ORCID Profile
0000-0002-9949-1983
Current Organisation
The University of Edinburgh
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Publisher: The Endocrine Society
Date: 05-2016
DOI: 10.1210/EN.2015-2032
Abstract: The endometrium consists of stromal and epithelial compartments (luminal and glandular) with distinct functions in the regulation of uterine homeostasis. Ovarian sex steroids, namely 17β-estradiol and progesterone, play essential roles in modulating uterine cell proliferation, stromal-epithelial cross-talk and differentiation in preparation for pregnancy. The effect of androgens on uterine function remains poorly understood. The current study investigated the effect of the non-aromatizable androgen dihydrotestosterone (DHT) on mouse endometrial function. Ovx female mice were given a single sc injection (short treatment) or 7 daily injections (long treatment) of vehicle alone (5% ethanol, 0.4% methylcellulose) or vehicle with the addition of 0.2 mg DHT (n=8/group) and a single injection of bromodeoxyuridine 2 hours prior to tissue recovery. Treatment with DHT increased uterine weight, the area of the endometrial compartment and immunoexpression of the androgen receptor in the luminal and glandular epithelium. Treatment-dependent proliferation of epithelial cells was identified by immunostaining for MKi67 and bromodeoxyuridine. Real-time PCR identified significant DHT-dependent changes in the concentrations of mRNAs encoded by genes implicated in the regulation of the cell cycle (Wee1, Ccnd1, Rb1) and stromal-epithelial interactions (Wnt4, Wnt5a, Wnt7a, Cdh1, Vcl, Igf1, Prl8, Prlr) as well as a striking effect on the number of endometrial glands. This study has revealed a novel role for androgens in regulating uterine function with an effect on the glandular compartment of the endometrium. This previously unrecognized role for androgens has implications for our understanding of the role of androgens in regulation of endometrial function and fertility in women.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2016
DOI: 10.1038/SREP19970
Abstract: The endometrium is a complex, steroid-dependent tissue that undergoes dynamic cyclical remodelling. Transformation of stromal fibroblasts (ESC) into specialised secretory cells (decidualization) is fundamental to the establishment of a receptive endometrial microenvironment which can support and maintain pregnancy. Androgen receptors (AR) are present in ESC in other tissues local metabolism of ovarian and adrenal-derived androgens regulate AR-dependent gene expression. We hypothesised that altered expression/activity of androgen biosynthetic enzymes would regulate tissue availability of bioactive androgens and the process of decidualization. Primary human ESC were treated in vitro for 1–8 days with progesterone and cAMP (decidualized) in the presence or absence of the AR antagonist flutamide. Time and treatment-dependent changes in genes essential for a) intra-tissue biosynthesis of androgens (5α-reductase/SRD5A1, aldo-keto reductase family 1 member C3/AKR1C3), b) establishment of endometrial decidualization (IGFBP1, prolactin) and c) endometrial receptivity (SPP1, MAOA, EDNRB) were measured. Decidualization of ESC resulted in significant time-dependent changes in expression of AKR1C3 and SRD5A1 and secretion of T/DHT. Addition of flutamide significantly reduced secretion of IGFBP1 and prolactin and altered the expression of endometrial receptivity markers. Intracrine biosynthesis of endometrial androgens during decidualization may play a key role in endometrial receptivity and offer a novel target for fertility treatment.
Publisher: Cold Spring Harbor Laboratory
Date: 30-05-2022
DOI: 10.1101/2022.05.30.493728
Abstract: Decidualisation is the hormone-dependent process of endometrial remodelling that is essential for fertility and reproductive health. It is characterised by dynamic changes in the endometrial stromal compartment including differentiation of fibroblasts, immune cell trafficking and vascular remodelling. Deficits in decidualisation are implicated in disorders of pregnancy such as implantation failure, intra-uterine growth restriction, and pre-ecl sia. Androgens are key regulators of decidualisation that promote optimal differentiation of stromal fibroblasts and activation of downstream signalling pathways required for endometrial remodelling. We have shown that androgen biosynthesis, via 5α-reductase-dependent production of dihydrotestosterone, is required for optimal decidualisation of human stromal fibroblasts in vitro , but whether this is required for decidualisation in vivo has not been tested. In the current study we used steroid 5α-reductase type 1 (SRD5A1) deficient mice ( Srd5a1-/- mice) and a validated model of induced decidualisation to investigate the role of SRD5A1 and intracrine androgen signalling in endometrial decidualisation. We measured decidualisation response (weight roportion), transcriptomic changes, and morphological and functional parameters of vascular development. These investigations revealed a striking effect of 5α-reductase deficiency on the decidualisation response. Furthermore, vessel permeability and transcriptional regulation of angiogenesis signalling pathways, particularly those that involved vascular endothelial growth factor (VEGF), were disrupted in the absence of 5α-reductase. In Srd5a1-/- mice, injection of dihydrotestosterone co-incident with decidualisation restored decidualisation responses, vessel permeability, and expression of angiogenesis genes to wild type levels. Androgen availability declines with age which may contribute to age-related risk of pregnancy disorders. These findings show that intracrine androgen signalling is required for optimal decidualisation in vivo and confirm a major role for androgens in the development of the vasculature during decidualisation through regulation of the VEGF pathway. These findings highlight new opportunities for improving age-related deficits in fertility and pregnancy health by targeting androgen-dependent signalling in the endometrium.
