Is Enclomiphene Safe?
Is Enclomiphene Safe?
A Complete Evidence-Based Guide to Enclomiphene Citrate for Men's Testosterone Optimization
Medically Reviewed by Courtney LaSumner Bass, NP • 14-Minute Read • Last Updated: December 2025
Introduction: The Search for Smarter Testosterone Therapy
For decades, testosterone replacement therapy (TRT) has been the gold standard for treating hypogonadism—the clinical condition characterized by abnormally low testosterone levels. While TRT effectively restores testosterone to normal ranges, it comes with a significant trade-off: suppression of the body's natural hormone production pathway, including potential fertility impairment through reduced sperm production.
Enter enclomiphene citrate—a medication that has generated substantial interest among men seeking testosterone optimization without sacrificing fertility. Unlike TRT, which provides exogenous (external) testosterone, enclomiphene works by stimulating your body's own testosterone production machinery.
But is enclomiphene safe? What does the clinical evidence actually show? And is it the right choice for you?
In this comprehensive guide, we'll examine the peer-reviewed research, mechanism of action, safety profile, and clinical evidence surrounding enclomiphene—giving you the information you need to have an informed conversation with your healthcare provider.
What Is Enclomiphene Citrate?
Enclomiphene citrate is a selective estrogen receptor modulator (SERM)—a class of medications that selectively block estrogen receptors in certain tissues while having minimal effect on others. If you're familiar with clomiphene citrate (brand name Clomid), enclomiphene is one of its two component molecules.
The Chemistry Behind Clomiphene
Clomiphene citrate, which has been FDA-approved since the 1960s for treating female infertility, is actually a mixture of two stereoisomers (mirror-image molecules) with very different biological effects:
Enclomiphene (trans-isomer, 62% of clomiphene): Acts primarily as an estrogen antagonist (blocker), which is responsible for stimulating testosterone production
Zuclomiphene (cis-isomer, 38% of clomiphene): Acts as an estrogen agonist (activator), has a longer half-life, and is associated with many of clomiphene's side effects including mood changes and elevated estradiol
Research suggests that the therapeutic benefits of clomiphene come primarily from enclomiphene, while zuclomiphene contributes to unwanted estrogenic side effects. This insight led to the development of pure enclomiphene as a standalone treatment.
FDA Approval Status: What You Need to Know
Important: Enclomiphene citrate is not FDA-approved as a standalone medication. The pharmaceutical company Repros Therapeutics developed enclomiphene under the brand names Androxal and EnCyzix for treating secondary hypogonadism in men. However, in December 2015, the FDA issued a Complete Response Letter indicating the Phase 3 study design was no longer adequate to demonstrate clinical benefit.
In January 2018, the European Medicines Agency also recommended refusal of marketing authorization. By April 2021, development of enclomiphene was discontinued for all indications.
Despite lacking FDA approval as a standalone drug, enclomiphene can be legally prescribed by healthcare providers and prepared by compounding pharmacies. The FDA does not approve or verify compounded medications for safety, effectiveness, or quality—making it essential to work with a knowledgeable healthcare provider and reputable compounding pharmacy.
How Enclomiphene Works: Mechanism of Action
Understanding how enclomiphene works requires a brief tour of the hypothalamic-pituitary-gonadal (HPG) axis—the hormonal control system that regulates testosterone production.
The HPG Axis: Your Body's Testosterone Control Center
Under normal conditions, testosterone production follows this pathway:
Hypothalamus releases gonadotropin-releasing hormone (GnRH) in pulsatile fashion
Pituitary gland responds by secreting luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
Testes respond to LH by producing testosterone in Leydig cells, while FSH stimulates Sertoli cells to support sperm production
Feedback loop: Testosterone is converted to estradiol by aromatase enzyme, and estradiol signals the hypothalamus/pituitary to reduce GnRH, LH, and FSH—completing the negative feedback loop
Where Enclomiphene Intervenes
Enclomiphene blocks estrogen receptors specifically in the hypothalamus and pituitary gland. By preventing estrogen from exerting its negative feedback, enclomiphene essentially "tricks" the brain into thinking testosterone levels are lower than they actually are.
The result: increased GnRH secretion, elevated LH and FSH release, and enhanced testosterone production—all through your body's natural machinery.
The Critical Difference from TRT
This mechanism creates a fundamental distinction from traditional testosterone replacement:
TRT: Provides external testosterone, which signals the brain to shut down natural production (via negative feedback), leading to suppressed LH/FSH and reduced sperm production
Enclomiphene: Stimulates internal testosterone production while maintaining or even increasing LH, FSH, and sperm production
Clinical Evidence: What Does the Research Show?
Let's examine the peer-reviewed evidence for enclomiphene's efficacy in treating hypogonadism.
