Role of Dehydroepiandrosterone Supplementation in Improving Intracytoplasmic Sperm Injection Outcome for Women with Expected Poor Ovarian Response

Background: As regard to adjuvant supplementations, nowadays dehydroepiandrosterone (DHEA) is widely used all over the world and is considered to be a potential agent to ameliorate the assisted reproduction technologies outcomes of infertile women with poor ovarian reserve. Objective: To find out the role of DHEA supplementation in improving intracytoplasmic sperm injection (ICSI) outcome for infertile women with expected poor ovarian response in controlled ovarian stimulation. Setting: Assisted reproduction unit of Obstetrics and Gynecology Department, Faculty of Medicine, Valley University, Egypt. Duration: From April 2016 to May 2018. Study Design: A randomized double-blinded controlled trial. Methods: One hundred and forty infertile women with expected poor ovarian response prepared for ICSI procedure were included in this study. Patients were divided into two groups; group I (DHEA group) included 70 patients received 25 mg DHEA 12 weeks prior to ICSI cycle and group II (placebo group) included 70 patients received a placebo. Results: There was a highly statistically significant difference in basal AFC at start of ICSI cycle in group I (who received DHEA supplementation for 12 weeks prior to ICSI procedure) than in group II (13.8 ± 5.3 versus 10.7 ± 4.6 respectively) with P < 0.001. There were mildly statistically with expected poor ovarian response in ICSI procedure. So DHEA supplementations could be an important adjuvant for infertile women with expected poor ovarian response in ICSI procedure.


Introduction
Assisted reproductive technology (ART) represented mainly in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) is considered the corner stone in solving infertility problem especially with global increase in obesity which has a negative impact on fertility and ovarian reserve [1]. Dehydroepiandrosterone (DHEA) is a multifunctional prohormone secreted from adrenal gland and acts as a precursor for both estradiol and testosterone synthesis [2] also has been reported to increase pregnancy and live birth rates especially in poor responders [3]. Besides dehydroepiandrosterone (DHEA) has been sought to improve fertilization rates and increase quality embryos [4] [5] [6] [7].
Dehydroepiandrosterone (DHEA) is considered one of the most common two adjuvant therapies in IVF and ICSI but due to lack of sufficient randomized controlled trials (RCTs) in this topic, the actual beneficial effects of adjuvant therapies especially dehydroepiandrosterone are debated and so far unclear [8]. Dehydroepiandrosterone was considered an active agent in improvement of IVF outcomes particularly in poor responders [9] [10]. High concentration of dehy dehydroepiandrosterone in the follicular fluid was associated with good ovarian response as regard to increase in the number of mature oocytes, besides it was associated with increase in (fertilization, implantation and live birth) rates [11].
Many studies reported that, the improving effect of dehydroepiandrosterone on IVF and ICSI outcomes could be explained as DHEA enhanced mitochondrial function and decreased the apoptosis of cumulus cells (CCs) [12] [13]. Ovarian reserve tests were classified into biochemical basal tests and provocative tests and ultrasound scanning of the ovaries on day 2 or 3 of menstrual cycle. Day-3 follicle-stimulating hormone (FSH) was the first test that was introduced in 1988, then clomiphene citrate challenge test (CCCT) in 1989, gonadotrophin releasing-hormone (GnRH) agonist in 1989, inhibin B in 1997, antral follicular count (AFC) in 1997, and finally antimüllerian hormone (AMH) in 2002. Most of these tests have poor predictive values, often for their indirect way for ovarian reserve assessment (e.g. FSH, CCCT and GnRH agonist) also they have sometimes intracycle or intercycle variability (e.g. FSH) [14] [15]. The most reliable

Aim of Work
The aim of this study was to find out the role of dehydroepiandrosterone (DHEA) supplementation in improving ICSI outcome for infertile women with expected poor ovarian response.

Methodology
This study was conducted on 140 infertile women undergoing ICSI procedure with expected poor ovarian response (POR) according to presence of Bologna criteria, from ESHRE (European Society of Human Reproduction and Embryology) [1]. Infertile women had been defined as poor responders when they had at least two of the following three criteria; 1) women with advanced age (

Statistical Analysis
Analysis and statistical presentation of this study were conducted, using the mean, standard error, unpaired student t-test, linear correlation coefficient, Paired t-test and chi-square tests by using the Statistical Program for Social Sciences (SPSS Inc., Version 21.0, Chicago, IL, USA). A two sided P < 0.05 was considered to be a mildly statistically significant, p < 0.01 was considered to be moderately significant and p < 0.001 was considered highly significant.

