Ovarian Stimulation – IVF Protocols
During the first phase of the IVF cycle, medication for ovarian stimulation and oocyte production is administered to the patient.
A sufficient number of good quality oocytes are required, so as to maximise IVF success rates. Ideally, 8 – 15 oocytes should be collected at oocyte retrieval.
There are several protocols of medicine – induced ovarian stimulation, aiming at the production of sufficient oocytes. Without any medication, ovaries produce one mature oocyte each month.
All IVF protocols include FSH (follicle stimulating hormone) injections; FSH is responsible for oocyte maturation.
In general, 3 types of medicines are used in ovarian stimulation protocols:
1. A medicine to suppress the production of luteinizing hormone (LH), which is responsible for ovulation when the oocyte is mature. This is necessary in order to prevent premature ovulation and oocyte loss. 2 types of medicines are used :
o GnRH – agonists (gonadotropin releasing hormone, which regulates the FSH and LH production), such as Arvekap (triptorelin) and Daronda (leuprorelin).
o GnRH – antagonists, such as Cetrotide (cetrorelix) and Orgalutran (genirelix).
2. A medicine that contains FSH (or a combination of FSH/LH), to stimulate multiple oocyte maturation: Altermon, Gonal-F, Menopur, Merional, Puregon.
3. A medicine that contains chorionic gonadotropin (human chorionic gonadotropin, HCG – Pregnyl or r-HCG – Ovitrelle), which triggers the final oocyte maturation. Please read here more about the role of hormones and medication.
In most cases, FSH – induced stimulation takes 8-14 days, depending on the protocol, until oocytes produced are mature.
Although the target of stimulation is to collect sufficient oocytes (8 – 15) at oocyte retrieval, stimulation must be performed with great attention, so as to avoid ovarian hyperstimulation, which causes unpleasant symptoms to patients (bloating, pain, nausea, vomiting). In rare cases, symptoms are particularly intense and possibly dangerous for the patient; then, Ovarian Hyperstimulation Syndrome (OHSS) is diagnosed.
Thus, medication dosage must be sufficient – but not excessive –, so as to yield sufficient oocytes. In case lower dosage than required is administered, fewer oocytes are produced and IVF success rates are reduced.
During the stimulation phase, the role of the reproduction gynaecologist is:
• To select the appropriate stimulation protocol, as well as the right dosage,
• To monitor the stimulation course and make all necessary adjustments in dosage,
• To trigger the final oocyte maturation by administering chorionic gonadotropin at the right moment. Administering chorionic gonadotropin too early or too late may reduce success rates or increase the risk of hyperstimulation.
Picture: Ultrasonogram depicting multiple follicles (dark areas) in an ovary under stimulation. The measured follicular diameter reaches 15 mm. Most follicles of that size (15-20 mm) will yield mature oocytes at oocyte retrieval.
Ovarian stimulation is monitored in 2 ways: by performing an ovarian ultrasonogram every 2-4 days and by monitoring hormone levels via blood tests. More specifically:
• With stimulation, we aim at producing at least 4 follicles, with a diameter of 15-24mm. Ideally, for IVF, we need at least 8 follicles with a diameter of 13-20mm. Our target is to retrieve approximately 8-15 good quality oocytes.
• Estrogen levels are very important. Namely, estradiol (E2) levels are below 60 pg/ml before stimulation and rise significantly along with follicular maturation: before the administration of chorionic gonadotropin, estradiol levels usually fluctuate between 1000 and 4000 pg/ml or 3.600-12.000 pmol/l.
Picture: graph showing estradiol levels during the ovarian stimulation phase. Initially, levels are very low and reach 1000 - 4000 pg/ml before chorionic gonadotropin is administered for the final follicular maturation.
• The chorionic gonadotropin injection is administered when estradiol levels and follicular size are ideal. Chorionic gonadotropin is necessary for the final oocyte maturation.
• Oocyte retrieval is scheduled to be performed 34 hours after the administration of chorionic gonadotropin.
How many oocytes are required in order to achieve pregnancy with the aid of IVF?
Usually, it isn’t difficult to stimulate multiple oocyte maturation. However, sometimes ovaries respond poorly and finally produce few oocytes. The ovaries potential to produce several oocytes during the stimulation phase can be predicted quite accurately during an ultrasonogram, when immature follicles are counted.
The minimum number of oocytes required for an IVF cycle depends on many factors, such as the follicular size, the woman’s age, the results of previous stimulations, as well as the couple’s and doctor’s intention to proceed with oocyte retrieval, even if a small number of oocytes is collected.
Some reproduction gynaecologists may claim that at least 5 follicles with a minimum diameter of 14mm are required, while others may proceed with the retrieval of even one oocyte. Based on our experience, success rates are quite reduced with less than 3 (almost) mature oocytes. However, if ovaries seem unable to produce more oocytes in a future cycle, we proceed with the retrieval of even one oocyte.
Patients predicted to respond poorly to ovarian stimulation are those with few, immature follicles, women over 37, those who have high FSH levels and generally, those who have symptoms of low ovarian reserve.