• Overview:hCG
  • hCG -- produced by the placenta; excreted into the urine
  • glycoprotein; 92-amino acid a-chain + 145-amino acid b-chain.
    • a-chain-- closely resembles FSH, LH, TSH a-chain
    • b-chain-- closely resembles LH b-chain
    • Similar to LH structurally;
    • Used to treat women & men with LH deficiency
  • Function:hcG
    • Ovarian corpus luteum stimulation to produce progesterone
    • placental maintenance

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• Pharmacokinetics:hCG
  • intramuscular administration; well-absorbed
  • half-life: 8 hours (compared to LH half-life -- 30 minutes)

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• Pharmacodynamics:hCG
  • human chorionic gonadotropin (hCG) stimulates gonadal steroid hormone production
    • Cells affected:
      • female: interstitial & corpus luteum cells produce progesterone
      • male: Leydig cells produce testosterone
    • hCG administration: simulates midcycle LH surge ® promote ovulation in hypogonadotropic states

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• Clinical Uses:hCG
  • Diagnostic:hCG
    • pre-pubertal boys with undescended gonads: hCG can distinguish between retained testes (cryptorchid) and retracted testes (pseudocryptorchid)
      •  if transient testicular descent occurs with hCG administration ®permanent pubertal descent
      •  if transient testicular descent does not occur with hCG administration, orchiopexy will be required to insurer spermatogenesis
    • Constitutional puberty delay vs. hypogonadotropic hypogonadism: distinguished using repetitive hCG administration
      •  with hCG administration: serum testosterone & estradiol levels increase in constitutional puberty delay -- not in hypogonadotropic hypogonadism states

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  • Therapeutic:hCG
    •  hCG + human menotropin ® ovulation in women with hypogonadotropic hypogonadism or as part of in vitro fertilization approach
    •  hCG: testicular testosterone stimulation in men with hypogonadotropic hypogonadism (increased intratesticular testosterone ® promotes spermatogenesis; menotropins often also required for fertility)

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• Toxicity:hCG
  • headache, edema, gynecomastia, pretentious puberty, depression, hCG antibody production (rare)
•  Contraindications:hCG
  • presence of androgen-dependent neoplasia
  • presence of precocious puberty

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Prolactin

• Structure:prolactin
  • 198-amino acid peptide
  • Site of production: anterior pituitary
  • resembles growth hormone
• Function:prolactin-- hormone primarily responsible for lactation
  • lactation requires appropriate circulating concentrations of progestins, estrogen, corticosteroids & insulin.

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• Abnormal prolactin levels:
  • Deficiency:prolactin-- may be associated with pituitary deficiency states
    • Manifestations:
      •  lactation failure
      •  luteal phase defect
  • Excess:prolactin --may be associated with hypothalamic destruction due to reduced dopamine delivery to the pituitary {dopamine = prolactin-inhibiting hormone}
    • Hyperprolactinemia may cause:
      1.  galactorrhea
      2.  hypogonadism
    • Hyperprolactinemia symptomatic management:
      • administration of bromocriptine & other dopamine agonists inhibit prolactin secretion

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Bromocriptine and Other Dopamine Agonists

• Overview:bromocriptine & other dopamine agonists
  • Bromocriptine:
    • Background:bromocriptine
      • most widely used drug for treating hyperprolactinemia
      • ergot derivatives: dopamine agonist properties
      • decreases serum prolactin
      • shrinks pituitary (prolactin-secreting) tumors

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    • Mechanism of Action:bromocriptine
      • dopamine-like action
      • Site of action:
        1. reduces dopamine turnover in the tuberoinfundibular neurons of the arcuate nucleus (increasing hypothalamic dopamine)
        2. pituitary: activates dopamine receptors causing prolactin release inhibition
    • Effects on other hormones:
      • normal subjects: increases pituitary growth hormone release
      • patients with acromegaly: suppresses growth hormone release (paradoxical response)
  • Pergolide -- also used for hyperprolactinemia management
• Clinical Uses:bromocriptine
  • Prolactin-secreting adenomas
    • bromocriptine-- initial treatment
    • 85% response rate at six months-- judged by tumor size reduction and decreasing serum prolactin levels
  • Amenorrhea-Galactorrhea:
    • bromocriptine -- management of clinical sequelae of hyperprolactinemia, including:
      • amenorrhea, galactorrhea, infertility, hypogonadism
      • amenorrhea/galactorrhea recurrence if treatment is discontinued
  • Physiologic lactation:
    • bromocriptine-prolactin secretion suppression following parturition/abortion ® prevents breast engorgement when breastfeeding not desired/required
    • possible increase in stroke risk in women receiving bromocriptine postpartum

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  • Acromegaly:
    • bromocriptine +/- pituitary surgery, radiation therapy, octreotide: treatment of acromegaly
    • bromocriptine responsiveness in these patients depends on prolactin as well as growth hormone secretion by pituitary tumor
  • Parkinson's Disease:
    • Bromocriptine:
      • Overview:bromocriptine
        • ergot alkaloid--partial agonist at presynaptic dopamine D₂ receptors
        • Used to treat hyperprolactinemia (at lower doses)
        • Oral administration; variably absorbed from the GI tract; the plasma levels -- 1-2 hours
        • Excreted in bile & feces

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      • Clinical Use:bromocriptine
        • first-line drug in Parkinsonism
        • compared with levodopa: less likelihood of response fluctuation and dyskinesias
        • Variable clinical use of bromocriptine (sometimes early in treatment; sometimes prescribed to patients becoming refractory to levodopa)
        •  customization of levodopa and bromocriptine required on a patient to patient basis to achieve optimal clinical response
        •  Hypotensive reaction to bromocriptine: ® care required during initial dosing
        • Stop Treatments If: psychiatric disturbance, ergotism, cardiac arrhythmia, erythromelalgia (painful, swollen feet)

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•  Adverse Effects: bromocriptine:
  • In patients with small pituitary adenomas:
    • discontinue following conception since adenoma growth does not occur during pregnancy
  • Patients with large pituitary adenomas:
    • discontinue but monitor for tumor progression: if tumor growth persists during pregnancy, bromocriptine will be required
  •  Gastrointestinal:bromocriptine
    • Common initial side effect: anorexia, nausea, vomiting {reduced when medication is taken with food)
    • Others GI side effects:
      • constipation, dyspepsia, symptoms of reflux esophagitis
      • peptic ulceration with bleeding
  •  Cardiovascular:bromocriptine
    • Common: postural/orthostatic hypotension (early in therapy)
    • digital vasospasm -- occurs with long-term treatment {reversible by decreasing dosage}
    • cardiac arrhythmias: indication for drug discontinuation
  • Dyskinesias:bromocriptine
    • similar to levodopa dyskinesias; reduction in total dopaminergic agents indicated
  • Mental Disturbances:bromocriptine
    • More common/severe with bromocriptine than with levodopa. Symptoms include:
      • confusion, hallucinations, delusions, etc.
      • psychiatric effects dissipate with drug discontinuation
  • Miscellaneous Adverse Effect:bromocriptine
    • headache, nasal congestion, pulmonary infiltrates, erythromelalgia (may be associated with arthralgia), increased arousal

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