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Oral study drug · evidence from male hypogonadism trials
Enclomiphene
Enclomiphene trials found a rise in testosterone. Sperm counts stayed normal in longer studies. This does not prove a fertility benefit.
- The six-week and 16-week trials tested different plans.
- Hormone and sperm findings do not prove symptom relief or a fertility benefit.
Enclomiphene citrate is an oral drug. It was studied in men with secondary hypogonadism. The trials checked hormone levels.
The separate 16-week Phase III studies also measured sperm concentration.
The six-week dose-finding paper tested fixed oral doses once daily: 6.25, 12.5 and 25 mg. It compared these with 5 g/day of testosterone gel applied to the skin. Separate Phase III studies ran for 16 weeks.
They compared the drug with testosterone gel and placebo. Testosterone rose in both sources. In the Phase III paper, sperm concentration stayed in the normal range with enclomiphene.
Sperm production declined with the gel. These are hormone and semen findings. They do not establish symptom relief, pregnancy, live birth or a fertility benefit.
What matters first
- Keep the studies separate: The six-week dose-finding paper is one study. The 16-week ZA-304 and ZA-305 paper covers two others. ZA-203 and ZA-302 are separate registry records. They must not be pooled.
- These are study doses: The oral amounts come from controlled research. They do not set a dose or dose-escalation plan for a reader. The six-week groups stayed on fixed doses.
- The gel amount means the whole formulation: “5 g” is the weight of testosterone gel applied to the skin. It is not 5 g of active testosterone. It is not an oral dose.
- Lab changes have limits: A rise in testosterone, LH, FSH or sperm concentration is a measured finding. By itself, it does not show better symptoms, fertility, pregnancy or live birth.
- The US search has limits: No enclomiphene-only product was found in the US databases checked on September 7, 2026. That does not settle worldwide status. It also does not decide if compounding is allowed or if someone should take the drug.
The six-week dose-finding study
The two-center trial used random group assignment. It enrolled men aged 18–65 with secondary hypogonadism. The enclomiphene groups were single-blind.
The testosterone-gel group was open-label. People took the assigned oral dose daily between 7 and 10 a.m. for six weeks. The team measured 24-hour hormone profiles on day 1 and day 42.
One last blood draw came after a one-week washout.
| Six-week study arm | Route and schedule | Per-protocol n | Day 1 24-hour mean testosterone, ng/dL | Day 42 24-hour mean testosterone, ng/dL |
|---|---|---|---|---|
| Enclomiphene citrate 6.25 mg | Oral, once daily for six weeks | 12 | 262 ± 80 | 391 ± 222 |
| Enclomiphene citrate 12.5 mg | Oral, once daily for six weeks | 7 | 280 ± 67 | 426 ± 140 |
| Enclomiphene citrate 25 mg | Oral, once daily for six weeks | 12 | 300 ± 88 | 586 ± 145 |
| Transdermal testosterone gel 5 g | Applied to the skin daily for six weeks | 13 | 325 ± 108 | 546 ± 233 |
The values are means ± SD from Table 1. They are measured group values, not placebo-adjusted changes. There was no placebo group.
The abstract also gives day-42 values at time zero. These were 604 ± 160 ng/dL for 25 mg enclomiphene and 500 ± 278 ng/dL for the gel. Those are single-time-point values.
They are not the table’s 24-hour means. The difference at time zero was not statistically significant (P=0.23).
Enclomiphene raised testosterone and LH. The 12.5 and 25 mg groups also had significant FSH increases. The gel raised testosterone but suppressed LH and FSH.
Some testosterone and LH effects remained one week after treatment. That does not establish a schedule of intermittent dosing.
IGF-1 fell with enclomiphene. The paper says the meaning was uncertain. Technical problems prevented growth-hormone tests.
This six-week group had no reported sperm-count result. Nor did the paper show a symptom benefit, pregnancy or live birth. Its discussion cites sperm findings from other studies.
Those findings are not results from these people.
The six-week paper’s counts do not reconcile
The paper gives several counts. They answer different questions. One set has no explanation:
- The abstract, Patients section and Results give 48 men. They call these men enrolled, randomized or part of the intent-to-treat group. The paper does not give the number screened.
- The Patients section gives group counts of 16, 14, 16 and 14. These total 60. The paper does not explain the gap from 48. There is no basis to relabel 60 as the number screened.
- Four men started with testosterone above 350 ng/dL. They were left out of the per-protocol analysis. The paper reports 44 per-protocol completers. Tables 1–3 give 12, 7, 12 and 13. These sum to 44.
- Table 4 is labeled intent-to-treat. It gives 12, 10, 12 and 13. Those sum to 47, not the stated 48.
The 44 per-protocol counts belong only with the Table 1 results. The other counts remain as reported. They cannot be repaired by guesswork or borrowed from another trial.
The separate 16-week Phase III studies
ZA-304 and ZA-305 were two parallel multicenter studies. Both used random group assignment. They were double-blind, double-dummy and placebo-controlled.
The men were overweight, aged 18–60, and had secondary hypogonadism. Hormones were checked through 16 weeks. Semen was collected twice near enrollment and twice at treatment end.
The FDA’s 2022 briefing gives 256 treated people across both trials:
| Phase III treatment group | Treated n | Study rule |
|---|---|---|
| Enclomiphene citrate 12.5 mg | 43 | Oral once daily |
| Enclomiphene citrate 12.5 mg with possible increase to 25 mg | 42 | Oral once daily; the protocol increased the dose at week 4 when total testosterone was below 450 ng/dL |
| Testosterone gel | 85 | Topical active comparator |
| Placebo | 86 | Double-dummy placebo control |
The week-4 increase was a rule for one study group. It was not a general dose-escalation plan. The Phase III abstract does not give a gel mass.
