Female Infertility - Postgraduate Level

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Definition and Epidemiology

• Prevalence in the USA: 7.4% to 15.5% of couples
• About 90% of couples should conceive within 12 months
• Spontaneous conception is less likely with: age >42, infertility duration >4 years, severe endometriosis, or severe tubal disease

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INITIAL ASSESSMENT

• Menstrual cycle regularity, cycle length, dysmenorrhea, intermenstrual bleeding
• Pelvic pain or dyspareunia (suggesting endometriosis or PID)
• Prior pregnancies and outcomes
• History of PID, STIs, pelvic or abdominal surgery
• DES intrauterine exposure
• Review of systems for thyroid, adrenal, pituitary dysfunction (galactorrhea, hirsutism, weight changes)
• Coital frequency, sexual dysfunction
• Family history: premature ovarian failure, hereditary conditions (cystic fibrosis, thalassemia, Tay-Sachs)

• Height, weight, BMI, body habitus
• Hair distribution (hirsutism)
• Thyroid palpation
• Breast exam (galactorrhea)
• Pelvic exam: uterine size, adnexal masses, uterosacral nodularity

1. Semen analysis
2. Confirmation of ovulation
3. Documentation of tubal patency
4. Ovarian reserve screening

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DIAGNOSTIC ALGORITHM

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CAUSES OF FEMALE INFERTILITY IN DETAIL

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1. OVULATORY FACTOR (21-36% of female infertility)

• WHO Class I (Hypogonadotropic hypogonadism): hypothalamic/pituitary failure - low FSH, LH, E2 (e.g., hypothalamic amenorrhea, anorexia nervosa, exercise-related amenorrhea)
• WHO Class II (Normogonadotropic): normal FSH, LH - includes PCOS (most common)
• WHO Class III (Hypergonadotropic hypogonadism): elevated FSH - premature ovarian insufficiency/failure

1. Oligo-ovulation or anovulation (oligomenorrhea/amenorrhea)
2. Hyperandrogenemia (elevated androgens) or hyperandrogenism (clinical signs)
3. Polycystic ovaries on ultrasound

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2. TUBAL AND PERITONEAL FACTOR (16-28% of female infertility)

• Pelvic inflammatory disease (PID) - C. trachomatis is the most important cause
• Previous pelvic/abdominal surgery
• Ectopic pregnancy (with salpingectomy)
• Endometriosis with tubal/peritoneal involvement
• Salpingitis isthmica nodosa
• Tuberculosis (common in developing countries)

• Proximal tubal occlusion (can mimic spasm - false positive 11% on HSG)
• Distal tubal occlusion/hydrosalpinx - causal in 85% of all tubal infertility
• Peritubal adhesions

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3. UTERINE FACTORS (up to 15% of couples)

• Müllerian anomalies: bicornuate, unicornuate, septate, didelphys uterus
• DES exposure in utero: T-shaped uterus, hypoplastic uterus

• Leiomyomas: submucosal > intramural > subserosal for fertility impact. Leiomyomas have not been shown to be a direct cause of infertility; however, submucosal and cavity-distorting intramural fibroids should be removed.
• Intrauterine synechiae/Asherman syndrome: caused by trauma to the basalis layer, usually iatrogenic after uterine evacuation, myomectomy, or TB. Causes amenorrhea, menstrual irregularities, recurrent pregnancy loss.
• Endometrial polyps: incidence 6-32% in infertile women; disordered endometrial receptivity mechanism; polypectomy improves IUI pregnancy rates 2.1-fold.
• Endometritis: plasma cells in endometrium found in 56.8% of unexplained infertility patients; treat with antibiotics.
• Luteal phase defect and endometrial receptivity issues.

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4. DIMINISHED OVARIAN RESERVE (DOR)

• Iatrogenic: chemotherapy, pelvic radiation, ovarian surgery
• Pelvic endometriosis and adhesions
• Immunologic factors
• Genetic: FMR1 premutation (fragile X), Turner syndrome mosaicism

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5. ENDOMETRIOSIS AND PELVIC FACTOR

• Distortion of tubo-ovarian anatomy (adhesions)
• Impaired implantation (altered endometrial receptivity)
• Toxic peritoneal environment affecting gametes
• Decreased ovarian reserve (endometrioma)
• Occult mechanisms in minimal/mild disease

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6. CERVICAL FACTOR

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7. UNEXPLAINED INFERTILITY (8-28%)

• Occult male factor (impaired sperm DNA integrity despite normal semen analysis)
• Oocyte factors (premature zona hardening, mitochondrial dysfunction, aberrant spindle formation)
• Luteinized unruptured follicle syndrome (25% in unexplained infertility vs 10% in fertile women)
• Occult endometriosis
• Undiagnosed pelvic pathology
• Immunologic factors, chronic endometritis, uterine microbiome abnormalities

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INVESTIGATIONS

Ovarian Reserve Testing

Tubal Patency Testing

Hormone Panel (Ovulatory Workup)

