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Male Infertility - Causes & Management of Azoospermia

(M.S. Main Exam - 10 Mark Answer | Based on Berek & Novak's Gynecology)

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DEFINITION

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PART 1: CAUSES OF MALE INFERTILITY

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FLOWCHART 1: Classification of Male Infertility Causes

MALE INFERTILITY
        |
        |_______________|_______________|
        |               |               |
  PRE-TESTICULAR    TESTICULAR    POST-TESTICULAR
  (Endocrine/       (Primary       (Obstructive/
   Hormonal)         Gonadal)       Transport)

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A. PRE-TESTICULAR CAUSES (Hormonal / Endocrine)

Failure of hypothalamic-pituitary axis to stimulate the testes

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B. TESTICULAR CAUSES (Primary Gonadal Failure)

Testes present but cannot produce sperm normally

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C. POST-TESTICULAR CAUSES (Obstructive / Functional)

Sperm produced but cannot be delivered

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TABLE: Distribution of Male Infertility (WHO Study of 7,057 men)

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PART 2: AZOOSPERMIA - DEFINITION & CLASSIFICATION

• Affects ~1% of all men and ~10-15% of infertile men

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FLOWCHART 2: Approach to Azoospermia

AZOOSPERMIA
(No sperm on 2 semen analyses)
           |
           |
    History + Exam
    FSH, LH, Testosterone
    Karyotype, Y-microdeletion
           |
    ________|_________
   |                  |
FSH Normal/Low    FSH Elevated
   |                  |
OBSTRUCTIVE       NON-OBSTRUCTIVE
(Post-testicular)  (Testicular)
   |                  |
Testes normal     Testes small/atrophic
   |                  |
Transrectal US    Testicular Biopsy (TESE)
   |                  |
Reconstructable?  Sperm found? → ICSI
   |
Vasectomy reversal
or MESA/PESA + ICSI

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AZOOSPERMIA IN DETAIL

TYPE 1: PRE-TESTICULAR AZOOSPERMIA

• Low FSH
• Low LH
• Low Testosterone
• Normal testicular size

• Gonadotropin therapy - hCG + FSH (human menopausal gonadotropin / recombinant FSH)
  • hCG 1500-2000 IU IM 3x/week to restore testosterone
  • Add FSH after 3-6 months if no sperm
• This can restore spermatogenesis in up to 90% of cases
• Pulsatile GnRH therapy (via pump) - for hypothalamic causes
• If fertility achieved, ICSI as backup

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TYPE 2: TESTICULAR (NON-OBSTRUCTIVE) AZOOSPERMIA

• High FSH (hallmark - indicates primary testicular failure)
• High LH
• Low testosterone
• Small, firm testes

• Karyotype (detect Klinefelter 47,XXY)
• Y-chromosome microdeletion testing (AZFa, AZFb, AZFc)
  • AZFa/AZFb deletions: NO sperm retrievable (TESE futile)
  • AZFc deletions: ~50-70% sperm retrieval by TESE

Non-Obstructive Azoospermia
           |
    Karyotype + Y-microdeletion
           |
     AZFa/AZFb deletion?     AZFc deletion / Klinefelter?
           |                           |
    NO TESE (futile)           TESE/microTESE
    → Donor sperm / Adoption    → ICSI if sperm found
                                → Donor sperm if TESE fails

• Testicular Sperm Extraction (TESE): Biopsy of testicular tissue to find residual sperm
• Microdissection TESE (microTESE): Under microscope, identify dilated tubules likely to contain sperm; 40-60% success in non-obstructive azoospermia
• Retrieved sperm used for ICSI
• If no sperm obtained: Donor sperm or adoption

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TYPE 3: POST-TESTICULAR (OBSTRUCTIVE) AZOOSPERMIA

• Normal FSH (testes making sperm, just blocked)
• Normal testosterone
• Normal testicular size
• Fructose absent if ejaculatory duct blocked

• Transrectal ultrasound (TRUS) - detects ejaculatory duct cysts/obstruction
• Scrotal ultrasound - epididymal dilation
• CFTR gene testing (if CBAVD suspected)

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MANAGEMENT OF OBSTRUCTIVE AZOOSPERMIA

A. Vasectomy Reversal

• Vasovasostomy - reanastomosis of cut vas deferens
  • Best within 10 years of vasectomy (patency 75%, pregnancy 55%)

  • 15 years: patency 30%, pregnancy 25%

• Vasoepididymostomy - if obstruction at epididymis level

B. Sperm Retrieval Techniques (for ICSI)

C. Ejaculatory Duct Obstruction

• Transurethral resection of ejaculatory ducts (TURED) - if midline cyst or calcification causing blockage
• Can restore ejaculatory function in 50-65% of cases

D. CBAVD (Congenital Bilateral Absence of Vas Deferens)

• No surgical reconstruction possible
• Testicular sperm retrieval (TESE/PESA) + ICSI
• Must screen female partner for CFTR mutations - if both carry CFTR, 25% risk of child with cystic fibrosis
• Genetic counseling mandatory before proceeding

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FLOWCHART 3: Complete Management Algorithm for Azoospermia

