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Enclomiphene: Double testosterone without injections

Enclomiphene: double testosterone without injections

Written by

Alexander Grant, MD, PhD: Urologist & Men’s health advocate

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For some men with low T who want fertility, daily enclomiphene can restore testosterone while keeping sperm production active.

“If you want testosterone up and sperm production intact, a SERM like enclomiphene can be the right lever. It stimulates your own axis rather than replacing it.”

Alexander Grant, MD, PhD — Urologist and researcher specializing in men’s reproductive health and hormone balance

The relationship

Enclomiphene is the trans isomer of clomiphene, a selective estrogen receptor modulator (SERM), that blocks estrogen’s feedback at the hypothalamus and pituitary. That raises luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which drive the testes to produce testosterone and sperm. Randomized trials show enclomiphene elevates testosterone while maintaining sperm counts, unlike topical testosterone, which commonly suppresses them [1,2].

In a phase II trial, enclomiphene increased morning testosterone and kept semen parameters stable; testosterone gel increased testosterone but reduced spermatogenesis [1]. Two phase III studies in 2015–2016 repeated the core pattern: testosterone normalized and LH/FSH rose on enclomiphene, while gonadotropins fell, and sperm counts declined on gel testosterone [2].

A pooled review of these trials concluded that therapy with enclomiphene “restores rather than replaces,” often preserving fertility, though long-term symptom data remain limited [3]. Guidelines from major societies still use exogenous testosterone as the first line for classic hypogonadism, but acknowledge fertility-preserving options such as SERMs in selected men [5,6].

How it works

HPG axis release: blocking estrogen feedback

The hypothalamic-pituitary-gonadal axis coordinates hormone signals. As a SERM, enclomiphene reduces estrogen’s brake at the hypothalamus. That increases gonadotropin-releasing hormone pulses, which raise LH/FSH and testicular testosterone output [1,3].

Testosterone restoration without testicular shutdown

Enclomiphene raises endogenous testosterone while keeping LH/FSH active. In contrast, exogenous testosterone suppresses LH/FSH and often lowers sperm counts. Head-to-head trials document maintained sperm concentration with enclomiphene and marked reductions with gel testosterone [1,2].

Isomer biology and tolerability

Clomiphene is a mixture of two stereoisomers: zuclomiphene (cis) and enclomiphene (trans). Reviews and preclinical work suggest zuclomiphene behaves more estrogenically and has a longer half-life, while enclomiphene is the main driver of LH/FSH rise [3]. Animal data report adverse reproductive effects with high-dose zuclomiphene, supporting interest in the single-isomer approach [2,7].

Dosing pattern and monitoring

Trials used daily dosing, commonly 12.5–25 mg, with checks at 4–16 weeks for testosterone, LH/FSH, estradiol, and semen parameters when fertility matters [1,2]. Monitoring follows hypogonadism guidance: repeat early morning total testosterone on two days, add free testosterone when total is borderline or SHBG is abnormal [5,6].

Diagnostic thresholds: Meta-analyses and guideline syntheses indicate that symptomatic men with total testosterone below 350 ng/dL (≈12 nmol/L) are most likely to benefit from therapy. If the total is borderline, measure free testosterone; values below 100 pg/mL (≈10 ng/dL) strengthen the diagnosis [4,9,10].

Regulatory status and access

Enclomiphene is not FDA-approved for men as of 2016–2025 reviews, despite completed phase II and III studies. Expert summaries note investigational status and canceled regulatory meetings in 2015; access in the U.S. has largely come through compounding arrangements under clinician oversight [3].

Conditions linked to it

Secondary hypogonadism with fertility goals.
For men who want paternity, enclomiphene offers testosterone restoration while preserving semen parameters in trials [1–3].

Obesity-associated low testosterone.
Phase III studies enrolled overweight men with secondary hypogonadism and showed normalized testosterone with maintained sperm counts on enclomiphene [2]. Reviews highlight the utility of SERM therapy in men with high aromatase activity from adipose tissue [3].

Idiopathic secondary hypogonadism.
When pituitary signals are low-normal and testes are structurally intact, a SERM can restore LH/FSH drive and raise testosterone, with data from multiple enclomiphene trials [1–3].

Symptoms and signals

  • Fewer morning erections and lower sex drive that persist for months.
  • Low energy, slower recovery after workouts, and reduced strength.
  • More body fat around the waist and less lean muscle.
  • Low mood, irritability, or reduced motivation.
  • Brain fog and slower focus during work or training.
  • Poor sleep, especially with snoring or apnea risk.
  • Fertility concerns: lower semen volume or delayed conception.

