What is the recommended treatment protocol for a male patient with hypogonadism (low sex hormone production) and fertility issues using enclomiphene (clomiphene citrate)?

Enclomiphene Protocol for Hypogonadism with Fertility Preservation

Critical First Principle

For men with hypogonadism who desire current or future fertility, gonadotropin therapy (hCG with or without FSH) is the guideline-recommended first-line treatment, not selective estrogen receptor modulators (SERMs) like enclomiphene. 1

However, enclomiphene represents a practical alternative when gonadotropin therapy is not feasible due to cost, availability, or patient preference, as it preserves fertility while raising testosterone through endogenous stimulation. 2, 3, 4, 5

Absolute Contraindication

• Never prescribe exogenous testosterone therapy to men seeking fertility—it suppresses LH and FSH through negative feedback, causing oligospermia or azoospermia that can take months to years to reverse. 1

Pre-Treatment Evaluation

Confirm Diagnosis

• Two separate morning total testosterone levels <300 ng/dL with symptoms of hypogonadism 6
• Measure FSH, LH, prolactin, and thyroid function to characterize the type of hypogonadism 1
• Obtain baseline semen analysis (two samples separated by 2-3 months) to document fertility potential 1

Identify Optimal Candidates

Enclomiphene works best in men with secondary (hypogonadotropic) hypogonadism where the pituitary retains responsiveness. 2, 4, 5

Predictors of robust response include: 6

• Mean testicular volume ≥14 mL (hazard ratio 2.2 for response)
• Baseline LH ≤6 IU/mL (hazard ratio 3.5 for response)
• Younger age and absence of severe testicular atrophy

Poor candidates include: 1

• Primary testicular failure (elevated FSH >7.6 IU/L with testicular atrophy)
• Complete AZFa or AZFb Y-chromosome microdeletions
• Severe obesity requiring metabolic optimization first

Enclomiphene Dosing Protocol

Standard Regimen

• Enclomiphene citrate 12.5-25 mg orally once daily 2, 4, 5
• The trans-isomer (enclomiphene) provides the therapeutic benefit without the prolonged half-life and adverse effects of the cis-isomer (zuclomiphene) found in mixed clomiphene citrate 4, 5

Alternative: Mixed Clomiphene Citrate

If pure enclomiphene is unavailable:

• Clomiphene citrate 25-50 mg orally every other day or daily 1, 3
• This contains both isomers but remains effective for fertility preservation 3

Monitoring Schedule

Initial Assessment (4 weeks)

• Total testosterone, free testosterone, LH, FSH 2, 6
• Assess for symptomatic improvement

3-Month Evaluation

• Repeat testosterone, LH, FSH 2, 6
• Semen analysis to document sperm concentration improvement 2
• Successful biochemical response defined as: increase of ≥200 ng/dL in total testosterone 6

6-Month and Ongoing

• Testosterone levels every 6 months 6
• Semen analysis every 6 months if fertility is actively being pursued 2
• Monitor for adverse effects (headache, mood changes, visual disturbances) 3

Expected Outcomes

Testosterone Response

• Mean testosterone increase: 300 ng/dL from baseline 6
• 62% of men achieve robust response (≥200 ng/dL increase) 6
• Mean on-treatment testosterone: 467-545 ng/dL 2, 6
• Concomitant LH rise of 5-6 IU/mL confirms hypothalamic-pituitary-testicular axis stimulation 2, 6

Fertility Preservation

• Enclomiphene elevated sperm counts in 100% of men at both 3 and 6 months in comparative studies 2
• Sperm concentrations achieved: 75-334 million/mL 2
• Maintains intratesticular testosterone production essential for spermatogenesis 3, 4, 5
• Meta-analysis shows significant improvement in fertility rates with SERM therapy 3

Comparison to Testosterone Gel

• Testosterone gel was ineffective in raising sperm counts above 20 million/mL in all men at 3 months 2
• Only enclomiphene maintained elevated sperm counts at follow-up 2

Critical Pitfalls to Avoid

When Enclomiphene is Insufficient

Recognize that SERMs have limited benefits compared to assisted reproductive technology (ART). 1

• If total motile sperm count <5 million on repeated analysis, counsel that IUI success rates are reduced and IVF/ICSI should be considered 1
• For non-obstructive azoospermia, microsurgical testicular sperm extraction (micro-TESE) offers 40-50% sperm retrieval rates even with elevated FSH 1

When to Switch to Gonadotropins

If enclomiphene fails to normalize testosterone or improve sperm parameters after 6 months: 1

• hCG 500-2500 IU subcutaneously 2-3 times weekly as first-line
• Add FSH injections after testosterone normalizes on hCG if sperm counts remain low
• Combined hCG and FSH therapy provides optimal outcomes for secondary hypogonadism with fertility goals

Metabolic Optimization

Address reversible causes before or concurrent with enclomiphene: 1

• Weight loss through low-calorie diets can reverse obesity-associated secondary hypogonadism
• Physical activity correlates with testosterone improvement (though modest, 1-2 nmol increase)
• Correct thyroid dysfunction, hyperprolactinemia, and eliminate interfering medications

Discontinuation and Follow-Up

• Testosterone levels return to pretreatment values within 1 month after stopping enclomiphene 2
• If fertility goals are achieved and testosterone replacement becomes necessary, transition to appropriate testosterone formulation 1
• Consider sperm cryopreservation (2-3 ejaculates) before any future gonadotoxic exposures or if considering eventual testosterone therapy 1

Strength of Evidence

The guideline-based recommendation remains gonadotropin therapy for secondary hypogonadism with fertility concerns (strong recommendation). 1 Enclomiphene represents an off-label alternative supported by research evidence showing efficacy in raising testosterone while preserving spermatogenesis, particularly useful when gonadotropins are not accessible. 2, 6, 3, 4, 5