Lecture

• Prolactin


  A polypeptide hormone containing 198 amino acids, with molecular weight of 22,000 daltons
• Circulating forms of prolactin

  • Small (mol wt. 22,000)
  • Big (mol wt. 50,000)
  • Big-big (mol wt. >100,000)
• The small form of prolactin is biologically active and 80% of the hormone is secreted in this form

  
• Lactotrophs


  Chromophobe cells in the pituitary gland where prolactin is stored, located mainly in the lateral areas of the gland
• Prolactin is also synthesized in decidua and endometrial tissues and secreted into the circulation and amniotic fluid if pregnancy occurs
• Prolactin levels in adult women

  Mean levels of 8ng/ml
• Half-life of unbound prolactin

  20 minutes
• Main functions of prolactin


  • Stimulate growth of mammary tissues (mammogenic)
  • Secrete milk into the alveoli (lactogenic)
• Prolactin receptors are present in the plasma membranes of mammary cells and many other tissues
• Prolactin synthesis and release control

  1. Inhibition by dopamine (major physiologic inhibitor)

  2. Stimulation by serotonin and thyrotropin-releasing factor
• There is no hypothalamic pituitary releasing factor (PRF) identified
• The rise in prolactin levels during sleep appears to be controlled by serotonin
• Prolactin secretion pattern


  Episodic, with serum levels fluctuating throughout the day and menstrual cycle, with peak levels at midcycle
• There is a decline in basal prolactin concentration and pulse frequency during the luteal phase of the menstrual cycle
• Estrogen levels


  Stimulate prolactin production and release, increasing prolactin levels in females at puberty and during pregnancy
• Estrogen inhibits the action of prolactin on the breast, preventing lactation during pregnancy
• Prolactin levels decline rapidly after delivery, and lactation is initiated
• Other stimuli for prolactin production

  • Nipple and breast stimulation
  • Exercise, sleep and stress
  • Noonday meal
• Maximal prolactin levels are observed during nighttime while asleep, with a smaller increase in the early afternoon
• The best time to obtain a blood sample for prolactin level determination is in the morning, after a period of rest and without any recent exercise, stress and breast manipulation
• If prolactin elevation is less than 70 mIU/ml, the test should be repeated after 1 hour of rest in a quiet room
• Hyperprolactinemia


  Elevation of prolactin beyond physiologic levels, usually >20 to 25 ng/ml
• Effects of hyperprolactinemia


  • Disorders of gonadotrophin and sex-steroid function resulting in menstrual cycle derangement (oligomenorrhea and amenorrhea), anovulation and improper lactation or galactorrhea
• Mechanism of gonadotrophin interference by hyperprolactinemia

  1. Alterations in GnRH release due to a rise in hypothalamic dopamine levels by a short-loop feedback which fails to inhibit prolactin

  2. Interference with the positive estrogen effect on midcycle LH release

  3. Direct inhibition of basal and gonadotrophin-induced ovarian secretion of estradiol and progesterone
• Hyperprolactinemia is present in 15% of all anovulatory women and 20% of all women with amenorrhea of undetermined cause
• Galactorrhea


  Non-puerperal secretion of watery or milky fluid from the breasts that contains neither pus nor blood
• The diagnosis of galactorrhea is confirmed by observing multiple fat droplets in the fluid when it is examined under low power magnification
• 62% of women with galactorrhea have hyperprolactinemia, and 30-80% of women with hyperprolactinemia have galactorrhea
• The incidence of hyperprolactinemia is higher (88%) in those women with galactorrhea who have amenorrhea and low estrogen levels than in those women with galactorrhea and normal menses, oligo- or amenorrhea with normal estrogen levels (49%)
• Causes of hyperprolactinemia


  • CNS disorders (hypothalamic and pituitary causes)
  • Hypothyroidism
  • Chronic renal disease
  • Chronic stimulation of the breast nerve
  • Pharmacologic agents
• Hypothalamic causes of hyperprolactinemia


  • Diseases of the hypothalamus that produce alterations in the normal portal circulation of dopamine
• Hypothalamic diseases causing hyperprolactinemia

  • Craniopharyngioma
  • Infiltration of the hypothalamus by sarcoidosis, histiocytosis, leukemia, or carcinoma
• Pituitary causes of hyperprolactinemia


  • Pituitary tumors (adenomas)
  • Lactotroph hyperplasia
  • Empty sella syndrome/Primary empty sella syndrome
  • Prolactinomas
• Prolactinomas


  • Present in more than 1 in 10 individuals in the general population
  • 50% of women with hyperprolactinemia have a prolactinoma
  • Higher incidence when PRL > 100 ng/mL, and nearly all individuals with PRL > 200 ng/mL have a prolactinoma
  • Incidence is higher in individuals with a more profound disturbance of hypothalamic-pituitary-ovarian function
  • If galactorrhea is the only symptom (no hyperprolactinemia and oligomenorrhea or amenorrhea), radiologic imaging is not necessary
  • Microadenomas rarely progress, with 7-25% showing regression and a benign clinical course, and pregnancy is beneficial for women with functional hyperprolactinemia or PRL-secreting microadenoma
• Hypothyroidism as a cause of hyperprolactinemia

  Decreased negative feedback of T4 on HPO axis = TRH increase = PRL production
• Chronic renal disease as a cause of hyperprolactinemia


  Due to decrease in metabolic clearance
• Other causes of hyperprolactinemia


  • Any chronic stimulation of the breast nerve (e.g. herpes zoster, chest trauma)
  • Pharmacologic agents
• Signs and symptoms of hyperprolactinemia

  • Oligomenorrhea or amenorrhea
  • Galactorrhea
  • Visual disturbances (observed among patients with very large tumors)
• Diagnostic techniques for hyperprolactinemia

  • Blood tests (prolactin, FSH, estradiol, TSH, ACTH, thyroid function tests, insulin tolerance tests)
  • Imaging techniques (hypocycloidal tomogram, CT scan, MRI)
  • Visual field determination (for large macroadenomas)

  
• Management of hyperprolactinemia


  • Expectant treatment (for functional hyperprolactinemia or microadenoma without desire for pregnancy)
  • Medical therapy (bromocriptine, methysergide, metergoline, cabergoline for macroadenomas or microadenomas in anovulatory women desiring pregnancy)
  • Surgical treatment (transphenoidal microsurgical resection for those who fail to respond to medical therapy)
  • Radiation treatment (only as adjunctive for incomplete operative removal of large tumors)