Enclomiphene: how it works, research, and risks

A balance holds a bead chain on one side and a clear lens on the other.

Testosterone treatment can bring a low testosterone level up. It can also suppress the signals that tell the testes to make testosterone and sperm. For someone hoping to have children, that trade-off matters. Enclomiphene was developed to stimulate the body’s own testosterone production while preserving those signals. Source

The distinction is promising, but it has limits. Trials have measured testosterone and sperm counts; they have not established that enclomiphene improves the chance of pregnancy or live birth. Enclomiphene is not FDA-approved. Compounded medicines and approved medicines have different regulatory status, even when both require a prescription.

This article explains the mechanism, the human research, and the questions that matter before considering treatment. It is for information, not a substitute for diagnosis or individual medical advice. The regulatory discussion concerns the United States.

What the studies show

Regulatory status: Enclomiphene is not FDA-approved. The application for Androxal received an FDA Complete Response Letter in 2015, meaning it could not be approved in its submitted form. The company’s announcement described concerns about study design and demonstrating clinical benefit. Source
Research stage: Phase II and phase III randomized controlled trials are available. They provide evidence about hormone levels and sperm counts, rather than an approved indication or a complete long-term safety record.
Availability: Compounding is a separate regulatory pathway. FDA’s May 14, 2026 list places enclomiphene citrate in category 1, under evaluation for section 503A compounding. That listing is not drug approval or a blanket assurance that any pharmacy may supply it in any state. FDA list
Chemical identity: Enclomiphene has an entry in PubChem, CID 1548953. A chemical database entry establishes identity, not clinical effectiveness. Source
Mechanism: It reduces estrogen’s negative feedback on the hypothalamus and pituitary, increasing luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These signals can stimulate testosterone production and support sperm production when the testes can respond.
Main findings: Two phase III trials enrolled 256 overweight men aged 18–60 with secondary hypogonadism and baseline total testosterone at or below 300 ng/dL. Over 16 weeks, mean testosterone rose from approximately 205 ng/dL to 413–446 ng/dL in the enclomiphene groups, with reported comparisons against placebo of p = 0.0007 and p = 0.0368. Sperm concentrations were preserved, unlike the reduction seen with topical testosterone, AndroGel 1.62%. These are laboratory outcomes, not proof of improved fertility or equivalent overall clinical benefit. Source

What is enclomiphene?

Enclomiphene is the trans isomer of clomiphene, a medicine used in reproductive care for decades. Clomiphene contains two geometric isomers: enclomiphene, the trans form, and zuclomiphene, the cis form. They are an isomer mixture, not a racemic mixture of mirror-image molecules.

The two forms behave differently. Enclomiphene mainly acts as an estrogen receptor antagonist in the feedback system that regulates testosterone. Zuclomiphene has partial estrogen agonist activity and persists longer in the body. Separating the isomers was intended to retain the testosterone-stimulating action while avoiding prolonged exposure to zuclomiphene.

The proposed product Androxal did not obtain FDA approval. In December 2015, the developer reported that FDA considered the phase III study designs inadequate to demonstrate clinical benefit and recommended additional phase III work. The announcement also mentioned entry criteria, dose titration, and laboratory-method validation. It does not establish the outcome of every subsequent development decision. Source

The practical distinction remains: evidence that a substance raises testosterone is not, by itself, evidence that an approved medicine improves symptoms, health, or reproductive outcomes. Compounded enclomiphene should not be presented as an FDA-approved version of Androxal.

How enclomiphene works in the body

Estrogen feedback in the hypothalamus and pituitary

Estrogen helps regulate testosterone production in men. Within the hypothalamic-pituitary-gonadal, or HPG, axis, estrogen provides negative feedback that reduces the release of gonadotropin-releasing hormone, LH, and FSH. This feedback prevents the system from running continuously at its highest output.

Enclomiphene changes that feedback through its action at estrogen receptors. The pituitary can then release more LH and FSH. LH signals the Leydig cells in the testes to produce testosterone; FSH helps support the processes involved in sperm production. The testosterone increase comes from stimulating the existing pathway rather than supplying testosterone from outside the body. Source

That mechanism depends on an ability to respond. Increasing the signal cannot reliably overcome severe primary testicular failure, and a plausible mechanism does not guarantee a particular patient’s response.

