Androgen signaling in decidualizing human endometrial stromal cells enhances resistance to oxidative stress

Kajihara, Takeshi; Tochigi, Hideno; Prechapanich, Japarath; Uchino, Satomi; Itakura, Atsuo; Brosens, Jan J.; Ishihara, Osamu

doi:10.1016/j.fertnstert.2011.10.017

Cited by 39 publications

(29 citation statements)

References 45 publications

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“…This hypothesis is supported by evidence that transient androgen supplementation significantly increased the embryo implantation rate and clinical pregnancy rate in poor responders [9]. However, embryo implantation defects coinciding with aberrant expression of avb3 integrin, glycodelin, estrogen receptor a, and HOXA10 have also been observed in polycystic ovarian syndrome patients with chronic hyperandrogenism [17,18]. These paradoxical phenomena reveal that endometrial development and embryonic implantation may require appropriate androgen levels, but the relationship will require further investigation.…”

Section: Discussionmentioning

confidence: 95%

“…AR controls genes essential for cytoskeletal organization and cell cycle regulation and cooperates with the progesterone receptor (PR) to promote endometrial stromal fibroblast differentiation into secretory epithelioid-like decidual cells [16]. Androgen also enhances the process of decidual transformation and inhibits apoptosis of decidual endometrial fibroblasts by promoting resistance to oxidative stress [17]. Moreover, androgen increases AR expression in normal endometria and then amplifies the effects of AR expression [16].…”

Section: Discussionmentioning

confidence: 99%

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Low testosterone levels in women with diminished ovarian reserve impair embryo implantation rate: a retrospective case-control study

Lü

Shen

Yang

et al. 2014

J Assist Reprod Genet

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Objective To investigate the association of basal testosterone (T) levels with the outcome of in vitro fertilization (IVF) in women with diminished ovarian reserve (DOR). Methods Complete clinical data on the first 223 IVF cycles in women with DOR were retrospectively analyzed. The associations of basal follicle stimulating hormone, luteinizing hormone, estradiol, and T levels with ovarian response and IVF outcome were studied. Results Basal T levels were significantly different between pregnant and non-pregnant women. However, basal T levels showed no correlation with controlled ovarian hyperstimulation parameters after adjusting for age. The association of basal T levels with pregnancy rate was significant after adjusting for other impact factors. Using receiver operating characteristic (ROC) analysis, the basal T level of 1.115 nmol/ L for predicting pregnancy outcome had a sensitivity of 82.80 % and specificity of 58.09 %. The women were divided into two groups based on this value; although the clinical characteristics and ovarian stimulation parameters were similar, the clinical pregnancy (16.18 % (11/68) vs. 40.15 % (53/ 132), respectively, p=0.000) and implantation rates (10.07 % (15/149) vs. 22.41 % (65/290), respectively, p=0.002) were significantly different in the low and high T level groups. Conclusion In women with DOR, the basal T level presented a positive association with pregnancy outcome in IVF. The poor reproductive outcome observed in women with lower basal T levels may be due to the decreased implantation rate.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Low testosterone levels in women with diminished ovarian reserve impair embryo implantation rate: a retrospective case-control study

Lü

Shen

Yang

et al. 2014

J Assist Reprod Genet

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“…AR-dependent signalling is reported to regulate the F-actin polymerisation and stress fibre formation, necessary for the acquisition of the motile phenotype of decidual cells (Cloke et al 2008). Furthermore, DHT is reported to increase resistance to oxidative stress in a dose-dependent manner during in vitro decidualisation of ESCs through regulation of superoxide dismutase 2 (SOD2) expression, which was associated with decreased hydrogen peroxidestimulated apoptosis (Kajihara et al 2012). Regulation of mitochondrial SOD2 expression may in part be controlled by forkhead box protein O1 (FOXO1), an upstream transcription factor reported to be upregulated in ESCs decidualised in the presence of DHT (Kajihara et al 2012).…”

Section: Decidualisationmentioning

confidence: 99%

“…Furthermore, DHT is reported to increase resistance to oxidative stress in a dose-dependent manner during in vitro decidualisation of ESCs through regulation of superoxide dismutase 2 (SOD2) expression, which was associated with decreased hydrogen peroxidestimulated apoptosis (Kajihara et al 2012). Regulation of mitochondrial SOD2 expression may in part be controlled by forkhead box protein O1 (FOXO1), an upstream transcription factor reported to be upregulated in ESCs decidualised in the presence of DHT (Kajihara et al 2012). In the decidualised endometrium, cells form gap junctions for the exchange of small molecules, and disruption of gap junction formation severely impacts on decidualisation and pregnancy outcomes (Laws et al 2008, Yu et al 2011).…”

