pit5

Overview: Gonadotropin-releasing hormone (GnRH)
- Synthesis site: arcuate nucleus of the hypothalamus
- Controls gonadotropins FSH & LH release

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Chemistry:GnRH
- decapeptide
- For pharmacological use -- synthetic forms (analogs)
  - Leuprolide, nafarelin, buserelin, goserelin, histrelin
  - Synthetic forms -- more potent & longer lasting then GnRH

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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 & pituitary

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Pharmacodynamics:GnRH
- Binding site: receptors on pituitary gonadotropes
- pulsatile IV administration (frequency every 1-4 hours) ® FSH & LH secretion stimulation
- continuous GnRH administration (or GnRH analog depot formulation) ® inhibition of gonadotropin release

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Clinical Uses:GnRH
- Diagnostic Applications:GnRH
  - Assessment of delayed puberty-- (a) constitutional delay or (b) 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})
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- 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, polycystic ovary syndrome, 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.
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- Toxicity: GnRH
  - For diagnosis, occasional headache, abdominal discomfort, flushing
  - GnRH analogs: initial bone pain exacerbation in prostate cancer & hot flushes {both sexes}
  - Increased risk of osteoporosis in women if treatment > 6 months duration

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Follicle-Stimulating Hormone (FSH)

Overview:FSH
- Glycoprotein hormone
- Synthesis site: anterior pituitary

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Function:FSH
- FSH + LH (luteinizing hormone): gonadal function regulation-- mediated by increasing cAMP levels in gonadal tissue
- FSH -- principal function:
  - gametogenesis and follicular development stimulation in women
  - spermatogenesis in men
- FSH site of action: immature ovarian follicular cells ® promoting development of the mature follicle and oocyte
  - FSH + LH required for correct ovarian steroidogenesis
    - {LH stimulates and production; FSH stimulates androgen conversion into estrogens (granulosa cells)}
- Testes-- Site of action for FSH: Sertoli cells, enhance androgen-binding protein production

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Modified FSH molecules
- Obtained from postmenopausal women's urine
- one agent --FSH-like characteristics; 4% potency
- another agent --LH-like characteristics
- FSH-LH combination: menotropins
- Another preparation: also from postmenopausal women's urine but with no LH is urofollitropin

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Leutinizing Hormone (LH)

Glycoprotein hormone (two chains)
Site of synthesis: anterior pituitary
Major physiological role:
- regulation of gonadal steroid hormone production
- Site of action-- male:
  - testicular Leydig cells® stimulation of testosterone production
- Site of action -- female:
  - mature follicle ®induce ovulation;
  - stimulation of corpus luteum (in menstrual cycle luteal phase) ® to produce progesterone & androgens
- Note: no LH preparation available for clinical use. Human chorionic gonadotropin (very similar structure) may be used as a leutinizing hormone substitute

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