Douglas A. Gibson, Ph. D. , Ioannis Simitsidellis, Ph. D

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Dehydroepiandrosterone enhances decidualization in women of advanced reproductive age Douglas A. Gibson, Ph.D., Ioannis Simitsidellis, Ph.D., Olympia Kelepouri, M.Sc., Hilary O.D. Critchley, M.D., Philippa T.K. Saunders, Ph.D. Fertility and Sterility Volume 109, Issue 4, Pages 728-734.e2 (April 2018) DOI: 10.1016/j.fertnstert.2017.12.024 Copyright © 2018 The Authors Terms and Conditions

Figure 1 Dehydroepiandrosterone (DHEA) increases androgen synthesis during decidualization. Human endometrial stromal fibroblasts (HESFs) were treated with either vehicle control (VC), decidualization (DEC) media, or DEC media supplemented with 10 nM DHEA (DEC DHEA) (A, B) or DEC media supplemented with either 10 or 100 nM DHEA (C, D). (A, B) Secretion of both T and dihydrotestosterone (DHT) was detected in DEC groups at all time points and significantly increased in DEC DHEA (supplemented with 10 nM DHEA) compared with DEC alone. Neither T nor DHT was detected in hESFs treated with VC (not shown). (C, D) HESFs were decidualized for 4 days and supplemented with 10 nM or 100 nM DHEA. T and DHT were significantly increased in a dose-dependent manner with increasing DHEA concentrations. Dotted lines show circulating concentrations of T in women (Table 1). n = 6–16 patients, duplicate treatments. Two-way ANOVA (A, B) or Kruskal-Wallis test (C, D). ***P<.001; ****P<.0001. Fertility and Sterility 2018 109, 728-734.e2DOI: (10.1016/j.fertnstert.2017.12.024) Copyright © 2018 The Authors Terms and Conditions

Figure 2 Increased androgen production is driven by precursor availability and not changes in enzyme expression. (A) Concentrations of mRNAs encoding AKR1C3 were assessed by quantitative polymerase chain reaction at 1, 2, 4, and 8 days of treatment. Expression of AKR1C3 increased over time with decidualization (DEC) treatment but was not changed by coincubation with dehydroepiandrosterone (DHEA), although at day 1 DEC DHEA was increased compared with vehicle control (VC) (n = 6; P<.01). (B) Concentrations of AKR1C3 protein were assessed by Western blot in Human endometrial stromal fibroblast lysates after 4 days and were significantly increased with DEC (P<.01) and DEC DHEA (P<.05) treatment compared with controls but were not different between DEC and DEC DHEA. n = 4–5 patients, duplicate treatments. *P<.05; ** P<.01. AU = arbitrary units. Fertility and Sterility 2018 109, 728-734.e2DOI: (10.1016/j.fertnstert.2017.12.024) Copyright © 2018 The Authors Terms and Conditions

Figure 3 Dehydroepiandrosterone (DHEA) supplementation enhances expression of decidualization and endometrial receptivity markers. Human endometrial stromal fibroblasts were treated as in Figure 1A and 1B, and expression of IGFBP1, PRL, and SPP1 was assessed by quantitative polymerase chain reaction and ELISA. Concentrations of mRNAs encoding IGFBP1 (A), PRL (D), and SPP1 (G) were assessed by quantitative polymerase chain reaction; expression of all three markers increased over time with decidualization (DEC) treatment and were enhanced by DHEA treatment, which was apparent after 4 days and most pronounced by 8 days of treatment. Cotreatment with DHEA significantly increased secretion of IGFBP1 (B, C) and PRL (E, F) compared with DEC alone. Secretion of SPP1 protein (H and I) was significantly increased with DEC DHEA after 8 days of treatment. n = 6 patients, duplicate treatments. Two-way ANOVA (A, D, G), or one-sample t test (B, C, E, F, H, I). *P<.05; **P<.01; ***P<.001; ****P<.0001. Fertility and Sterility 2018 109, 728-734.e2DOI: (10.1016/j.fertnstert.2017.12.024) Copyright © 2018 The Authors Terms and Conditions

Supplemental Figure 1 Dose-dependent impact of dehydroepiandrosterone (DHEA) on expression of decidualization markers. To determine the impact of varying concentrations of DHEA on decidualization, immortalized human endometrial stromal cells (SHT290) were treated with either vehicle control (VC), decidualization (DEC) media, or DEC media supplemented with 0.1, 1, 10, or 100nM DHEA (DEC DHEA) for 4 days. Expression of mRNAs encoding IGFBP1 and PRL were determined by quantitative polymerase chain reaction. n = 3, triplicate treatments. One-way ANOVA with Tukey's multiple comparisons test (IGFBP1) or Kruskal-Wallis with Dunn's multiple comparison test (PRL). *P<.05; ***P<.001; ****P<.0001. Fertility and Sterility 2018 109, 728-734.e2DOI: (10.1016/j.fertnstert.2017.12.024) Copyright © 2018 The Authors Terms and Conditions

Supplemental Figure 2 DHEA supplementation enhances secretion of decidualization and endometrial receptivity markers. Primary hESF were treated with either vehicle control (VC), DEC media, or DHEA-supplemented DEC media (DEC DHEA) for up to 8 days. Concentrations of IGFBP1, PRL, and SPP1 were measured by ELISA. Median IGFBP1 and PRL concentrations plotted at each time point and treatment. SPP1 was measured by ELISA in day 4 and day 8 supernatants from hESF treated with DEC and DEC DHEA. n = 6 patients, duplicate treatments. Two-way ANOVA. *P<.05; **P<.01; ***P<.001; ****P<.0001. Fertility and Sterility 2018 109, 728-734.e2DOI: (10.1016/j.fertnstert.2017.12.024) Copyright © 2018 The Authors Terms and Conditions