What is pulsatile Gonadotropin-Releasing Hormone (GnRH) therapy for inducing ovulation?

What is Pulsatile GnRH Therapy for Ovulation Induction?

Pulsatile GnRH therapy is a physiologic method of inducing ovulation that mimics the natural pulsatile release of gonadotropin-releasing hormone from the hypothalamus, delivered via a portable pump either subcutaneously or intravenously, and is particularly effective for women with functional hypothalamic amenorrhea (FHA) who have insufficient endogenous GnRH release. 1, 2

How It Works

Pulsatile GnRH therapy restores the natural hormonal cascade by delivering small pulses of synthetic GnRH at regular intervals (typically every 60-90 minutes), which stimulates the pituitary gland to release FSH and LH in a physiologic pattern. 3, 4 This contrasts with traditional ovulation induction using exogenous gonadotropins (FSH/LH injections), which bypass the hypothalamic-pituitary axis entirely and deliver hormones directly to the ovaries. 3

The therapy requires a portable pump that delivers precise doses of GnRH through either:

• Subcutaneous route: 15 micrograms per pulse every 90 minutes (preferred for most patients due to safety and patient acceptability) 4
• Intravenous route: 75 nanograms per kilogram per pulse (reserved for patients who don't respond to subcutaneous therapy, as IV produces higher amplitude GnRH peaks) 3, 5

Why It's Superior for Functional Hypothalamic Amenorrhea

For women with FHA, pulsatile GnRH therapy is more effective than exogenous gonadotropins and should be the preferred treatment approach. 6, 2 The evidence supporting this is compelling:

• Ovulation rates of 77-81% are achieved in women with FHA, with ongoing pregnancy rates of 63-70% per patient 1
• The therapy works by "waking up" the dormant hypothalamic-pituitary-ovarian axis rather than bypassing it 1
• It carries a much lower risk of multiple pregnancy and ovarian hyperstimulation compared to gonadotropins 7, 8

Important Prerequisites Before Starting

Before initiating pulsatile GnRH therapy, women with FHA must achieve a BMI ≥18.5 kg/m² and address underlying energy deficits. 1, 9, 2 This is critical because:

• Energy deficit is the fundamental cause of FHA, and attempting ovulation induction without correcting this can compromise outcomes 1, 9
• The Endocrine Society guidelines emphasize that addressing energy balance through reduced excessive exercise, adequate nutrition, and stress management must come first 9, 2
• Once spontaneous menstrual cycles resume, couples should be allowed to conceive naturally before pursuing ovulation induction 1

Clinical Monitoring and Safety

One major advantage of pulsatile GnRH therapy is the simplified monitoring protocol that doesn't require intensive estradiol surveillance, unlike gonadotropin therapy. 3 Monitoring typically includes:

• Serial ultrasound scanning to track follicular development 4
• Serum gonadotropin and estradiol measurements 4
• Treatment is stopped after ovulation, with hCG given for luteal support 8

The risk of ovarian hyperstimulation is significantly lower than with gonadotropins, even in women with polycystic ovarian morphology (PCOM) features—approximately 10-12.5% at equivalent doses. 1

Special Considerations for FHA with PCOM Features

Women with FHA who also have polycystic ovarian morphology (FHA-PCOM) respond equally well to pulsatile GnRH therapy as those without PCOM. 1 Key points:

• Up to 43% of women with FHA may have PCOM features, which can complicate diagnosis 9
• Despite PCOM appearance, if there are clear signs of energy deficiency and estrogen deficiency (thin endometrium, LH:FSH ratio <1), the diagnosis remains FHA 9
• Pulsatile GnRH therapy achieves similar ovulation rates (77-81%) and pregnancy rates (63-70% per patient) regardless of PCOM presence 1
• A small percentage may develop hormonal profiles suggestive of PCOS during prolonged treatment, but this is uncommon 1

Why Not Clomiphene Citrate?

Clomiphene citrate is not recommended as first-line treatment for FHA because it requires sufficient endogenous estrogen levels to work effectively, which most women with FHA lack. 1, 6 The evidence shows:

• No randomized trials support clomiphene use in FHA 1
• Success rates remain uncertain even with prolonged use 1
• The Endocrine Society suggests it might be considered only after FHA recovery when estrogen levels are adequate, but even then the benefit is unclear 1

Practical Advantages Over Gonadotropins

Pulsatile GnRH therapy offers several practical benefits that make it particularly suitable for women experiencing stress-related infertility:

• Can be administered in an office setting by most physicians without specialized monitoring 3
• Gives patients increased sense of control over their treatment 7
• Avoids the need for daily injections of multiple gonadotropins 3, 7
• Significantly lower risk of high-order multiple pregnancies (twins occurred in only 2 of 20 pregnancies in one series, with no higher-order multiples) 8

When to Consider Alternative Approaches

If subcutaneous pulsatile GnRH doesn't produce a response, consider:

• Switching to intravenous administration (more effective due to higher amplitude peaks) 4, 5
• Adding clomiphene citrate to increase pituitary sensitivity to GnRH 4
• Increasing pulse frequency from 90 minutes to 60 minutes in select cases 8

However, women with elevated LH secretion during the follicular phase may not respond well to pulsatile GnRH and should be considered for alternative treatments. 4