Results
2 cases (2.8%) in group I and 5 cases (7.1%) in group II had cancelled ICSI cycle due to failure of follicular recruitment.
There were no statistically significant differences between group I and group II as regard to patient's basal characteristics with p value > 0.05 (Table 1). There A. E.-N. Abd El-Gaber Ali, M. M. Khodry Open Journal of Obstetrics and Gynecology was a highly statistically significant difference in basal AFC at start of ICSI cycle in group I than in group II (13.8 ± 5.3 versus 10.7 ± 4.6 respectively) with P < 0.001 (Table 2). There were mildly statistically significant differences between group I and group II as regard to increase in the number and quality of retrieved oocytes, increased in endometrial thickness, fertilization rate and embryo quality with p value < 0.05 (Table 3, Figure 1 & Figure 2) but there was no statistically significant difference between the 2 groups as regard to the duration of stimulation (days), the dose of gonadotrophins (IU) and in the pregnancy (chemical and clinical) rates with p value > 0.05 (Table 3 and Figure 3).

Discussion
Androgens have been proved in promotion the recruitment and in initiation the growth of primordial follicles and in the significant increase in number of primordial, pre-antral and antral follicles by up-regulation of IGF-1 [17]. Also androgens have a role in up-regulation of FSH receptor expression inside granulosa cells that could potentiate the FSH action [18] and to play a role in paracrine regulation in final maturation of the follicles and also minimize follicular atresia [19].
Dehydroepiandrosterone (DHEA) also has a role in decline incidence of aneuploidy in embryos that can be explained by induction of good quality oocytes [20]. Many studies has reported the benefits of DHEA in poor responders, but In 2000, Casson et al. [3] was the first who reported that DHEA could be used as adjuvant supplementation in poor responders may lead to an enhance- and Placebo group in our study as regard to age, BMI, duration, AMH and basal AFC with p value > 0.05 (Table 1). The AFC had a highly statistically significant increase in DHEA group after 12 weeks of DHEA supplementation (Table 2).
Also this study reported that the number and quality of oocytes in DHEA group was increased with mildly statistically significant differences with (p value = 0.05) ( Table 3 & Figure 1). However there was no significant difference in gonadotrophin doses (IU) or in the duration of stimulation (Table 3).
In other hand this study had showed that embryos quality in DHEA group had a mildly significant difference in relation to placebo group with p value < 0.05 (Figure 2) but as regard to pregnancy rates, were slightly high (both chemical and clinical) in DHEA group but still had no statistically significant difference with p value > 0.05 ( Figure 3) and this can be explained the effect of DHEA supplementation 12 weeks prior to ICSI cycles increased oocytes number and qualities so enhanced fertilization rates and increased the percentages of good quality embryos in group I that enhanced embryo implantation so it had contributed in slight increase in pregnancy rates.
Many studies in literature had been discussed the beneficial effect of DHEA administration prior to ICSI or IVF cycles in poor responders and reported wonderful results as DHEA was very effective as supplementation for enhancement basal follicular count, oocyte number and quality, and may had a positive effect on embryo quality with or without increase in pregnancy rates, from these studies, Kuan-Hao et al. [21] study showed that antral follicle count was significantly increased, from 2.8 ± 1.0 before DHEA supplementation to 4.1 ± 1.2, and an increase in numbers of retrieved oocytes (from 2.4 ± 1.1 before DHEA supplementation to 4.2 ± 1.2; p < 0.01), also increased fertilized ova (1.7 ± 0.5 increased to 3.8 ± 1.1; p < 0.001), Day 3 embryos increased (from 1.7 ± 0.5 before supplementation to 3.7 ± 1.1; p < 0.001) and transferred embryos had increased (from 1.7 ± 0.8 before treatment to 2.8 ± 0.8; p < 0.01)]. Also Hyman et al. [22] reported a significant increase in AFC (5.3 ± 2.8 with DHEA versus 3.6 ± 1.5 in placebos; p < 0.001). The results of this study showed an improvement in basal AFC, oocyte number, quality, fertilization rate and embryo quality that may encourage assisted reproductive centers to use DHEA in infertile patients with expected poor ovarian response to improve the results and success rate of ICSI and IVF cycles so save time and decrease cost of repeated cycles. As regard to the optimal period of DHEA supplementation prior to ICSI or IVF cycles, different protocols has been reported in literature as 2, 3 or 4 months prior to ART cycles, Barad et al. [20] reported DHEA administration for more than months prior to ICSI which had increased cumulative pregnancy success rate, Gleicher et al. [20] reported more than 2 months of DHEA administration had a significant reduction in rate of miscarriage and Gleicher et al. [4] reported 1 -3 months of DHEA supplementation had a significant reduction in embryos with aneuploidy, finally Open Journal of Obstetrics and Gynecology Fusi et al. [24] used DHEA more than 3 months in infertile women and had an increase in spontaneous pregnancy rate.
Limitation of this study was related to the small sample size (because many patients refused to be involved in the study) and applied only for ICSI procedure so further studies including large samples size in all varieties of assisted reproduction technology as IVF and IUI should be done to verify the exact benefits of DHEA supplementation in infertile women with expected poor ovarian.

Conclusion & Recommendation
Dehydroepiandrosterone (DHEA) supplementations improved basal AFC, increased the number & quality of oocytes and increased quality of embryos in infertile patients with expected poor ovarian response in ICSI procedure. So this study suggested DHEA supplementations as an effective adjuvant for infertile women with expected poor ovarian response in next ICSI procedure.