Can enclomiphene citrate be used to preserve testicular function in adult males with hypogonadism (low sex hormone production) or low testosterone levels undergoing Testosterone Replacement Therapy (TRT)?

Can Enclomiphene Citrate Preserve Testicular Function During TRT?

Enclomiphene citrate cannot be used concurrently with TRT to preserve testicular function, as TRT itself suppresses the hypothalamic-pituitary-gonadal axis regardless of enclomiphene use. However, enclomiphene citrate is an excellent alternative to TRT for men with secondary hypogonadism who wish to preserve fertility and testicular function.

Understanding the Fundamental Incompatibility

• Exogenous testosterone from TRT causes direct negative feedback on the hypothalamus and pituitary, suppressing LH and FSH secretion, which leads to testicular atrophy and azoospermia 1, 2
• Enclomiphene works by blocking estrogen receptors at the hypothalamus and pituitary to increase endogenous LH and FSH production 3
• These mechanisms are fundamentally opposed—TRT shuts down the axis that enclomiphene is trying to stimulate 3
• The exogenous testosterone from TRT will override any stimulatory effect of enclomiphene on gonadotropin secretion 1

Enclomiphene as an Alternative to TRT (Not Concurrent Use)

For men with secondary hypogonadism who desire fertility preservation, enclomiphene citrate should be used instead of TRT, not alongside it 2, 3.

Evidence for Enclomiphene Monotherapy

• Enclomiphene citrate increased total testosterone to 525 ± 256 ng/dL at 6 months in men with secondary hypogonadism, comparable to testosterone gel (545 ± 268 ng/dL) 3
• Critically, enclomiphene elevated sperm counts in 7/7 men at 3 months and 6/6 men at 6 months, with concentrations ranging from 75-334 × 10⁶/mL 3
• In contrast, testosterone gel was ineffective in raising sperm counts above 20 × 10⁶/mL in all five men at 3 months 3
• Meta-analysis of 1,279 patients showed enclomiphene increased total testosterone by 2.60 (95% CI 1.82-3.38) while preserving spermatogenesis 4

Predictors of Enclomiphene Response

• Mean testicular volume ≥14 mL predicts better response (HR 2.2, P < 0.01) 5
• Baseline LH level ≤6 IU/mL predicts robust response (HR 3.5, P < 0.001) 5
• Approximately 62% of men achieve a ≥200 ng/dL increase in total testosterone with enclomiphene therapy 5

Clinical Algorithm for Men Desiring Fertility Preservation

Step 1: Confirm Secondary Hypogonadism

• Measure morning total testosterone (8-10 AM) on two separate occasions, confirming levels <300 ng/dL 1, 2
• Measure LH and FSH to confirm secondary (low or low-normal gonadotropins) rather than primary hypogonadism 1, 2
• If patient desires fertility now or in the future, TRT is absolutely contraindicated 1, 2

Step 2: Initiate Enclomiphene Monotherapy

• Start enclomiphene citrate 12.5-25 mg daily or clomiphene citrate 25-50 mg three times weekly 1, 6, 7
• Enclomiphene is the trans-isomer with less estrogenic activity and fewer side effects compared to the racemic clomiphene mixture 3
• This approach stimulates endogenous testosterone production while maintaining intratesticular testosterone and spermatogenesis 3, 4

Step 3: Monitor Response

• Check testosterone levels at 2-3 months to assess response 1
• Measure LH and FSH—these should increase with enclomiphene, confirming axis stimulation 3
• Obtain semen analysis at 3-6 months to document preserved or improved sperm parameters 3

Step 4: Alternative if Enclomiphene Fails

• If testosterone remains low after 3 months on enclomiphene, add or switch to gonadotropin therapy (hCG 500 IU subcutaneously 3 times weekly plus FSH 75-150 IU three times weekly) 1, 8, 2
• This directly stimulates testicular Leydig and Sertoli cells, bypassing the hypothalamic-pituitary axis 8, 2

Why Concurrent Use Doesn't Work

• TRT suppresses the hypothalamic-pituitary-gonadal axis through negative feedback, causing LH and FSH levels to drop to near-zero 1, 2
• Even if enclomiphene blocks estrogen receptors centrally, the high circulating testosterone from TRT will continue to suppress GnRH pulsatility through androgen receptors 1
• The result: testicular atrophy and azoospermia occur despite enclomiphene use 1, 2
• Studies demonstrating enclomiphene efficacy specifically excluded men on concurrent TRT 3, 4

Safety Profile of Enclomiphene

• Enclomiphene has fewer side effects than TRT, with reported adverse events (headache, dizziness, gynecomastia) occurring in <10% of patients 4
• No serious adverse events have been reported in clinical trials 4
• Unlike TRT, enclomiphene does not cause erythrocytosis, as it does not elevate testosterone to supraphysiologic levels 6, 4
• Enclomiphene improves symptoms of hypogonadism, including sexual function, with effect sizes comparable to TRT 7, 4

Critical Pitfalls to Avoid

• Never prescribe enclomiphene concurrently with TRT expecting to preserve fertility—this is physiologically futile 1, 2, 3
• Never start TRT without explicitly confirming the patient does not desire fertility, as suppression can be prolonged and potentially irreversible 1, 2
• Do not assume all men with hypogonadism are candidates for enclomiphene—it only works in secondary hypogonadism where the testes can respond to gonadotropin stimulation 2, 3
• Men with primary hypogonadism (elevated LH/FSH) will not respond to enclomiphene and require either TRT (if fertility not desired) or assisted reproductive techniques 1, 2

Expected Outcomes with Enclomiphene

• Small but significant improvements in sexual function and libido, comparable to TRT 7, 4
• Preservation or improvement of sperm parameters, with most men achieving sperm concentrations >75 × 10⁶/mL 3
• Improvement in bone mineral density and reduction in body mass index 7
• Little to no effect on physical functioning, energy, vitality, or cognition—similar to TRT 1

Bottom Line

Enclomiphene citrate is an alternative to TRT, not an adjunct. For men with secondary hypogonadism who desire fertility preservation, enclomiphene should replace TRT entirely. The two therapies work through opposing mechanisms and cannot be used together effectively. If a patient is already on TRT and desires fertility, TRT must be discontinued and replaced with enclomiphene or gonadotropin therapy, with recovery taking 6-24 months 8, 2.