What are the guidelines for prescribing enclomiphene (clomiphene) and is it safe?

Prescribing Enclomiphene: Guidelines and Safety Profile

Enclomiphene citrate (the trans-isomer of clomiphene citrate) is FDA-approved exclusively for ovulatory dysfunction in women, not for male hypogonadism, though it is commonly used off-label in men with demonstrated safety and efficacy. 1

FDA-Approved Indication (Women)

Patient Selection Criteria

Before prescribing enclomiphene for ovulatory dysfunction, confirm the following 1:

• Not pregnant (mandatory exclusion)
• No ovarian cysts (except polycystic ovary syndrome)
• No abnormal vaginal bleeding (rule out neoplastic lesions first)
• Normal liver function (absolute contraindication in liver disease, especially decompensated cirrhosis) 2, 1
• Adequate endogenous estrogen levels (assessed via vaginal smears, endometrial biopsy, urinary estrogen assay, or progesterone withdrawal bleeding) 1
• Pelvic examination required before each treatment course 1

Dosing Protocol for Women

• Start on day 5 of the menstrual cycle 1
• Initial dose: 50 mg daily for 5 days 1
• Maximum duration: 6 total cycles (including 3 ovulatory cycles) 1
• Use lower doses to minimize multiple follicular development and reduce multiple pregnancy risk 2
• Success rates: Approximately 80% ovulation rate, 50% pregnancy rate among those who ovulate 3

Contraindications and Precautions (Women)

The following are absolute contraindications 2, 1:

• Liver disease (particularly decompensated cirrhosis)
• Pregnancy
• Ovarian enlargement (except PCOS)
• Undiagnosed abnormal vaginal bleeding
• Insufficient endogenous estrogen (hypogonadotropic hypogonadism)

Off-Label Use in Men (Male Hypogonadism)

Evidence Base

While the FDA label explicitly states "there are no adequate or well-controlled studies that demonstrate the effectiveness of clomiphene citrate in the treatment of male infertility" 1, substantial research demonstrates both efficacy and safety for off-label use in men 4, 5, 6.

Patient Selection for Men

Enclomiphene is appropriate for 4, 7:

• Secondary hypogonadism (hypothalamic-pituitary dysfunction)
• Men desiring fertility preservation (maintains spermatogenesis unlike exogenous testosterone)
• Baseline testosterone <300 ng/dL with symptomatic hypogonadism 5
• Obesity or metabolic syndrome with associated hypogonadism 7

Dosing Protocol for Men (Off-Label)

• Standard dose: 25-50 mg daily or every other day 8, 5
• Expected testosterone increase: Approximately 200 ng/dL mean increase 8
• Eugonadism achievement: 88% of men achieve normal testosterone levels 5
• Symptom improvement: 77% report improved hypogonadal symptoms 5

Monitoring Requirements for Men

Laboratory monitoring schedule 8, 5:

• Baseline: Total testosterone, bioavailable testosterone, LH, FSH, estradiol
• Follow-up intervals: 3,6,9, and 12 months initially
• PSA monitoring: Not routinely necessary (no significant changes observed) 8
• Hematocrit monitoring: Not routinely necessary (remains within normal range) 8
• Estradiol: Expect significant increases (monitor for symptoms) 5

Safety Profile

Common Side Effects

In women 1:

• Multiple pregnancy risk: 7.98% (6.9% twins, 0.5% triplets)
• Ovarian hyperstimulation syndrome (especially with multifollicular development) 2, 3
• Altered serum lipid profiles 2

In men (off-label use) 8, 5:

• Mood changes: 5% of long-term users
• Blurred vision: 3% of long-term users
• Breast tenderness: 2% of long-term users
• Overall side effect rate: Only 8% in long-term studies 5

Serious Adverse Events

No significant adverse events reported in men treated with clomiphene citrate for up to 84 months 5. The safety profile is equivalent to testosterone gels and placebo in short-term studies 7.

Long-Term Safety Data

Extended use beyond 3 years in men demonstrates 5:

• Maintained efficacy: No decline in testosterone response
• Sustained symptom improvement: 77% continue to report benefit
• No increase in adverse events: Safety profile remains stable
• No PSA elevation: Mean PSA 1 ng/dL (95% CI 0.8-1.1) 8
• No polycythemia: Hematocrit 49% (95% CI 41-53) 8

Critical Safety Warnings

Absolute Contraindications

• Liver disease (especially decompensated cirrhosis) 2, 1
• Pregnancy 1
• Ovarian cysts (except PCOS in women) 1

Important Caveats

• Not FDA-approved for male infertility or hypogonadism despite widespread off-label use 1
• Testicular tumors and gynecomastia reported in males (causal relationship not established) 1
• Uterine fibroids: Use caution in women due to potential fibroid enlargement 1
• Endometrial biopsy required in older women before treatment (increased endometrial carcinoma risk) 1
• Long half-life of zuclomiphene (cis-isomer): May persist for >1 month, potentially exposing early pregnancy 1

Drug Interactions

Monitor for serotonergic syndrome and cytochrome P450 interactions when combined with other medications, though this is primarily relevant to clomipramine (a related compound) rather than enclomiphene 9.