A. Patient Selection and Baseline Assessment

• Indications: Anovulation or oligo-ovulation (e.g. PCOS, hypothalamic dysfunction, pituitary dysfunction).
• Exclude contraindications to pregnancy.
• Identify medical disorders and treat it before induction
• Baseline tests (Day 2–5 of cycle):
o FSH, LH, Estradiol, TSH, Prolactin
o Pelvic ultrasound (antral follicle count, ovarian morphology)
o Semen analysis of partner
o Tubal patency assessment (e.g. HSG/SIS/Laparoscopy) at baseline assessment if some risk factors present. Following are the risk factors
i) Age 35 years or more
ii) Infertility for >3 years
iii) History of pelvic surgery (Salpingectomy, Myomectomy, C/S)
iv) H/O tuberculosis, Chlamydial infection
v) H/O MR, Abortion and childbirth
Otherwise, Tubal Patency Test can be done after 6 ovulatory cycles in anovulatory patients (RCOG, Adam Balen,UK)

HSG/SIS — If there is no risk factor
Laparoscopy — If there is presence of risk factor/s

B. Stepwise Ovulation Induction Protocol for PCOS

Diagnosis: Any two of three features. Oligomenorrhoea, Signs of hyperandrogenism and, Polycystic morphology on USG

First-line: Oral Agents

1. Letrozole (Preferred)
   • Start Letrozole 2.5–5 mg daily from Day 2–6 or Day 3–7 for 5 days.
   • Monitor follicular growth by TVS On D12 and afterwards if needed.
   • If no ovulation → increase dose next cycle (up to 10 mg).
   • If no Ovulation add adjuvant Metformin (1500-2500mg daily according to BMI) and Myoinositol 2 gm daily for 3 months.
   • After 3 months continue metformin and start stimulation with previous dose.
   • If no ovulation add 2nd line therapy
2. Clomiphene Citrate (Alternative)
   • 50 mg daily from Day 2–6 for 5 days.
   • TVS monitoring from Day 12 onwards.
   • If no ovulation → increase by 50 mg increments per cycle (max 150 mg daily FDA approved).
   • If no Ovulation add adjuvant Metformin (1500-2500mg daily according to BMI) and Myoinositol 2 gm daily for 3 months.
   • After 3 months continue metformin and start stimulation with previous dose.
   • If no ovulation add 2nd line therapy

2nd line drug (Injectable)
• If no ovulation, add gonadotropin 75 mg on D3 and D8 along with highest dose of Letrozole/CC and metformin.

Third line (Surgery)
If no ovulation – LOD by following the rule of 4.
• Spontaneous ovulation may or may not occur
• If no ovulation again oral drug Letrozole/CC and low dose Gonadotropin 75 unit on D3 and D8.
If no ovulation, refer the patient to tertiary centre specialist.

Purpose of monitoring

• To see the number and size of the follicle. To avoid both under and hyperstimulation.
• 1-3 mature (17×17 mm) follicles are optimum.
• To assess endometrial development. A triple line of ≥8mm is optimum
• To assess quality of egg (not always)
o Oestradiol on the day of maturity (200-300pg/mL per mature follicle.
o Progesterone on D21, ≥10 ng/mL indicates ovulation with good follicle

Special notes:

1. Do not start induction without semen analysis report
2. Cycles must be monitored until and unless mature follicle develops
3. If mature follicle develops ovulation triggering is not needed except IUI.
4. If someone wants to trigger; it should not be done blindly. Must be done after observing mature follicles at least average size of 18-20 mm of two diameters. 5000 IU is enough.
5. Luteal support is not needed if follicle development is optimum. If someone wants to give should be given after ovulation or 40 hours after triggering. Tab dydrogesterone oral 10 mg twice daily or Micronized progesterone vaginal capsule 200 mg daily.

Summary

• First-line: Letrozole (preferred)
• Alternative: Clomiphene citrate
• Second-line: Gonadotropins
• Third-line: LOD surgery
• Adjuvants: Metformin + Myoinositol
• Referral: Tertiary centre if resistant to all therapies

FLOW CHART OF STIMULATION

1. LETROZOLE (Preferred)

• 2.5–5 mg daily (Day 2–6 or 3–7)
• TVS monitoring on Day 12 onwards
│
├── Ovulation achieved → Timed intercourse/IUI
│
└── No ovulation → Increase dose (max 10 mg)
│
▼
➤ Add adjuvant therapy:

• Metformin 1500–2500 mg/day (BMI-based)
• Myoinositol 2 g/day × 3 months
  │
  After 3 months → Continue Metformin + restart Letrozole at previous dose
  │
  ├── Ovulation achieved → Timed intercourse/IUI
  └── No ovulation → Proceed to 2nd-line
  │
  ▼

2. CLOMIPHENE CITRATE (Alternative)

• 50 mg daily (Day 2–6) × 5 days
• TVS monitoring from Day 12 onwards
│
├── Ovulation achieved → Timed intercourse/IUI
└── No ovulation → Increase by 50 mg/cycle (max 150 mg/day)
│
▼
➤ Add adjuvant therapy:

• Metformin 1500–2500 mg/day
• Myoinositol 2 g/day × 3 months
  │
  After 3 months → Continue Metformin + restart CC at previous dose
  │
  ├── Ovulation achieved → Timed intercourse/IUI
  └── No ovulation → Proceed to 2nd-line
  │
  ▼

2nd LINE: GONADOTROPIN THERAPY

• Add FSH 75 IU on Day 3 and Day 8
• Combine with highest Letrozole/CC dose + Metformin
│
├── Ovulation achieved → Timed intercourse/IUI
└── No ovulation → Proceed to 3rd-line
│
▼

3rd LINE: LOD (Laparoscopic Ovarian Drilling)

• Perform following “Rule of 4”
(≤4 punctures, 4 sec, 40 W, 4 mm depth)
│
├── Spontaneous ovulation → Observe
└── No ovulation → Retry Letrozole/CC + low-dose FSH (75 IU D3, D8)
│
▼
If still anovulatory → REFER to tertiary specialist centre

C. Ovulation induction protocol for HYPO-HYPO

Diagnosis only by hormone test. FSH, LH, E2 all are low
• NO ORAL DRUG
• Only Gonadotropin HMG
• Start with 75 IU daily and start monitoring from D10
• Better to refer to tertiary centre.

Compiled By

Prof. Rashida Begum

Contributors

1. Prof Dr Fawzia Hossain
2. Prof Rowshon Ara
3. Dr Amrita Saha
4. Dr Amena Fardous
5. Dr Ananna Zakia
6. Dr Sabiha Islam
7. Dr Tasrina Akhter
8. Dr Jinat Fatema
9. Dr Farzana Akter