Endocrine Abstracts

Although classical and non-classical signaling of testosterone (T) has been observed in the testis, the enigma of the non-classical pathway is not fully resolved. While some researchers favor the androgen receptor (AR), others propose a membrane-bound receptor for non-classical T signaling. Although silencing of the AR in Sertoli cells (SC) resulted in infertility and suggested no involvement of the non-classical pathway, recent experiments using an inhibitor of the non-classi...

Sex hormone-binding globulin (SHBG) is a high-affinity binding protein for androgens and estrogens. According to the “free hormone hypothesis”, SHBG regulates the free sex steroid fraction and restricts androgen bioactivity. SHBG has also been independently associated with diabetes, osteoporosis etc., but whether this represents causality or residual confounding remains unconfirmed. We studied mice overexpressing human SHBG. Using multiligand liquid chromatography ta...

Prostate cancer often develops anti-androgen resistance, possibly via AR mutations which change AR antagonists to agonists. There is an urgent need for novel therapies which ideally show increased anticancer activity, whilst overcoming current drug resistance. Enobosarm has anabolic effects on muscle and bone tissues whilst having no effect on the prostate – often used to combat cachexia in advanced lung cancer. Here we describe the activity of novel chemically modified E...

Although androgen insensitivity syndrome (AIS) is commonly suspected as a cause of a 46,XY disorder of sex development (DSD), only about half of these cases can be attributed to an inactivating mutation within the coding sequence (CDS) of the androgen receptor (AR) gene. This led to the hypothesis that disrupted AR activation in AIS may also be caused by a defect in a co-factor of AR-activity. However, so far mutations in AR co-factors leading to AIS have not been ide...

Endometriosis is a hormone-dependent disorder, characterised by growth of endometrial tissue outside the uterus. It has been reported that 30–40% of women with infertility have endometriosis. Transformation of human endometrial stromal fibroblasts (hESC) (termed decidualisation) is accompanied by increased steroid synthesis and is fundamental to the establishment of a receptive endometrial microenvironment, which can support and maintain pregnancy. Evidence suggests that ...

Transgender patients are treated by down-regulation oft he pituitary gland and the gonads with GnRH- analogues and the opposite male or female sex steroids, followed by gonadectomy. After gonadectomy, the GnRH analogue is discontinued while the treatment with sex steroids (estrogen or testosterone) is continued. This offers the unique possibility to study the effects of sex steroids on bone density, metabolism, and other regulatory systems in the opposite sex. We present data ...

Sexually dimorphic organogenesis of the prostate is a key function of androgens during mammalian development. Mesenchymal AR signalling is essential for prostate development, while epithelial AR is not required. Within the mesenchyme there are distinct mesenchymal subsets that show differential effects of androgens; androgens regulate the thickness of the urethral smooth muscle layer, while in the inductive mesenchymal pad, androgens stimulate branching and growth of prostate ...

The stromal compartment changes with cancer, with an emergence in activated fibroblasts. These stromal changes, which occur with cancer initiation and throughout progression, are known to influence the hallmarks of cancer and are becoming increasingly studied for prognostic and therapeutic purposes. Androgen receptor (AR) signalling in stromal cells is important in prostate cancer and these cancer stromal communications, yet the mechanisms underpinning stromal AR contribution ...

Epigenetic reprogramming including altered transcription factor binding and altered patterns of chromatin and DNA modifications are now accepted as the hallmark of aggressive cancers. We show that global changes in chromatin structure and chromatin accessibility in prostate tumour tissue can define castrate-resistant prostate cancer and be used to inform the discovery of gene-level classifiers for therapy. In addition, we show that the androgen receptor overexpression alone, w...

Changes in glycan composition are common in cancer and can play important roles in all of the recognised hallmarks of cancer (1). We recently identified glycosylation as a global target for androgen control in prostate cancer cells and further defined a set of 8 glycosylation enzymes (GALNT7, ST6GalNAc1, GCNT1, UAP1, PGM3, CSGALNACT1, ST6GAL1 and EDEM3), which are also significantly up-regulated in prostate cancer tissue (4). These 8 enzymes are under direct control of the and...

It is well established that sex steroid deficiency induces bone loss, resulting in osteoporosis. Consequently, global androgen receptor knock out (ARKO) mice have trabecular and cortical osteopenia. Bone cell-specific ARKOs however, have a much less pronounced bone phenotype, suggesting that androgens have an influence on processes in other systems or organs which in turn have an impact on bone metabolism. The kidney is a likely candidate, as it plays an important role in calc...

Prostate cancer (PC) becomes resistant to chronic castration via an adaptive increase in androgen receptor (AR) axis activity. AR overexpression, however, is a liability that can be exploited therapeutically through rapid cycling between high supraphysiologic and low castrate levels of serum testosterone (T), (Bipolar Androgen Therapy (BAT)). In a pilot study, 14 men with CRPC treated with BAT showed a 50% PSA and objective response. A larger study was initiated in which asymp...

With the wide-spread use of abiraterone/enzalutamide for CRPC, there is an urgent need to understand and reverse resistance to these treatments. Studies have implicated glucocorticoid receptor (GR) as activating androgen receptor (AR) signalling and driving resistance. Here we studied progesterone receptor (PR), which is phylogenetically most closely related to the AR. We first used digital droplet PCR in prostate cancer (PCa) cell lines and observed >10 times higher level...

Prostate cancer is currently treated with hormonal therapies, which aim to block the production and/or action of androgens. However, tumours eventually progress to castration-resistant prostate cancer and there is a great need for new therapeutic approaches. We have designed and tested engineered repressors which could be effective in circumstances where current therapies fail. These consist of two modules: an interaction domain, which binds directly to the androgen receptor (...

Prostate cancer (PCa) is driven by the androgen receptor (AR) signalling axis and begins with prostatic intraepithelial neoplasia (PIN), progressing to invasive adenocarcinoma and eventually metastatic disease. It is treated with androgen deprivation therapies, to which, in late-stage disease, tumours often become resistant and proliferation occurs in a low androgen environment. Mutation of the PTEN tumour suppressor gene is found in approximately 30% of primary human prostate...

Enzalutamide (Enza) is a second-generation antiandrogen currently used in the clinic for treatment of metastatic prostate cancer. It significantly prolonged survival of men with metastatic castration resistant prostate cancer after chemotherapy by a median of 4.8 months in comparison to the placebo group. However, in a subset of patient’s beneficial effect of Enza cannot be observed, while others who initially respond eventually develop resistance towards the treatment. U...

The androgen receptor (AR) signaling pathway is central to the emergence of castration-resistant prostate cancer (CRPC). miR-32 is an androgen regulated miRNA which is differentially expressed in CRPC compared to benign prostatic hyperplasia (BPH) and able to provide a significant growth advantage to LNCaP cells. To study how increased miR-32 expression contributes to prostate cancer formation and/or progression in vivo, we have established transgenic mice expressing ...