Preserving hormonal signaling

Because enclomiphene stimulates production rather than replacing testosterone, LH and FSH can rise during treatment instead of being suppressed. This is the central reason researchers have studied it in men who want to preserve sperm production. It does not mean that testicular function or fertility is guaranteed to remain normal throughout treatment.

A 2013 pharmacodynamic study by Wiehle and colleagues enrolled 48 men with secondary hypogonadism, baseline total testosterone below 350 ng/dL, and LH below 12 IU/L. Participants received 6.25, 12.5, or 25 mg of enclomiphene daily, or 5 g of AndroGel daily, for six weeks. At day 42, the 25-mg enclomiphene group had mean total testosterone of 604 ± 160 ng/dL. LH and FSH increased above baseline, whereas transdermal testosterone suppressed gonadotropins. Source

This small, short study demonstrates the hormonal contrast. It cannot establish lifelong preservation of the axis, long-term safety, or a pregnancy benefit.

Studied doses and pharmacokinetics

Enclomiphene has been studied as an oral medicine. In the same six-week dose-finding study, all three doses increased total testosterone. The 25-mg group reached 604 ± 160 ng/dL, compared with 500 ± 278 ng/dL in the testosterone-gel group. The between-group comparison was not statistically significant, p = 0.23; the numerical difference is not evidence of superiority.

Pharmacokinetic research, much of it conducted in women receiving clomiphene, suggests that enclomiphene clears more quickly than zuclomiphene. This supports a difference in persistence between the isomers, but those studies do not directly establish the optimal schedule for men taking pure enclomiphene. Source Source

The doses here describe research, not a self-treatment plan. There is no FDA-approved enclomiphene dosing label. Any prescribing decision requires an individual assessment of the diagnosis, formulation, response, and risks.

What the research says about effectiveness

Testosterone levels and sperm preservation

The strongest direct evidence comes from phase II and III randomized controlled trials. Kim and colleagues reported two double-blind, placebo-controlled phase III studies, ZA-304 and ZA-305, involving 256 overweight men aged 18–60. Entry criteria included total testosterone at or below 300 ng/dL and LH below 9.4 IU/L. Participants received enclomiphene, AndroGel 1.62%, or placebo for 16 weeks.

Mean testosterone in the enclomiphene groups rose from approximately 205 ng/dL to 446 and 413 ng/dL in the respective trials. The reported comparisons with placebo were p = 0.0007 and p = 0.0368. Sperm concentrations increased by 12–15% in the enclomiphene groups, compared with decreases of 33–57% in the AndroGel groups, with p < 0.001 reported for the sperm comparisons. These results concern selected men with secondary hypogonadism, not every cause of low testosterone.

A multicenter phase II trial reported by Wiehle and colleagues in 2014, NCT01270841, compared oral enclomiphene with 1% topical testosterone gel. Both raised testosterone, but their effects on pituitary signals differed: enclomiphene increased LH and FSH and preserved sperm counts, whereas testosterone gel suppressed those signals. The study also assessed estradiol. It would be misleading to describe the LH responses as equivalent simply because testosterone increased in both groups. Source Source

Related research helps explain the mechanism but should not be confused with a trial of pure enclomiphene. Miller and colleagues gave 50 mg of clomiphene daily for 30 days to 12 healthy men aged 25–38 in an open-label study. Testosterone increased by 146% with a standard error of the mean of 23%; LH increased by 177% ± 34%, and FSH by 170% ± 33%. That study used the clomiphene isomer mixture. Its findings demonstrate stimulation of the hormonal pathway, not the clinical effectiveness of enclomiphene in men with hypogonadism. Source

Across these studies, sperm counts are a useful reproductive marker. They are not interchangeable with the chance of conception, time to pregnancy, or live birth. A couple’s fertility involves more than a single semen measurement.

Tolerability compared with clomiphene

A 2024 retrospective study by Saffati and colleagues followed 66 men who took clomiphene and subsequently switched to enclomiphene. Median testosterone changes were 166 versus 98 ng/dL, a difference that was not statistically significant, p = 0.20. Estradiol changed by −5.92 pg/mL during enclomiphene treatment versus +17.50 pg/mL during clomiphene treatment, p = 0.001.