Phase II Dose-Finding Studies
A landmark 2013 study published in BJU International by Wiehle et al. evaluated three doses of enclomiphene (6.25mg, 12.5mg, and 25mg) versus transdermal testosterone gel in 44 men with secondary hypogonadism.
Key findings after 6 weeks of treatment:
Mean testosterone at 25mg dose: 604 ± 160 ng/dL (compared to baseline <350 ng/dL)
Testosterone gel group: 500 ± 278 ng/dL
Both enclomiphene and testosterone gel increased testosterone within 14 days
Enclomiphene increased LH and FSH; testosterone gel suppressed them
Effects on LH and testosterone persisted for at least 1 week after stopping treatment
Fertility Preservation: The Sperm Count Advantage
A critical study by Kaminetsky et al. (2013) in the Journal of Sexual Medicine compared enclomiphene to testosterone gel in 12 hypogonadal men who had previously used topical testosterone.
Remarkable findings:
Enclomiphene group: Sperm concentrations ranged from 75 to 334 million/mL (normal is >15 million/mL)
Testosterone gel group at 3 months: No men had sperm counts above 20 million/mL
Both treatments achieved similar testosterone levels (~525-545 ng/dL at 6 months)
Phase III Trials in Obese Men
Kim et al. (2016) published Phase III results in BJU International from two parallel studies (ZA-304 and ZA-305) evaluating enclomiphene versus testosterone gel in overweight men with secondary hypogonadism.
Results after 16 weeks:
Both treatments increased testosterone levels from baseline
Enclomiphene preserved sperm counts while testosterone gel caused oligospermia (low sperm count) in over half of participants
Only ~15% of enclomiphene users became oligospermic versus >50% of TRT users
2024 Meta-Analysis: Synthesizing the Evidence
A comprehensive 2024 systematic review and meta-analysis published in Clinics analyzed randomized controlled trials comparing SERMs (clomiphene and enclomiphene) to placebo, testosterone gel, or hCG in men with functional hypogonadism.
Pooled findings:
SERM therapy increased total testosterone by 273.76 ng/dL (95% CI: 191.87-355.66 ng/dL; p<0.01)
LH increased by 4.66 IU/L (95% CI: 3.37-5.94 IU/L; p<0.01)
FSH increased by 4.59 IU/L (95% CI: 2.88-6.30 IU/L; p<0.01)
Safety Profile: Side Effects and Risks
Understanding enclomiphene's safety profile requires examining both the clinical trial data and comparing it to alternatives like clomiphene and TRT.
Common Side Effects from Clinical Trials
Phase II and III clinical trials in over 1,400 participants reported the following adverse events:
Headache: ~3% of patients
Hot flashes: Reported at low frequency
Nausea: Mild, typically transient
Dizziness: ~1% of patients
Abdominal discomfort: Uncommon
Elevated estradiol: Observed in some patients
Research has found no evidence of drug toxicity, and rates of adverse events did not appear significantly different from placebo in controlled trials. Most side effects were considered mild to moderate in intensity.
Rare but Serious Risks
Clinical trials identified several uncommon but potentially serious adverse events associated with enclomiphene use:
Venous thromboembolic events (blood clots): Five cases reported in clinical trials; notably, four of these patients had multiple pre-existing risk factors for thromboembolism
Cardiac disorders: Higher incidence than placebo observed
Elevated PSA: Prostate-specific antigen increases reported
Increased red blood cells (erythrocytosis): Observed in some patients
Eye disorders: Visual disturbances reported rarely
Psychiatric disorders: Mood changes noted in some cases
Enclomiphene vs. Clomiphene: Fewer Side Effects?
A 2024 study published in Translational Andrology and Urology by Saffati et al. retrospectively analyzed 66 patients who were prescribed clomiphene citrate and later switched to enclomiphene.
Key finding: Patients on clomiphene reported adverse events 18.18% of the time compared to just 3.45% on enclomiphene—an approximate 80% reduction in adverse event rate.
Additionally, enclomiphene increased testosterone levels without raising estradiol, unlike clomiphene which significantly elevated estradiol (a contributor to mood swings, gynecomastia, and other estrogenic side effects).
Liver and Lipid Safety
Enclomiphene has demonstrated no irregularities in liver function tests, and no adverse events have been reported through the FDA's Adverse Event Reporting System related to hepatotoxicity.
Interestingly, clinical studies have observed improvements in lipid profiles with enclomiphene use, including significant decreases in total cholesterol and LDL cholesterol—a potential cardiovascular benefit.
Long-Term Safety Data
Important limitation: Enclomiphene's long-term safety has not been extensively studied. Most clinical trials lasted 6-16 weeks, with limited data beyond one year.
