Introduction
The birth of the first IVF baby resulted from the transfer of single embryo from a spontaneous ovulation cycle by Steptoe and Edwards in 1978. Soon after this ground breaking event, controlled ovarian hyperstimulation (COH) was introduced. The availability of a high number of oocytes facilitated the pregnancy rate of IVF treatment. However, after more than forty years of experience, there are still women who respond poorly to stimulation, resulting in only few oocytes at retrieval, a reduced number of embryos available for transfer and a poor pregnancy rate. The prevalence of poor ovarian responders among infertile women is reported to vary between 5.6% and 35.1% depending on differences in the definition of poor ovarian response but according to recent reviews, it seems to have slightly increased (6, 23). Though there might be numerous causes for the poor ovarian response. The European Society for Human Reproduction and Embryology (ESHRE) working group on poor ovarian response (POR) has finally given a common definition of “poor responder,” where at least two of the following three features must be present: (a) advanced maternal age or any other risk factor for POR; (b) a previous POR; and (c) an abnormal ovarian reserve test.
In the field of assisted reproductive technologies great steps forward have been made in recent years in terms of clinical knowledge and technological development especially in IVF laboratories. One of the fundamental steps to success is still related to the number of oocytes retrieved after hormonal stimulation. In fact, with lower number of retrieved oocytes, fewer embryos are there to be selected and transferred and thus lower pregnancy rates per transfer and lower cumulative pregnancy rates per started cycle. Ovarian follicles mature over a period of approximately 2–4 months. Ovarian stimulation in IVF cycles has traditionally been focused on the stimulation of antral follicles, which develop during the last 2 weeks of this maturation process, to increase the number of mature follicles for oocyte retrieval. However, successful ovarian stimulation with gonadotrophins is limited by the requirement of the presence of multiple antral follicles (1). The stimulation and synchronization of earlier follicles prior to traditional ovarian stimulation may thus further improve IVF outcomes, particularly for poor responders (21). The follicles require about 6–8 weeks after the initiation of androgen supplementation to achieve synchronization and become mature enough to respond to ovarian stimulation with gonadotrophins (14, 15, 16). Based on this, many patients could potentially benefit from androgen supplementation(DHEA) beginning weeks or months prior to starting their IVF cycle.
The beneficial effect of metformin on ovulation induction with clomiphene in clomiphene-resistant and obese women with polycystic ovary syndrome was originally reported in 1998 (22). Metformin is a drug that affects metabolism and induces ovulation by reducing the circulating concentration of insulin. Onset of metformin is slow and gradual. To clinically improve ovulation, it may require up to 6 months of treatment with metformin.
In present study, we aim to investigate the impact of adjuvant agents: DHEA and Metformin on the number of oocytes retrieved, pregnancy rates and live birth rates in the poor ovarian responders. The differences in the effect of adjuvant agents on IVF outcomes between the aged and the younger poor responders were compared. This study could be helpful in determining the influence of DHEA and metformin on controlled ovarian hyperstimulation.