Uterine Cavity Assessment

• SIS (saline infusion sonography): first-line for cavity
• 3D transvaginal ultrasound: Müllerian anomalies
• Hysteroscopy: gold standard for cavity pathology
• MRI: uterine anomalies, adenomyosis, fibroid mapping

Genetic Testing (Selected Cases)

• Karyotype: POI/POF, recurrent pregnancy loss
• FMR1 premutation: premature ovarian insufficiency
• Carrier testing: CF, thalassemia, fragile X (based on ethnicity and family history)
• CFTR gene: in setting of male CBAVD (female partner testing indicated)

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MANAGEMENT

Diagnostic Algorithm for Anovulation

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A. Management of Ovulatory Dysfunction

PCOS Treatment (stepped approach)

• Weight loss in overweight/obese patients. Weight loss of ~20 pounds increases spontaneous conception rates.
• Exercise, reduced caloric intake

• Maximum 6 ovulatory cycles with CC or letrozole before stepping up
• Resistance: failure to ovulate at maximum dose

• FSH injections; low initial dose 37.5-75 IU/day; step-up protocol
• Monitor with serial transvaginal USS + E2 levels
• Trigger with hCG when 1-2 follicles reach 16-18 mm; E2 150-300 pg/mL per dominant follicle
• Ovulation in 43-83%, pregnancy 21-29% (vs clomiphene-resistant population)
• Risk of OHSS and multiple gestation (36%); use GnRH agonist trigger if OHSS risk high
• Maximum dose rarely exceeds 225 IU/day

• Alternative to gonadotropins for CC-resistant PCOS
• 3-15 punctures per ovary by electrocautery/laser
• Within 12 months: ovulation 52%, pregnancy 26-48%, live birth 13-32%
• No multiple gestation risk
• Complications: adhesions, recurrence of anovulation, theoretical ovarian failure

1. Primary ovarian failure with elevated FSH
2. Uncontrolled thyroid/adrenal dysfunction
3. Intracranial lesion (pituitary tumor)
4. Undiagnosed abnormal uterine bleeding
5. Ovarian cysts not due to PCOS
6. Sex hormone-dependent tumors
7. Pregnancy

Hyperprolactinemia Treatment

• MRI pituitary to exclude macroadenoma
• Dopamine agonists are first-line:
  • Bromocriptine: 1.25-7.5 mg/day; normalizes prolactin and restores ovulation in 80-90%
  • Cabergoline: 0.25 mg twice weekly (better tolerated, more effective)
• Spontaneous ovulation resumes when prolactin normalizes

Hypothalamic Amenorrhea

• Weight restoration, treat eating disorder, reduce exercise
• Pulsatile GnRH therapy: IV/SC administration every 60-90 min to restore pulsatile FSH/LH release
• Exogenous gonadotropins (FSH + LH/hMG): if pulsatile GnRH unavailable
• Avoid CC (ineffective in hypogonadotropic state)

Thyroid Disease

• Treat hypothyroidism with levothyroxine - spontaneous ovulation may resume
• Treat hyperthyroidism; fertility usually improves with euthyroid state

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B. Management of Tubal Factor Infertility

• Proximal tubal catheterization/cannulation via HSG or hysteroscopy: restores patency in up to 85%; reocclusion rate 30%
• Ongoing pregnancy rates 12-44%
• Microsurgical tubocoronal anastomosis: pregnancy rates up to 68% (small studies)
• If persistent occlusion or recurrence → IVF

• Distal disease causes 85% of all tubal infertility
• Hydrosalpinx reduces IVF success rates; salpingectomy or proximal occlusion of the hydrosalpinx before IVF is recommended
• Salpingostomy for distal occlusion in selected young patients (<35 years) with mild disease, normal tubal mucosa, minimal adhesions
• IVF for older patients, severely damaged tubes, bilateral disease

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C. Management of Uterine Factor

• Submucosal and cavity-distorting intramural fibroids: remove before infertility treatment
• Non-cavity-distorting intramural fibroids: utility of removal is unknown
• Hysteroscopic myomectomy: preferred for submucosal fibroids
• Laparoscopic/open myomectomy: for intramural/subserosal
• GnRH agonists pre-operatively to shrink large (>5-6 cm) fibroids and reduce blood loss
• Uterine artery embolization: relatively contraindicated in fertility-desiring women

• Hysteroscopic resection of synechiae - treatment of choice
• Post-operative estrogen therapy (1 month) ± IUD placement to prevent adhesion reformation
• TB endometritis: very poor prognosis

• Hysteroscopic polypectomy: 2.1-fold improvement in pregnancy rates before IUI
• Curettage or blind avulsion also used

• Uterine septum: hysteroscopic metroplasty (most common and treatable anomaly)
• Bicornuate uterus: abdominal metroplasty (Strassman procedure) in selected cases
• DES-related anomalies: generally managed with ART

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D. Management of Diminished Ovarian Reserve (DOR)

