What is the appropriate diagnostic workup and first‑line management for a woman of reproductive age with primary infertility (trying to conceive ≥12 months, or ≥6 months if ≥35 years)?

Female Infertility: Diagnostic Workup and First-Line Management

When to Initiate Evaluation

Begin infertility evaluation after 12 months of regular unprotected intercourse in women under 35 years, but accelerate to 6 months in women aged 35 years or older. 1, 2

• Women ≥35 years experience accelerated fertility decline (approximately 3% per year between ages 35-45), making earlier intervention critical despite only modest improvements in treatment success rates 2, 3
• For women under 35 with regular cycles, waiting 12 months is appropriate because 50% of couples who fail to conceive in the first 6 months will conceive spontaneously in the next 6 months without intervention 4
• Do not wait 12 months if the woman has oligo-amenorrhea, known/suspected tubal disease, endometriosis, or a subfertile male partner 1, 5

Simultaneous Partner Evaluation

Evaluate both partners concurrently from the outset—never assess the female partner in isolation. 1

• Male factors contribute to approximately 50% of infertility cases (26% male factor alone, plus additional cases with combined factors) 6, 1, 5
• Delaying male evaluation wastes time and exposes women to unnecessary testing and interventions 1
• Order semen analysis for the male partner at the same visit you initiate female workup 1

Essential Female Diagnostic Workup

History Components

Document the following specific elements 5:

• Duration of attempted conception and coital frequency/timing
• Menstrual cycle regularity (oligo-amenorrhea suggests ovulatory dysfunction)
• Previous pregnancies, miscarriages, or ectopic pregnancies
• History of pelvic inflammatory disease, STIs (especially chlamydia), or pelvic surgery (indicates tubal factor risk)
• Symptoms of hyperandrogenism (hirsutism, acne—suggests PCOS)
• Galactorrhea or visual changes (suggests hyperprolactinemia)
• Dysmenorrhea or dyspareunia (suggests endometriosis)
• Smoking, alcohol, recreational drugs, caffeine >5 cups/day (all reduce fertility) 5
• Use of commercial vaginal lubricants (most reduce fertility) 5

Physical Examination

Perform targeted assessment 5:

• Calculate BMI (obesity and being underweight both reduce fertility)
• Thyroid palpation (thyroid dysfunction impairs ovulation)
• Signs of hyperandrogenism (hirsutism, acne)
• Pelvic examination for structural abnormalities, adnexal masses, or tenderness

Laboratory Testing

Order the following panel 7, 5:

• Serum FSH, LH, and estradiol (cycle day 2-4) to assess ovarian reserve
• Anti-Müllerian hormone (AMH) as an additional ovarian reserve marker 7
• TSH to exclude thyroid dysfunction 5
• Prolactin if galactorrhea, irregular cycles, or other symptoms present 5
• Mid-luteal progesterone (cycle day 21 in 28-day cycle) to confirm ovulation 5

Imaging Studies

Transvaginal ultrasound is the initial imaging modality of choice 6:

• Assess antral follicle count (ovarian reserve marker) 6
• Measure ovarian volume (>10 mL suggests PCOS) 6, 5
• Count follicles (>25 small follicles in one ovary suggests PCOS) 6, 5
• Identify uterine abnormalities (fibroids, polyps, congenital anomalies) 6, 7
• Detect endometriomas or other adnexal pathology 6

Hysterosalpingography (HSG) to assess tubal patency should be performed when 6, 5:

• History of pelvic inflammatory disease, STIs, or pelvic surgery exists
• Other causes have been excluded
• Proceeding toward assisted reproductive technology

MRI is not first-line imaging but may be useful for detailed evaluation of Müllerian anomalies or complex endometriosis 6

Common Causes and Their Prevalence

Understanding the distribution helps prioritize evaluation 6, 1, 5:

• Ovulatory disorders: 21% (PCOS accounts for 70% of anovulatory cases)
• Male factor: 26%
• Tubal damage: 14% (often from chlamydia or PID)
• Endometriosis: affects 33% of infertile women
• Unexplained: 28%

First-Line Management Based on Findings

If Elevated BMI with Otherwise Normal Workup

Prescribe intensive lifestyle modification as definitive first-line therapy 1:

• Weight reduction through diet and exercise (obesity directly reduces fertility)
• Smoking cessation (mandatory)
• Eliminate alcohol and recreational drugs
• Reduce caffeine to <5 cups daily
• Discontinue commercial vaginal lubricants
• Educate about the 6-day fertile window ending on ovulation day (characterized by stretchy cervical mucus) 1
• Recommend intercourse every 1-2 days starting soon after menses 1
• Reassess after 6 months in women ≥35 years 1

Do not offer bariatric surgery or GLP-1 agonists as first-line infertility management 1

If Anovulation/Oligo-ovulation Identified

• Refer to reproductive endocrinology for ovulation induction (typically clomiphene citrate or letrozole as first-line agents)
• Address underlying causes (PCOS, thyroid dysfunction, hyperprolactinemia) 5

If Tubal Factor Suspected or Confirmed

• Refer to reproductive endocrinology for consideration of tubal surgery versus IVF 5
• Laparoscopy may be both diagnostic and therapeutic for endometriosis 6

If Male Factor Identified

• Refer male partner to urology for further evaluation and management 1

If Unexplained Infertility

• Refer to reproductive endocrinology after completing basic workup 1
• Treatment typically progresses from ovarian stimulation with intrauterine insemination to IVF

Critical Pitfalls to Avoid

• Do not delay evaluation in women ≥35 years—the 6-month threshold is evidence-based given age-related fertility decline 1, 2
• Do not evaluate only the female partner—concurrent male assessment is mandatory 1
• Do not assume regular cycles guarantee fertility in women approaching age 40 7
• Do not perform fertility workup before 12 months in women <35 with regular cycles and no risk factors, as this increases false-positive diagnoses and exposes couples to unnecessary treatment complications (ovarian hyperstimulation, multiple pregnancies) 4
• Do not give false reassurance that lifestyle modification alone will resolve all cases—set realistic expectations and timelines for reassessment 1

When to Refer to Reproductive Endocrinology

Immediate referral is warranted for 1, 7:

• Women aged ≥40 years (more immediate evaluation and treatment needed) 2
• Women aged 35-39 after 6 months of failed conception 1, 2
• Women aged 45-55 with any infertility duration 7
• Known severe male factor
• Known tubal occlusion
• Diminished ovarian reserve (elevated FSH, low AMH, low antral follicle count)
• Failed ovulation induction in primary care setting

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