Androgen metabolism in adipose tissue and liver and the impact of female androgen excess

Anthony, Amarah Viola (2023). Androgen metabolism in adipose tissue and liver and the impact of female androgen excess. University of Birmingham. Ph.D.

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Abstract

Androgens are key regulators of metabolic and reproductive health in women. Imbalances in androgen metabolism can lead to conditions of female hyperandrogenism, such as polycystic ovary syndrome (PCOS). PCOS is associated with an extensive list of comorbidities including adipose dysregulation and metabolic associated steatotic liver disease (MASLD). Activation of C19 androgens via intracrine pathways within metabolically active tissues, such as adipose and liver, are important determinants of local androgen action. Both classic and 11-oxygenated androgens contribute to female hyperandrogenism, yet despite the importance of 11-oxygenated in female androgen excess, the tissue-specific pathways of these androgens are not fully understood. Adipose tissue is a key tissue involved in the activation classic and 11-oxygenated androgen precursors, via the enzyme Aldo Keto Reductase family 1 member 3 (AKR1C3), and therefore plays a central role in the systemic metabolic health of women with hyperandrogenism. The liver is also a major site of systemic androgen metabolism and known to express androgen-activating enzymes. Even though liver and adipose are important metabolic tissues and androgen target tissues, there is a need to delineate the local/intracrine pathways of androgen metabolism to be able to better understand the tissue specific links between androgen excess and metabolic complications. Here, I demonstrate the importance of AKR1C3 regulation on androgen metabolism in adipose tissue. I also describe the liver as a site of androgen deactivation which rapidly inactivates androgens via A-ring reduction of both classic and 11-oxygenated androgens.

Multi-steroid profiling of ex vivo female adipose tissue incubation models revealed AKR1C3 as the key enzyme of androgen activation in adipose, activating both classic and 11-oxygenated androgen precursors androstenedione and 11-ketoandrostenedione to their respective active metabolites. Activation of 11-oxygenated androgens by AKR1C3 was seven-fold greater than activation of classic androgens. Selective inhibition of AKR1C3 significantly reduced the generation of active androgens, with a greater effect on 11-oxygenated androgens. AKR1C3 inhibition could therefore prove to be a successful therapeutic target to treat female hyperandrogenism.

Ex vivo human liver tissue incubations, together with normothermic machine liver perfusion, identified the liver as a site of androgen inactivation for both classic and 11-oxygenated androgens, predominantly leading to the formation of inactive end stage A-ring reduced metabolites. 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) played a key role for the regulation of the levels of 11-oxygenated androgens, by converting active 11-keto androgens and their 11-keto precursors to their inactive, 11β-hydroxy counterparts. The liver therefore does not contribute to intracrine androgen activation, and these results provide a strong foundation upon which a deeper understanding of the involvement of androgen metabolism in the comorbidities of female hyperandrogenism, such as MASLD, can be built.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):