AZOOSPERMIA
      |
  ────────────────────────────────────────────
  |              |                |
History        Exam           Investigations
  |              |                |
- Prior surgery - Testis size  - Semen analysis x2
- Infections   - Varicocele   - FSH, LH, Testosterone
- Trauma       - CBAVD        - Prolactin
- STI          - Hypospadias  - Karyotype
                               - Y-microdeletion
                               - TRUS, scrotal US
      |
  ─────────────────────────
  |                         |
FSH Normal               FSH Elevated
Small vol / no fructose   Small testes
  |                         |
OBSTRUCTIVE              NON-OBSTRUCTIVE
(Post-testicular)        (Testicular)
  |                         |
  |                    ─────────────────
  |                    |               |
  |               Y-microdeletion?  Klinefelter?
  |                    |               |
  |              AZFa/b: TESE    microTESE
  |               futile          or TESE
  |                    |               |
  |              Donor sperm    Sperm found?
  |                           Yes → ICSI
  |                           No → Donor sperm
  |
  ─────────────────────
  |                   |
CBAVD          Other obstruction
  |                   |
TESE/PESA     Surgical repair?
  + ICSI             |
  + CFTR test    ─────────────
               |             |
          Vasectomy      Epididymal/
          reversal       ED obstruction
               |             |
         Vasovasostomy   PESA/MESA
         or              + ICSI
         Vasoepididymostomy  or TURED

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ICSI (Intracytoplasmic Sperm Injection) - The Key ART

• Used in 93% of ART cycles for male factor infertility (Berek & Novak)
• A single viable sperm is injected directly into the oocyte cytoplasm
• Bypasses barriers of motility, capacitation, acrosome reaction, zona binding
• Indication in male factor: <2 million motile sperm, <5% motility, or surgically retrieved sperm
• Pregnancy outcomes comparable to conventional IVF in non-male factor couples

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DONOR SPERM

• Non-obstructive azoospermia with failed TESE
• AZFa or AZFb deletion (no retrievable sperm)
• Severe genetic conditions where own sperm transmission is undesirable
• Single women / same-sex couples
• Fresh donor sperm NOT recommended (HIV seroconversion window)
• Frozen samples quarantined 6 months, donor retested before use
• Donors screened for HIV, Hep B/C, syphilis, gonorrhea, chlamydia, CMV, and genetic disorders

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SUMMARY TABLE: Azoospermia at a Glance

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QUICK RECALL MNEMONICS

• V - Varicocele
• I - Idiopathic
• T - Testicular failure (Klinefelter, orchitis)
• A - Anatomical (CBAVD, obstruction)
• M - Medication/Chemotherapy
• I - Infection (STIs, TB)
• N - Neurological (retrograde ejaculation)
• E - Endocrine (HH, thyroid, prolactin)
• D - DNA/Genetic (Y-microdeletion, AZF)

• MESA / PESA → Obstructive azoospermia
• TESE / microTESE → Non-obstructive azoospermia

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EXAM TIP (M.S. Main Exam Format)

1. Introduction / Definition (1 mark)
2. Classification of causes with table (3 marks)
3. Definition and classification of azoospermia (1 mark)
4. Investigations in azoospermia (1 mark)
5. Management flowchart (2 marks)
6. Surgical options / ICSI / Donor (2 marks)

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Anovulatory Infertility - Definition, Investigation & Management

(M.S. Final Exam - 10 Mark Answer | Berek & Novak's Gynecology)

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DEFINITION

• Anovulation accounts for ~25-30% of all female infertility cases
• It is the most treatable cause of female infertility
• Normal ovulation requires intact function of: Hypothalamus → Pituitary → Ovary → Uterus (outflow tract)

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NORMAL OVULATION - QUICK RECAP

Hypothalamus
    ↓  (GnRH - pulsatile)
Pituitary
    ↓  (FSH + LH)
Ovary
    ↓  (Estrogen → LH surge → Ovulation → Corpus luteum → Progesterone)
Endometrium
    ↓
Menstruation (if no pregnancy)

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WHO CLASSIFICATION OF ANOVULATION

KEY POINT (Berek & Novak): WHO Group II (PCOS-associated normogonadotropic anovulation) is associated with evidence of estrogen production and normal levels of prolactin and FSH. WHO Group III (hypergonadotropic hypogonadism) includes individuals with elevated serum FSH.

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CAUSES OF ANOVULATION (By WHO Group)

FLOWCHART 1: Causes of Anovulatory Infertility

ANOVULATORY INFERTILITY
           |
    ________|__________________________________________
    |              |              |                    |
WHO Group I    WHO Group II   WHO Group III       WHO Group IV
(Low FSH/E2)  (Normal FSH)   (High FSH, Low E2)  (High Prolactin)
    |              |              |                    |
Hypothalamic   PCOS           Premature Ovarian    Prolactinoma
 causes      (most common)    Insufficiency (POI)  Drug-induced
    |              |              |                Hypothyroidism
- Stress       - Idiopathic   - Autoimmune         Post-partum
- Anorexia     - Obesity      - Genetic            (Sheehan's)
- Exercise     - Hyperandrogenism  - Fragile X      
- Weight loss  - Insulin      - Iatrogenic         
- Kallmann       resistance     (chemo/radiation)  
  syndrome     - CAH (late    - Turner's           
- Tumors         onset)         syndrome (if       
- Craniopharyngioma           primary amenorrhea)  

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INVESTIGATIONS IN ANOVULATORY INFERTILITY

STEP 1: Confirm Anovulation

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STEP 2: Find the Cause (Investigations)

STEP 1: Rule out pregnancy → β-hCG

STEP 2: Thyroid + Prolactin
         TSH → if abnormal: thyroid cause
         Prolactin → if elevated: hyperprolactinemia

