TRT vs Clomiphene: Effect on IGF-1

Nelson Vergel

Founder, ExcelMale.com

Key human studies that have measured circulating IGF-1 after giving testosterone, clomiphene or enclomiphene


#Intervention (dose & route)Study population & designTreatment lengthMean change in IGF-1*Notes
1Testosterone enanthate 300 mg IM weekly11 healthy young men, double-blind crossover RCT6 wk↑ ≈ 15 % (Table 1: ~216 → 247 µg/L)Rise occurred without GH change; nandrolone did not raise IGF-1
2Testosterone 100 mg IM q2 wk28 healthy men ≥65 y, placebo-controlled RCT26 wk↑ 22 % (≈112 → 137 µg/L)Parallel 60 % rise in nocturnal GH secretion
3Transdermal testosterone 5 g 1 % gel daily13 men ≥65 y with low T, vs AI or placebo6 mo↑ +15 µg/L vs placebo (p = 0.03)IGF-1 rise required aromatisation; aromatase-inhibitor arm showed no change
4Testosterone enantate 250 mg IM q4 wk (replacement)8 hypopituitary men already on GH5 wkNo change (352 ± 135 → unchanged)Suggests T needs intact GH axis to raise IGF-1
5Enclomiphene 6.25–25 mg oral daily44 men with secondary hypogonadism, single-blind phase II RCT6 wk↓ ≈ 40 % (baseline 94–101 → 50-62 µg/L)Fall greater than with testosterone gel (gel ~-13 %)
6Enclomiphene 25 mg oral daily12 men with secondary hypogonadism, open-label6 moIGF-1 trended ↓ (numerical data not published)IGF-1 measured alongside sperm endpoints
7Clomiphene 50 mg oral daily16 male acromegalics uncontrolled on standard therapy3 mo↓ 41 % (424 → 250 ng/mL); 44 % normalisedGH unchanged; T rose 209 %
8Clomiphene single 5-day course (50 mg bid)10 healthy women & 8 women with PCOS5 d↓ ≈ 23 % (297 → 230 µg/L in normals)Decline not linked to androgen changes
9Clomiphene (25–50 mg daily)142 hypogonadal men, retrospective cohort (2025)6–12 mo↓ median -18 µg/L; ↓≥30 µg/L in 27 %Magnitude varied; no frank IGF-1 deficiency reported
*Absolute values converted to µg/L where reported (1 µg/L ≈ 1 ng/mL).


Patterns that emerge

  1. Testosterone therapy tends to raise IGF-1 modestly
    • Acute or medium-term studies in eugonadal or older hypogonadal men consistently show a 15-25 % rise. The effect parallels increases in GH pulse frequency or mass and is blunted if GH secretion is fixed (hypopituitary patients) or aromatisation is blocked.
  2. Clomiphene almost always lowers IGF-1
    • Whether given briefly to women or for months to men (acromegaly, hypogonadism), IGF-1 falls by 15-40 %. The drop is not accompanied by a fall in GH, supporting a hepatic, estrogen-receptor–mediated inhibition of IGF-1 synthesis.
  3. Enclomiphene behaves like clomiphene, not testosterone
    • In the only detailed pharmacodynamic study, all doses reduced IGF-1 by ~40 % in six weeks, more than testosterone gel. Authors attribute this to ER antagonism at the liver despite rising estradiol.
  4. Magnitude matters clinically
    • Even the largest falls with SERMs kept IGF-1 within the adult reference range in most subjects, so frank GH-deficiency symptoms were not seen.
    • Testosterone-related rises were modest; reaching the upper-normal IGF-1 range is uncommon at replacement doses.

Mechanistic take-aways

MechanismTestosteroneClomiphene / Enclomiphene
GH secretion↑ GH pulse frequency & burst mass (requires aromatisation) GH unchanged in most reports
Hepatic IGF-1 synthesisStimulated secondarily by higher GH & estradiol → net ↑ IGF-1Direct ER-α antagonism in liver → net ↓ IGF-1 despite unchanged or ↑ GH
Net IGF-1 directionSlight-to-moderate increaseConsistent decrease

Practical implications for clinicians & researchers

  • Choice of therapy if IGF-1 optimisation is desired
    • For men needing androgen repletion and wishing to augment IGF-1 (e.g., sarcopenia), exogenous testosterone is favourable.
    • Clomiphene/enclomiphene are excellent for preserving fertility but will not raise—and may lower—IGF-1, something to monitor in patients with marginal IGF-1 or GH-sensitive conditions.
  • Monitoring
    • Measure IGF-1 at baseline and after 3–6 months when using SERMs, especially in patients with low-normal IGF-1, acromegaly under treatment, or bone health concerns.
    • In testosterone therapy, a repeat IGF-1 can help confirm adequate oestrogen conversion and may explain gains in lean mass.
  • Research gaps:
    • Long-term (>1 y) IGF-1 data with enclomiphene are missing.
    • Direct head-to-head trials of clomiphene vs testosterone on IGF-1/GH in the same hypogonadal male cohorts would clarify differential metabolic effects.

These consolidated human data show a clear divergence: testosterone replacement nudges IGF-1 upward via GH activation, whereas clomiphene and enclomiphene lower IGF-1, probably through hepatic anti-oestrogen action.
 
 
 
 

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