What are the guidelines for prescribing enclomiphene (clomiphene) and what precautions should be taken?

Prescribing Enclomiphene (Clomiphene Citrate) for Ovulatory Dysfunction

Clomiphene citrate should be initiated at 50 mg daily for 5 days starting on cycle day 3-5, with mandatory pelvic examination before each treatment course and ultrasound monitoring of at least the first cycle to assess follicular response and prevent multiple pregnancy. 1

Patient Selection Criteria

Before prescribing clomiphene, confirm the following mandatory requirements:

• Not pregnant - Verify negative pregnancy test 1
• No ovarian cysts - Except in polycystic ovary syndrome (PCOS) patients; pelvic examination required before each course 1
• No abnormal vaginal bleeding - If present, evaluate for neoplastic lesions before treatment 1
• Normal liver function - Document baseline hepatic function 1
• Adequate endogenous estrogen - Assess via vaginal smears, endometrial biopsy, urinary estrogen assay, or bleeding response to progesterone 1

Optimal Candidates

Patients most likely to succeed with clomiphene therapy include those with 1:

• Polycystic ovary syndrome (PCOS)
• Amenorrhea-galactorrhea syndrome
• Psychogenic amenorrhea
• Post-oral-contraceptive amenorrhea
• Secondary amenorrhea of undetermined etiology

Dosing Protocol

Standard Initiation

• Start with 50 mg daily for 5 days beginning on cycle day 5 (or days 3-5 of the menstrual cycle) 1
• If ovulation does not occur at 50 mg, increase to 100 mg daily for 5 days in the next cycle 2
• Reserve 150-200 mg doses only for patients who fail lower dosages 2

Special Populations

• Clomiphene-sensitive patients: Consider starting at 12.5 mg daily for 5 days if patient has history of ovarian cyst formation on standard doses 3
• Obese patients: Weight reduction should precede or accompany therapy, as increased BMI consistently predicts decreased response 4

Treatment Duration

• Limit to 6 ovulatory cycles as initial treatment course 1, 4
• May extend to maximum of 12 cycles total if patient continues to ovulate but has not conceived 4
• Cumulative conception rate plateaus by cycle 12 and approaches normal population rates 4
• Do not exceed 12 cycles due to potential association with borderline or invasive ovarian tumors with prolonged use 4

Critical Monitoring Requirements

First Cycle (Mandatory)

• Ultrasound monitoring to assess follicular response and minimize risks of hyperstimulation and multiple pregnancy 4
• Document number and size of developing follicles 5
• Adjust subsequent cycle dosing based on first cycle response 4

Ongoing Monitoring

• Pelvic examination before each treatment course 1
• Basal body temperature charting or other ovulation confirmation methods 1
• Triglyceride monitoring in patients with preexisting or family history of hyperlipidemia 1
• Properly timed intercourse in relationship to ovulation 1

Major Precautions and Contraindications

Visual Symptoms (Critical Warning)

• Discontinue immediately if any visual disturbances occur (blurring, scotomata, flashing lights) 1
• Visual symptoms may be prolonged and possibly irreversible, especially with increased dosage or duration 1
• Perform complete ophthalmologic evaluation before resuming treatment 1
• Warn patients that visual symptoms may impair driving or operating machinery 1

Ovarian Hyperstimulation

• Instruct patients to report any abdominal/pelvic pain, weight gain, or distention immediately 1
• If ovarian enlargement occurs, withhold treatment until ovaries return to pretreatment size 1
• Risk increases with multifollicular development 5

Multiple Pregnancy Risk

• 20-30% of clomiphene pregnancies result in multiple gestations when more than 2-3 dominant follicles develop 5
• Counsel patients extensively about complications of multiple pregnancy 1
• Consider cycle cancellation if more than 3 follicles >17mm develop 5
• Alternative: aspiration of excess follicles at time of ovulation trigger 5

Metabolic Concerns

• Hypertriglyceridemia can occur, especially with higher doses or longer duration 1
• Pancreatitis has been reported 1
• Screen triglycerides before initiating therapy in at-risk patients 1

Absolute Contraindications

Do not prescribe clomiphene in patients with 1:

• Pregnancy
• Ovarian cysts (except PCOS)
• Undiagnosed abnormal vaginal bleeding
• Liver disease or abnormal liver function
• Uncontrolled thyroid or adrenal dysfunction
• Pituitary tumor or hyperprolactinemia (treat underlying cause first)

Pre-Treatment Workup

Required Evaluations

• Endometrial biopsy in women of advancing age to exclude endometriosis and endometrial carcinoma 1
• Thyroid function tests 1
• Prolactin level 1
• Male factor evaluation - Semen analysis to exclude male infertility 1
• Assessment for uterine fibroids (use caution as clomiphene may enlarge fibroids) 1

Insulin Resistance Assessment

• Particularly important in PCOS patients 6
• Consider metformin co-therapy in clomiphene-resistant patients with insulin resistance 6

Common Pitfalls to Avoid

• Never use clomiphene for male infertility - Testicular tumors and gynecomastia reported in males; cause-effect relationship unknown 1
• Do not combine with other ovulation-inducing drugs without specialist consultation - No universally accepted standard regimen 1
• Avoid empirical use in unexplained infertility - Data are inconclusive and benefits questionable 6
• Do not skip pelvic examination before each course - Risk of missing ovarian enlargement or cysts 1
• Never ignore visual symptoms - May indicate serious adverse effects requiring immediate discontinuation 1

Expected Outcomes

• Ovulation rate: 70-80% of appropriately selected patients 2
• Pregnancy rate after 3 ovulatory cycles: Approximately 50% 2
• Spontaneous abortion rate: 20.4% (similar to general population) 1
• Multiple pregnancy rate: Increased compared to natural conception, primarily twins 1