Gonadotropin-Releasing Hormone (GnRH., luteinizing hormone-releasing hormone (LHRH);Gonadorelin)

• Overview:  Gonadotropin-releasing hormone (GnRH)

  • Synthesis site: arcuate nucleus of the hypothalamus

  • Controls gonadotropins FSH and LH release

• Chemistry:GnRH

  • Decapeptide

  • For pharmacological use synthetic forms (analogs) include:

    •  Leuprolide, nafarelin, buserelin, goserelin, histrelin

    •  Synthetic forms tend to be more potent and longer lasting then GnRH

• Pharmacokinetics:  GnRH

  • GnRH Route of Administration: IV or subcutaneous

  • GnRH analogues Route of Administration: subcutaneous, nasal spray, intramuscular

  • GnRH half-life: 4 minutes

  • GnRH analog half-life: three hours

  • Sites of degradation: hypothalamus and pituitary

• Pharmacodynamics:  GnRH

  • Binding site: receptors on pituitary gonadotropes

  • Pulsatile IV administration (frequency every 1-4 hours):   FSH and LH secretion stimulation

  • Continuous GnRH administration (or GnRH analog depot formulation):  inhibition of gonadotropin release

• Clinical Uses:  GnRH

  • Diagnostic Applications:  GnRH

    •  Assessment of delayed puberty is described as either a constitutional delay or  due to hypogonadotropic hypogonadism

      • LH response to GnRH distinguishes between causes.

      • Following subcutaneous GnRH bolus:

        • Peak LH response > 15.6 mIU/mL:   normal (indicating puberty will occur soon)

        • Peak LH response impaired suggests hypogonadotropic hypogonadism (probably indicative of pituitary/hypothalamic dysfunction  (could be still seen in constitutional adolescence delay)

  •  Therapeutic Applications:  GnRH

    • Stimulation: Infertility due to hypothalamic hypogonadotropic hypogonadism (both sexes)

      • GnRH:  stimulation of pituitary function

      • Programmable pump technology allows pulsatile GnRH treatment (frequency: every 90 minutes)

    • Inhibition: management of prostate cancer, uterine fibroids, endometriosis,  precocious puberty

      • By continuous administration of GnRH analog agonists (leuprolide, nafarelin, goserelin and, histrelin)

    • Other uses:

      •  in vitro fertilization approaches: GnRH analog

        1. Suppression of endogenous gonadotropin release

        2. Then exogenous gonadotropins added to promote synchronous follicular development.

  •  Toxicity:  GnRH

    • For diagnosis, occasional headache, abdominal discomfort, flushing

    • GnRH analogs: initial bone pain exacerbation in prostate cancer and hot flushes (both sexes)

    • Increased risk of osteoporosis in women if treatment > 6 months duration

     

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