ENCLOMIPHENE CITRATE VS. CLOMIPHENE CITRATE FOR MEN: RISKS VERSUS REWARDS
Introduction
This article explores these questions in-depth, helping patients and physicians make informed decisions.
What Are Clomiphene and Enclomiphene Citrate?
Clomiphene citrate (brand name: Clomid) is an FDA-approved medication for inducing ovulation in women, but it has been used off-label for male hypogonadism and infertility for over 40 years. Clomiphene is a racemic mixture of two isomers: Zuclomiphene (cis) and Enclomiphene (trans).
Enclomiphene citrate is the purified trans-isomer of clomiphene. It was investigated as a standalone treatment for secondary hypogonadism in men but has not received FDA approval despite completing Phase II and III trials under the brand name Androxal.
Both medications act as estrogen receptor antagonists in the hypothalamus, tricking the brain into thinking estrogen levels are low, thereby stimulating increased release of gonadotropins (LH and FSH) from the pituitary, which in turn increases endogenous testosterone and sperm production.
Pharmacology and Mechanism of Action
Clomiphene Citrate
- Racemic mixture: 38% Enclomiphene (trans) and 62% Zuclomiphene (cis)
- Half-lives:
- Enclomiphene: ~10 hours
- Zuclomiphene: ~30–50 days (can accumulate over time)
- Action: Competitive inhibition of estrogen receptors in the hypothalamus increases GnRH → LH and FSH → testosterone and spermatogenesis
- Drawback: The cis isomer (Zuclomiphene) has long-lasting estrogenic activity, possibly contributing to side effects like mood swings, gynecomastia, and decreased libido
Enclomiphene Citrate
- Single isomer (trans) only
- Shorter half-life (~10 hours) → Less accumulation
- More potent stimulation of LH and FSH without residual estrogenic effects
- Intended to mimic physiological diurnal testosterone rhythm more effectively than clomiphene
Key Difference: Enclomiphene provides more selective hypothalamic-pituitary stimulation, avoiding the long-acting estrogenic effects of Zuclomiphene.
Availability and FDA Status
| Feature | Clomiphene Citrate | Enclomiphene Citrate |
|---|---|---|
| FDA-Approved | Yes (for female infertility only) | No (investigational in men; never approved) |
| Route | Oral | Oral (compounded) |
| Prescription in Men | Off-label | Compounded only (off-label use) |
| Commercial Name (Men) | None | Formerly Androxal (not marketed) |
Clomiphene is widely available in generic form. Enclomiphene is not FDA-approved but is available through compounding pharmacies, usually under strict physician supervision.
Impact on Serum Testosterone and Sperm Production
Testosterone Levels
Both medications stimulate endogenous testosterone production.
- Clomiphene increases testosterone by 100–200% in many men [1]
- Enclomiphene has been shown to restore testosterone to mid-normal ranges (450–600 ng/dL) in hypogonadal men [2], with less suppression of LH and FSH than exogenous testosterone
A Phase III trial (Topline Study, 2015) demonstrated Enclomiphene significantly raised testosterone levels in men with secondary hypogonadism, comparable to injectable testosterone but with preserved fertility [3].
Spermatogenesis
Unlike exogenous testosterone (which often suppresses sperm production), both Clomiphene and Enclomiphene:
- Stimulate FSH → Promotes Sertoli cell function and spermatogenesis
- Maintain or improve sperm concentration, motility, and morphology
One study showed that 67% of azoospermic men treated with Clomiphene for 6 months developed sperm in ejaculate [4]. Enclomiphene has similar fertility-preserving effects, with early data suggesting slightly superior outcomes in sperm count maintenance [5].
Side Effects and Safety Profiles
Clomiphene Citrate
- Mood changes, irritability, depression
- Visual disturbances (blurred vision, floaters)
- Gynecomastia
- Fatigue, acne, weight gain
- Rare: venous thromboembolism
These effects are believed to be due in part to accumulation of Zuclomiphene, the long-acting estrogenic isomer.
Enclomiphene Citrate
- Fewer mood and visual side effects reported
- No gynecomastia in trials
- Less risk of estrogenic accumulation
- Still requires regular liver function monitoring and hormonal profiling
Enclomiphene is generally better tolerated, with fewer CNS and estrogen-related effects, especially in long-term use.