The authors reported lower odds of recorded adverse events with enclomiphene: odds ratio 0.18, 95% confidence interval 0.07–0.44, p = 0.02. Reported events included reduced libido, lower energy, and mood changes. However, patients switched treatments without a washout period, and treatment durations and hormone baselines differed. This was not a randomized comparison and cannot establish that enclomiphene is generally safer. Source

A separate 2023 retrospective study by Thomas and colleagues included 78 men: 46 taking enclomiphene at 12.5–25 mg daily and 32 taking clomiphene at 50 mg every other day. Mean ages were approximately 41–42, and treatment lasted at least three months. In the enclomiphene group, mean LH increased from 3.1 to 5.5 mIU/mL, p = 0.004; FSH increased from 4.4 to 7.4 mIU/mL, p = 0.027; and total motile sperm count increased from 0.73 to 4.01 million, p = 0.039. Both treatments raised testosterone without a significant adverse change in semen volume or sperm concentration. Source

These observations are encouraging for further research. They do not settle comparative long-term safety or show that an individual will experience the same hormone or semen changes.

How does enclomiphene differ from TRT and clomiphene?

Enclomiphene, testosterone replacement therapy, and clomiphene can all increase measured testosterone. They do so through different mechanisms, with different implications for sperm production and different regulatory histories.

TRT supplies testosterone from outside the body. Feedback reduces LH and FSH, which can reduce intratesticular testosterone and sperm production. A 2013 review by Crosnoe and colleagues, drawing on 28 references from 1990–2013, described exogenous testosterone as a preventable cause of male infertility.

That review discussed an integrated analysis of hormonal male-contraception trials. The estimated probabilities of recovering a sperm concentration of 20 million/mL after stopping treatment were 67% by six months, 90% by 12 months, and 100% by 24 months. These modeled estimates came from selected contraception-study participants. They are not a guarantee that every man using TRT will recover fertility on that schedule. Duration of treatment and individual circumstances matter. Source

In the main enclomiphene trials, topical testosterone raised serum testosterone while reducing sperm production. Enclomiphene raised testosterone while preserving sperm concentrations. This difference is a reason to discuss reproductive plans before starting testosterone treatment, rather than discovering its effects on sperm production afterward.

Clomiphene contains both enclomiphene and zuclomiphene. In a 2017 observational study by Helo and colleagues, 15 men taking 25 mg of clomiphene daily had used it for an average of 25.9 months. Their mean age was 36 and mean BMI was 32.0. Mean serum zuclomiphene was 44.0 ng/mL, compared with enclomiphene at 2.2 ng/mL: a ratio of 20:1. Zuclomiphene therefore predominated in circulation during prolonged treatment.

Its persistence is a plausible explanation for some differences between the formulations. The study does not prove that accumulated zuclomiphene causes mood or visual symptoms, or that pure enclomiphene eliminates those risks. Source

A 2025 meta-analysis of randomized trials pooled clomiphene and enclomiphene studies. Compared with placebo, SERM treatment increased total testosterone by a mean 273.76 ng/dL, 95% confidence interval 191.87–355.66, p < 0.01. Pooled LH and FSH differences were 4.66 and 4.59 IU/L, respectively. Total testosterone did not differ significantly between SERM and testosterone-gel groups. The testosterone estimate had substantial heterogeneity, I² = 89%, so the pooled number should not be treated as a predictable individual response. Source

A 2022 clomiphene review included 19 studies, four randomized and 15 observational, with 1,642 participants and treatment durations of 1.5–52 months. Reported adverse effects occurred in fewer than 10% of participants, and no serious adverse events were reported in the included studies. That is reassuring within the limits of the available reporting; it does not prove an absence of rare harms. Clomiphene findings also cannot simply be transferred to pure enclomiphene. Source

What side effects are known?