Long-term data from clomiphene studies (which includes zuclomiphene) showed that 88% of participants who took clomiphene for more than 3 years achieved and maintained normal testosterone levels, with only 8% reporting minor side effects. However, clomiphene and enclomiphene are not identical, and more enclomiphene-specific long-term research is needed.
Who Should NOT Take Enclomiphene?
Enclomiphene is not appropriate for everyone. The following conditions represent contraindications or require careful consideration:
Absolute Contraindications
Primary hypogonadism: Enclomiphene works by stimulating the testes to produce testosterone. If the testes themselves are damaged or dysfunctional (primary hypogonadism), enclomiphene will not be effective
Pre-existing blood clot risk: Due to the slight risk of thromboembolic events
Current anticoagulant (blood thinner) use: Drug interaction concerns
History of liver disease: Enclomiphene is metabolized by the liver via CYP2D6 enzymes
Pituitary tumors (adenomas): Requires endocrinologist evaluation
Known allergy to enclomiphene or clomiphene: Obvious contraindication
Uncontrolled thyroid or adrenal dysfunction: Hormonal imbalances should be addressed first
Conditions Requiring Caution
Cardiovascular disease or risk factors (hypertension, diabetes, smoking)
History of stroke or heart attack
Prostate conditions (BPH or history of prostate cancer)
Congenital GnRH deficiency, hemochromatosis, or craniopharyngiomas
Dosing Protocols: What the Research Shows
Clinical trials have evaluated several dosing strategies for enclomiphene citrate.
Standard Dosing from Clinical Trials
6.25 mg daily: Low starting dose; provides meaningful testosterone increase with minimal side effects
12.5 mg daily: Most commonly used dose; provides robust testosterone response (67-150% increase in free testosterone)
25 mg daily: Maximum studied dose; achieved testosterone levels of 604 ng/dL in Phase II trials; dose-dependent response plateaus at this level
Important: Studies evaluating 50 mg daily found non-dose-dependent steady-state levels, suggesting 25 mg represents the optimal ceiling for most patients.
Timeline of Effects
14 days: Testosterone levels begin rising into normal range
6 weeks: Peak effects observed in clinical trials
Half-life: Approximately 10 hours (enclomiphene clears faster than zuclomiphene)
Legacy effect: Testosterone and LH remain elevated for at least 1 week after discontinuation, unlike TRT which causes immediate suppression upon stopping
Required Monitoring
Before starting and during enclomiphene therapy, baseline labs should include:
Total and free testosterone
LH and FSH
Estradiol
Sex hormone-binding globulin (SHBG)
Complete blood count (CBC) including hematocrit
Comprehensive metabolic panel (liver function)
Lipid panel
PSA (prostate-specific antigen)
Enclomiphene vs. Traditional TRT: A Comparison
Understanding when enclomiphene may be preferable to traditional TRT—and vice versa—is essential for treatment selection.
Advantages of Enclomiphene Over TRT
Fertility preservation: Maintains or enhances sperm production while TRT suppresses it
No testicular atrophy: Testes continue functioning normally
No transference risk: Unlike topical testosterone, no risk of transferring hormone to partners or children
Physiologic testosterone levels: Produces natural range testosterone; TRT can cause supraphysiologic (excessively high) levels
Stimulates natural production: Works with your body's machinery rather than replacing it
Oral administration: Daily pill rather than injections, gels, or pellets
Legacy effect: Effects persist after discontinuation; TRT requires gradual tapering to avoid crash
When TRT May Be More Appropriate
Primary hypogonadism: If the testes can't produce testosterone, enclomiphene won't work
Severe hypogonadism: Very low testosterone (<150 ng/dL) may require more aggressive intervention
Men who have completed family building: Fertility preservation no longer a concern
Inadequate response to SERMs: Some men don't respond sufficiently to enclomiphene
Need for more extensive clinical data: TRT has decades of long-term safety data; enclomiphene does not
What Happens When You Stop Taking Enclomiphene?
Unlike TRT, which requires careful tapering and often HCG or SERM support to restore natural function, enclomiphene has a more favorable discontinuation profile.
Key findings:
Testosterone, LH, and FSH levels remain elevated for at least 1 week after stopping
Gradual return to baseline levels occurs over approximately 1 month
No evidence of "crash" or severe withdrawal symptoms
Natural testosterone production was not suppressed during treatment, so recovery is typically smooth
This "legacy effect" contrasts sharply with TRT, where stopping exogenous testosterone can leave men with severely suppressed natural production requiring months to recover.
Key Takeaways: Is Enclomiphene Right for You?
