What is the recommended protocol for low-dose gonadotropin (Gn) therapy in patients with Polycystic Ovary Syndrome (PCOS) and hyperandrogenism?

Low-Dose Gonadotropin Therapy Protocol for PCOS with Hyperandrogenism

Low-dose gonadotropin therapy in PCOS with hyperandrogenism should be reserved for women seeking pregnancy who have failed clomiphene citrate, using a stepwise protocol starting at 75 IU FSH daily for 14 days with incremental increases of 37.5 IU every 7 days, not exceeding 300 IU daily or 35 days of treatment. 1, 2, 3

When to Use Low-Dose Gonadotropin Therapy

This is NOT first-line therapy. The treatment hierarchy for PCOS women seeking pregnancy is critical 1:

• Step 1: Weight loss (even 5% reduction) and exercise program 1
• Step 2: Clomiphene citrate (achieves 80% ovulation rate, 50% conception rate) 1
• Step 3: Low-dose gonadotropins only after clomiphene failure 1

The hyperandrogenism component does not change this algorithm—it simply confirms the PCOS diagnosis 1, 4.

The Specific Low-Dose Protocol

Initial Dosing (First Cycle)

Start with 75 IU FSH subcutaneously daily for 14 days 2, 3, 5:

• Administer subcutaneously in abdomen, upper arm, or upper leg 2
• Do NOT start with doses less than 37.5 IU (unstudied and not recommended) 3
• Continue this starting dose for the full 14 days before any adjustment 2, 3

Dose Adjustments

If ovarian response is inadequate after 14 days, increase by 37.5 IU increments every 7 days 1, 2, 3:

• Maximum daily dose: 300 IU 2, 3
• Maximum treatment duration: 35 days 2, 3
• Never increase more frequently than every 7 days 2, 3
• Never increase by more than 37.5 IU per adjustment 2, 3

Subsequent Cycles

Base the starting dose on the previous cycle's response 2, 3:

• Women who responded well to 75 IU: restart at 75 IU 2
• Women who required higher doses: may start at that effective dose 2
• Still respect the 300 IU maximum daily dose 2, 3

Monitoring Requirements

Ultrasound and Hormonal Monitoring

Monitor follicular development with ultrasound AND serum estradiol levels 2, 3:

• Continue treatment until adequate follicular response (follicular growth and/or estradiol rise) 2, 3
• The goal is monofollicular development (one mature follicle) 1
• Two to three follicles is acceptable 6, 5

Critical Safety Thresholds

Withhold hCG and cancel the cycle if estradiol exceeds 2,000 pg/mL on the last day of gonadotropin therapy 1:

• This indicates excessive ovarian response and OHSS risk 1
• Discourage intercourse when OHSS risk is elevated 2, 3
• PCOS women are inherently at higher risk for OHSS 2, 3

Triggering Ovulation

When pre-ovulatory conditions are met, administer hCG 5,000-10,000 USP units one day after the last gonadotropin dose 1, 2, 3:

• Encourage daily intercourse starting the day before hCG administration until ovulation is apparent 2, 3
• Schedule luteal phase follow-up 2

Why Low-Dose Over Conventional Protocols

Low-dose gonadotropin therapy induces high rates of monofollicular development with significantly lower OHSS risk compared to conventional high-dose protocols 1:

• OHSS occurred in only 1/23 cycles with low-dose FSH versus 13/23 cycles with conventional GnRH agonist/HMG protocols in hyper-responsive PCOS women 6
• Pregnancy rates were actually superior with low-dose FSH (6 pregnancies) versus conventional protocols (1 pregnancy) in the same study 6
• Unifollicular response achieved in 53% of cycles, with 2-3 follicles in 30% of cycles 5

FSH Preparation Selection

Either urinary FSH or recombinant FSH can be used, though recombinant FSH may offer advantages 7, 8:

• Recombinant FSH showed superior pregnancy rates in some studies (though not all) 7
• Urinary FSH has a demonstrated lower OHSS risk compared to hMG preparations (which contain LH) when used without GnRH agonists 8
• The evidence comparing preparations remains limited, but both are acceptable 8

Special Considerations for Hyperandrogenism

The hyperandrogenism in PCOS does not alter the gonadotropin protocol itself, but requires baseline management 1:

• Androgen levels paradoxically increase during gonadotropin stimulation despite rising FSH and falling LH 6
• This does not compromise treatment efficacy 6
• For women NOT seeking pregnancy, manage hyperandrogenism with oral contraceptives or antiandrogens first 1

Critical Pitfalls to Avoid

Do not use conventional high-dose protocols in PCOS women 1:

• PCOS women are exquisitely sensitive to gonadotropins 2, 3
• Starting doses higher than 75 IU or rapid dose escalation dramatically increases OHSS and multiple pregnancy risk 1

Do not skip clomiphene citrate as first-line therapy 1:

• Gonadotropins are more expensive, require intensive monitoring, and carry higher complication rates 2, 3
• Reserve gonadotropins strictly for clomiphene-resistant cases 1

Do not administer hCG if estradiol exceeds 2,000 pg/mL or if more than 3 mature follicles develop 1, 2, 3:

• This is the most critical safety measure to prevent severe OHSS 1
• Cycle cancellation is preferable to life-threatening complications 2, 3

Obese PCOS women require longer stimulation and higher total gonadotropin doses but achieve similar pregnancy rates 5:

• Do not abandon treatment prematurely in obese patients 5
• Weight loss remains the optimal first intervention 1