Some small studies suggest better tolerability with enclomiphene than with clomiphene, but the comparative evidence is limited. The 66-person retrospective study is not enough to establish the frequency of uncommon harms or safety over many years. There is no FDA-approved enclomiphene label providing a definitive adverse-effect profile. Source

Reported effects and effects considered during monitoring include:

Headaches: Reported in enclomiphene research. The trials do not provide a complete picture of their frequency across all patients and treatment durations. Source
Higher estradiol: Testosterone can be converted to estradiol, so stimulating testosterone production can also increase estradiol. A change should be interpreted alongside symptoms and the broader hormone pattern. Source
Acne or oily skin: Increased androgen activity can affect the skin. The cited study concerns masculinizing testosterone therapy in transgender patients, not pure enclomiphene, so it supports the biological concern rather than an enclomiphene-specific frequency estimate. Source
Mood changes: Recorded in the comparative clomiphene/enclomiphene study. Fewer were documented after switching to enclomiphene, but the observational design limits conclusions about causation and relative risk. Source

Other concerns require attention, although their frequency with enclomiphene is not established by these sources:

Visual disturbances: These have been reported with clomiphene. It is not established that pure enclomiphene carries a reliably lower risk. New visual symptoms warrant prompt medical assessment. Source
Erythrocytosis or polycythemia: Testosterone treatment can raise red blood cell measures. The cited risk evidence comes from TRT, not a direct estimate for enclomiphene. A complete blood count can help monitor this concern when clinically appropriate. Source
PSA changes: Research on prostate-specific antigen largely concerns testosterone replacement. Monitoring decisions for enclomiphene need individual assessment rather than assuming the same measured risk or a universal screening schedule. Source

A clinician may monitor hormones, blood counts, and prostate-related measures according to age, symptoms, history, and treatment response. Stimulating endogenous testosterone does not automatically remove the effects that testosterone can have on blood cell production or other tissues. At the same time, findings from TRT should be clearly identified as indirect evidence when applied to enclomiphene. Source

Who has enclomiphene been studied for?

Secondary hypogonadism with fertility goals

Most direct research involves men with secondary hypogonadism: low testosterone associated with inadequate signaling from the hypothalamus or pituitary, rather than primary failure of the testes. Researchers have been particularly interested in men who want to preserve sperm production.

Low testosterone together with low or inappropriately normal LH and FSH can fit that diagnosis. The pattern does not, on its own, establish the cause or show that a SERM is the right treatment. A clinician needs to consider symptoms, repeat testosterone testing, other hormone results, and possible reversible causes.

The testes must retain enough function to respond to stimulation. Enclomiphene cannot be expected to overcome primary testicular failure simply by raising LH and FSH further. A reproductive assessment may also require semen analysis rather than relying on hormone levels as a substitute.

Stimulating testosterone without suppressing the axis

Another reason for interest is symptomatic testosterone deficiency in men who prefer an approach that stimulates their own production. This may include men concerned about sperm suppression during TRT, testicular volume, or future reproductive plans.

These preferences are legitimate reasons for discussion, but they are not approved indications. Nor do they establish that enclomiphene will improve symptoms or preserve testicular volume in every case. The cause of low testosterone, potential alternatives, and the uncertainty around a compounded, unapproved treatment all belong in that decision.

Prescribing judgment and compounding rules are separate considerations. A clinician’s decision to prescribe does not turn a compounded product into an FDA-approved medicine or establish its suitability for every patient with a low laboratory result.

Who should avoid enclomiphene or seek specialist assessment?

There is no FDA-approved enclomiphene prescribing label with a validated list of contraindications. The following are reasons for caution, specialist evaluation, or choosing another approach; some are inferred from related therapies rather than directly tested in enclomiphene trials:

Primary hypogonadism, including testicular failure associated with Klinefelter syndrome: increasing LH and FSH may not overcome the testes’ inability to respond. Source
Active or suspected hormone-sensitive cancer: Prostate or male breast cancer requires specialist assessment before testosterone-raising treatment. The cited testosterone guideline does not establish that all testicular cancers are androgen-sensitive. A history of testicular cancer needs its own assessment rather than a blanket assumption about its biology. Source
Severe liver disease: Metabolism and drug exposure may be affected. The cited CYP2D6 study concerns clomiphene metabolism in laboratory systems; it does not directly quantify risk or define a formal contraindication for pure enclomiphene. Source
Known hypersensitivity to enclomiphene, clomiphene-related compounds, or ingredients in the preparation.
Inability to complete appropriate follow-up: Treatment decisions require assessment of symptoms, hormone response, and relevant safety measures. Taking a testosterone-raising drug without follow-up makes unexpected changes harder to detect.