STEP 3: FSH + LH + Estradiol (E2) on Day 2-3
         ↓Low FSH + Low E2 → WHO Group I (Hypothalamic-pituitary)
         ↓Normal FSH + Normal E2 → WHO Group II (PCOS)
         ↓HIGH FSH + Low E2 → WHO Group III (POI)

STEP 4: If PCOS suspected:
         - LH:FSH ratio (>2:1 in PCOS)
         - Testosterone, DHEA-S, 17-OHP (rule out CAH)
         - Fasting glucose + insulin (insulin resistance)
         - AMH (anti-Müllerian hormone) - elevated in PCOS
         - TVS: polycystic ovarian morphology (≥12 follicles per ovary OR ovarian volume >10cc)

STEP 5: If WHO Group I (Low FSH):
         - MRI pituitary/hypothalamus
         - GnRH stimulation test
         - Bone density (DEXA)

STEP 6: If WHO Group III (High FSH):
         - Karyotype (Turner syndrome)
         - FMR1 premutation (Fragile X)
         - Antiovarian antibodies
         - AMH (very low/undetectable in POI)

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KEY INVESTIGATIONS TABLE (Berek & Novak)

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MANAGEMENT OF ANOVULATORY INFERTILITY

FLOWCHART 2: Management Algorithm

ANOVULATORY INFERTILITY
           |
     ______|_______________________
    |              |               |
WHO Group I    WHO Group II     WHO Group III    WHO Group IV
(Low FSH)     (PCOS - Normal)  (High FSH - POI) (High Prolactin)
    |              |               |                |
    |           ↓ Weight loss   Egg donation     Dopamine agonist
    |           (if obese)      IVF-OD           Bromocriptine /
    |              |            Hormone therapy   Cabergoline
    |         Letrozole (1st)       |
    |         or Clomiphene         |
Pulsatile    (2nd line)        Spontaneous
GnRH pump       |              pregnancy rare
or              |              (5-10% POI)
Gonadotropins  If fails:
(hCG + FSH)   Gonadotropins
               (FSH injections)
               If fails:
               IVF

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MANAGEMENT BY WHO GROUP

WHO GROUP II (PCOS - Most Common - Must Know in Detail)

Step 1: Lifestyle Modification (First-Line for Obese PCOS)

• Weight loss of even 5% can restore ovulation spontaneously
• Reduce daily caloric intake by 500 kcal + regular exercise
• Weight loss → improves insulin sensitivity → reduces androgens → restores ovulation
• (Berek & Novak: "Given that even a 5% weight loss may improve pregnancy rates, weight loss should be encouraged in all overweight and obese infertility patients")

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Step 2: Ovulation Induction Agents

A. LETROZOLE (Femara) - NOW FIRST-LINE for PCOS

• Aromatase inhibitor (off-label use since 2001)
• Mechanism: Blocks estrogen synthesis → ↑FSH from pituitary → follicle development
• Shorter half-life (48 hours) vs clomiphene (2 weeks) → fewer antiestrogenic endometrial effects
• Dose: 2.5 mg/day orally, Days 3-7 of cycle (can increase to 5-7.5 mg)
• Superior to clomiphene in PCOS:
  • Landmark RCT (750 women, PCOS): Letrozole cumulative live birth 27.5% vs 19.1% with clomiphene
  • Twin rate: Letrozole 3.4% vs Clomiphene 7.4%

B. CLOMIPHENE CITRATE (Clomid) - Second Line

• Selective Estrogen Receptor Modulator (SERM)
• Mechanism: Blocks estrogen receptors in hypothalamus → increases GnRH pulsatility → ↑FSH + LH → follicle development
• Requires a functional hypothalamic-pituitary-ovarian axis
• Dose: 50 mg/day orally, Days 3-7 (or Days 5-9); max 150 mg/day
• Over 6 months:
  • Ovulation rate: 49%
  • Pregnancy rate: 23.9%
  • Live birth rate: 22.5%
• Side effects: Hot flushes, mood swings, breast tenderness, antiestrogenic effect on endometrium/cervix, multiple gestation ~8% (mostly twins)
• Clomiphene resistance: Failure to ovulate with 150mg/day for 3 cycles

CLOMIPHENE / LETROZOLE PROTOCOL:
Day 3: TVS baseline (check for cysts)
Day 3-7: Drug administration
Day 10-14: TVS follicle tracking
Follicle ≥18mm: hCG trigger (Ovidrel 250 mcg SC or hCG 10,000 IU)
36 hours post-trigger: IUI or timed intercourse
Day 21: Serum progesterone to confirm ovulation

C. METFORMIN (Insulin Sensitizer)

• Reduces insulin resistance in PCOS → reduces androgen production → can restore ovulation
• Not as effective alone for ovulation induction as letrozole
• May be combined with letrozole/clomiphene in insulin-resistant/obese PCOS
• Dose: 500-2000 mg/day (start low, titrate up to reduce GI side effects)

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Step 3: Gonadotropin Therapy (if oral agents fail)

• FSH injections (recombinant FSH: Gonal-F, Puregon) ± LH
• Requires close ultrasound monitoring (risk of ovarian hyperstimulation syndrome - OHSS and multiple pregnancy)
• Low-dose step-up protocol preferred in PCOS to minimize OHSS risk:
  • Start with 37.5-75 IU FSH/day
  • Increase by 37.5 IU every 5-7 days if no response
• Used with IUI or timed intercourse

