Summary of Study Findings:
"Reduced IGF-1 Levels Following Clomiphene Treatment for Male Hypogonadism" (Journal of the Endocrine Society, 2025)
Objective:
To investigate whether clomiphene citrate—a selective estrogen receptor modulator used off-label to treat male hypogonadism—affects serum insulin-like growth factor-1 (IGF-1) levels in men without acromegaly.
Study Design:
- Retrospective analysis of 20 hypogonadal men (ages 27–76) treated with clomiphene 50 mg three times weekly for ≥3 months.
- All had IGF-1 levels measured via LC-MS within 12 months before and 24 months after starting treatment.
- Patients had a variety of underlying etiologies including prolactinomas, clinically nonfunctioning pituitary tumors (CNFTs), Rathke cleft cysts, colloid cysts, or idiopathic hypogonadism.
Key Results:
- IGF-1 Decline:
- 15 of 20 men (75%) experienced a decrease in IGF-1 standard deviation (SD) scores.
- The median IGF-1 SD change was −0.60 (IQR: −1.2 to 0.0) (P < .01).
- 2 patients (10%) had IGF-1 reductions >2 SD, which may be clinically significant.
- Testosterone Increase:
- All patients had increases in total testosterone (TT) (median +216 ng/dL, P < .0001).
- 9 patients had increases in free testosterone; 4 experienced decreases; 1 was unchanged; 6 lacked sufficient data.
- No Strong Correlation:
- The decrease in IGF-1 had only weak, non-significant correlations with increases in TT (r = 0.36; P = .12) and free testosterone (r = 0.20; P = .45).
Subgroup Findings:
- Prolactinoma patients (5/5): TT increased 9–576% (median +421%). IGF-1 decreased in 3/5 with a median SD change of −0.2.
- CNFT patients (6/6): 100% had IGF-1 reductions (median SD change −1.35).
- Idiopathic hypogonadism: 4/5 patients had IGF-1 declines (median SD change −0.6).
- Outliers:
- Patients 14 and 19 had the most marked IGF-1 reductions (−2.3 and −2.1 SD), both with CNFTs, possibly reflecting underlying susceptibility to GH pathway disruption.
- Neither reported symptomatic improvement, raising concern about clinical significance.
Interpretation:
Clomiphene citrate, though effective in restoring testosterone levels and preserving fertility, may suppress IGF-1 production in some men, potentially via estrogen-mediated inhibition of GH signaling (through SOCS-3 activation). This reduction could result in adverse outcomes like fatigue, decreased muscle mass, or worsened insulin sensitivity—particularly in individuals with predisposing pituitary pathology.
Conclusion:
Clomiphene therapy can significantly lower serum IGF-1 in hypogonadal men, with clinically significant reductions (>2 SD) in some cases. Monitoring of IGF-1 levels is recommended, especially in those with prior pituitary disease or unexplained fatigue despite adequate testosterone response.
