Gonadorelin (GnRH) Mechanism and Use in Secondary Hypogonadotropic Hypogonadism
Gonadorelin is synthetic gonadotropin-releasing hormone (GnRH) that, when administered in pulsatile fashion via portable pump, directly stimulates the pituitary to produce LH and FSH, thereby restoring testosterone production and spermatogenesis in men with secondary hypogonadotropic hypogonadism while preserving fertility. 1, 2
Mechanism of Action
- Gonadorelin is a decapeptide identical to native hypothalamic GnRH that binds to GnRH receptors on gonadotropic cells in the anterior pituitary 1, 3
- Pulsatile administration (typically every 90-120 minutes) mimics physiologic hypothalamic secretion patterns and stimulates synthesis and release of LH and FSH 4, 2
- LH stimulates testicular Leydig cells to produce testosterone, while FSH acts on Sertoli cells to support spermatogenesis 1, 3
- Critical distinction: Pulsatile delivery is essential—continuous administration paradoxically suppresses gonadotropin production through receptor desensitization, the opposite therapeutic effect 1, 3
Clinical Application in Secondary Hypogonadotropic Hypogonadism
Delivery Method
- Administered via small portable computerized infusion pump connected to a subcutaneous catheter 4, 2
- Typical dosing: 1-5 micrograms every 90 minutes subcutaneously 4, 5
- Treatment duration: 12-24 weeks to achieve initial response, with ongoing therapy required to maintain spermatogenesis 4, 2
Expected Outcomes
- Testosterone levels normalize within 12 weeks of treatment 4, 5
- Testicular growth occurs in all treated patients 2
- Virilization (improved libido, potency, secondary sexual characteristics) develops as testosterone rises 4, 2
- Spermatogenesis develops in approximately 85% of patients (58 of 68 in one series), with sperm appearing in ejaculate after 4-6 months of therapy 2
- Pregnancy achievement documented in multiple cases, including after 181 days of treatment in one report 4, 2
Transition to Maintenance Therapy
- Once spermatogenesis is established, treatment can be simplified by switching from pulsatile GnRH to hCG injections 1-2 times weekly (intramuscular or subcutaneous) 2
- Spermatogenesis is maintained or even improved on hCG monotherapy after initial GnRH induction 2
- FSH analogues may be added to hCG if sperm counts remain suboptimal 6, 7
Advantages Over Alternative Treatments
- Unlike exogenous testosterone therapy, gonadorelin preserves fertility by maintaining endogenous gonadotropin stimulation rather than suppressing it through negative feedback 6, 7
- Stimulates both testosterone production AND spermatogenesis simultaneously, whereas testosterone monotherapy causes azoospermia 6, 7
- Provides physiologic hormone patterns that support testicular growth, not just virilization 2
- More effective than gonadotropin therapy alone for initial induction in hypothalamic causes of hypogonadism 2
Patient Selection and Diagnostic Considerations
Ideal Candidates
- Men with confirmed secondary (hypogonadotropic) hypogonadism: low testosterone with low or inappropriately normal LH and FSH 6, 7
- Hypothalamic causes including idiopathic hypogonadotropic hypogonadism, pituitary stalk interruption syndrome, or functional suppression 2, 5
- Men desiring fertility preservation or restoration 6, 2
Diagnostic Requirements Before Treatment
- Measure serum LH, FSH, and total testosterone to confirm secondary hypogonadism pattern 6, 7
- Check prolactin to exclude hyperprolactinemia (if elevated, obtain MRI to rule out pituitary adenoma) 7
- Perform semen analysis to establish baseline fertility status 6
- Consider karyotype and Y-chromosome microdeletion testing if severe oligospermia or azoospermia present 8
Practical Considerations and Patient Counseling
- Patients must wear the portable pump continuously, which some find cumbersome, though motivation for fertility typically ensures good adherence 2
- Treatment does not interfere significantly with daily activities once patients adapt to pump use 4, 2
- Response monitoring: Check testosterone, LH, and FSH at 12 weeks; perform semen analysis at 4-6 months 4, 5
- Critical pitfall: Gonadorelin cannot distinguish between constitutional delayed puberty and permanent hypogonadotropic hypogonadism in prepubertal patients, as both show similar gonadotropin responses 2
Alternative Diagnostic Use
- Native GnRH can be administered as a single dose to test pituitary reserve of LH and FSH, though this diagnostic application is distinct from therapeutic pulsatile use 3
- Long-term GnRH stimulation testing (7 days) does not reliably differentiate constitutional delay from permanent hypogonadotropic hypogonadism 2