What is the initial treatment approach for a 35-year-old nulligravid (never pregnant) woman with primary infertility, no medical problems, and a husband with normal semen analysis (seminalysis)?

Initial Treatment for 35-Year-Old Woman with Primary Infertility and Normal Male Partner

Begin with clomiphene citrate 50 mg daily for 5 days starting on cycle day 5, and if ovulation does not occur after the first cycle, increase to 100 mg daily for 5 days in subsequent cycles. 1

Rationale for Immediate Ovulation Induction

At age 35, this patient requires expedited evaluation and treatment after 6 months of failed conception attempts, and immediate treatment is warranted given her age-related decline in fecundity. 2, 3 The most pragmatic first-line approach is empiric ovulation induction with clomiphene citrate, as ovulatory dysfunction accounts for approximately 25% of infertility cases and can be effectively managed in the primary care setting. 4, 5, 6

Complete Initial Workup (Concurrent with Treatment)

While initiating treatment, complete the following essential evaluations:

Female Partner Assessment

• Document ovulation status with serum progesterone level on cycle day 21 (mid-luteal phase). 5
• Assess ovarian reserve with day 3 FSH and estradiol levels, as women over 35 benefit from this testing to determine treatment options and likelihood of success. 2, 4
• Evaluate uterine and tubal patency with hysterosalpingography if no risk factors for obstruction exist, or proceed directly to hysteroscopy/laparoscopy if history suggests endometriosis, pelvic infections, or ectopic pregnancy. 2, 5
• Obtain transvaginal ultrasound to evaluate uterine anatomy and antral follicle count. 2

Male Partner Confirmation

• Verify normal semen analysis was performed correctly: at least two samples collected 2-3 months apart, with assessment of concentration, motility, and morphology. 7, 6

Clomiphene Citrate Treatment Protocol

Dosing Algorithm

• Start with 50 mg daily for 5 days beginning on cycle day 5 (or 5 days after progestin-induced withdrawal bleed if amenorrheic). 1
• Time intercourse from days 5-10 after completing the clomiphene course, as ovulation typically occurs during this window. 1
• If no ovulation occurs after first cycle, increase to 100 mg daily for 5 days in the next cycle (may start as early as 30 days after previous course, after excluding pregnancy). 1
• If ovulation occurs at 50 mg, do not increase the dose in subsequent cycles, as there is no advantage to higher doses once ovulation is achieved. 1

Treatment Duration and Endpoints

• Discontinue clomiphene after 3 ovulatory cycles without pregnancy and proceed to assisted reproductive technologies. 1
• Discontinue after 3 cycles if ovulation does not occur and reevaluate for alternative diagnoses or treatments. 1
• Total treatment should not exceed 6 cycles, as long-term cyclic therapy beyond this is not recommended. 1

Critical Age-Related Considerations

For women aged 35-38, proceed rapidly through 3-4 cycles of ovulation induction before considering IVF. 6 However, if this patient is closer to 38-40 years old, immediate IVF may be considered as first-line treatment given the steep decline in female fecundity with age. 6 The decision between ovulation induction and immediate IVF should factor in:

• Exact age within the 35-40 range
• Ovarian reserve testing results (FSH, antral follicle count)
• Patient preference regarding time to pregnancy versus invasiveness of treatment

When to Escalate to Assisted Reproductive Technology

Proceed to IVF if:

• No pregnancy after 3-4 ovulatory cycles with clomiphene 6
• Poor ovarian reserve on testing (consider oocyte donation) 4
• Tubal obstruction or severe tubal disease identified on imaging 6
• Endometriosis discovered during workup 6
• Patient age approaches 40 years during treatment 6

Common Pitfalls to Avoid

• Do not delay evaluation or treatment in women over 35, as every month of delay reduces success rates. 2, 3
• Do not continue clomiphene beyond 6 total cycles, as this provides no additional benefit and delays more effective treatments. 1
• Do not increase clomiphene dose beyond 100 mg daily for 5 days, as higher doses are not recommended and do not improve outcomes. 1
• Do not assume "unexplained infertility" without completing full workup, including documentation of ovulation, tubal patency, and confirmed normal semen analysis. 3
• Do not overlook lifestyle modifications: counsel on smoking cessation, weight optimization if BMI is abnormal, limiting alcohol, and timing intercourse every 1-2 days after menstruation ends. 2, 4