Enclomiphene effectively raises testosterone: Clinical trials demonstrate increases of 200-300+ ng/dL, with testosterone reaching normal physiologic ranges (500-600+ ng/dL) within 6 weeks
Fertility is preserved: Unlike TRT, enclomiphene maintains or enhances sperm production—making it ideal for men who want children now or in the future
Side effects are generally mild: Headache, hot flashes, and nausea occur in a small percentage of patients; serious adverse events are rare
Fewer side effects than clomiphene: By eliminating the estrogenic zuclomiphene isomer, enclomiphene demonstrates an ~80% reduction in adverse event rates
Not FDA-approved: Available only through compounding pharmacies with a prescription; quality depends on pharmacy reputation
Not for everyone: Men with primary hypogonadism, blood clot risk, or liver disease should not use enclomiphene
Long-term data is limited: Most studies lasted weeks to months; more research on long-term safety is needed
Ready to Explore Your Options?
At Arsenal Men's Health, we understand that optimizing testosterone isn't one-size-fits-all. Whether enclomiphene, traditional TRT, or another approach is right for you depends on your individual health profile, goals, and circumstances.
Our team, led by Courtney LaSumner Bass, NP—a board-certified nurse practitioner and military veteran—provides comprehensive hormone evaluation and personalized treatment plans for men across Utah.
What to expect:
Thorough lab work to assess your hormone levels
In-depth consultation about your symptoms and goals
Evidence-based recommendations tailored to you
Discreet, convenient telehealth appointments
Ongoing monitoring and support
Book Your Free Consultation Today
Call (385) 666-6292 or visit arsenalmenshealth.com
Medical Disclaimer: This article is for informational purposes only and does not constitute medical advice. Treatment decisions are made by licensed medical providers based on individual patient evaluation. Enclomiphene citrate is not FDA-approved and is available only through compounding pharmacies. Compounded medications are not FDA-verified for safety, effectiveness, or quality. Always consult with a qualified healthcare provider before starting any medication.
References
Wiehle RD, Cunningham GR, Pitteloud N, et al. Testosterone restoration by enclomiphene citrate in men with secondary hypogonadism: pharmacodynamics and pharmacokinetics. BJU Int. 2013;112(8):1188-1200. doi:10.1111/bju.12363
Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med. 2013;10(6):1628-1635. doi:10.1111/jsm.12116
Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int. 2016;117(4):677-685. doi:10.1111/bju.13337
Rodriguez KM, Pastuszak AW, Lipshultz LI. Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert Opin Pharmacother. 2016;17(11):1561-1567. doi:10.1080/14656566.2016.1204294
Saffati G, Kassab J, Orozco Rendon D, et al. Safety and efficacy of enclomiphene and clomiphene for hypogonadal men. Transl Androl Urol. 2024;13(9):1984-1990. doi:10.21037/tau-24-238
Huijben M, Lock MTWT, de Kemp VF, et al. Clomiphene citrate for men with hypogonadism: a systematic review and meta-analysis. Andrology. 2022;10(3):451-469. doi:10.1111/andr.13146
van Breda HMK, Pouw S, Lock MTWT, et al. Clomiphene citrate: A potential alternative for testosterone therapy in hypogonadal males. Endocrinol Diab Metab. 2023;6(3):e416. doi:10.1002/edm2.416
Krzastek SC, Sharma D, Abdullah N, et al. Long-term safety and efficacy of clomiphene citrate for the treatment of hypogonadism. J Urol. 2019;202(5):1029-1035. doi:10.1097/JU.0000000000000396
Thomas J, Suarez Arbelaez MC, Narasimman M, et al. Efficacy of clomiphene citrate versus enclomiphene citrate for male infertility treatment: a retrospective study. Cureus. 2023;15(7):e41476. doi:10.7759/cureus.41476
Wiehle RD, Fontenot GK, Wike J, et al. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertil Steril. 2014;102(3):720-727. doi:10.1016/j.fertnstert.2014.06.029
Hill S, Arutchelvam V, Quinton R. Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men. IDrugs. 2009;12(2):109-119. PMID: 19204885
Kuchakulla M, Narasimman M, Camayo A, Meneses V, Ramasamy R. Clomiphene citrate for male hypogonadism and infertility: an updated review. Androgens. 2021;2(1):95-108. doi:10.1089/andro.2020.0005
Wheeler KM, Sharma D, Kavoussi PK, et al. Clomiphene citrate for the treatment of hypogonadism. Sex Med Rev. 2019;7(2):272-276. doi:10.1016/j.sxmr.2018.10.001
Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559. doi:10.1210/jc.2009-2354
Clomiphene or enclomiphene citrate for the treatment of male hypogonadism: a systematic review and meta-analysis of randomized controlled trials. Clinics. 2024. doi:10.1016/j.clinsp.2024.100523
