Dysregulation of Steroid Hormone Receptors in Motor Neurons and Glia Associates with Disease Progression in ALS Mice

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting motor neurons which shows sexual dimorphism in its incidence, age of onset, and progression rate. All steroid hormones, including androgens, estrogens, and progestogens, have been implicated in modulating ALS. Increasing evidence suggests that steroid hormones provide neuroprotective and neurotrophic support to motor neurons, either directly or via surrounding glial cell interactions, by activating their respective nuclear hormone receptors and initiating transcriptional regulatory responses. The SOD1G93A transgenic mouse also shows sex-specific differences in age of onset and progression, and remains the most widely used model in ALS research. To provide a more comprehensive understanding of the influences of steroid hormone signaling in ALS, we systemically characterized sex hormone receptor expression at transcript and protein levels, cellular localization, and the impact of disease course in lumbar spinal cords of male and female SOD1G93A mice. We found that spinal motor neurons highly express nuclear androgen receptor (AR), estrogen receptor (ER)α, ERβ, and progesterone receptor with variations in glial cell expression. AR showed the most robust sex-specific difference in expression and was downregulated in male SOD1G93A mouse spinal cord, in association with depletion in 5α-reductase type 2 isoform, which primarily metabolizes testosterone to 5α-dihydrotestosterone. ERα was highly enriched in reactive astrocytes of SOD1G93A mice and ERβ was strongly upregulated. The 5α-reductase type 1 isoform was upregulated with disease progression and may influence local spinal cord hormone levels. In conclusion, steroid hormone receptor expression is dynamic and cell-type specific in SOD1G93A mice which may provide targets to modulate progression in ALS.

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Steroid hormone receptor expression and action in bone

Clinical Science ◽

10.1042/cs0980217 ◽

2000 ◽

Vol 98 (2) ◽

pp. 217-240 ◽

Cited By ~ 64

Author(s):

Rosemary BLAND

Keyword(s):

Steroid Hormones ◽

Hormone Receptor ◽

Bone Cells ◽

Steroid Hormone ◽

Hormonal Control ◽

Receptor Expression ◽

Bone Architecture ◽

Steroid Hormone Receptor ◽

Hormone Action ◽

Hormone Receptor Expression

The skeleton is a complex tissue, and hormonal control of bone remodelling is elaborate. The important role that steroid hormones play in bone cell development and in the maintenance of normal bone architecture is well established, but it is only relatively recently that it has become possible to describe their precise mechanism of action. This review focuses not only on the steroid hormones (oestrogens, corticosteroids, androgens and progesterone), but also on related hormones (vitamin D, thyroid hormone and the retinoids), all of which act via structurally homologous nuclear receptors that form part of the steroid/thyroid receptor superfamily. By examining the actions of all of these hormones in vivo and in vitro, this review gives a general overview of the current understanding of steroid hormone action in bone. In addition, a comprehensive review of steroid hormone receptor expression in bone cells is included. Finally, the role that future developments, such as steroid hormone receptor knockout mice, will play in our understanding of steroid hormone action in bone is considered.

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Fallopian tube epithelial cells express androgen receptor and have a distinct hormonal responsiveness when compared with endometrial epithelium

Human Reproduction ◽

10.1093/humrep/deaa177 ◽

2020 ◽

Vol 35 (9) ◽

pp. 2097-2106 ◽

Cited By ~ 1

Author(s):

A Maclean ◽

E Bunni ◽

S Makrydima ◽

A Withington ◽

A M Kamal ◽

...

Keyword(s):

Androgen Receptor ◽

Hormone Receptor ◽

Hormone Receptors ◽

Steroid Hormone ◽

Receptor Expression ◽

Steroid Hormone Receptors ◽

Short Term ◽

Endometrial Epithelium ◽

Hormone Receptor Expression

Abstract STUDY QUESTION How does steroid receptor expression, proliferative activity and hormone responsiveness of the fallopian tube (FT) epithelium compare to that of the endometrial epithelium? SUMMARY ANSWER Proliferative indices, hormone receptor expression-scores and in vitro response to oestrogen and androgens of the human FT demonstrate a distinct pattern from the matched endometrium. WHAT IS KNOWN ALREADY The FT epithelium exists as a continuum of the endometrium, and both express steroid hormone receptors. The ovarian steroid hormones regulate cyclical proliferation and regeneration of the endometrium, but their effects on steroid hormone receptor expression and proliferation in the FT have not yet been fully elucidated. STUDY DESIGN, SIZE, DURATION We included women with proven fertility, undergoing hysterectomy and bilateral salpingo-oophorectomy for benign, gynaecological conditions at Liverpool Women’s NHS Foundation Trust. They had no known endometrial or tubal pathology and were not on hormonal treatments for at least 3 months preceding sample collection in this prospective observational study (conducted between 2010 and 2018). A full-thickness sample of the endometrium and a sample from the FT were collected from each woman. PARTICIPANTS/MATERIALS, SETTING, METHODS The differential protein and mRNA levels of steroid hormone receptors, oestrogen receptors α and β, androgen receptor (AR) and progesterone receptor (PR), and the proliferative marker (Ki67) of the endometrium and the FT tissue samples from 47 healthy women undergoing surgery (37 premenopausal and 10 postmenopausal) were investigated using immunohistochemistry and quantitative real-time PCR. The comparative responsiveness to oestrogen and androgen of the endometrium and the fimbrial end of the FT was analysed using an in vitro short-term explant culture model. The endpoints assessed in the explants were the changes in mRNA and protein levels for AR, PR and the epithelial proliferative index after 24 h treatment with oestradiol (E2) or dihydrotestosterone (DHT). MAIN RESULTS AND THE ROLE OF CHANCE The premenopausal endometrial functionalis glands (FG) displayed the well-known cyclic variation in cellular proliferation and steroid receptor scores. Compared with the endometrial FG, the matched FT epithelium (both fimbrial or isthmic ends) displayed a significantly lower proportion of cells expressing Ki67 (2.8% ± 2.2%, n = 18 vs 30.0% ± 26.3%, n = 16, P = 0.0018, respectively) accompanied with a significantly higher AR immunoscores (6.7 ± 2.7, n = 16 vs 0.3 ± 1.0, n = 10, P = 0.0136). The proportion of cells expressing Ki67 and the AR immunoscores of the FT epithelium correlated positively with endometrial luminal epithelium (r = 0.62, P = 0.005, and r = 0.68, P = 0.003, respectively). In vitro experiments suggested the tubal explants to be apparently less responsive to E2 yet more sensitive to DHT compared with the matched endometrium explants. LIMITATIONS, REASONS FOR CAUTION The short-term in vitro nature of the tissue explant cultures used in the study may not be representative of how different anatomical regions of the endometrium and FT behave in vivo. Our study included a high proportion of older premenopausal women with a regular menstrual cycle, which may therefore affect extrapolation of findings to a younger group. WIDER IMPLICATIONS OF THE FINDINGS Advancing our understanding of tubal and endometrial epithelial cell function has important implications for the diagnosis and treatment of diseases such as infertility, ectopic pregnancy, endometriosis and cancer. STUDY FUNDING/COMPETING INTEREST(S) The work included in this article was funded by Wellbeing of Women project grants RG1073 and RG2137 (D.K.H.) and Wellbeing of Women Entry-Level Scholarship ELS706 (A.M). A.M. was also supported by an NIHR ACF fellowship grant. Further support received from Liverpool Women’s Hospital NHS Trust (S.M.), University of Liverpool (E.B. and A.W.). All authors declare there are no conflicts of interest. TRIAL REGISTRATION NUMBER N/A

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