Mechanism of action of Leuprolide

Mechanism of Action of Leuprolide (Lupron)

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Introduction

Leuprolide is a synthetic gonadotropin-releasing hormone (GnRH) agonist used in conditions like prostate cancer, endometriosis, uterine fibroids, and central precocious puberty. Initially, it stimulates the pituitary gland, but with continuous use, it leads to receptor desensitization, suppressing gonadotropins and resulting in decreased sex hormone levels.

Leuprolide Mechanism of Action
Mechanism of action of Leuprolide

Step-by-Step Mechanism of Action

  1. Initial GnRH Receptor Activation
    Leuprolide binds to pituitary GnRH receptors, causing a temporary surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) — known as the “flare effect.”
  2. Pituitary Receptor Downregulation
    With continuous exposure, the receptors become desensitized and downregulated, halting further gonadotropin release.
  3. Suppression of LH/FSH
    Decreased LH and FSH production leads to reduced sex hormone synthesis (testosterone and estradiol).
  4. Hypogonadism Effect
    Sex hormone levels fall to castrate or postmenopausal levels, reducing stimulation of hormone-dependent tissues.
  5. Therapeutic Outcomes
    Alleviates symptoms and slows disease progression in hormone-sensitive conditions.
Mechanism of action of Leuprolide flowchart
Leuprolide mechanism of action flowchart

Pharmacokinetic Parameters

ParameterValue
Route of AdministrationSubcutaneous or intramuscular injection
Time to Peak (Tₘₐₓ)1–3 hours (short-acting)
Half-Life~3 hours (immediate), longer with depot forms
Depot Form1– to 6-month formulations available
Protein Binding~45%
MetabolismPeptidase degradation
ExcretionPrimarily renal, as inactive peptides

Clinical Uses

  • Prostate cancer
  • Endometriosis
  • Uterine fibroids
  • Central precocious puberty
  • Hormonal regulation in assisted reproduction

Adverse Effects

  • Flare reaction (initial testosterone/estrogen surge)
  • Hot flashes
  • Decreased libido
  • Osteoporosis with long-term use
  • Injection site reactions
  • Mood swings, depression

Comparative Analysis

FeatureLeuprolide (GnRH Agonist)Degarelix (GnRH Antagonist)
MechanismGnRH receptor stimulation → downregulationDirect GnRH receptor blockade
Flare EffectYes (requires antiandrogen cover)No
Onset of ActionSlower (2–4 weeks)Rapid (within days)
RouteDepot injectionMonthly subcutaneous injection
Hormone SuppressionEffective after downregulationImmediate

MCQs

1. Leuprolide acts on which receptor?
A. Estrogen receptor
B. GnRH receptor
C. Androgen receptor
D. Progesterone receptor
Answer: B

2. What is the initial response to leuprolide?
A. Hormone suppression
B. Hormone surge (flare)
C. No effect
D. Blockade of estrogen receptor
Answer: B

3. Continuous use of leuprolide leads to:
A. Increased FSH/LH
B. GnRH receptor downregulation
C. Androgen receptor antagonism
D. Enhanced fertility
Answer: B

4. Primary therapeutic effect of leuprolide is:
A. Hormone synthesis increase
B. Hormone suppression
C. Immune stimulation
D. Antioxidant activity
Answer: B

5. Depot formulation is designed for:
A. Fast clearance
B. Sustained release
C. Oral bioavailability
D. Liver bypass
Answer: B

6. Major concern with long-term use:
A. Hair loss
B. Bone loss (osteoporosis)
C. Hypoglycemia
D. Hyperkalemia
Answer: B

7. Leuprolide is not administered via:
A. IM injection
B. SC injection
C. Oral tablet
D. Depot injection
Answer: C

8. During the “flare” phase, which hormone surges?
A. Dopamine
B. Testosterone or estrogen
C. Insulin
D. Oxytocin
Answer: B

9. What enzyme breaks down leuprolide?
A. CYP3A4
B. Peptidases
C. MAO
D. COMT
Answer: B

10. Compared to antagonists, agonists like leuprolide:
A. Work immediately
B. Cause initial flare
C. Are used only in women
D. Have no depot form
Answer: B

FAQs

1. What is the “flare effect”?
A temporary rise in sex hormones during the first days of treatment due to GnRH receptor activation.

2. Can leuprolide be taken orally?
No. It must be injected to be effective.

3. How soon does suppression start?
Full suppression typically occurs within 2–4 weeks of continuous use.

4. Why is bone health monitored?
Chronic hormone suppression can lead to decreased bone mineral density.

5. Is leuprolide used in children?
Yes—for conditions like central precocious puberty.

References

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