This is not an exhaustive list. Medical history, other medicines, fertility goals, and the reason for the low testosterone result may change the assessment substantially.

What is enclomiphene’s regulatory status in the United States?

Enclomiphene is not FDA-approved for any indication. The 2015 Complete Response Letter for Androxal concerned whether the submitted studies demonstrated clinical benefit, along with study-entry, titration, and laboratory-method issues. The developer’s announcement said FDA recommended additional phase III studies. It is not evidence for a specific later filing history or for a claim that FDA’s only concern was cardiovascular safety. Source

FDA’s May 14, 2026 category list includes enclomiphene citrate among substances under evaluation for section 503A compounding. Category 1 is not the same as inclusion on a final approved-drug list. FDA’s interim compounding policy has conditions, and pharmacies must also meet applicable legal requirements. An advertised prescription service should not be mistaken for FDA approval or nationwide availability. FDA list FDA compounding policy

There is no FDA-approved over-the-counter enclomiphene product. It should not be represented as a dietary supplement. Availability depends on the particular provider, pharmacy, and applicable requirements; a provider’s shipping restrictions do not establish a state-wide ban. Chemical details are available under PubChem CID 1548953, but PubChem is not a prescribing or regulatory approval database. Source U.S. Department of Defense information

What tests are useful before treatment?

Testing begins with confirming the problem, not simply ordering the same large panel for everyone. Hypogonadism is diagnosed from compatible symptoms or signs together with consistently low testosterone. The Endocrine Society recommends repeating a morning, fasting total testosterone measurement to confirm a low result. Other tests help distinguish causes and assess relevant risks. Guideline

Total testosterone: Establishes a baseline and can be followed during treatment. A single low result does not by itself confirm hypogonadism. Repeat morning measurements and the clinical picture matter before discussing treatment targets.
Free testosterone: The fraction not bound to SHBG or albumin. It can be helpful when total testosterone is borderline or SHBG is altered. Free testosterone is distinct from the broader term bioavailable testosterone, which can include albumin-bound testosterone.
Luteinizing hormone, LH: Low or inappropriately normal LH alongside low testosterone supports a secondary pattern, but does not independently confirm its cause or establish suitability for enclomiphene. A treatment-related rise can demonstrate a hormonal response.
Follicle-stimulating hormone, FSH: Helps assess pituitary and testicular signaling. It contributes to the distinction between primary and secondary disorders, but a blood FSH result is not a direct measurement of sperm production or fertility. Semen analysis answers different questions.
Estradiol: Provides context before a treatment that may increase testosterone conversion to estradiol. One baseline estradiol concentration does not measure the body’s aromatization rate or reliably predict whether estradiol-related symptoms will develop.
Sex hormone-binding globulin, SHBG: Affects the relationship between total and free testosterone. High SHBG can make total testosterone appear less informative about the free fraction. Interpretation should account for the clinical situation and the measurement method.
Prolactin: Elevated prolactin can suppress reproductive signaling and cause secondary hypogonadism. If indicated, testing helps identify a potentially treatable cause that may need a different approach. A result must be interpreted rather than assumed to exclude every pituitary disorder. Source
Complete blood count, CBC: Establishes hemoglobin, hematocrit, and other blood cell measures. Testosterone-related erythrocytosis is a reason to consider follow-up. The cited mechanistic study concerns testosterone administration, not an enclomiphene-specific risk estimate. Source
Prostate-specific antigen, PSA: Testing depends on age, individual risk, and shared decision-making. The cited Endocrine Society TRT guideline discusses monitoring for men aged 55–69 and men aged 40–69 at increased prostate cancer risk; it does not prescribe a universal enclomiphene PSA test for everyone over 40. Source
Comprehensive metabolic panel: May provide useful liver-related, kidney-related, and electrolyte measurements when clinically indicated. It is not a complete assessment of either organ and is not automatically required in every person with a low testosterone result.

Total and free testosterone, LH, FSH, estradiol, and SHBG can help describe the hormonal response, but the selection of tests should follow the diagnostic question. Establishing useful baseline values makes later changes easier to interpret; it does not eliminate uncertainty about benefits or safety.