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Step 4: Surgical Option - Laparoscopic Ovarian Drilling (LOD)

• For clomiphene-resistant PCOS when gonadotropins not available/affordable
• Electrocautery or laser creates 4-8 punctures per ovary
• Mechanism: Destroys androgen-secreting stroma → ↓androgens, ↓LH → restores FSH/LH ratio → spontaneous ovulation
• Ovulation rate: ~80%, Pregnancy rate: ~50% over 1 year
• Advantage over gonadotropins: No OHSS risk, reduced multiple pregnancy risk
• Risk: Adhesion formation, ovarian damage if overdone

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Step 5: IVF (if all above fail)

• Controlled ovarian hyperstimulation + egg retrieval + ICSI/ET
• GnRH antagonist protocol preferred in PCOS (reduces OHSS)
• Freeze-all strategy for OHSS risk patients

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WHO GROUP I (Hypogonadotropic Hypogonadism - Low FSH)

(Berek & Novak: "Pulsatile GnRH agonist therapy simulates normal physiology and offers some advantages over gonadotropin injections, including fewer multiple gestations and less OHSS while maintaining excellent pregnancy rates")

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WHO GROUP III (Hypergonadotropic Hypogonadism - POI)

• No effective treatment to restore own ovulation in most cases
• Spontaneous pregnancy in ~5-10% only
• Definitive treatment: Egg Donation IVF (OD-IVF)
  • Donor oocytes fertilized with partner's sperm → embryo transfer into recipient
  • Success rates: 40-60% per transfer
• Hormone Replacement Therapy (HRT) for symptoms + bone protection
• Genetic counseling (Fragile X, Turner mosaic)

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WHO GROUP IV (Hyperprolactinemia)

Dopamine Agonists (First-Line)

• Side effects of bromocriptine: nausea, vomiting, postural hypotension, headache
• Begin bromocriptine with low dose 1.25 mg at night with food to minimize side effects
• Cabergoline: Safe at time of conception (review of >700 cases showed no increased malformation risk)
• If macroadenoma: MRI pituitary, neurosurgery consult
• If drug-resistant: Transsphenoidal surgery

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HYPOTHYROIDISM (Special Cause)

• Prevalence among reproductive-age women: 2-4% (Berek & Novak)
• Menstrual abnormalities (including anovulation) in 23-68% of overtly hypothyroid women
• Treatment: Levothyroxine → restores euthyroid state → resumes ovulation
• Screen all anovulatory patients with TSH

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SUMMARY FLOWCHART: Complete Management of Anovulatory Infertility

ANOVULATORY INFERTILITY (confirmed by history/progesterone/BBT)
                        |
               β-hCG → NEGATIVE
                        |
              TSH | Prolactin | FSH+LH+E2
                        |
         _______________|____________________________
        |               |              |             |
  TSH ↑           Prolactin ↑     FSH High       FSH Normal
  (Hypothyroid)   (Hyperprolactin) (WHO III)      (WHO I or II)
        |               |              |             |
  Levothyroxine  Dopamine agonist  Egg donation  FSH Low → WHO I
                 (Bromocriptine/   IVF-OD        FSH Normal → WHO II
                  Cabergoline)          |             |
                                  HRT for       WHO I:
                                  symptoms    Pulsatile GnRH
                                             or Gonadotropins
                                               WHO II (PCOS):
                                               ↓
                                          Step 1: Weight loss
                                               ↓
                                          Step 2: Letrozole (1st line)
                                               or Clomiphene
                                               ↓
                                          Step 3: Metformin
                                          (add if insulin resistant)
                                               ↓
                                          Step 4: Gonadotropins
                                          (Low-dose step-up)
                                               ↓
                                          Step 5: LOD
                                          (Laparoscopic Ovarian Drilling)
                                               ↓
                                          Step 6: IVF

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MONITORING OVULATION INDUCTION (Berek & Novak)

• Serial TVS follicle tracking from Day 10 onwards
• When dominant follicle ≥18-20 mm: hCG trigger shot given
• IUI or timed intercourse 36 hours after trigger
• Day 21 serum progesterone to confirm ovulation
• OHSS prevention: Cancel cycle if >3 large follicles; consider freeze-all; GnRH antagonist protocols

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KEY COMPLICATIONS TO MENTION

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EXAM SUMMARY TABLE

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MNEMONIC: "PCOS MANAGEMENT = LMGSI"

• L - Lifestyle (weight loss first)
• M - Metformin (insulin sensitization)
• G - Gonadotropins (if oral agents fail)
• S - Surgery (LOD - laparoscopic ovarian drilling)
• I - IVF (last resort)

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Asherman Syndrome (Intrauterine Synechiae)

Definition, Investigation & Management

M.S. Main Exam - 10 Mark Answer | Berek & Novak's Gynecology

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DEFINITION

• Partial or complete obliteration of the uterine cavity
• Presents with amenorrhea, hypomenorrhea, infertility, recurrent pregnancy loss
• Most common cause: uterine curettage following pregnancy complications
• Genital tuberculosis is a common cause in developing countries (including India)

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NORMAL ENDOMETRIUM vs ASHERMAN SYNDROME

NORMAL UTERUS                    ASHERMAN SYNDROME
                                         
  Free uterine cavity           Cavity bridged by adhesions
  ___________                   ___________
 |           |                 |___|   |___|
 |   Open    |       →         |adhesion|
 |  cavity   |                 |___|   |___|
 |___________|                  (partial/complete obliteration)
 
