What is the recommended dosage and treatment protocol for Clomiphene (clomiphene citrate) in women with infertility due to anovulation?

Clomiphene Citrate Dosage and Treatment Protocol for Anovulatory Infertility

For women with infertility due to anovulation, the recommended dosage of clomiphene citrate is 50 mg daily for 5 days, starting on or about the 5th day of the menstrual cycle, with dose increases to 100 mg daily only if ovulation does not occur after the initial course. 1

Initial Assessment and Patient Selection

• Clomiphene citrate is specifically indicated for women with:

  • Ovulatory dysfunction desiring pregnancy
  • Polycystic ovary syndrome (PCOS)
  • Amenorrhea of various etiologies
  • Normal estrogen levels (as estimated from vaginal smears or endometrial biopsy)
  • No ovarian cysts (except in PCOS)
  • No abnormal vaginal bleeding
  • Normal liver function

• Contraindications:

  • Pregnancy
  • Liver disease
  • Abnormal uterine bleeding
  • Primary pituitary or ovarian failure

Treatment Protocol

Starting Dose and Timing

• Begin with 50 mg daily for 5 days 1
• If patient has had recent uterine bleeding, start on approximately day 5 of the cycle
• If no recent bleeding, treatment can be started at any time

Monitoring Response

• Ovulation typically occurs 5-10 days after completing the course of clomiphene
• Appropriate tests to determine ovulation should be performed:
  • Basal body temperature monitoring
  • Ultrasound monitoring (particularly important to minimize risk of multiple pregnancy) 2
  • Luteal phase progesterone levels

Dose Adjustments

• If ovulation occurs at 50 mg, maintain this dose for subsequent cycles
• If no ovulation occurs, increase to 100 mg daily for 5 days for the next cycle 1
• Wait at least 30 days between treatment courses
• Do not exceed 100 mg/day or extend beyond 5 days per course 1

Duration of Treatment

• If no ovulation occurs after three courses of therapy, discontinue clomiphene and reevaluate the patient
• If three ovulatory responses occur without pregnancy, discontinue treatment
• Total treatment should not exceed approximately six cycles 1, 3

Special Considerations

Multiple Pregnancy Risk Management

• Ultrasound monitoring is crucial to prevent multiple pregnancies
• Withhold treatment if more than two dominant follicles >15 mm or more than five follicles >10 mm are present 2
• Multiple pregnancy rates increase significantly with more than two dominant follicles (6% with two follicles, 14% with three follicles) 2

Alternative Approaches for Resistant Cases

• For clomiphene-resistant cases, consider:
  • Extended 10-day course (100 mg for 10 days) may be effective in some women who fail to respond to standard 5-day regimens 4
  • Gonadotropin therapy (with doses ≤75 IU) may provide higher live birth rates but with comparable multiple pregnancy rates 2

Treatment Efficacy

• Clomiphene induces ovulation in approximately 70-80% of appropriately selected patients 5, 6
• Pregnancy rates of approximately 50% can be expected in women who ovulate 5
• Cumulative conception rates approach those of normal population by 6-12 treatment cycles 3

Potential Side Effects and Risks

• Multiple pregnancies (5-10%)
• Ovarian hyperstimulation syndrome (rare with clomiphene alone)
• Visual disturbances
• Hot flashes
• Mood changes
• Potential negative effects on cervical mucus and endometrium
• Possible increased risk of ovarian tumors with prolonged use (>12 cycles) 3

Important Caveats

• Clomiphene is not recommended for male infertility treatment 1
• Not recommended for functional hypothalamic amenorrhea unless there are sufficient endogenous estrogen levels 2
• Weight reduction should be an important part of therapy in overweight anovulatory women, as increased BMI is consistently associated with decreased response to clomiphene 3
• Timing intercourse to coincide with expected ovulation (5-10 days after completing the course) is crucial for success 1

By following this protocol and carefully monitoring response, clomiphene citrate offers an effective first-line treatment for women with anovulatory infertility, with reasonable pregnancy rates and manageable risks when properly administered.