How might laboratory results change during treatment?

If enclomiphene stimulates the intended pathway, LH, FSH, and testosterone may rise. The magnitude varies, and not every patient reaches a normal testosterone level or experiences symptom improvement. A higher LH or FSH value shows a response in hormonal signaling; it is not a complete measure of testicular function or fertility.

Estradiol may increase as more testosterone is available for conversion. Clinicians interpret changes alongside symptoms, the assay, and the overall hormone pattern rather than treating every numerical rise as a problem. Semen results may remain stable or improve, but preservation is not guaranteed and needs direct assessment when fertility matters.

Hemoglobin and hematocrit may also warrant follow-up. The rationale partly comes from studies of testosterone administration, so it should not be presented as a precise estimate of enclomiphene’s risk. Baseline measurements allow changes to be assessed over time. Source Source Source Source

Laboratory improvement is one part of follow-up. Whether the person feels better, whether reproductive goals are being met, and whether adverse effects appear are separate questions.

Frequently asked questions

What is the difference between enclomiphene and clomiphene?

Clomiphene combines enclomiphene, the trans isomer, and zuclomiphene, the cis isomer. Enclomiphene mainly reduces estrogen feedback that limits LH and FSH release; zuclomiphene has partial estrogen agonist activity and persists longer.

In the 2017 study of 15 men taking 25 mg of clomiphene daily for an average of 25.9 months, circulating zuclomiphene exceeded enclomiphene by approximately 20:1. Pure enclomiphene avoids exposure to the zuclomiphene component. Whether this explains better tolerability remains a hypothesis supported by limited comparative observations, not a settled safety advantage. Source

Does enclomiphene affect fertility?

Trials support preservation of sperm concentrations during treatment in selected men with secondary hypogonadism. In the two phase III studies of 256 overweight men aged 18–60, testosterone reached mean values of 413–446 ng/dL after 16 weeks. The reported proportions with sperm concentrations below 15 million/mL were 2–5% with enclomiphene versus 24–49% with AndroGel 1.62%, with p < 0.001 for the comparison.

Stimulating FSH as well as LH provides a plausible explanation for the difference from TRT. However, these results do not demonstrate improved pregnancy or live-birth rates. Baseline semen quality, testicular disease, and other reproductive factors still matter. Source

Can enclomiphene be used long term to raise testosterone?

Long-term evidence for pure enclomiphene remains limited. It should not be inferred from a short hormone-response study or from the longer history of clomiphene use.

The 2022 clomiphene review included 19 studies and 1,642 participants treated for 1.5–52 months. Fewer than 10% had reported adverse effects, and no serious adverse events were reported in the included studies. Some studies assessed androgen-deficiency symptoms and metabolic measures, but findings across different designs are not a definitive long-term enclomiphene safety record. Source

If treatment continues, follow-up should address symptoms, hormone response, and relevant safety measures. Testing may include blood counts, prostate-related assessment, or liver-related tests depending on the individual situation. Continuing treatment is a clinical decision, not an automatic consequence of a higher testosterone result.

Who should not take enclomiphene?

Primary testicular failure may make stimulation ineffective. Active or suspected hormone-sensitive cancer, severe liver disease, hypersensitivity, or inability to complete appropriate follow-up are reasons for specialist assessment or another approach.

These concerns are not a substitute for an approved prescribing label, which enclomiphene does not have. Some derive from related medicines and hormone biology rather than direct enclomiphene trials. A complete medical assessment is needed before considering a compounded preparation.

How quickly does enclomiphene raise testosterone?

In the six-week phase II study of 48 men taking 6.25–25 mg daily, testosterone increases were evident within two weeks. At week six, the 25-mg group averaged 604 ± 160 ng/dL. LH and FSH responses also appeared during the early weeks. Source

A clinician may assess hormone response after roughly four to eight weeks, while semen changes generally need a longer observation period, often three months or more. These are clinical assessment intervals, not an FDA-approved protocol or a guarantee about when symptoms will improve.

Is enclomiphene FDA-approved?