Section: Decidualisationmentioning

confidence: 99%

Regulation of androgen action during establishment of pregnancy

Gibson¹,

Simitsidellis²,

Saunders³

2016

Journal of Molecular Endocrinology

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During the establishment of pregnancy, the ovarian-derived hormones progesterone and oestradiol regulate remodelling of the endometrium to promote an environment that is able to support and maintain a successful pregnancy. Decidualisation is characterised by differentiation of endometrial stromal cells that secrete growth factors and cytokines that regulate vascular remodelling and immune cell influx. This differentiation process is critical for reproduction, and inadequate decidualisation is implicated in the aetiology of pregnancy disorders such as foetal growth restriction and preeclampsia. In contrast to progesterone and oestradiol, the role of androgens in regulating endometrial function is poorly understood. Androgen receptors are expressed in the endometrium, and androgens are reported to regulate both the transcriptome and the secretome of endometrial stromal cells. In androgen-target tissues, circulating precursors are activated to mediate local effects, and recent studies report that steroid concentrations detected in endometrial tissue are distinct to those detected in the peripheral circulation. New evidence suggests that decidualisation results in dynamic changes in the expression of androgen biosynthetic enzymes, highlighting a role for pre-receptor regulation of androgen action during the establishment of pregnancy. These results suggest that such enzymes could be future therapeutic targets for the treatment of infertility associated with endometrial dysfunction. In conclusion, these data support the hypothesis that androgens play a beneficial role in regulating the establishment and maintenance of pregnancy. Future studies should be focussed on investigating the safety and efficacy of androgen supplementation with the potential for utilisation of novel therapeutics, such as selective androgen receptor modulators, to improve reproductive outcomes in women.

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“…It can also explain differences observed in this group of women in phenotypes of hyperplasia, cancer, and poor reproductive outcomes. In an in vitro experiment, Kajihara et al [21] investigated the effect of androgens on the expression of genes involved in oxidative stress resistance in decidualized human endometrial stromal cells. These cells, isolated from hysterectomy specimens were decidualized with 8-bromo cyclic adenosine monophosphate (8-br-cAMP) and progesterone in the presence or absence of dihydrotestosterone at various concentrations.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Menstrual preconditioning for the prevention of major obstetrical syndromes in polycystic ovary syndrome

Brosens

Benagiano

2015

American Journal of Obstetrics and Gynecology

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The presence of multiple ovarian cysts, anovulation, and endometrial progesterone resistance in the neonate seems remarkably similar to ovarian and endometrial features of the polycystic ovary syndrome (PCOS) of adolescent and adult women. In fact, in the absence of cyclic menstruations after menarche, the neonatal progesterone resistance is likely to persist and adversely affect young women with PCOS at the time of pregnancy after induction of ovulation, because any persisting defect in progesterone response can interfere with the process of decidualization and trophoblast invasion. The primigravid woman with PCOS therefore is likely to be at risk of defective deep placentation as manifested by the increased risk of major obstetric syndromes. A recent, large epidemiologic study has demonstrated that the risk of preeclampsia and preterm delivery is elevated in the 13- to 15-year old group, although it does not persist in the 16- to 17-year old group. It is proposed therefore that induction of ovulation in the infertile nulligravid woman with PCOS should be preceded by a period of progesterone withdrawal bleedings to achieve full endometrial progesterone response by the time of pregnancy. The cyclic administration of clomiphene citrate for a period to be determined by vascular response may be an appropriate tool to reduce the risk of major obstetric syndromes by menstrual preconditioning.

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Androgen signaling in decidualizing human endometrial stromal cells enhances resistance to oxidative stress

Cited by 39 publications

References 45 publications

Low testosterone levels in women with diminished ovarian reserve impair embryo implantation rate: a retrospective case-control study

Low testosterone levels in women with diminished ovarian reserve impair embryo implantation rate: a retrospective case-control study

Regulation of androgen action during establishment of pregnancy

Menstrual preconditioning for the prevention of major obstetrical syndromes in polycystic ovary syndrome

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