What is the recommended approach for a comprehensive infertility workup in individuals or couples experiencing difficulty conceiving, particularly for women over 35 years old?

Infertility Workup

For women over 35 years old, initiate a comprehensive infertility evaluation after only 6 months of unprotected intercourse without pregnancy, and evaluate both partners simultaneously from the outset. 1, 2

Timing of Evaluation

• Begin evaluation after 6 months of failed conception in women ≥35 years, compared to 12 months in younger women 1, 2
• For women over 40 years, immediate evaluation and treatment are warranted 3
• Start evaluation immediately if either partner has known infertility risk factors including irregular menstrual cycles, prior pelvic inflammatory disease, endometriosis, or bilateral cryptorchidism in men 2

Female Partner Evaluation

Medical and Reproductive History

Document the following specific elements:

• Duration and pattern of infertility: How long attempting pregnancy, coital frequency and timing, level of fertility awareness, results of any previous evaluation 1, 2
• Reproductive history: Gravidity, parity, pregnancy outcomes and complications, age at menarche, cycle length and characteristics, onset/severity of dysmenorrhea 1
• Medical conditions affecting reproduction: Thyroid disorders, hirsutism, polycystic ovary syndrome, other endocrine disorders 1, 2
• Surgical and infection history: Past pelvic surgery with indications and outcomes, pelvic inflammatory disease, sexually transmitted diseases 1
• Symptoms review: Thyroid disease symptoms, pelvic or abdominal pain, dyspareunia, galactorrhea, hirsutism 1

Physical Examination

Perform a focused examination assessing:

• General measurements: Height, weight, BMI calculation 1, 2
• Thyroid examination: Identify enlargement, nodules, or tenderness 1, 2
• Clinical breast examination: Assess for galactorrhea 1
• Signs of androgen excess: Hirsutism, acne, male-pattern hair distribution 1, 2
• Pelvic examination: Evaluate for pelvic/abdominal tenderness, organ enlargement or mass, vaginal or cervical abnormalities, uterine size/shape/position/mobility, adnexal masses or tenderness, cul-de-sac abnormalities 1

Initial Laboratory Testing

• Thyroid function tests: Screen for both hypo- and hyperthyroidism, as both affect ovulation 2
• Ovulation documentation: Serum progesterone level at cycle day 21 to confirm ovulation 4
• Ovarian reserve testing (particularly for women >35 years): Day 3 FSH and estradiol levels, or antral follicle count on transvaginal ultrasound 5

Imaging Studies

• Transvaginal ultrasound as initial imaging to evaluate uterine cavity, assess for fibroids or polyps, count antral follicles, and determine ovarian reserve 1, 2
• Tubal patency assessment: Hysterosalpingography for women with no risk factors for tubal obstruction 4
• For women with history of endometriosis, pelvic infections, or ectopic pregnancy, proceed directly to hysteroscopy or laparoscopy rather than hysterosalpingography 4

Male Partner Evaluation

Reproductive History

Assess the following critical elements:

• Fertility history: Frequency and timing of intercourse, prior fertility with current or previous partners, duration of current infertility 1, 2
• Developmental history: Childhood illnesses including cryptorchidism, pubertal timing 2
• Gonadotoxin exposure: Heat exposure, anabolic steroid use, chemotherapy, radiation 2
• Medications: Prescription medications and recreational drug use 2
• Sexual function: Erectile or ejaculatory dysfunction 2

Physical Examination

Perform a detailed genital examination:

• Penile examination: Location of urethral meatus to identify hypospadias 2
• Testicular assessment: Measure testicular size and consistency 1, 2
• Vas deferens and epididymides: Confirm presence and consistency of both structures 2
• Varicocele detection: Assess for presence of varicocele 2
• Secondary sex characteristics: Evaluate body habitus, hair distribution, breast development 2
• Digital rectal examination 2

Semen Analysis

• Obtain two semen analyses separated by at least one month to confirm persistent abnormalities 1, 2, 6
• Assess ejaculate volume, pH, sperm concentration, total motile sperm count, and sperm morphology using strict Kruger criteria 2
• If semen analysis is normal according to WHO criteria, a single test is sufficient 1
• Any abnormal semen parameters require referral to a male reproductive specialist 2, 6

Additional Male Testing When Indicated

• If sperm concentration <10 million/mL, order karyotype and Y-chromosome microdeletion analysis before considering ICSI 6
• Measure serum FSH, LH, and total testosterone to identify correctable endocrine causes 6

Critical Pitfalls to Avoid

• Never evaluate only one partner—both partners must be assessed simultaneously from the outset 1, 2, 6
• Never prescribe testosterone to men desiring fertility—it completely suppresses spermatogenesis through negative feedback and causes azoospermia 2, 6
• Avoid using vaginal lubricants during the fertile window, as most commercially available products reduce fertility 1, 2
• Do not delay female partner evaluation while treating male factor, as female age critically impacts outcomes 6
• Recognize that semen analysis alone cannot distinguish fertile from infertile men; clinical context is essential 1, 2

Lifestyle Counseling

Provide specific guidance on modifiable factors:

• Intercourse timing: Every 1-2 days beginning soon after menstrual period ends increases likelihood of pregnancy 1
• Ovulation tracking: Discuss methods to determine or predict ovulation including over-the-counter kits, digital applications, or cycle beads 1
• Weight optimization: Fertility rates are lower in women who are very thin or obese 1
• Caffeine limitation: Reduce consumption to less than five cups per day 1
• Smoking, alcohol, and recreational drugs: Discourage all of these as they reduce fertility 1, 2

When to Refer

• Any abnormal semen parameters require referral to male reproductive specialist for complete evaluation 2, 6
• Azoospermia or severe oligospermia (<5 million/mL) mandate specialist evaluation 6
• Women with suspected tubal disease, endometriosis requiring surgical diagnosis, or complex uterine abnormalities need subspecialty referral 4
• If no pregnancy after 3-4 cycles of ovulation induction with clomiphene citrate in primary care, refer to reproductive endocrinologist 6, 4