No. Androxal received a Complete Response Letter in 2015. The developer reported that FDA questioned whether the study design adequately demonstrated clinical benefit and recommended further phase III studies. Source

A compounded prescription is not an approved indication. FDA’s category 1 compounding listing means enclomiphene citrate is under evaluation; supply must meet applicable requirements. It should not be described as an FDA-approved testosterone or fertility treatment.

Which blood tests should be considered before starting?

The first priority is confirming the diagnosis with symptoms or signs and repeat morning testosterone testing. Free testosterone may be useful when SHBG is altered or total testosterone is borderline. LH and FSH help distinguish a primary from a secondary pattern, while estradiol and SHBG may add context.

Prolactin can help investigate a potentially treatable cause. A CBC, PSA assessment, or metabolic panel may be appropriate according to age, risks, symptoms, and the proposed treatment. No fixed panel independently confirms the diagnosis or guarantees that enclomiphene is suitable. Hormone results and semen analysis also answer different questions.

Important safety information

Enclomiphene is not FDA-approved. Its proposed product, Androxal, received a Complete Response Letter in 2015. Compounding and prescribing decisions are subject to applicable requirements and do not establish approval, proven long-term safety, or a benefit for every patient.

Potential concerns include hormone changes, headaches, skin symptoms, mood changes, visual disturbances, and changes in blood counts or PSA. Some are reported in enclomiphene studies; others are inferred from clomiphene or TRT. Their frequencies cannot all be described as established for pure enclomiphene. New visual symptoms need prompt medical attention.

Primary testicular failure, suspected hormone-sensitive cancer, significant liver disease, hypersensitivity, and difficulties with monitoring require individual assessment. Availability is provider- and jurisdiction-dependent; there is no FDA-approved over-the-counter enclomiphene product.

Sources and references

Crosnoe LE, Grober E, Ohl D, Kim ED (2013). Exogenous testosterone: a preventable cause of male infertility. Translational andrology and urology, 2(2), 106-13. https://doi.org/10.3978/j.issn.2223-4683.2013.06.01 Publication

U.S. Securities and Exchange Commission. (n.d.). Newsrelease.htm. https://sec.gov/Archives/edgar/data/897075/000117184315006596/newsrelease.htm Publication

PubChem (National Library of Medicine). (n.d.). Enclomiphene. https://pubchem.ncbi.nlm.nih.gov/compound/1548953 Publication

Kim ED, McCullough A, Kaminetsky J (2016). Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU international, 117(4), 677-85. https://doi.org/10.1111/bju.13337 Publication

Rodriguez KM, Pastuszak AW, Lipshultz LI (2016). Enclomiphene citrate for the treatment of secondary male hypogonadism. Expert opinion on pharmacotherapy, 17(11), 1561-7. https://doi.org/10.1080/14656566.2016.1204294 Publication

Wiehle R, Cunningham GR, Pitteloud N, Wike J, Hsu K, Fontenot GK, Rosner M, Dwyer A, Podolski J (2013). Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics. BJU international, 112(8), 1188-200. https://doi.org/10.1111/bju.12363 Publication

Ghobadi C, Mirhosseini N, Shiran MR, Moghadamnia A, Lennard MS, Ledger WL, Rostami-Hodjegan A (2009). Single-dose pharmacokinetic study of clomiphene citrate isomers in anovular patients with polycystic ovary disease. Journal of clinical pharmacology, 49(2), 147-54. https://doi.org/10.1177/0091270008328096 Publication

Wiehle RD, Fontenot GK, Wike J, Hsu K, Nydell J, Lipshultz L, ZA-203 Clinical Study Group (2014). Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertility and sterility, 102(3), 720-7. https://doi.org/10.1016/j.fertnstert.2014.06.004 Publication

Miller GD, Moore C, Nair V, Hill B, Willick SE, Rogol AD, Eichner D (2019). Hypothalamic-Pituitary-Testicular Axis Effects and Urinary Detection Following Clomiphene Administration in Males. The Journal of clinical endocrinology and metabolism, 104(3), 906-914. https://doi.org/10.1210/jc.2018-01159 Publication

Saffati G, Kassab J, Orozco Rendon D, Hinojosa-Gonzalez DE, Kronstedt S, Lipshultz LI, Khera M (2024). Safety and efficacy of enclomiphene and clomiphene for hypogonadal men. Translational andrology and urology, 13(9), 1984-1990. https://doi.org/10.21037/tau-24-238 Publication