Monitoring During Treatment
| Monitoring Parameter | Frequency | Target |
|---|---|---|
| Total Testosterone | Every 6–8 weeks | 450–900 ng/dL |
| LH and FSH | Baseline, then q3 months | Should rise or remain steady |
| Estradiol | Every 6–12 weeks | < 40 pg/mL (balance required) |
| Semen Analysis | q3–6 months | Check sperm concentration, motility |
| Liver Function Tests | Baseline, then annually | ALT/AST within normal range |
| Prolactin | Baseline if symptoms | Should remain normal |
Monitoring ensures efficacy, avoids overtreatment, and checks for adverse effects, particularly with long-term use.
Prescribing Patterns: How Common Are These Drugs in Men?
- Clomiphene is widely prescribed off-label by urologists and reproductive endocrinologists for:
- Secondary hypogonadism
- Low testosterone with preserved fertility
- Idiopathic male infertility
- Enclomiphene is less commonly used, available only via compounding. Despite promising clinical trial results, it has not secured FDA approval, limiting its reach.
In a 2020 AUA survey of reproductive urologists, Clomiphene was the first-line medical therapy for men with secondary hypogonadism desiring fertility preservation [6].
Unique Characteristics: Pros and Cons
Clomiphene Citrate
Pros:
- Generic and inexpensive
- Well-studied in both men and women
- Readily available
Cons:
- Accumulation of Zuclomiphene
- Estrogenic side effects (gynecomastia, mood swings)
- Requires more careful monitoring of estradiol
Enclomiphene Citrate
Pros:
- Targets only the active isomer
- Rapid clearance = less accumulation
- Lower incidence of estrogenic side effects
- Preserves diurnal testosterone rhythm
Cons:
- Not FDA approved
- Must be compounded, increasing variability and cost
- Limited long-term safety data
Legal and Liability Considerations
Off-Label Use
Both medications are used off-label in men, but with different risk implications:
- Clomiphene citrate is FDA-approved for use in women, and its off-label use in men is widespread. It is supported by decades of research and is considered standard of care by many reproductive urologists.
- Enclomiphene citrate, on the other hand, is not FDA-approved for any use and must be obtained via compounding pharmacies. Physicians who prescribe it take on a greater degree of legal liability, especially if adverse events occur.
Key Medicolegal Considerations
- Informed consent is critical: Discuss with patients that neither drug is FDA-approved for men, and enclomiphene is compounded and not subjected to the same manufacturing standards.
- Documentation: Clearly document rationale, discussions of risks/benefits, and informed consent.
Best practice: Consider developing a formal informed consent form specifically for off-label and compounded hormonal therapies.
Conclusion: Which One Should You Choose?
Both Clomiphene and Enclomiphene have a role in the management of male hypogonadism and infertility—particularly in men who wish to preserve fertility.
| Criteria | Clomiphene | Enclomiphene |
|---|---|---|
| FDA Status | Approved (women) | Not approved |
| Use in Men | Off-label | Off-label compounded only |
| Sperm Preservation | Yes | Yes |
| Side Effects | More estrogenic | Fewer, shorter half-life |
| Monitoring Burden | Moderate | Moderate |
| Physician Liability | Lower | Higher (due to compounding) |
| Cost | Lower | Higher |
Clomiphene citrate remains the first-line option due to availability, cost, and decades of clinical experience. However, enclomiphene citrate offers a promising alternative, particularly for men who experience side effects from Clomiphene or require a more physiologic testosterone profile.
Final Thoughts
For patients: If you are considering treatment for low testosterone and want to preserve fertility, both options can be effective. Discuss the pros and cons with your physician, including the regulatory status of each drug.
For physicians: Choose wisely, document thoroughly, and stay informed about evolving data. As personalized medicine evolves, so too will our options for treating male hypogonadism with fertility in mind.
References
AUA Male Reproductive Health Survey, 2020.
Katz, DJ et al. “Clomiphene Citrate and Testosterone Replacement Therapy for Male Hypogonadism: An Evidence-Based Review.” Current Urology Reports, 2012.
Kaminetsky, J. et al. “The Efficacy of Enclomiphene Citrate in Men With Secondary Hypogonadism: Phase III Trials.” Journal of Clinical Endocrinology & Metabolism, 2015.
Repros Therapeutics. “Androxal (Enclomiphene Citrate) Phase III Topline Data.” 2015.
Hsieh, TC et al. “Clomiphene citrate effects on testosterone/estradiol ratio in male infertility.” Fertility and Sterility, 2005.
Kim, ED et al. “Comparison of enclomiphene citrate versus transdermal testosterone in men with secondary hypogonadism.” Fertility and Sterility, 2015.