IVF stimulation protocols, explained simply

When the clinic sends the ‘protocol’, many patients receive a table of dates, doses and drug names without any explanation. Understanding the logic helps to avoid mistakes and to ask the right questions if anything changes along the way.

The two objectives of any stimulation

1. To stimulate: injections of FSH (sometimes combined with LH) cause several follicles to grow instead of just one.
2. To prevent premature ovulation: without blocking, the brain would trigger ovulation as soon as the follicles are large enough, before the egg retrieval.

The protocols differ mainly in how the second objective is achieved.

The antagonist protocol: the current standard

Stimulation begins on the 2nd or 3rd day of the period. Around the 5th or 6th day, or when the follicles reach approximately 13–14 mm, a GnRH antagonist (cetrorelix, ganirelix) is added, which immediately blocks ovulation. Treatment generally lasts 9 to 12 days until the trigger.

Its advantages: shorter duration, fewer injections, and, above all, a significantly lower risk of hyperstimulation, particularly as it allows an agonist trigger. ESHRE recommends it as the first-line protocol for most patients, with birth rates comparable to those of the long protocol.

The long agonist protocol

The process begins by ‘resting’ the ovaries with a GnRH agonist (such as triptorelin), started during the luteal phase of the previous cycle, for around two weeks. Stimulation then begins. The whole process lasts three to four weeks.

It is still used in certain situations, for example in cases of endometriosis or to better schedule the date of egg retrieval. It takes longer and involves more injections.

The short (flare-up) protocol

The agonist is started at the same time as stimulation, to take advantage of its initial stimulating effect. It has been used in poor responders, although no superiority has been demonstrated; it is now less common.

Progestogen-primed stimulation (PPOS)

Instead of an injectable antagonist, ovulation is suppressed using an oral progestogen (such as dydrogesterone or medroxyprogesterone). This is cheaper and simpler, but as the progestogen renders the endometrium unsuitable for implantation, all embryos are frozen and transferred at a later date. This strategy is common in egg donation (for the donor) and in egg freezing.

Mild stimulation and the natural cycle

Lower doses, sometimes combined with letrozole or clomiphene citrate, or even no stimulation at all. Fewer eggs are obtained, but with less medication and at a lower cost. Useful for some poor responders or in cases where there are contraindications to hormone treatment. See poor response.

The trigger

When the follicles are ready, an injection triggers final maturation:

• hCG (e.g. Ovitrelle): the standard method, allowing for a fresh transfer.
• GnRH agonist (only with the antagonist protocol): significantly reduces the risk of hyperstimulation; often followed by the freezing of all embryos.
• Dual trigger: both used together, in certain situations.

The egg retrieval takes place 34 to 36 hours later; see the egg retrieval procedure.

Practical instructions

• Inject at a fixed time, with no more than one to two hours’ variation from one day to the next.
• Store the pens in the fridge as per the instructions (some can be kept at room temperature once opened).
• Make a note of each dose. If you miss a dose or make a mistake, call the clinic rather than trying to ‘catch up’ on your own.
• Monitoring scans (every two to three days) can be carried out at home and then in Greece; the clinic will adjust the doses based on the results.

For information on medicines and their prices in Greece, see this article.

Frequently asked questions