 Basalis intact               Basalis destroyed
 Menstruation normal          Amenorrhea / Hypomenorrhea
 Implantation possible        Implantation impossible

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CAUSES / ETIOLOGY

FLOWCHART 1: Causes of Asherman Syndrome

ASHERMAN SYNDROME - CAUSES
              |
    __________|__________________________________________
    |                    |                              |
COMMONEST            LESS COMMON                  RARE / SPECIAL
(Pregnancy-related)   (Non-obstetric)              (Infections)
    |                    |                              |
- D&C for incomplete  - Myomectomy                - Genital TB ← 
  abortion             - Hysteroscopic surgery       VERY COMMON
- D&C for missed       - Cesarean section           in India
  abortion             - Diagnostic curettage      - Schistosomiasis
- Evacuation for       - Cervical procedures       - Endometritis
  pregnancy            (cone biopsy, LEEP)         - IUD-related
  termination          - Uterine packing             infection
- Postpartum           - Caustic abortifacients    - Tuberculosis
  hemorrhage           - Hysterectomy               (basalis layer
  (curettage)            (subtotal)                  destroyed)

Berek & Novak Key Point: "The causes of intrauterine adhesions are often iatrogenic, with patients typically reporting intraoperative or postoperative complications of uterine evacuations for incomplete pregnancy loss, pregnancy termination, or postpartum hemorrhage. In developing countries, Asherman syndrome caused by genital tuberculosis is quite common."

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PATHOPHYSIOLOGY (Easy Explanation)

Trauma to basalis layer of endometrium
              ↓
Basalis cannot regenerate endometrium
              ↓
Raw surfaces of anterior + posterior uterine walls
come in contact and stick together
              ↓
Fibrous adhesion formation (synechiae)
              ↓
         Partial or complete cavity obliteration
              |
    __________|_________
    |                   |
PARTIAL              COMPLETE
Hypomenorrhea        Amenorrhea
Dysmenorrhea         Infertility
RPL                  Pelvic pain
                     Hematometra (if cervix blocked)

The basalis layer (deep layer of endometrium) does NOT shed during menstruation. It is the regenerative layer. When it is damaged, the endometrium CANNOT grow back properly, and scar tissue fills in instead.

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CLASSIFICATION / GRADING OF ASHERMAN SYNDROME

American Fertility Society (AFS) / European Society (ESGE) Classification:

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CLINICAL FEATURES / SYMPTOMS

SYMPTOMS OF ASHERMAN SYNDROME
              |
    __________|_____________________________________________
    |              |              |             |          |
Menstrual      Fertility      Pain        Pregnancy    TB-related
problems       problems       symptoms    complications  (extra)
    |              |              |             |
Amenorrhea    Infertility    Dysmenorrhea  Recurrent
Hypomenorrhea                             miscarriage
(most common)  Implantation  Hematometra   Placenta
               failure       (cyclic pain  accreta/
                             + no flow)    previa
                                           Preterm delivery

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INVESTIGATIONS

FLOWCHART 2: Investigation Algorithm

SUSPECTED ASHERMAN SYNDROME
(Amenorrhea / Hypomenorrhea after uterine procedure)
              |
         β-hCG (rule out pregnancy)
              |
     ─────────────────────────────
     |                           |
Progestogen challenge          TVS (Transvaginal Ultrasound)
(Medroxyprogesterone 10mg      |
 x 10 days)                    |
     |                   Normal/thin         Adhesions seen?
NO withdrawal bleed      endometrium         (echogenic bands)
= Suggests Asherman      = Suggests           ↓
  OR hypo-estrogenic     endometrial         HSG or SIS
  state                  failure             ↓
     |                              Filling defects = adhesions
     |
Estrogen + Progestogen
(conjugated estrogen 1.25mg
 x 21 days + progestogen last
 10 days)
     |
Still no bleed
= Confirms Asherman Syndrome
(uterine cause)
     ↓
HYSTEROSCOPY (Gold Standard)

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INVESTIGATIONS IN DETAIL

1. Progestogen Challenge Test (Functional Test)

• Medroxyprogesterone acetate 10 mg/day x 10 days
• No withdrawal bleed → either no estrogen OR no functioning endometrium
• Then give estrogen + progestogen - still no bleed = confirms uterine cause (Asherman)

2. Hysteroscopy - GOLD STANDARD (Berek & Novak)

• Direct visualization of the uterine cavity
• Shows adhesions as pale, avascular fibrous bands crossing the cavity
• Can be diagnostic AND therapeutic (operative hysteroscopy)
• Scheduled in early follicular phase (Day 6-10)
• Office hysteroscopy: sensitivity 72% for cavity abnormalities vs operative hysteroscopy

3. Hysterosalpingography (HSG)

• X-ray dye study - shows filling defects or irregular cavity outline
• Advantages: Also assesses tubal patency
• Limitations: 50% sensitivity vs hysteroscopy; false positives from air bubbles/mucus; radiation + contrast
• Shows "Swiss cheese" or "honeycomb" pattern of adhesions

4. Transvaginal Ultrasound (TVS)

• 2D TVS: 0% PPV for intrauterine adhesions (Berek & Novak - TVS alone is unreliable for adhesions)
• May show thin/irregular endometrium, hematometra
• Not adequate as sole investigation

