sagittal (right) MRI images of a prolactinoma (slim arrow)

Image: “Prolactinoma” by Tajana Tešan Tomić et al. License: CC BY 4.0, edited by Lecturio.

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.

References

  1. Kasper, Fauci, Hauser, Longo, Jameson, & Loscalzo. (2015). Harrison’s Principles of Internal Medicine (19th ed., pp. 2266-2267).
  2. Kumar, V., Abbas, A.K., & Aster, J. (2014). Robbins Basic Pathology (9th ed., pp. 719-720).

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