Can enclomiphene be used to treat secondary hypogonadism in men who want to preserve fertility, and what are its dosing, contraindications, side effects, monitoring, and alternatives?

Enclomiphene for Secondary Hypogonadism with Fertility Preservation

Enclomiphene is an effective alternative to testosterone therapy for men with secondary hypogonadism who want to preserve fertility, as it stimulates endogenous testosterone production while maintaining spermatogenesis. 1, 2

Understanding Enclomiphene vs. Traditional Clomiphene

Enclomiphene is the trans-stereoisomer of clomiphene citrate, functioning as a selective estrogen receptor modulator (SERM) that blocks estrogen's negative feedback at the hypothalamus and pituitary. 1, 2 This mechanism increases LH and FSH secretion, which in turn stimulates testicular testosterone production and maintains spermatogenesis—the critical advantage over exogenous testosterone. 2, 3

The key distinction is that enclomiphene preserves the hypothalamic-pituitary-testicular axis, whereas testosterone therapy suppresses it and causes azoospermia. 4, 2

Clinical Efficacy Data

Testosterone Restoration

• Enclomiphene increases serum testosterone from baseline levels of approximately 165 ng/dL to 525 ng/dL at 6 months, achieving eugonadal levels comparable to testosterone gel. 3
• The testosterone elevation is sustained throughout treatment, with physiological restoration rather than supraphysiologic peaks seen with injections. 1, 3
• LH and FSH levels increase appropriately with enclomiphene (unlike with testosterone gel), confirming restoration of normal endogenous production. 3, 5

Fertility Preservation

• Enclomiphene elevated sperm counts in 100% of treated men (7/7 at 3 months, 6/6 at 6 months), with concentrations ranging from 75-334 × 10⁶/mL. 3
• In contrast, testosterone gel failed to raise sperm counts above 20 × 10⁶/mL in all men at 3 months and only 2/5 men at 6 months. 3
• Sperm parameters remain elevated even at follow-up after enclomiphene treatment. 3

Long-Term Safety and Symptom Improvement

• In a retrospective study of 400 men treated with clomiphene citrate (the racemic mixture containing enclomiphene), 88% achieved eugonadism and 77% reported improved hypogonadal symptoms when treated for more than 3 years. 6
• Only 8% reported side effects, most commonly mood changes (5 patients), blurred vision (3 patients), and breast tenderness (2 patients). 6
• No significant adverse events occurred in any patient during long-term treatment. 6

Dosing Recommendations

While enclomiphene as a pure compound is not yet FDA-approved for male hypogonadism, clomiphene citrate (which contains enclomiphene) is used off-label at 25-50 mg three times per week. 7 Clinical trials have used enclomiphene at doses that effectively raise testosterone to mid-normal ranges. 3, 5

For men with secondary hypogonadism desiring fertility, start with clomiphene citrate 25 mg three times weekly (Monday/Wednesday/Friday), measure testosterone at 2-3 months, and titrate to 50 mg three times weekly if needed to achieve testosterone levels of 450-600 ng/dL. 7, 6

Monitoring Requirements

• Measure morning total testosterone (8-10 AM) at 2-3 months after initiation, then every 6-12 months once stable. 7
• Check LH and FSH to confirm appropriate stimulation of the hypothalamic-pituitary axis. 3, 5
• Monitor estradiol levels, as enclomiphene treatment significantly increases estradiol (though this is expected and not necessarily harmful). 6
• Obtain semen analysis at 3-6 months to document preserved or improved sperm production. 3, 5
• Unlike testosterone therapy, hematocrit monitoring is not required, as enclomiphene does not cause erythrocytosis. 8

Contraindications

• Primary hypogonadism (elevated LH/FSH with low testosterone) is an absolute contraindication, as the testes cannot respond to gonadotropin stimulation. 8
• Active male breast cancer (theoretical concern, though not documented in trials). 7
• Men who do not desire fertility preservation may prefer testosterone therapy for cost and convenience, though enclomiphene remains a valid option. 8