5. Saline Infusion Sonography (SIS) / Sonohysterography

• Instil saline into cavity during TVS → distends cavity → adhesions appear as densely echogenic and cystic areas
• Better tolerated than HSG
• Can assess uterine contour + adnexa simultaneously
• 3D SIS: excellent for congenital anomalies

6. MRI Pelvis

• For complex cases, fibroids, adenomyosis
• Best soft tissue detail

7. Endometrial Biopsy

• If TB suspected: biopsy + AFB culture + PCR for MTB
• Histology: fibrosis, absence of functioning glands

8. Additional (if TB suspected)

• ESR, Montoux test, CXR
• Endometrial TB culture (gold standard for genital TB)
• PCR MTB on endometrial tissue

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INVESTIGATION TABLE SUMMARY

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MANAGEMENT

FLOWCHART 3: Complete Management Algorithm

CONFIRMED ASHERMAN SYNDROME
              |
    __________|___________
    |                     |
PATIENT WANTS         PATIENT DOES NOT
FERTILITY              WANT FERTILITY
    |                     |
    |              Hormone therapy (cyclic)
    |              to protect endometrium
    ↓
HYSTEROSCOPIC ADHESIOLYSIS
(Treatment of Choice)
              |
    __________|__________________
    |              |             |
Filmy adhesions  Mixed        Dense/severe
(scissors)       (scissors +  (resectoscope
                  cautery)    scissors/energy)
              |
  ─────────────────────────────────
  |                               |
POSTOPERATIVE               SECOND-LOOK
PREVENTION OF                HYSTEROSCOPY
ADHESION REFORMATION         (6-8 weeks later)
  |                               |
Intrauterine                 Confirm lysis
barrier device               complete
  +                          Re-lyse if needed
Estrogen therapy

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STEP 1: HYSTEROSCOPIC ADHESIOLYSIS (Definitive Treatment)

• Performed under direct visualization
• Scissors preferred over electrocautery/laser (less thermal damage to remaining endometrium)
• Aim: Restore normal uterine cavity shape and volume
• Distension media: Saline (normal/mild) or glycine (operative with monopolar energy)
• Direction: Lyse central adhesions first, then peripheral
• Abdominal ultrasound guidance: Reduces risk of perforation in severe cases
• Laparoscopic guidance: For severe obliteration to avoid perforation

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STEP 2: PREVENTION OF ADHESION REFORMATION

A. Intrauterine Barrier Devices

B. Estrogen Therapy (Endometrial Regeneration)

• Medroxyprogesterone acetate 10 mg/day × 10-14 days

C. Second-Look Hysteroscopy

• Performed 6-8 weeks after initial adhesiolysis
• Assesses cavity restoration
• Any residual adhesions re-lysed
• May be repeated (2-3 sessions for severe cases)

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STEP 3: OUTCOMES AND PROGNOSIS

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SPECIAL SITUATIONS

Genital Tuberculosis (Important for India)

• Most common cause of Asherman syndrome in developing countries
• Mycobacterium tuberculosis destroys the basalis layer completely
• Dense, fibrous, avascular adhesions form - cannot regenerate
• Treatment: Anti-TB therapy first (6-9 months DOTS) → then adhesiolysis
• Prognosis: Very poor even after complete adhesiolysis
• Surrogate pregnancy (gestational surrogacy) may be the only option

Cervical Stenosis (Post-Asherman)

• Adhesions at cervical canal level
• Presents as: Amenorrhea + cyclic pelvic pain + hematometra
• Management: Cervical dilation ± hysteroscopic lysis

Hematometra

• Blood trapped above complete cervical/uterine stenosis
• TVS: Distended uterus with echogenic fluid
• Emergency dilation of cervix + drainage

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COMPLETE MANAGEMENT SUMMARY FLOWCHART

AMENORRHEA / HYPOMENORRHEA AFTER UTERINE PROCEDURE
                        |
                β-hCG (rule out pregnancy)
                        ↓
             Progestogen challenge → No withdrawal bleed
                        ↓
    Estrogen + Progestogen challenge → Still no bleed
                        ↓
                   TVS / SIS / HSG
                   (Suspect Asherman)
                        ↓
              DIAGNOSTIC HYSTEROSCOPY
              (Gold standard - confirms)
                        ↓
              HYSTEROSCOPIC ADHESIOLYSIS
              (Scissors / Resectoscope)
              (US-guided if severe)
                        ↓
         INTRAUTERINE BARRIER (Foley/IUD/Hyaluronate)
                     +
         ESTROGEN THERAPY (2.5 mg conjugated E x 1 month)
                     +
         PROGESTIN LAST 10-14 DAYS
                        ↓
              SECOND-LOOK HYSTEROSCOPY
                     (6-8 weeks)
                        ↓
                    REPEAT if needed
                        ↓
          FERTILITY OUTCOME ASSESSMENT
              |               |
     Pregnancy achieved   No pregnancy
                              |
                         IVF / Surrogacy
                         (TB cases)

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COMPLICATIONS OF ASHERMAN SYNDROME

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COMPLICATIONS OF SURGICAL TREATMENT (Hysteroscopy)

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KEY EXAM POINTS (M.S. Format)

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MNEMONIC: "ASHERMAN = ADSC PE"

• A - Amenorrhea / hypomenorrhea (symptom)
• S - Synechiae (fibrous adhesions)
• H - Hysteroscopy (gold standard investigation + treatment)
• E - Estrogen (post-op to regenerate endometrium)
• R - RPL (recurrent pregnancy loss)
• M - Myomectomy / D&C (common causes)
• A - Anti-adhesion device (Foley catheter/IUD postoperatively)
• N - No fertility in TB cases (poor prognosis)

