Human Chorionic Gonadotropin (hCG)

• Overview:  hCG

  • hCG -- produced by the placenta; excreted into the urine

  • Glycoprotein; 92-amino acid a-chain + 145-amino acid b-chain.

    • α-chain-- closely resembles FSH, LH, TSH α-chain

    • β-chain-- closely resembles LH β-chain

    • Similar to LH structurally;

    • Used to treat women and men with LH deficiency

  • Function:  hcG

    • Ovarian corpus luteum stimulation to produce progesterone

    • Placental maintenance

• Pharmacokinetics:  hCG

  • Intramuscular administration; well-absorbed

  • Half-life: 8 hours (compared to LH half-life -- 30 minutes)

• Pharmacodynamics:  hCG

  • Human chorionic gonadotropin (hCG) stimulates gonadal steroid hormone production

    • Cells affected:

      • Female: interstitial and corpus luteum cells produce progesterone

      • Male: Leydig cells produce testosterone

    • hCG administration: simulates midcycle LH surge:   promote ovulation in hypogonadotropic states

• 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 and estradiol levels increase in constitutional puberty delay -- not in hypogonadotropic hypogonadism states

  • 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)

• Toxicity:  hCG

  • Headache, edema, gynecomastia, pretentious puberty, depression, hCG antibody production (rare)

•   Contraindications:  hCG

  • Presence of androgen-dependent neoplasia

  • Presence of precocious puberty

Prolactin

• Structure:  prolactin

  • 198-amino acid peptide

  • Site of production: anterior pituitary

  • Resembles growth hormone

• Function:  prolactin, a hormone primarily responsible for lactation

  • Lactation requires appropriate circulating concentrations of progestins, estrogen, corticosteroids and insulin.

• 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 and other dopamine agonists inhibit prolactin secretion

Bromocriptine and Other Dopamine Agonists

• Overview:  bromocriptine and 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

  • 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

• 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 and feces

  • 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)

  •   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

Primary Reference: Fitzgerald, P.A. and Klonoff, D.C. Hypothalamic and Pituitary Hormones, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 603-618.

Primary Reference: Biller, Beverly M. K. and Daniels, Gilbert, H. Neuroendocrine Regulation and Diseases of the Anterior Pituitary and Hypothalamus, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1972-1998

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