The effect of dehydroepiandrosterone supplementation on ovarian response is associated with androgen receptor in diminished ovarian reserve women

Abstract

BackgroundDiminished ovarian reserve(DOR) is associated with female infertility and poor response to ovarian stimulation. Our objective was to assess the effect of dehydroepiandrosterone(DHEA) on DOR women and to explore whether the improvement of ovarian response after DHEA supplementation was dependent on the expression levels of androgen receptor(AR).MethodsA prospective cohort study was performed in the Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital during August 2014 to August 2016. 103 DOR women who completed the study were divided into the DHEA group (n = 53), which received DHEA supplementation (25 mg three times a day) for 8 weeks, and the control group (n = 50), which did not receive DHEA, before the IVF cycles. Serum hormone levels(FSH, LH, E2, T, DHEAs, AMH, INHB), antral follicle count(AFC) and the expression of AR and FSH receptor(FSHR) in granulosa cells(GCs) were measured, meanwhile ovarian response parameters and IVF outcomes were compared. The GCs from another 36 DOR women were cultured with different concentrations of DHEA in vitro. Then, we compared the expression of AR and FSHR in GCs according to the different numbers of oocytes retrieved both in DHEA and control group.ResultsIn the present study, DHEA supplementation resulted in significantly higher levels of serum T(P = 0.047), DHEAs(P = 0.019) and AR mRNA expression in GCs(P = 0.049). In vitro experiment, the protein and mRNA expression of AR and FSHR in the preovulatory GCs were significantly increased in response to DHEA supplementation(P <0.05). No significant differences were found in ovarian reserve, ovarian response, or IVF outcomes between the two groups. Subgroup analyses showed the levels of AR and FSHR mRNA in GCs were significantly increased in DHEA group with ≥5 oocytes retrieved(P <0.05).ConclusionDHEA supplementation can increase the expression of AR in preovulatory GCs both in vivo and in vitro. The selective beneficial effects of DHEA supplementation on ovarian response in DOR women may depend on the increasing expression of AR and FSHR in GCs.Trial registrationThe Chinese Clinical Trial Registry (ChiCTR-IPR-15006126). Retrospectively Registered 19 March 2015.

Androgens and ovarian function: translation from basic discovery research to clinical impact

“…However, animal studies have clearly shown that androgens increase FSH receptor expression, and synergize with FSH to stimulate follicle growth and follicle responsiveness to FSH (Weil et al 1999, Wang et al 2001, Sen et al 2014. In support of this synergistic interaction, DHEA supplementation was reported to significantly increase protein and mRNA FSH receptor expression in preovulatory granulosa cells collected from POR patients (Hu et al 2017). Another potential mechanism by which androgen pre-treatment may mediate a beneficial effect is by maintaining follicle health.…”

“…Studies have reported that DHEA administration has improved antral follicle numbers, oocyte retrieval numbers, fertilization rates, embryo implantation rates, embryo quality, clinical pregnancy rates and live birth rates in some women (observations from studies summarized in Table 2). However, there are also a noteworthy number of studies, including well-designed placebo-controlled randomized control trials (RCTs), which have reported no consistent improvement in any endpoints assessed after exposure of women to DHEA prior to ovarian stimulation (Artini et al 2012, Yeung et al 2014, Kara et al 2014, Vlahos et al 2015, Hu et al 2017, Narkwichean et al 2017, Li et al 2018.…”

DHEAS and Human Development: An Evolutionary Perspective

“…For instance in prostate-derived LNCaP tumor cells, DHEA acts at the androgen receptor (AR) and beta estrogen receptor beta (ER-beta) at similar affinities, but the effects at ERbeta appear to be more physiologically relevant (100). In contrast, DHEA does appear to have demonstrable effects on AR mRNA expression in ovarian granulosa cells (101). Thus, the actions of DHEAS are unlikely to be sufficiently characterized as that of a weak androgen alone, and it is important to consider the specific tissue and/or organ involved.…”

Fertility preservation in Hodgkin&rsquo;s lymphoma patients that undergo targeted molecular therapies: an important step forward from the chemotherapy era

“…23 – 28 The risk of infertility is higher after the age of 30, as the follicle reserve diminishes with age. 29 – 33 A large Norwegian study enrolled women diagnosed with and treated for HL, and reported that patients aged under 25 years had the same risk of infertility as the patients older than 30 years, but with delayed complications (15 vs 2 years). 34 …”