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Unexplained Infertility - Definition, Investigation & Management

M.S. Final Exam | Based on Berek & Novak's Gynecology

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DEFINITION

• Normal semen parameters (male factor excluded)
• Evidence of ovulation (ovulatory factor excluded)
• Patent fallopian tubes (tubal factor excluded)
• No other obvious cause identified

• Accounts for ~30% of all infertile couples
• Even without treatment, 20% will conceive in the next 12 months and >50% within 36 months
• "It is likely that technology is limited in terms of diagnosing all causes for infertility" - Berek & Novak

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WHY "UNEXPLAINED"? - The Concept

INFERTILITY EVALUATION
         |
    Standard Tests
(Semen Analysis + Ovulation + Tubes + Uterus)
         |
    ALL NORMAL
         |
 Does NOT mean "no cause"
         |
    Means "current technology CANNOT detect the cause"
         |
 = UNEXPLAINED INFERTILITY
   (Diagnosis of EXCLUSION)

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PART 1: CRITERIA FOR DIAGNOSIS

What Must Be Normal Before Calling It "Unexplained"?

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PART 2: PROPOSED MECHANISMS (Why Does It Happen?)

FLOWCHART 1: Proposed Mechanisms of Unexplained Infertility

UNEXPLAINED INFERTILITY
         |
    _____|_______________________________________________
    |          |          |         |         |        |
Luteinized  Immunologic  Occult   Sperm    Endometriosis  Genetic/
Unruptured  Factors     Tubal    DNA      (occult/        Epigenetic
Follicle               Factors  damage   minimal)        Factors
Syndrome                        
(LUF)

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1. Luteinized Unruptured Follicle (LUF) Syndrome

• Follicle luteinizes (makes progesterone) but never ruptures to release the egg
• Normal LH surge, normal progesterone on Day 21 → all tests NORMAL
• But egg is never released → infertility
• Thought to occur in up to 25% of unexplained infertility patients - more than twice the rate in fertile women
• Diagnosis: Only confirmed by serial TVS (follicle grows but never collapses)
• Treatment implication: IVF (bypasses the need for follicle rupture - egg directly aspirated)

2. Immunological Factors

• Antisperm antibodies - may agglutinate/immobilize sperm in female reproductive tract
• TH1/TH2 imbalance - Progesterone shifts immune system toward TH2 (anti-inflammatory) to support implantation. If this shift fails → immune rejection of embryo
• Antiphospholipid antibodies - more prevalent in unexplained infertility than fertile women; however, NOT found to adversely affect IVF outcomes → routine screening NOT recommended
• Uterine Natural Killer cells (UNK) - account for >70% of leukocytes in secretory endometrium
  • Express Killer Immunoglobulin Receptors (KIR) - interact with trophoblast HLA-C antigens
  • High-risk KIR A/homozygous C2 combination → 51% increased risk of pregnancy loss even with euploid embryos

3. Occult Tubal Dysfunction

• Tubes appear patent on HSG but have subtle functional abnormalities
• Impaired ciliary motility, damaged endosalpinx
• Cannot be detected on standard testing

4. Sperm DNA Fragmentation

• Normal semen analysis does NOT assess sperm DNA integrity
• High DNA fragmentation → fertilization failure, poor embryo quality, miscarriage
• TUNEL assay is the best correlating test (Berek & Novak)
• May explain cases of unexplained infertility + repeated IVF failure

5. Occult/Minimal Endometriosis

• Peritoneal endometriosis not visible on TVS or MRI
• Only detectable at diagnostic laparoscopy
• Creates a toxic peritoneal environment hostile to oocytes/sperm/embryos
• Berek & Novak: "For young couples with unexplained infertility, especially those with a desire to have more than one child, diagnostic laparoscopy may be a good option for the evaluation and possible treatment of endometriosis"

6. Epigenetic/Genetic Factors

• Sperm epigenetic changes (histone modifications, DNA methylation abnormalities)
• Oocyte quality defects not detectable by standard tests
• Embryo genetic defects at implantation stage

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PART 3: PROGNOSIS - Natural Conception Chances

Key message for exam: In young couples with good prognostic factors, unexplained infertility "may merely reflect the lower extreme of normal fertility" - Berek & Novak.

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PART 4: MANAGEMENT

FLOWCHART 2: Management Algorithm for Unexplained Infertility

UNEXPLAINED INFERTILITY CONFIRMED
            |
     Age assessment + Duration
            |
    ________|_______________________________________
    |                                              |
Age <35, Duration <2 yrs               Age ≥35 OR Duration >2 yrs
Good prognostic factors                Poor prognostic factors
    |                                              |
Expectant management                     Proceed to treatment
(6-12 months)                                     |
    |                                    __________|___________
No pregnancy?                            |                    |
    |                              Age 35-40             Age >40 / Poor
    ↓                                   |                 ovarian reserve
  Treatment                        IVF (preferred)            |
                                   IUI/SOH considered      IVF directly
                                   (lower efficacy)

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TREATMENT OPTIONS (Stepwise Approach - Traditional vs Current Evidence)

Traditional Approach (Now Questioned)

Step 1: Expectant management
Step 2: Clomiphene + IUI (CC/IUI)
Step 3: Gonadotropins + IUI (FSH/IUI)
Step 4: IVF

