Adjuncts for ovarian stimulation may help in poor responders
Despite advances in the field of assisted reproductive technologies, the definition and management of poor ovarian response (POR) to gonadotrophin stimulation remains challenging. Speaking at the 7th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2017), held in Kuala Lumpur recently, an expert shared his thoughts on the use of adjuncts in the management of POR.
A better definition of POR needed
Poor ovarian response is defined as an unquantified, inadequate follicular response to standard in vitro fertilization (IVF) stimulation, said Dr. Roger Hart, professor of reproductive medicine at the School of Women’s and Infants Health, University of Western Australia. However, there is a lot of ambiguity in the definition. Elaborating on the difficulty in defining POR, Hart said the interpretation of ‘standard’ stimulation could differ among places of practice. Moreover, what should be used to measure the end point: follicles or eggs?
Currently, a clear cut definition of POR is lacking. Generally, the number of oocytes retrieved, total dose of follicle stimulating hormone (FSH) required prior to trans-vaginal oocyte aspiration (TVOA), number of follicles seen on ultrasound prior to TVOA and peak oestradiol levels are used to measure and define response to gonadotrophin stimulation.
Potential adjuncts for ovarian stimulation
There are different stimulation regimes such as egg donation, natural cycle IVF, long-acting follicle stimulating hormone (FSH), luteal commencement of FSH, antagonist cycle and long-down regulation, among others, explained Hart.
An adjunct may play a useful role in POR, suboptimal responders and patients with polycystic ovarian syndrome (PCOS), said Hart. Examples of adjuncts are luteinizing hormone (LH), selective oestrogen receptor modulators (SERMS), aromatase inhibitors, androgens, growth hormone, aspirin and antioxidants.
Adjunct androgens may have a role in POR with low live birth rate, said Hart. The rationale is that androgens can increase follicular insulin like growth factor (IGF)-1, leading to an up-regulation of FSH receptors preventing granulose cell apoptosis or increased antral follicle count. [Fertil Steril 2009;92(1):13–18. Doi: 10.1016/j.fertnstert.2009.03.081]
As for POR with low egg number, androgens or growth hormone may be useful, he continued. Growth hormones work in a similar way as androgens do. [Biomed Res Int 2014;2014:352098] According to a meta-analysis in which Hart was involved in, adjunct growth hormone decreased the duration of ovarian stimulation needed for oocyte retrieval, increased the number of oocytes collected compared to placebo, and improved several early clinical parameters. Nevertheless, it did not increase the chance of a live birth. [Curr Opin Obstet Gynecol 2017. Doi: 10.1097/GCO.0000000000000360]
Giving metformin as an adjunct for stimulation, before and during IVF or intra-cytoplasmic sperm injection, can reduce the risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS, said Hart. [Cochrane Database Syst Rev 2009;(2):CD006105. Doi:10.1002/14651858.CD006105.pub2] Metformin helps to regulate insulin levels, thus preventing hyperinsulinaemia and hyperandrogenism suppression of ovarian response. However, large randomized controlled trials are needed to discover if adjunct metformin will increase live birth and pregnancy rates.
Poor ovarian response to gonadotrophin stimulation can be tricky to manage in assisted conception. Future research aimed at improving understanding of the mechanism behind ovarian function and its regulation is necessary to formulate more effective management plans.