Can women use enclomiphene (clomiphene) for infertility?

Can Women Use Enclomiphene for Infertility?

Yes, women can and should use enclomiphene (clomiphene citrate) as the first-line treatment for ovulation induction in anovulatory infertility, as it is the most effective medication for this indication with well-established safety and efficacy. 1, 2

Primary Indication and Effectiveness

• Clomiphene citrate is the treatment of first choice for normally estrogenized, anovulatory women (WHO group II anovulation), which includes conditions like polycystic ovary syndrome (PCOS). 1, 2

• Among women with pure anovulatory infertility, approximately 80% will ovulate with clomiphene treatment, and about 50% of those who ovulate will conceive. 1

• Clomiphene is superior to metformin for achieving live births in infertile women with PCOS, with live-birth rates of 22.5% for clomiphene versus only 7.2% for metformin over 6 months of treatment. 3

• The cumulative conception rate continues to rise through 12 treatment cycles and approaches that of the normal fertile population when other subfertility factors are excluded. 2

Dosing and Treatment Duration

• Start with 50 mg daily for 5 days (typically cycle days 5-9), and titrate to the minimum effective ovulation-inducing dose in subsequent cycles. 4

• Treatment should continue for at least 6 cycles before considering more complex interventions, as conception rates continue to rise through this period. 2

• Limit treatment to a maximum of 12 cycles due to concerns about prolonged exposure and potential ovarian tumor risk. 5, 2

• Lower doses should be used when possible to minimize multiple follicular development and reduce multiple pregnancy risk. 6

Critical Safety Considerations and Monitoring

Contraindications:

• Clomiphene is absolutely contraindicated in women who are already pregnant, as it provides no benefit and animal studies show embryo-fetal loss and structural malformations. 5

• Avoid in patients with liver disease, especially decompensated cirrhosis. 6

• Should only be used when sufficient endogenous estrogen levels are present (not in hypogonadotropic hypogonadism). 6

Monitoring Requirements:

• Ultrasound monitoring is essential to detect multiple follicular development, minimize ovarian hyperstimulation risk, and reduce multiple pregnancy rates. 2

• Appropriate tests must be performed each cycle to confirm ovulation occurred and to exclude pregnancy before starting the next cycle. 5

• Patients must be evaluated carefully to exclude ovarian enlargement or cyst formation between each treatment cycle. 5

Adverse Effects and Risks

Multiple Pregnancy:

• The multiple pregnancy rate is approximately 6% with clomiphene alone, which is significantly higher than spontaneous conception but lower than with gonadotropins. 3

• Multiple pregnancies include risks of bilateral tubal pregnancy and coexisting tubal/intrauterine pregnancy. 5

Ovarian Hyperstimulation:

• Ovarian hyperstimulation syndrome is a potential complication, especially with multifollicular development. 6

Pregnancy Outcomes:

• The spontaneous abortion rate is approximately 20.4%, which is within the expected range for subfertile populations. 5

• Recent population-based data suggest a modestly increased risk of perinatal death (stillbirth or neonatal death within 28 days), with an adjusted odds ratio of 1.54 for singleton pregnancies conceived with clomiphene. 7 However, this may reflect underlying infertility rather than the medication itself.

• Available human epidemiologic data do not show an increased risk of congenital anomalies above background population rates. 5

Other Side Effects:

• Clomiphene can alter serum lipid profiles. 6

• Vasomotor symptoms and ovulatory symptoms are common. 3

• Psychological effects (mood changes, anxiety) have been reported, though more commonly documented in men. 8

Long-term Concerns:

• Prolonged use may increase the risk of borderline or invasive ovarian tumors, which is another reason to limit treatment to 12 cycles maximum. 5, 2

Drug Accumulation Considerations

• Zuclomiphene (the less active isomer) accumulates progressively across consecutive treatment cycles, reaching a plateau after approximately 3 cycles, while enclomiphene does not accumulate. 4

• The combined maximum concentration of both isomers remains well below levels demonstrated to have adverse effects in vitro. 4

Patient Selection Factors

• Increased body mass index is the only factor consistently associated with decreased response to clomiphene; therefore, weight reduction should be an important component of therapy before or concurrent with clomiphene treatment. 2

• Basal hormone concentrations do not predict treatment outcome. 2

• An elevated luteinizing hormone level immediately post-clomiphene may predict adverse pregnancy outcomes in women who conceive. 2

Alternative or Adjunctive Approaches

• If clomiphene fails after appropriate trials, low-dose gonadotropin therapy is recommended over high-dose protocols to induce monofollicular development with lower hyperstimulation risk. 1

• Combination therapy with metformin and clomiphene shows similar live-birth rates (26.8%) to clomiphene alone (22.5%), but with slightly lower multiple pregnancy rates (3.1% vs 6.0%). 3

• Weight loss of as little as 5% of initial body weight improves metabolic and reproductive abnormalities in PCOS and is associated with improved ovulation and pregnancy rates. 1