Publisher: Bioscientifica
Date: 04-2018
DOI: 10.1530/ERC-17-0449
Abstract: Endometrial cancer (EC) is the most common gynaecological malignancy. Obesity is a major risk factor for EC and is associated with elevated cholesterol. 27-hydroxycholesterol (27HC) is a cholesterol metabolite that functions as an endogenous agonist for Liver X receptor (LXR) and a selective oestrogen receptor modulator (SERM). Exposure to oestrogenic ligands increases risk of developing EC however, the impact of 27HC on EC is unknown. S les of stage 1 EC ( n = 126) were collected from postmenopausal women undergoing hysterectomy. Expression of LXRs ( NR1H3 , LXRα NR1H2 , LXRβ) and enzymes required for the synthesis ( CYP27A1 ) or breakdown ( CYP7B1 ) of 27HC were detected in all grades of EC. Cell lines originating from well-, moderate- and poorly-differentiated ECs (Ishikawa, RL95, MFE 280 respectively) were used to assess the impact of 27HC or the LXR agonist GW3965 on proliferation or expression of a luciferase reporter gene under the control of LXR- or ER-dependent promoters (LXRE, ERE). Incubation with 27HC or GW3965 increased transcription via LXRE in Ishikawa, RL95 and MFE 280 cells ( P 0.01). 27HC selectively activated ER-dependent transcription ( P 0.001) in Ishikawa cells and promoted proliferation of both Ishikawa and RL95 cells ( P 0.001). In MFE 280 cells, 27HC did not alter proliferation but selective targeting of LXR with GW3965 significantly reduced cell proliferation ( P 0.0001). These novel results suggest that 27HC can contribute to risk of EC by promoting proliferation of endometrial cancer epithelial cells and highlight LXR as a potential therapeutic target in the treatment of advanced disease.
Publisher: Wiley
Date: 27-04-2016
Publisher: Springer Science and Business Media LLC
Date: 09-11-2016
DOI: 10.1038/SREP36748
Abstract: In women, endometrial breakdown, which is experienced as menstruation, is characterised by high concentrations of inflammatory mediators and immune cells which account for ~40% of the stromal compartment during tissue shedding. These inflammatory cells are known to play a pivotal role in tissue breakdown but their contribution to the rapid scarless repair of endometrium remains poorly understood. In the current study we used a mouse model of menstruation to investigate dynamic changes in mononuclear phagocytes during endometrial repair and remodelling. Menstruation was simulated in MacGreen mice to allow visualisation of CSF1R + mononuclear phagocytes. Immunohistochemistry revealed dynamic spatio-temporal changes in numbers and location of CSF1R-EGFP + cells and Ly6G + neutrophils. Flow cytometry confirmed a striking increase in numbers of GFP + cells during repair (24 h): influxed cells were 66% F4/80 + Gr-1 + and 30% F4/80 − Gr-1 + . Immunostaining identified distinct populations of putative ‘classical’ monocytes (GFP + F4/80 − ), monocyte-derived macrophages (GFP + F4/80 + ) and a stable population of putative tissue-resident macrophages (GFP - F4/80 + ) localised to areas of breakdown, repair and remodelling respectively. Collectively, these data provide the first compelling evidence to support a role for different populations of monocytes/macrophages in endometrial repair and provide the platform for future studies on the role of these cells in scarless healing.
Publisher: Public Library of Science (PLoS)
Date: 22-01-2014
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Douglas Gibson.