Side Effects

• Mood changes (5% in long-term studies). 6
• Visual disturbances including blurred vision (3% in long-term studies). 6
• Breast tenderness or gynecomastia (2% in long-term studies, related to elevated estradiol). 6
• Elevated estradiol levels are expected and occur in most patients. 6

The side effect profile is significantly more favorable than testosterone therapy, with no risk of erythrocytosis, testicular atrophy, or cardiovascular concerns associated with supraphysiologic testosterone levels. 8, 6

Alternatives to Enclomiphene

For Men Desiring Fertility Preservation:

• hCG monotherapy (1,000-3,000 units subcutaneously 2-3 times per week) is the guideline-recommended first-line treatment for secondary hypogonadism with fertility concerns. 4, 8
• hCG directly stimulates testicular Leydig cells to produce testosterone while maintaining spermatogenesis. 4, 8
• If sperm counts remain low after 3-6 months of hCG, add recombinant FSH 75-150 units subcutaneously 2-3 times per week. 4
• Combined hCG plus FSH therapy provides optimal outcomes for fertility restoration. 4, 7

For Men NOT Desiring Fertility:

• Testosterone therapy is absolutely contraindicated in men seeking fertility preservation, as it causes prolonged and potentially irreversible azoospermia. 4, 7
• Transdermal testosterone gel 1.62% at 40.5 mg daily is first-line for men not concerned about fertility. 7
• Intramuscular testosterone cypionate or enanthate 100-200 mg every 2 weeks is a more economical alternative. 7

Clinical Algorithm for Treatment Selection

Step 1: Confirm Secondary Hypogonadism

• Two morning testosterone measurements <300 ng/dL. 7
• Low or low-normal LH and FSH (distinguishing secondary from primary hypogonadism). 7

Step 2: Assess Fertility Desires

• If fertility preservation is desired → Use enclomiphene/clomiphene citrate OR hCG (with or without FSH). 4, 8, 2
• If fertility is NOT a concern → Testosterone therapy is appropriate. 7

Step 3: Choose Between Enclomiphene and hCG

• Enclomiphene advantages: Oral administration, lower cost, no injection burden, no risk of erythrocytosis. 8, 1
• hCG advantages: Guideline-recommended first-line, more robust evidence for fertility restoration, can add FSH if needed. 4, 8

Step 4: Monitor Response

• At 2-3 months: Check testosterone, LH, FSH, and semen analysis. 3, 5
• If testosterone remains <450 ng/dL, increase dose or switch to hCG. 7
• If sperm counts are inadequate on hCG monotherapy, add FSH. 4

Critical Pitfalls to Avoid

• Never use testosterone therapy in men desiring fertility—this is an absolute contraindication that causes prolonged azoospermia. 4, 7
• Never assume a patient has primary hypogonadism without measuring LH and FSH—enclomiphene will not work in primary hypogonadism. 8
• Never diagnose hypogonadism on a single testosterone measurement—two morning values are required. 7
• Do not expect enclomiphene to improve energy, physical function, or cognition—these benefits are minimal even with testosterone therapy. 7
• Do not overlook lifestyle modification in obesity-associated secondary hypogonadism—weight loss can reverse the condition without medication. 7

Metabolic Benefits

Enclomiphene demonstrated an unanticipated favorable effect on fasting plasma glucose in clinical trials, which is particularly relevant given the bidirectional relationship between low testosterone and metabolic syndrome in men. 1 This makes enclomiphene especially attractive for men with obesity-associated secondary hypogonadism who desire fertility preservation. 1

Expected Treatment Outcomes

• Small but significant improvements in sexual function and libido (similar to testosterone therapy, with standardized mean difference of 0.35). 7
• Preservation or restoration of sperm production, with counts in the 75-334 × 10⁶/mL range. 3
• Maintenance of testicular volume (unlike testosterone therapy, which causes testicular atrophy). 8, 1
• Little to no effect on physical functioning, energy, vitality, or cognition—these limitations apply to all hypogonadism treatments. 7