The six-week study’s 5 g gel amount cannot be used for this table.
Total testosterone rose from baseline in all active groups. At 16 weeks, LH and FSH rose with enclomiphene and fell with the gel. The paper says sperm concentration stayed in the normal range with enclomiphene.
Sperm production fell markedly with testosterone gel.
These findings do not show better hypogonadal symptoms. The FDA briefing says the hormone findings did not establish a meaningful gain in signs or symptoms. The trials did not establish better fertility, pregnancy rates or live-birth rates.
Sperm concentration is a semen measure. It cannot stand in for those outcomes.
Four study identities that must not be pooled
| Source identity | What the checked source describes | Why it remains separate |
|---|---|---|
| Six-week dose-finding paper | Fixed oral 6.25, 12.5 or 25 mg enclomiphene arms and a 5 g/day skin-applied testosterone-gel arm | No placebo arm and no sperm-count result from this cohort; its internal enrollment and table counts conflict |
| ZA-304 and ZA-305 paper | Two 16-week Phase III studies of enclomiphene, testosterone gel and placebo | This is the paper that reports maintained sperm concentration with enclomiphene |
| ZA-302, NCT01739595 | A separate Phase III registry record with actual enrollment listed as 181 | It is not ZA-304 or ZA-305 and cannot supply their enrollment or treatment table |
| ZA-203, NCT01270841 | A separate three-month Phase II registry record with placebo, topical testosterone and 12.5 or 25 mg enclomiphene arms | It has no 6.25 mg arm and is not the six-week paper |
The ZA-203 registry has conflicting counts. Its design field gives actual enrollment of 83. Its participant flow gives 124 started and 73 completed.
The baseline safety table totals 121. Each count must keep its field label. None repairs the six-week paper’s separate conflict.
What the evidence does and does not answer
| Question | What the checked sources support |
|---|---|
| Did enclomiphene raise testosterone? | Yes. The six-week paper and the 16-week Phase III paper report increased total testosterone. |
| Did it affect LH and FSH? | Yes. Both sources report increases with enclomiphene; testosterone gel suppressed LH and FSH. |
| Did the six-week study measure sperm counts? | No sperm-count result is reported for that cohort. Hormone changes must not be relabeled as sperm or fertility outcomes. |
| What did Phase III report about sperm? | Sperm concentration remained in the normal range with enclomiphene, while spermatogenesis declined with testosterone gel. |
| Did the trials prove symptom relief? | No. The FDA briefing says the hormone findings did not establish clinically meaningful improvement in signs or symptoms. |
| Did the trials prove better fertility, pregnancy or live birth? | No. None of those clinical outcomes was established by the checked sources. |
Current US database check — September 7, 2026
The Drugs@FDA data page gave September 4, 2026 as its latest weekday update. The 12-table archive was downloaded and scanned in this session. It had no enclomiphene, Androxal or EnCyzix match.
As a positive control, its Products table did have nine clomiphene rows. A clomiphene product is not an enclomiphene-only product.
A fresh exact openFDA active-ingredient query for ENCLOMIPHENE returned HTTP 404. Its body said NOT_FOUND and No matches found. A fresh DailyMed query returned HTTP 200.
That result was empty, with total_elements: 0.
No enclomiphene-only product was found in the current US databases checked on September 7, 2026. This search result does not establish worldwide status. It does not decide if compounding is allowed. It is neither legal guidance nor a clinical recommendation.
Safety boundaries
The six-week paper has no counted adverse-event table from which to derive a reliable rate. Its short lab follow-up cannot establish long-term safety. The FDA briefing gives a historical regulatory assessment.
The checked sources do not make one selected trial table a complete safety profile. They do not support invented side-effect rates, a half-life or a safety comparison.
Reader questions
What is enclomiphene?
Enclomiphene citrate is an oral drug studied in men with secondary hypogonadism. The trials measured testosterone and related hormones. The separate 16-week Phase III studies also measured sperm concentration.
What doses were studied?
The six-week trial used fixed oral doses once daily: 6.25, 12.5 or 25 mg. The Phase III program had a 12.5 mg group. Another group could increase from 12.5 to 25 mg at week 4.
That rule applied when total testosterone was below 450 ng/dL. These were research groups, not personal dosing instructions.
Was the testosterone comparison 5 g of active testosterone?
No. The six-week comparison used 5 g/day of testosterone gel formulation applied to the skin. That is not 5 g of active testosterone.
It was not taken by mouth.
Did enclomiphene preserve fertility?
The Phase III paper reports sperm concentration in the normal range with enclomiphene. It did not establish better fertility, pregnancy or live birth. The six-week paper gave no sperm-count result for its own group.
Did enclomiphene improve low-testosterone symptoms?
The checked evidence does not establish that. The FDA briefing says the hormone findings did not establish a meaningful gain in signs or symptoms of hypogonadism.
Is enclomiphene currently approved in the United States?
No enclomiphene-only product was found in the sources checked on September 7, 2026. These were the current Drugs@FDA archive, openFDA active-ingredient search and DailyMed search. The result does not establish worldwide status.
It gives no advice about compounding or treatment.
Can these study amounts be used as a personal schedule?
No. The amounts come from controlled research in selected people. Fixed six-week doses and the Phase III study rule do not form a dosing recommendation for readers.