Rising from obscurity: 11β-hydroxy-androstenedione under the spotlight

Steroid hormones are small molecules that act as messengers in our bodies, regulating normal development and impacting on disease. These hormones are produced from cholesterol by the actions of enzymes− proteins which change cholesterol to form new steroids. This process takes place in steroidogenic tissue or organs. One such is the adrenal gland, responsible for the formation of hormones in the major branches or pathways of glucocorticoid-, mineralocorticoid- and sex hormone (or androgen) production. Although androgen production is limited in the adrenal, levels may increase in disease conditions and genetic disorders, affecting regulatory processes and disease progression. Steroid hormones are transported in the blood to target tissues where they exert effects and where they are also broken down or metabolised by other enzymes. The production and metabolism of steroid hormones are complex processes− a single steroid can be used by more than one enzyme thus forming a number of hormones, with enzymes also being able to act on and change a number of steroids. Steroid production and metabolism is therefore an intricate web of interlinked pathways.

General technologies used in steroid analyses are best suited to large numbers of samples determining single hormones. Developments on the analytical front in liquid chromatography-tandem mass spectrometry (LC-MS/MS) permit analyses of many hormones within a single sample as well as distinguishing between hormones that are almost identical. It is furthermore possible to analyse complete hormone panels evaluating production and metabolism within pathways with greater accuracy and in less time. Recent advances include the use of less expensive reagents with the added benefit of being environmentally friendly.

In our studies we analysed steroids in the H295R adrenal cell model exposed to stimulants that mimic effects of a physiological stress response and stimulants that affect hormones regulating blood pressure. Complete hormone profiles yielded valuable insights not only into hormone production but also in fluctuations within the pathways. In addition, these cells are commonly used to study compounds that disrupt the human endocrine system in which emphasis is placed on sex steroids analyses. LC-MS/MS analyses of hormone panels allow a more comprehensive study of environmental effects on all the hormones produced in the adrenal and not only on the sex steroids.

Investigating adrenal steroid metabolism in target tissue led us to investigations into prostate cancer (PCa). We previously reported 11-hydroxyandrostenedione (11OHA4), produced in H295R cells as one of the major androgens to be involved in PCa. This hormone has been sorely neglected for decades and has been overlooked in PCa treatment regimes. We since showed that 11OHA4 is further metabolised in LNCaP cells, a model for castration resistant PCa, to more potent androgens with effects comparable to those of dihydrotestosterone (DHT), possibly equally harmful if not also targeted in treatment therapies. Our results have challenged the position of DHT as the most potent and only sex steroid, together with testosterone, as the sole steroid contributors to PCa. The novel role of the HSD11B2 enzyme in PCa was highlighted in these studies where 11OHA4, an adrenal hormone with no biological activity was transformed by HSD11B2 to the potent androgens, 11-ketotestosterone and 11-ketodihydrotestosterone (11KDHT).

Improved analytical technologies, together with our studies in cell models, allowed us to capture snapshots of steroid hormone profiles in both the adrenal and prostate. New pathways have been identified in the prostate cell in which novel steroids are produced. The technological advances in steroid detection and analyses now present opportunities in the characterization of new steroids and unravelling complex pathways, contributing to a greater understanding of hormone production and metabolism.

Lise Barnard and Amanda C Swart
Department of Biochemistry, University of Stellenbosch, Stellenbosch, South Africa

 

Publication

Advances in the analytical methodologies: Profiling steroids in familiar pathways-challenging dogmas.
Bloem LM, Storbeck KH, Swart P, du Toit T, Schloms L, Swart AC
J Steroid Biochem Mol Biol. 2015 Sep

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