Gonadorelin

Gonadorelin is a synthetic decapeptide that is chemically identical to endogenous gonadotropin-releasing hormone (GnRH), naturally produced by the hypothalamus. With a molecular formula of C55H75N17O13 and molecular weight of 1182.311 g/mol, gonadorelin has been available for medical use since 1978 under the brand name Factrel. It functions by binding to GnRH receptors in the anterior pituitary gland, stimulating the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently act on the gonads to produce reproductive steroids. Gonadorelin has a biphasic half-life with a distribution phase of 2-10 minutes and terminal elimination of 10-40 minutes, requiring pulsatile administration to maintain physiologic efficacy. Unlike long-acting GnRH agonists (leuprolide, goserelin), gonadorelin stimulates rather than suppresses gonadotropin production, making it uniquely suited for fertility restoration. The peptide is FDA-approved for diagnostic testing of pituitary function and therapeutic use in hypogonadotropic hypogonadism, hypothalamic amenorrhea, and infertility. It is classified as FDA pregnancy category B, indicating no evidence of fetal harm in animal studies. While gonadorelin itself is not currently available for human clinical use in the United States, its analogues remain widely used in reproductive medicine, oncology, and pediatric endocrinology worldwide.

Fertility and Reproductive Function

• Hypothalamic Amenorrhea Treatment: Pulsatile GnRH therapy achieves ovulation rates of 91-96% in women with primary and secondary hypothalamic amenorrhea, with 75.6-85.2% ovulation rate per cycle and approximately 35% birth rate per cycle^[1][2]
• High Live Birth Success: 25-year cohort study demonstrated 65.9% live birth rate per treatment and 25.5% per cycle in functional hypothalamic amenorrhea patients, with 96% ovulation rate and predominantly monofollicular (single follicle) development^[3]
• Male Fertility Restoration: Pulsatile gonadorelin pump induced spermatogenesis in 90% of congenital hypogonadotropic hypogonadism males with median time to spermatogenesis of 6 months versus 14 months with cyclical gonadotropin therapy, resulting in natural pregnancies with sperm concentrations of 5.18-56.1 million/mL^[4]
• Low Multiple Pregnancy Risk: Meta-analysis shows low multiple gestation rates with pulsatile GnRH therapy, only slightly higher than general population, with one study reporting just 1.6% twin rate compared to high rates with gonadotropin therapy^[2][3]

Diagnostic Applications

• Pituitary Function Testing: Gold standard for differential diagnosis of hypogonadotropic hypogonadism versus constitutional delay of puberty, with 80% sensitivity and 86.4% specificity in males using peak LH cutoff of 9.74 IU/L^[5]
• Precocious Puberty Diagnosis: Validated as diagnostic standard for identifying central precocious puberty in children, with GnRH stimulation test demonstrating high accuracy for assessing hypothalamic-pituitary-gonadal axis integrity^[6]
• Endocrine Axis Evaluation: Measures luteinizing hormone and follicle-stimulating hormone response at 0, 30, 60, and 120 minutes post-administration, enabling precise differentiation between primary and secondary hypogonadism^[5]

Metabolic and Bone Health

• Bone Density Improvement: In young males with hypogonadotropic hypogonadism, 6 months of pulsatile gonadorelin treatment dramatically increased bone mineral density in lumbar spine, femoral neck, and total hip^[7]
• Metabolic Benefits: Treatment significantly decreased total cholesterol, fasting insulin, HOMA-IR (insulin resistance marker), and sex hormone-binding globulin while increasing body mass index in hypogonadotropic patients^[7]
• Testicular Development: Gonadotropin therapy enlarged testicular size from 2.1±1.6 to 8.1±4.6 mL and elevated serum testosterone from 0.9±0.5 to 15.1±8.2 nmol/L in congenital hypogonadotropic hypogonadism patients^[8]

