What is the recommended protocol for a young adult with hypogonadism to take enclomiphene (clomiphene citrate) to increase testosterone levels?

Enclomiphene Protocol for Young Adults with Hypogonadism

Diagnostic Confirmation Required Before Starting

Before initiating enclomiphene, you must confirm biochemical hypogonadism with two separate morning (8-10 AM) total testosterone measurements below 300 ng/dL, and measure LH/FSH to confirm secondary (not primary) hypogonadism. 1

• Obtain morning total testosterone on two separate occasions between 8-10 AM, with levels <300 ng/dL required for diagnosis 1
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin, especially if total testosterone is borderline 1
• Check LH and FSH levels: low or low-normal values with low testosterone confirm secondary hypogonadism, which is the appropriate indication for enclomiphene 1
• Document baseline hematocrit/hemoglobin and PSA (if over age 40) before treatment initiation 1

Critical Fertility Counseling

If the patient desires fertility preservation now or in the future, enclomiphene is the preferred treatment over testosterone replacement therapy, as it stimulates endogenous testosterone production while maintaining spermatogenesis. 2, 3

• Enclomiphene blocks estrogen negative feedback at the hypothalamus and pituitary, increasing LH and FSH secretion, which stimulates testicular testosterone production and preserves fertility 4, 3
• Testosterone replacement therapy is absolutely contraindicated in men seeking fertility, as it suppresses spermatogenesis and causes prolonged azoospermia 1, 2

Enclomiphene Dosing Protocol

Start enclomiphene at 12.5 mg orally once daily, with the option to increase to 25 mg daily based on testosterone response at 6-8 weeks. 3

• The 12.5 mg dose is the middle-range dose studied in clinical trials and provides a balance between efficacy and tolerability 3
• The 25 mg daily dose achieved mean testosterone levels of 604 ± 160 ng/dL after 6 weeks of continuous use in clinical trials 3
• Lower doses (6.25 mg) may be considered for patients concerned about side effects, though efficacy data is more limited 3
• Enclomiphene should be taken at the same time each day to maintain consistent hormone levels 3

Monitoring Schedule

Check testosterone, LH, FSH, and estradiol levels at 6-8 weeks after starting treatment, then every 6-12 months once stable levels are achieved. 1, 3

• At 6-8 weeks: measure morning total testosterone (target 500-600 ng/dL mid-normal range), LH, FSH, and estradiol 1, 3
• Enclomiphene increases testosterone within 2 weeks, but full assessment requires 6 weeks of continuous dosing 3
• Monitor hematocrit periodically and withhold treatment if >54% 1
• For men over 40, monitor PSA levels with urologic referral if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1

Expected Treatment Outcomes

Enclomiphene provides testosterone increases comparable to testosterone replacement therapy (median increase 166 ng/dL) with significantly fewer adverse effects and preserved fertility. 5, 3

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1
• Enclomiphene demonstrates lower estradiol changes compared to clomiphene citrate (-5.92 vs. 17.50 pg/mL, P=0.001) 5
• Adverse effects are significantly less frequent with enclomiphene compared to clomiphene, including decreased libido (P=0.001), reduced energy (P=0.044), and mood changes (P=0.03) 5
• Effects on LH and testosterone persist for at least one week after stopping treatment 3

Dose Adjustment Algorithm

If testosterone remains <500 ng/dL at 6-8 weeks on 12.5 mg daily, increase to 25 mg daily and recheck levels in another 6-8 weeks. 3

• Target mid-normal testosterone range of 500-600 ng/dL for optimal symptom improvement 1
• If testosterone exceeds 750 ng/dL, consider reducing dose to 6.25 mg daily 3
• Reassess symptoms at 12 months and discontinue if no improvement in sexual function, to prevent unnecessary long-term exposure without benefit 1

Adverse Effects and Safety Profile

Enclomiphene has a significantly lower adverse event profile compared to clomiphene citrate, with an odds ratio of 0.18 for adverse events. 5

• Most common side effects with long-term clomiphene use (which enclomiphene improves upon): mood changes (5%), blurred vision (3%), and breast tenderness (2%) 6
• Enclomiphene does not significantly affect TSH, ACTH, cortisol, lipids, or bone markers 3
• Both enclomiphene and testosterone replacement decrease IGF-1 levels, but suppression is greater with enclomiphene 3
• Long-term safety data for clomiphene citrate demonstrates safety and efficacy for up to 7 years with no significant adverse events 6

Absolute Contraindications

Do not prescribe enclomiphene to men with primary (testicular) hypogonadism, as their testes cannot respond to increased LH/FSH stimulation. 1

• Active or treated male breast cancer is an absolute contraindication 1
• Hematocrit >54% requires withholding therapy 1
• Primary hypogonadism (elevated LH/FSH with low testosterone) will not respond to enclomiphene, as the testes cannot produce testosterone despite gonadotropin stimulation 1

Critical Pitfalls to Avoid

Never start enclomiphene without confirming secondary (not primary) hypogonadism through LH/FSH measurement, as primary hypogonadism will not respond to this therapy. 1

• Do not diagnose hypogonadism based on symptoms alone without confirmed low testosterone on two separate morning measurements 1
• Do not use enclomiphene in eugonadal men (testosterone >300 ng/dL) even if symptomatic, as this violates evidence-based guidelines 1
• Do not assume all young men with low testosterone have secondary hypogonadism—always measure LH/FSH to distinguish primary from secondary causes 1
• Do not continue treatment beyond 12 months without documented improvement in sexual function 1

Comparison to Testosterone Replacement Therapy

Enclomiphene is preferred over testosterone replacement therapy in young men who may desire future fertility, as it maintains spermatogenesis while increasing testosterone levels. 2, 3

• Enclomiphene achieved mean testosterone of 604 ng/dL versus 500 ng/dL with transdermal testosterone (not statistically different, P=0.23) 3
• Unlike testosterone replacement, enclomiphene increases rather than suppresses LH and FSH, preserving testicular function 3
• Enclomiphene maintains the natural circadian rhythm of testosterone with morning elevations, mid-day troughs, and rising nighttime levels 3
• Testosterone replacement therapy permanently suppresses fertility in some men even after discontinuation 2