What is an appropriate fertility protocol for a woman or couple with infertility?

Fertility Protocol Design

For couples presenting with infertility, initiate concurrent evaluation of both partners immediately, as male factor contributes to 40-50% of cases, and proceed with a stepwise treatment algorithm based on specific diagnoses, prioritizing assisted reproductive technology (ART) for most conditions while avoiding empiric therapies with limited evidence. 1, 2

Initial Diagnostic Workup

Male Partner Evaluation

• Obtain two semen analyses separated by at least one month (ideally 2-3 months) to confirm persistent abnormalities 3, 4
• Measure serum FSH, LH, and total testosterone to identify correctable endocrine causes 3
• Perform physical examination focusing on:
  • Testicular volume (normal >12 mL; atrophy suggests spermatogenic failure) 1
  • Presence of palpable varicocele (affects sperm production and quality) 1, 4
  • Penile abnormalities that may impair sperm delivery 4
• If sperm concentration <10 million/mL, order karyotype and Y-chromosome microdeletion analysis before considering ICSI 4
• Document reproductive history including frequency/timing of intercourse, prior fertility, medication use (especially anabolic steroids), and gonadotoxin exposure 4

Female Partner Evaluation

• Assess ovarian reserve and ovulatory function 2
• Evaluate uterine cavity and tubal patency with transvaginal ultrasound as initial imaging 1
• Consider hysterosalpingography or sonohysterography with tubal contrast agent for tubal assessment 1
• Screen for thyroid dysfunction (TSH level), as both hypo- and hyperthyroidism affect ovulation 4
• Calculate BMI, as obesity and extreme thinness reduce fertility rates 1
• Assess for endometriosis, particularly if pelvic pain or dyspareunia present 1

Treatment Algorithm by Diagnosis

Unexplained Infertility (Normal Testing in Both Partners)

• For women <35 years with total motile sperm count (TMSC) >10 million: Initiate 3-4 cycles of intrauterine insemination (IUI) with ovarian stimulation using clomiphene citrate 50 mg daily for 5 days starting cycle day 5 1, 3, 5
• If no pregnancy after 3 IUI cycles or if woman ≥38-40 years: Proceed directly to IVF 3, 6
• Natural cycle IUI without ovarian stimulation has inferior outcomes and should not be used 1

Male Factor Infertility

Low Total Motile Sperm Count (5-10 million)

• Counsel that IUI success rates are significantly reduced with TMSC <5 million; proceed directly to IVF/ICSI 1
• For TMSC 5-10 million, may attempt 1-2 IUI cycles before advancing to IVF/ICSI 1

Asthenozoospermia (Low Motility) or Teratozoospermia

• IVF with intracytoplasmic sperm injection (ICSI) is first-line treatment, as it directly overcomes the motility/morphology defect 3
• Do not delay with empiric medical therapies, as they offer limited benefit compared to ART 1, 3

Clinical Varicocele with Abnormal Semen Parameters

• Offer varicocelectomy to improve fertility rates when female partner has good ovarian reserve 1
• Do not treat subclinical varicocele or varicocele in men with normal semen analysis 1

Hypogonadotropic Hypogonadism (Low FSH, LH, Testosterone)

• Initiate hCG injections to normalize testosterone, then add FSH analogues to optimize spermatogenesis 1, 3
• Refer to endocrinologist or male reproductive specialist 1
• Never prescribe testosterone monotherapy, as it completely suppresses spermatogenesis through negative feedback 1, 3

Idiopathic Infertility with Low-Normal Testosterone

• May consider aromatase inhibitors, hCG, or selective estrogen receptor modulators (SERMs), though benefits are limited relative to ART 1
• Counsel that supplements (antioxidants, vitamins) have questionable clinical utility with inadequate evidence for specific recommendations 1

Azoospermia (No Sperm in Ejaculate)

• For obstructive azoospermia: Microsurgical reconstruction is preferable to sperm retrieval when female partner has normal fertility potential 1
• For non-obstructive azoospermia (NOA): Perform microdissection testicular sperm extraction (micro-TESE) with IVF/ICSI 1
• Micro-TESE achieves successful sperm extraction 1.5 times more often than conventional TESE 1
• Inform NOA patients that pharmacologic manipulation with SERMs, aromatase inhibitors, and gonadotropins has limited data supporting use prior to surgical intervention 1

Female Factor Infertility

Anovulation/Ovulatory Dysfunction

• Start clomiphene citrate 50 mg daily for 5 days beginning cycle day 5 5
• If no ovulation after first cycle, increase to 100 mg daily for 5 days 5
• Do not exceed 100 mg/day for 5 days or continue beyond 6 total cycles 5
• If ovulation occurs but no pregnancy after 3 ovulatory cycles, discontinue clomiphene and proceed to IVF 5
• Letrozole (aromatase inhibitor) is an alternative ovulation induction agent, particularly for PCOS 6

Tubal Factor or Severe Endometriosis

• Proceed directly to IVF, as these conditions preclude natural conception or IUI success 6

Critical Pitfalls to Avoid

• Never prescribe testosterone to men desiring fertility—it causes azoospermia 1, 3
• Do not delay female partner evaluation while treating male factor, as female age critically impacts outcomes 3, 2
• Avoid prolonged empiric medical therapy in males; if no improvement after 3-6 months, advance to ART 1, 3
• Do not use vaginal lubricants, as most commercially available products reduce fertility 1
• Counsel smoking cessation, alcohol limitation, and avoidance of recreational drugs, as these impair fertility 1
• Recognize that male infertility is associated with increased testicular cancer risk and overall mortality; refer abnormal cases to specialists 4

Timing Considerations

• Women ≥35 years warrant expedited evaluation after only 6 months of failed conception 1, 2
• Women ≥40 years require immediate evaluation and consideration of direct IVF 2, 6
• Time intercourse to 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 ends 1

Referral Indications

• Any abnormal semen parameters require referral to male reproductive specialist 4
• Azoospermia or severe oligospermia (<5 million/mL) mandate specialist evaluation 4
• Refer to reproductive endocrinologist if no pregnancy after 3-4 IUI cycles or if immediate IVF indicated 3, 6