Ovulation Induction

• IUI Cycle Support: GnRH agonist effectively triggers ovulation with comparable rates to hCG in intrauterine insemination cycles, offering reduced risk of ovarian hyperstimulation syndrome^[9]
• Physiologic Ovulation: Mimics natural LH surge more closely than exogenous hCG, enabling monofollicular ovulation in 75% of cycles versus multiple follicle development common with gonadotropins^[3]
• Office-Based Treatment: Pulsatile GnRH can be safely administered in outpatient settings without requirement for intensive estradiol monitoring, unlike conventional gonadotropin therapy^[10]

Clinical Safety Profile

• Excellent Hepatic Safety: Six FDA-approved GnRH analogues (leuprolide 1985, goserelin 1989, histrelin 1991/2004, triptorelin 2000, degarelix 2008, relugolix 2021) have not been convincingly implicated in causing clinically significant liver injury, with zero cases attributable to GnRH analogues among nearly 1,000 drug-induced liver injury cases in population studies^[11]
• Low OHSS Risk: Meta-analysis of 35 studies with 1,002 women showed pulsatile GnRH treatment results in low incidence of ovarian hyperstimulation syndrome (OHSS) with only mild severity cases, significantly safer than gonadotropin therapy^[2]
• Minimal Adverse Events: 25-year cohort reported zero serious adverse events, 11.5% miscarriage rate (comparable to general population), zero congenital malformations, and normal newborn birth weights^[3]
• Single-Dose Diagnostic Safety: No allergic or hypersensitivity reactions encountered following single 100 microgram diagnostic doses, though such reactions theoretically possible with polypeptide hormones^[12]

Side Effects and Complications

• Ovarian Complications: Rare cases of ovarian hyperstimulation syndrome may cause fluid accumulation in stomach, chest, and heart area; ovarian torsion (twisting on blood supply) possible in fertility treatment contexts^[12]
• Allergic Reactions: Extremely rare hypersensitivity including difficulty breathing, throat closure, lip/tongue/face swelling, or hives requiring emergency attention^[12]
• Pituitary Risks: Use contraindicated with pituitary adenomas due to risk of hemorrhagic infarction (pituitary apoplexy) potentially causing sudden blindness^[12]
• Intravenous Administration: Pulsatile IV GnRH rarely associated with superficial thrombophlebitis at infusion sites^[2]

Contraindications and Precautions

• Absolute Contraindications: Hypersensitivity to gonadorelin or excipients, known or suspected pregnancy (despite Category B designation for diagnostic use), presence of pituitary adenoma^[12]
• Pediatric Use: Infants may be very sensitive to gonadorelin effects; use not recommended in this age group, though safe in children 12 years and older^[12]
• Initial Testosterone Surge: GnRH agonists (not gonadorelin itself) cause transient testosterone/estrogen surge before receptor downregulation, concerning in patients with large hormone-sensitive tumors^[11]

Regulatory Status and Availability

• FDA Approval: Gonadorelin approved under brand name Factrel since 1978; however, not currently available for human clinical use in United States though widely available internationally for veterinary use (FDA NADA #139-237 for cattle)^[12][13]
• Pregnancy Category: FDA Category B - reproduction studies in mice, rats, and rabbits at doses up to 50 times human dose revealed no evidence of fetal harm, though use during pregnancy generally avoided^[12]
• Long-term Effects: Hormone suppression with GnRH agonists (not gonadorelin) causes hot flashes, gynecomastia, erectile dysfunction, decreased libido, weight gain, fluid retention, fatigue, and metabolic consequences including osteoporosis and worsening diabetes^[11]

Quality of Evidence

• Diagnostic Use: Extensively validated with decades of clinical experience; considered gold standard for pituitary-gonadal axis evaluation^[5][6]
• Fertility Applications: Supported by systematic reviews, meta-analyses, and long-term cohort studies demonstrating consistent efficacy and safety profiles^[2][3][4]
• Cancer Treatment: GnRH agonists (structural analogues) widely used since 1980 for androgen deprivation in prostate cancer with well-established benefit-risk profiles^[14]