FSH Dosing and Ovarian Response in ART: Basics and Optimization

Abstract

In IVF/ICSI, exogenous FSH is administered (ovarian hyperstimulation) in order to achieve multi-follicular growth. The degree of ovarian response to such hyperstimulation varies greatly amongst women and both a low and excessive response are considered suboptimal. For a great part, the ovarian response seems to be determined by the dynamic ovarian reserve, i.e. the number of FSH sensitive antral follicles present at a certain moment in time. This dynamic ovarian reserve status can be estimated by measuring circulating anti-Müllerian hormone (AMH) or counting antral follicles (AFC) by transvaginal ultrasound. If, based on one or more ovarian reserve test (ORT) results, a suboptimal ovarian response is expected, treatment may be adjusted with the objective to optimize response. The main focus point of treatment optimization has been on individualizing the FSH dose. Although a dose-response relationship has been suggested for doses up to 200 IU a day, other characteristics that might influence serum FSH levels during exogenous administration and ovarian response (e.g. body weight, biological availability, drug dose stability and pharmacokinetics) are most often not considered. Moreover, whether improvement of ovarian response also increases efficacy in terms of live birth rate has not been shown. Therefore, most of current clinical practice regarding ‘FSH dose individualizing’ is merely empirical and further elucidation is needed. We aimed to study whether ovarian response is related to serum FSH levels as expression of the bioavailability of exogenously administered FSH and to determine the significance of ovarian reserve testing and subsequent FSH dose individualization in terms of costs, efficacy and safety. This thesis shows that that we are capable of reliably measuring serum FSH levels during stimulation with exogenous FSH, that ovarian response can be predicted by ORTs in different endocrine states and that ORT-based individualized FSH dosing can fine-tune ovarian response to some extent and may improve safety. However, it seems that ovarian reserve is more important in determining ovarian response than serum FSH levels per se. In addition, other factors influencing serum FSH levels after stimulation on the one hand and ovarian response on the other have still to be identified. As the degree of contribution of these additional factors such as body weight, bioactivity and FSH receptor polymorphism is unknown and show great overlap between women, using them in FSH individualization seems too ambitious at present. Most importantly, the attempts made to optimize ovarian response with an individualized FSH dose still fail to improve live birth rates and cost-effectiveness. Therefore, we currently recommend a maximum standard daily dose of 150 IU for all women starting IVF/ICSI. In women predicted for a hyper response a lower FSH dose might improve safety without compromising live birth rates, but it also t increases the risk of cycle cancellation rates for poor response. Therefore, further studies in women with a predicted hyper response should compare other safety management strategies (type of GnRH analogue co-treatment, GnRH agonist triggering or freeze-all strategy) and should be powered on clinically relevant safety outcomes while assessing live birth rates from a non-inferiority perspective.