What to do about it

1) Get tested the right way.
Schedule two early-morning total testosterone tests on different days, ideally off acute illness and heavy alcohol. Add free testosterone if total is borderline or if sex hormone-binding globulin (SHBG) is abnormal. Use the decision numbers that guide action: total <350 ng/dL or free <100 pg/mL with symptoms supports treatment consideration [5,9,10].

2) Choose a path: lifestyle, SERM therapy, or testosterone.
For men who want fertility or dislike injections, enclomiphene is a non-injectable option that can restore testosterone and preserve sperm counts in trials. Typical study doses were 12.5–25 mg daily with follow-up at 4–16 weeks. Watch estradiol, hematocrit, and semen parameters if trying to conceive [1–3]. If fertility is not a priority and symptoms are severe with very low levels, guideline-driven testosterone therapy remains standard care [5,6].

3) Monitor and adjust.
Recheck labs at 8–12 weeks, then every 6–12 months once stable: testosterone, LH/FSH, estradiol, hematocrit, and lipids. Track symptoms and semen analyses when relevant. Stop or switch if adverse effects occur or goals are not met [2,3,5].

Myth vs Fact

  • Myth: “Any testosterone treatment kills fertility for years.”
    Fact: Enclomiphene raised testosterone while keeping sperm counts in the normal range in controlled trials [1,2].
  • Myth: “If total T is 301 ng/dL you do not qualify.”
    Fact: Borderline totals still warrant free testosterone testing and symptom review. Free <100 pg/mL supports a diagnosis in context [9,10].
  • Myth: “Clomiphene and enclomiphene are the same.”
    Fact: Clomiphene mixes two isomers. Enclomiphene is the trans isomer that drives LH/FSH rise; zuclomiphene behaves more estrogenically and persists longer [3,7].
  • Myth: “Pills are ‘natural’ and risk-free.”
    Fact: SERMs can raise estradiol and cause headaches or abdominal discomfort. Monitoring is still required [3].

Bottom line

Enclomiphene is a daily tablet that can restore testosterone and preserve fertility in men with secondary hypogonadism. Trial evidence is consistent for hormones and semen counts, while longer symptom and safety data are still limited. Work with a clinician who understands SERM therapy, testing thresholds, and monitoring so you get results with the fewest trade-offs [1–3,5,6].

References

  1. Wiehle RD, Fontenot GK, Wike J, Hsu K, Nydell J, Lipshultz LI; ZA-203 Clinical Study Group. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertil Steril. 2014;102(3):720-727. PMID: 25044085.
  2. 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. PMID: 26496621.
  3. Rodriguez KM, Pastuszak AW, Lipshultz LI. Enclomiphene Citrate for the Treatment of Secondary Male Hypogonadism. Expert Opin Pharmacother. 2016;17(11):1561-1567. PMCID: PMC5009465. PMID: 27337642.
  4. Kaminetsky J, Werner M, Fontenot G, Wiehle R. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with secondary hypogonadism. J Sex Med. 2013;10(6):1628-1635. PMID: 23530575.
  5. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018;200(2):423-432. PMID: 29601923.
  6. Salonia A, Bettocchi C, Boeri L, et al. 2025 Update on Male Hypogonadism, Erectile Dysfunction, Premature Ejaculation, and Peyronie’s Disease: The 2025 EAU Sexual and Reproductive Health Guidelines. Eur Urol Focus. 2025; in press. PMID: 40340108.
  7. Fontenot GK, Wiehle RD, Nydell J, et al. Differential effects of isomers of clomiphene citrate on male mammals. Reprod Biol Endocrinol. 2016;14:7. PMID: 26220499.
  8. Hudson J, Khan T, Hamblin A, et al. Symptomatic benefits of testosterone treatment in patient populations with low testosterone: a systematic review, individual participant data meta-analysis, and network meta-analysis. Lancet Healthy Longev. 2023;4(11):e748-e762. PMID: 37804846.
  9. Davidiuk AJ, Broderick GA, McGree ME, Kohn TP. Adult-onset hypogonadism: evaluation and role of testosterone therapy. Transl Androl Urol. 2016;5(6):910-919. PMCID: PMC5182238.
  10. Shin YS, Kim MK, Jung JH, et al. The Optimal Indication for Testosterone Replacement Therapy in Men. World J Mens Health. 2019;37(3):276-286. PMCID: PMC6406807.
  11. Antonio L, Wu FCW, O’Neill TW, et al. Low free testosterone is associated with hypogonadal signs and symptoms in men with normal total testosterone levels: results from the European Male Ageing Study. J Clin Endocrinol Metab. 2016;101(7):2647-2657. PMID: 26909800.
  12. Thomas J, Friary A, Rana R, et al. Efficacy of Clomiphene Citrate Versus Enclomiphene Citrate in Hypogonadal Men: A Retrospective Analysis. Cureus. 2023;15(7):e41947. PMID: 37546076.

 

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