Poor response to ovarian stimulation is one of the major challenges assisted reproduction specialists must deal with.
There are no established criteria for defining a poor response. In fact, it was not until 2010 that the European Society of Human Reproduction and Embryology reached a consensus on its definition. It was determined that in order to confirm a poor response, at least 2 of the following criteria must be met:
- Age ≥ 40 years or any other risk factor for poor response (presence of endometriosis, absence of one ovary, etc.).
- A previous cycle with ≤ 3 oocytes retrieved using a standard stimulation protocol.
- Abnormal ovarian reserve test results (antral follicle count less than 5-7, Anti-Müllerian Hormone less than 0.5 – 1.1 ng/ml).
Normally, poor response to stimulation is the result of diminished ovarian reserve, which is in turn due to a lower number of follicles able to be stimulated using ovarian stimulation medication.
Recently, other factors which may be involved in poor response have been studied, such as a hypoandrogenic state (low levels of androgens) or a decrease/malfunction of follicle-stimulating hormone receptors (the hormone which stimulates follicle growth).
In regards to treatment for poor ovarian response, there are no widely accepted recommendations. Increasing the dose of gonadotropins (medication used for ovarian stimulation) has not shown, above certain levels, to improve the number of oocytes obtained.
One way of increasing ovarian androgens is to administer a medication we call aromatase inhibitors; these inhibitors prevent androgens from converting into oestrogens, in turn increasing the level of androgens. Nonetheless, recent studies have not proven this inhibitor to be effective in terms of live birth rates.
The other way to boost androgen levels in the ovaries is to use medications with LH activity during ovarian stimulation. This LH activity may improve a poor response, though there is currently not enough evidence to show that the use of this type of medication improves pregnancy rates in patients with poor ovarian response in cycles of IVF (In Vitro Fertilisation).
The use of transdermal testosterone (gel or transdermal patches) also increases androgen levels, as it is introduced externally. The results are encouraging, but further studies showing greater scientific evidence are necessary.
The use of GH (growth hormone) seems to increase live birth rates, as it improves the body’s response to the medication used during ovarian stimulation. However, the results are not completely significant due to the limited number of studies available, limited number of study participants and their sparse clinical diversity, creating the need for new studies. Moreover, growth hormone is costly and is not indicated for use in IVF in Spain, meaning it should not be recommended for use in everyday clinical practice.
Finally, there are patients who have receptors for FSH (follicle-stimulating hormone). These patients show better response to a certain type of gonadotropin owing to its composition. In these cases, administering this other type of gonadotropin could improve the ovarian response to stimulation.
As we have seen, poor response to ovarian stimulation presents us with a challenge given its multiple causes and lack of solutions. These factors should stimulate us to continue researching the mechanisms responsible for poor response, and to discover effective therapies for our patients.
José Martín Vallejo
Gynaecologist at Ginemed Valencia Assisted Reproduction Unit