Female Infertility: Evaluation & Treatment

Figure: Causes of infertility — Harrison's Principles of Internal Medicine, 22nd Ed.

Step 1 — Complete Evaluation Before Starting Treatment

Female causes account for 30–40% of infertility: ovulatory dysfunction, tubal/peritoneal factors, uterine pathology, and endocrine disorders.

Step 2 — Preconception Counseling (All Patients)

• Weight management: Obesity increases anovulatory cycles, miscarriage rates, and maternal complications. Weight loss in obese women improves spontaneous and drug-induced ovulation.
• Smoking cessation: Smoking damages oocyte DNA, reduces ovarian reserve (hastens menopause by 1–4 years), and raises ectopic pregnancy risk.
• Caffeine restriction: Limit to ≤2 cups/day during attempts and pregnancy.
• Timing intercourse: Fertile window is 5–6 days before ovulation; every 1–2 days during this window. LH kits can help time intercourse.
• Folic acid supplementation: 400 µg/day preconceptionally.
• Aneuploidy counseling: Advanced maternal age (>35) is associated with higher chromosomal error rates in oocytes.

Step 3 — Treatment by Etiology

A. Ovulatory Dysfunction (30–40% of female infertility; most treatable)

1. First-line: Letrozole (aromatase inhibitor) — preferred over clomiphene for PCOS (higher live birth rates)
2. First-line alternative: Clomiphene citrate (selective estrogen receptor modulator)
   • 60–80% of women with PCOS respond to these oral agents
3. Second-line: Metformin — added to oral agents in obese women with PCOS to further increase ovulation rates
4. Hypothyroidism / Hyperprolactinemia: Treat the underlying endocrine disorder before using ovulation induction agents
5. Hypothalamic amenorrhea: Weight gain + reduced exercise first; if no response → low-dose injectable gonadotropins (FSH ± LH) for monofollicular stimulation
6. Injectable gonadotropins (FSH/LH): Used when oral agents fail; require close monitoring (ultrasound + hormone levels) to prevent ovarian hyperstimulation syndrome (OHSS)

B. Tubal Factor Infertility (30–35% of female infertility)

• Hydrosalpinx / tubal occlusion from STI/PID: IVF is preferred — bypasses tubes entirely, offers highest success rates. Tubal repair is generally not recommended due to poor outcomes and high ectopic pregnancy risk.
• Salpingectomy for hydrosalpinges before IVF improves pregnancy rates by preventing efflux of toxic tubal fluid into the uterine cavity.
• Proximal tubal blockage on HSG: Attempt radiographically-guided tubal cannulation first.
• Post-tubal ligation: Decision between microsurgical reanastomosis vs. IVF depends on age, ovarian reserve, number of children desired, partner's sperm parameters, surgeon experience, and cost.

C. Uterine Factors (up to 15% of infertile couples)

D. Endometriosis

• Mild endometriosis (no tubal/peritoneal adhesions): Superovulation with IUI may be tried
• Moderate-severe (tubal adhesions, endometrioma): IVF is the treatment of choice
• Surgical resection of endometriomas before IVF: May be considered but can reduce ovarian reserve — weigh carefully

E. Diminished Ovarian Reserve / Premature Ovarian Insufficiency

• Step up from oral ovulation induction + IUI → IVF
• Overall live birth rates are lower
• Donor oocytes: A highly effective option — donor undergoes oocyte retrieval, eggs are fertilized with partner's sperm, and embryos are transferred to the patient's uterus

Step 4 — Assisted Reproductive Technologies (ART)

Intrauterine Insemination (IUI)

• Washed, concentrated sperm deposited into the uterine cavity via a soft catheter
• Used for: unexplained infertility, mild male factor, mild ovulatory dysfunction, endometriosis (mild)
• Often combined with ovulation induction
• Pregnancy rate: ~8–16% per cycle

In Vitro Fertilization (IVF)

• Indications: Tubal factor, moderate-severe endometriosis, diminished ovarian reserve, failed IUI, severe male factor
• Process:
  1. Ovarian stimulation with gonadotropins (FSH ± LH)
  2. GnRH antagonist to prevent premature LH surge
  3. Transvaginal oocyte retrieval under sedation
  4. Fertilization in laboratory (conventional IVF or ICSI)
  5. Embryo culture: 3 days (cleavage stage) or 5 days (blastocyst)
  6. Transcervical embryo transfer under ultrasound guidance
  7. Luteal phase progesterone support
  8. Cryopreservation of surplus embryos

ICSI (Intracytoplasmic Sperm Injection)

• A single morphologically normal sperm is injected directly into the oocyte
• Used for severe male factor infertility (sperm count <5 million/mL or motility <20%)
• Achieves ART success rates comparable to non-male factor couples

Preimplantation Genetic Testing (PGT)

• PGT-A (aneuploidy screening): Reduces miscarriage risk, especially in advanced maternal age
• PGT-M (monogenic disorders): Used when known genetic disease risk exists

Step 5 — Special Situations

Unexplained Infertility

• After complete negative workup (~30% of cases)
• Initial: Superovulation (letrozole/clomiphene) + IUI
• Escalate to IVF if no success after 3–6 cycles of IUI

Fertility Preservation (Cancer Patients)

• Oocyte cryopreservation or embryo cryopreservation before chemotherapy/radiation
• Chemotherapy can hasten ovarian failure — referral to reproductive specialist should not be delayed

Key Complications to Monitor

Summary Algorithm

Unexplained or Ovulatory → Letrozole/Clomiphene + IUI (3–6 cycles)
         ↓ (failure)
               IVF

Tubal factor / Hydrosalpinx → IVF ± Salpingectomy first

Uterine pathology → Hysteroscopic correction, then reassess

Endocrine cause → Treat underlying cause → then Ovulation Induction

Diminished Reserve / POI → IVF ± Donor Oocytes

Severe male factor → IVF + ICSI

• Harrison's Principles of Internal Medicine, 22nd Ed., Ch. 408
• Berek & Novak's Gynecology, Ch. on Infertility & ART
• Recent meta-analysis: Inositol for PCOS (PMID: 38163998, J Clin Endocrinol Metab 2024) supports inositol as an adjunct in PCOS management, consistent with current guidelines.