Thomas J, Suarez Arbelaez MC, Narasimman M, Weber AR, Blachman-Braun R, White JT, Ledesma B, Ghomeshi A, Jara-Palacios MA, Ramasamy R (2023). Efficacy of Clomiphene Citrate Versus Enclomiphene Citrate for Male Infertility Treatment: A Retrospective Study. Cureus, 15(7), e41476. https://doi.org/10.7759/cureus.41476 Publication

Helo S, Mahon J, Ellen J, Wiehle R, Fontenot G, Hsu K, Feustel P, Welliver C, McCullough A (2017). Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long-term clomiphene citrate treatment. BJU international, 119(1), 171-176. https://doi.org/10.1111/bju.13625 Publication

Hohl A, Chavez MP, Pasqualotto E, Ferreira ROM, Sande-Lee SV, Ronsoni MF (2025). Clomiphene or enclomiphene citrate for the treatment of male hypogonadism: a systematic review and meta-analysis of randomized controlled trials. Archives of endocrinology and metabolism, 69(5). https://doi.org/10.20945/2359-4292-2025-0093 Publication

Huijben M, Lock MTWT, de Kemp VF, de Kort LMO, van Breda HMK (2022). Clomiphene citrate for men with hypogonadism: a systematic review and meta-analysis. Andrology, 10(3), 451-469. https://doi.org/10.1111/andr.13146 Publication

Motosko CC, Zakhem GA, Pomeranz MK, Hazen A (2019). Acne: a side-effect of masculinizing hormonal therapy in transgender patients. The British journal of dermatology, 180(1), 26-30. https://doi.org/10.1111/bjd.17083 Publication

Jones SD, Dukovac T, Sangkum P, Yafi FA, Hellstrom WJ (2015). Erythrocytosis and Polycythemia Secondary to Testosterone Replacement Therapy in the Aging Male. Sexual medicine reviews, 3(2), 101-112. https://doi.org/10.1002/smrj.43 Publication

Kang DY, Li HJ (2015). The effect of testosterone replacement therapy on prostate-specific antigen (PSA) levels in men being treated for hypogonadism: a systematic review and meta-analysis. Medicine, 94(3), e410. https://doi.org/10.1097/MD.0000000000000410 Publication

Earl JA, Kim ED (2019). Enclomiphene citrate: A treatment that maintains fertility in men with secondary hypogonadism. Expert review of endocrinology & metabolism, 14(3), 157-165. https://doi.org/10.1080/17446651.2019.1612239 Publication

Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA (2018). Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism, 103(5), 1715-1744. https://doi.org/10.1210/jc.2018-00229 Publication

Ghobadi C, Gregory A, Crewe HK, Rostami-Hodjegan A, Lennard MS (2008). CYP2D6 is primarily responsible for the metabolism of clomiphene. Drug metabolism and pharmacokinetics, 23(2), 101-5. https://doi.org/10.2133/dmpk.23.101 Publication

Abbara A, Clarke SA, Nesbitt A, Ali S, Comninos AN, Hatfield E, Martin NM, Sam AH, Meeran K, Dhillo WS (2018). Interpretation of Serum Gonadotropin Levels in Hyperprolactinaemia. Neuroendocrinology, 107(2), 105-113. https://doi.org/10.1159/000489264 Publication

Bachman E, Travison TG, Basaria S, Davda MN, Guo W, Li M, Connor Westfall J, Bae H, Gordeuk V, Bhasin S (2014). Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. The journals of gerontology. Series A, Biological sciences and medical sciences, 69(6), 725-35. https://doi.org/10.1093/gerona/glt154 Publication

U.S. Food and Drug Administration (2026). Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act. Updated May 14, 2026. https://www.fda.gov/media/94155/download?attachment=

U.S. Food and Drug Administration. Bulk Drug Substances Used in Compounding Under Section 503A of the FD&C Act. https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503a-fdc-act

Operation Supplement Safety, U.S. Department of Defense (2026). Clomiphene and Enclomiphene: Drugs, Not Dietary Supplements. https://www.opss.org/article/clomiphene-and-enclomiphene-drugs-not-dietary-supplements