Evidence-Based Approach (Berek & Novak - Current Recommendation)

Step 1: Expectant management (young, good prognosis)
Step 2: IVF directly (preferred over IUI/SOH)
Step 3: ICSI or split IVF/ICSI (if IVF fails or risk of failed fertilization)
Optional: Diagnostic laparoscopy (young couple, desire >1 child)

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OPTION 1: EXPECTANT MANAGEMENT

• Indications: Age <35, infertility duration <2 years, good prognostic factors
• Counseling: 20% spontaneous pregnancy in 12 months; >50% in 36 months
• No active treatment initially
• Lifestyle advice: Weight optimization, smoking cessation, alcohol reduction, folic acid
• Duration: 6-12 months observation
• If no pregnancy after watchful waiting → proceed to active treatment

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OPTION 2: SUPEROVULATION WITH IUI (SOH/IUI)

What is Superovulation?

SUPEROVULATION PROTOCOL (Unexplained Infertility)
Day 2: Baseline TVS + E2 + Progesterone
Day 3: Start CC 100 mg x 5 days
  OR   Start FSH 150-300 IU/day (gonadotropins)
Day 10-14: TVS monitoring
2-3 dominant follicles ≥17-18 mm → hCG trigger
36 hours later → IUI (washed sperm)
Cancel if >4 follicles (OHSS + multiple pregnancy risk)
Day 21: Serum progesterone

Evidence for SOH/IUI in Unexplained Infertility:

FASTT Trial (Key RCT - Must Know for Exam):

• Randomized women age 21-39 with unexplained infertility
• CC/IUI vs FSH/IUI vs IVF
• IVF was superior in ongoing pregnancy rates, shorter time-to-pregnancy
• CC/IUI and FSH/IUI were inferior compared to IVF

Guzick et al. meta-analysis: Per-cycle pregnancy rates: gonadotropins/IUI 9%, superovulation alone 4%, IUI alone 5%

Berek & Novak conclusion: "CC/IUI or FSH/IUI is NOT the treatment of choice for unexplained infertility"

Why is SOH/IUI Still Used?

• Less expensive than IVF per cycle
• More accessible in developing countries
• Still used as an intermediate step in many settings despite inferior efficacy

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OPTION 3: IVF - PREFERRED TREATMENT

1. Bypasses tubal environment (occult tubal dysfunction overcome)
2. Bypasses follicle rupture (LUF syndrome overcome)
3. Allows direct sperm-egg interaction monitoring (occult fertilization failure detected)
4. Allows embryo selection (poor embryo quality identified)
5. Allows PGT-A (detect aneuploidy)
6. 30.7% ongoing pregnancy rate per cycle vs ~9% for FSH/IUI

IVF Protocol Options for Unexplained Infertility:

(Berek & Novak: "IVF and ICSI have comparable pregnancy or live birth rates in patients with unexplained infertility" - so ICSI is not routinely required but may be used to prevent total fertilization failure)

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OPTION 4: DIAGNOSTIC LAPAROSCOPY

• Young couple (female age <35)
• Desire for more than one child (want natural conception)
• Suspicion of endometriosis (dysmenorrhea, dyspareunia, raised CA-125)
• Before committing to IVF

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OPTION 5: ADDITIONAL INVESTIGATIONS (Advanced Testing)

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COMPLETE MANAGEMENT FLOWCHART

UNEXPLAINED INFERTILITY
(All standard tests normal: semen, ovulation, tubes, uterus, hormones)
                    |
             Age + Duration assessment
                    |
    ________________|_____________________________
    |                                            |
AGE <35, Duration <2 yrs                  AGE ≥35 OR >2 yrs
Good prognosis                            Diminished ovarian reserve?
    |                                            |
EXPECTANT MANAGEMENT                        ACTIVE TREATMENT
(6-12 months)                                    |
    |                                      ______|___________
    ↓ No pregnancy                         |                |
    |                                  Age 35-40        Age >40
CONSIDER:                                  |                |
1. Diagnostic laparoscopy            IVF preferred    IVF directly
   (if young, wants natural          (FASTT evidence)  (no delay)
    conception, symptoms of                |
    endometriosis)                   SOH/IUI: acceptable if
                                     cost/access issues
2. Sperm DNA fragmentation
   testing
                                     
3. IVF (first-line if active              ↓
   treatment decided)               IVF CYCLE
                                     (Conventional / Split / ICSI)
                                          ↓
                                    Failed fertilization?
                                     → ICSI next cycle
                                          ↓
                                    Recurrent IVF failure?
                                     → ERA (endometrial receptivity)
                                     → PGT-A
                                     → NK cell/KIR testing
                                     → Donor eggs (if poor reserve)

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PREGNANCY RATES COMPARISON TABLE

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SUMMARY TABLE: Key Points for Exam

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MNEMONIC: "UNEXPLAINED = LUFT KE"

• L - Luteinized Unruptured Follicle (most common occult mechanism)
• U - Uterine NK cells (immune implantation failure)
• F - Fertilization failure (occult)
• T - Tubal dysfunction (occult, functional)
• K - KIR/HLA-C mismatch
• E - Endometriosis (minimal/peritoneal, occult)
• (+) Sperm DNA damage

• Expectant (young, good prognosis)
• IVF (first-line active treatment - FASTT trial)
• Laparoscopy (young, desire natural conception, suspect endometriosis)

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