1. Autologous IVF with controlled ovarian stimulation
   • Stimulation protocols: microdose GnRH flare, GnRH antagonist, minimal stimulation
   • Adjuncts: DHEA (25 mg TID x 2-5 months), transdermal testosterone 10-12.5 mg x 14-28 days pretreatment, CoQ10, growth hormone, vitamin D, omega-3 fatty acids (varying evidence)
2. Donor oocyte IVF: live birth rates 40-60% regardless of recipient age
3. Donor embryo
4. Adoption

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E. Endometriosis-Associated Infertility

• Laparoscopic ablation/excision marginally improves spontaneous conception rates vs no treatment
• IUI + ovarian stimulation: empiric option
• IVF if above fails or if age-related DOR present

• Surgical excision of endometriosis and adhesiolysis improves fertility outcomes
• Ovarian endometrioma: cystectomy preferred over ablation (but increases DOR risk - laparoscopic hemostasis method matters per 2024 systematic review, PMID 38064608)
• ART/IVF is often first-line for Stage III/IV

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F. Management of Unexplained Infertility

• FASTT trial: For age 21-39, ongoing pregnancy rates: CC/IUI 7.6%, FSH/IUI 9.8%, IVF 30.7% - IVF clearly superior with shorter time to pregnancy
• FORT-T trial: For age 38-42, IVF had higher live birth rates than CC/IUI or FSH/IUI
• Meta-analysis of 1,159 participants: CC alone or CC/IUI showed no improvement in pregnancy/live birth vs no treatment or placebo

• IVF is first-line treatment for unexplained infertility based on evidence
• 2024 Australian/ESHRE guideline (PMID 39277816): recommends IVF as first-line treatment with or without ICSI for unexplained infertility
• Superovulation/IUI continues to be used in practice mainly due to lower per-cycle cost, patient preference, and insurance coverage

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G. Assisted Reproductive Technology (ART)

• IVF (conventional fertilization)
• ICSI (intracytoplasmic sperm injection) - for male factor or fertilization failure
• GIFT, ZIFT (largely abandoned due to improved IVF outcomes)
• Oocyte cryopreservation (fertility preservation)
• Embryo cryopreservation
• Preimplantation genetic testing (PGT-A/PGT-M)
• Gestational carrier / surrogacy
• Donor oocyte or embryo

1. Pituitary downregulation:
   • GnRH agonist (long protocol): started day 21 of preceding cycle; 10-14 days to achieve suppression; continued until hCG trigger
   • GnRH antagonist (flexible/fixed): started day 6 of stimulation or when leading follicle reaches 14 mm; advantages - shorter treatment, less OHSS risk
2. Controlled ovarian hyperstimulation (COH):
   • FSH ± LH (hMG) injections
   • Monitor with serial TVS and E2 levels (every 1-3 days after day 4-5)
3. Trigger injection:
   • hCG (conventional): when 2+ follicles ≥18 mm; ovulation 34-36 hours after
   • GnRH agonist trigger (leuprolide 500 mcg SC): preferred when OHSS risk high (PCOS, high E2, many follicles); requires progesterone luteal support
4. Oocyte retrieval: Transvaginal ultrasound-guided 34-36 hours after trigger
5. Fertilization: Conventional IVF or ICSI
6. Embryo transfer: Day 3 (cleavage stage) or day 5 (blastocyst)
7. Luteal phase support: Progesterone (vaginal/IM) from day of retrieval

• Ovarian Hyperstimulation Syndrome (OHSS): prevent with agonist trigger, coasting, cryopreservation all embryos, cabergoline
• Multiple gestation: serious complication; single embryo transfer policy reduces this
• Ectopic/heterotopic pregnancy
• Cycle cancellation
• Oocyte retrieval complications (bleeding, infection)
• Stress: most common reason for treatment discontinuation

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H. Fertility Preservation

• Cancer patients before chemotherapy/radiation
• Premature ovarian insufficiency risk
• Genetic conditions
• Social/elective freezing

• Oocyte cryopreservation (vitrification): established technique
• Embryo cryopreservation: most established
• Ovarian tissue cryopreservation and transplantation: experimental/established in select centers

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LIFESTYLE AND MODIFIABLE FACTORS

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SUMMARY: STEPWISE MANAGEMENT FRAMEWORK

Female Infertility Workup:
├── History + Physical Exam
├── Basic workup (BOTH partners simultaneously):
│   ├── Semen analysis (male)
│   ├── Ovulation documentation (progesterone, LH kits, USS)
│   ├── Ovarian reserve (AMH, day 3 FSH/E2, AFC)
│   ├── Tubal patency (HSG)
│   └── Uterine cavity (SIS or hysteroscopy)
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├── Anovulation identified → Letrozole first-line → CC → Gonadotropins → Drilling
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├── Tubal factor → IVF preferred over surgery (except proximal cannulation, reversal)
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├── Uterine factor → Hysteroscopic/surgical correction then ART if needed
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├── DOR → Autologous IVF → Donor oocyte IVF
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├── Endometriosis → Surgery for Stage III/IV → ART
│
└── Unexplained → IVF first-line (not CC/IUI per FASTT/FORT-T trials)

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RECENT GUIDELINES UPDATE

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