What are the initial steps and treatment options for individuals or couples experiencing infertility?

Infertility Practice Guideline

Definition and When to Initiate Evaluation

Initiate infertility evaluation after 12 months of regular unprotected intercourse in women under 35 years, and after 6 months in women 35 years or older. 1, 2, 3

• Begin evaluation immediately if either partner has known risk factors (oligo-amenorrhea, suspected uterine/tubal disease, endometriosis, known male subfertility, or previous pelvic infections) 2, 3
• For women over 40 years, immediate evaluation and treatment are warranted without waiting 3
• Evaluate both partners simultaneously from the outset—this is critical and non-negotiable 1, 2, 4

Male Partner Evaluation (Must Be Done Concurrently)

Initial Assessment

Order semen analysis immediately as the first diagnostic step for the male partner, requiring at least two samples collected one month apart after 2-3 days of abstinence. 1, 2, 4, 5

Medical History Components

• Reproductive history including prior fertility, childhood illnesses (cryptorchidism, mumps orchitis), and sexual function 1, 4, 5
• Systemic illnesses (diabetes, thyroid disorders, chronic infections) 4, 5
• Gonadotoxin exposure: anabolic steroids, chemotherapy, radiation, heat exposure, smoking 4, 5
• Current medications that may affect fertility 4, 5

Physical Examination Specifics

• Penile examination for hypospadias or other abnormalities 4, 5
• Testicular size measurement (normal >15 mL volume) and consistency 1, 5
• Palpation for varicocele (present in standing position) 4, 5
• Assessment of vas deferens and epididymides presence and consistency 5
• Evaluation of secondary sex characteristics 5

Mandatory Referrals and Further Testing

• Any abnormal semen parameters require referral to a male reproductive specialist 4
• Sperm concentration <10 million/mL requires endocrine evaluation (FSH, LH, testosterone, prolactin) and possible genetic testing 4
• Azoospermia or severe oligospermia <5 million/mL mandates karyotyping and Y-chromosome microdeletion analysis before considering ICSI 4

Critical Health Implications

• Men with abnormal semen parameters have significantly higher rates of testicular cancer and overall mortality compared to fertile men 4, 5
• Over 50% of male infertility cases stem from specific medical conditions with health implications beyond fertility 4, 5

Female Partner Evaluation

Medical History Components

• Duration of attempting pregnancy and frequency/timing of intercourse 2
• Previous pregnancies and outcomes (including miscarriages) 2
• Menstrual history: cycle length, regularity, duration, and associated symptoms 2, 5
• Previous surgeries (especially pelvic or abdominal) 5
• Medical conditions: thyroid dysfunction, diabetes, autoimmune disorders 2, 4
• Current medications, allergies, and family history of reproductive failure 2
• Lifestyle factors: smoking, alcohol intake, caffeine consumption, BMI 2

Physical Examination Specifics

• Height, weight, and BMI calculation 2, 5
• Thyroid examination for enlargement or nodules 2, 5
• Clinical breast examination 2, 5
• Assessment for signs of androgen excess (hirsutism, acne) 2
• Pelvic examination: vaginal/cervical abnormalities, uterine size/shape/position/mobility, adnexal masses or tenderness, signs of endometriosis 2, 5

Laboratory and Diagnostic Testing

Ovulatory Function Assessment

• Serum progesterone level on cycle day 21 (mid-luteal phase) to document ovulation 6
• Day 3 FSH and estradiol levels for ovarian reserve testing in women >35 years 2, 7

Structural Assessment

• Transvaginal ultrasound to evaluate uterine anatomy and antral follicle count 2, 7
• Hysterosalpingography (HSG) for women with no risk factors for tubal obstruction to assess tubal patency and uterine cavity 7, 6
• Hysteroscopy or laparoscopy for women with history of endometriosis, pelvic infections, or ectopic pregnancy 6

Thyroid Function

• TSH testing as thyroid dysfunction affects ovulation 4

Common Causes and Their Frequencies

• Male factor infertility: present in 50% of involuntarily childless couples 1
• Ovulatory dysfunction: approximately 25% of cases (70% of these have PCOS) 8
• Tubal disease: significant contributor requiring imaging assessment 8
• Unexplained infertility: diagnosed in up to 30% of couples after complete evaluation 3

Treatment Approaches Based on Diagnosis

Ovulatory Dysfunction

For women with anovulation, initiate ovulation induction with clomiphene citrate or letrozole (aromatase inhibitor) as first-line therapy. 8, 6

• Letrozole is effective for ovulation induction but carries FDA warnings about fetal harm and requires pregnancy testing before initiation and effective contraception during treatment 9
• Gonadotropins are second-line for ovulation induction but carry risks of multiple pregnancy (up to 36%) and ovarian hyperstimulation syndrome (1-5%) 8

Unexplained Infertility, Endometriosis, or Mild Male Factor

• Initial approach: 3-4 cycles of ovarian stimulation with timed intercourse or intrauterine insemination 8, 6, 10
• If unsuccessful after 3-4 cycles, proceed to IVF 8

Severe Male Factor or Bilateral Tubal Disease

• IVF with ICSI is indicated as first-line treatment 8

Age-Based Treatment Algorithms

• Women 38-40 years: consider immediate IVF as first-line strategy given declining fecundity 8
• Women >40 years: immediate IVF or consider oocyte donation for poor ovarian reserve 7

Elevated Sperm DNA Fragmentation

• First exclude and treat common risk factors (smoking, oxidative stress, poor lifestyle) 1
• Testicular sperm extraction (TESE) for ICSI may be offered on a case-by-case basis after full discussion with reproductive specialists, though evidence quality is low 1
• This approach should only be used after other treatments to reduce DNA fragmentation have failed 1

Lifestyle Modifications During Evaluation

• Intercourse every 1-2 days beginning soon after menstruation ends for women with regular cycles 2
• Smoking cessation and alcohol avoidance 2
• Weight optimization if BMI is extreme 2
• Limit caffeine consumption 2
• Antioxidant regimens may mitigate oxidative stress effects on sperm quality, though high-quality RCT evidence is lacking 1

Critical Pitfalls to Avoid

• Never evaluate only one partner—simultaneous evaluation is mandatory 1, 2, 4
• Do not rely on a single semen analysis; at least two samples one month apart are required 1, 4, 5
• Do not delay evaluation in women >35 years—initiate after 6 months, not 12 2, 3
• Semen analysis alone cannot distinguish fertile from infertile men; clinical context is essential 1
• Do not routinely measure reactive oxygen species (ROS) as no standardized testing methods exist and validation is lacking 1