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Steroid hormones synchronize a variety of functions throughout all stages of life. Importantly, steroid hormone-transforming enzymes are ultimately responsible for the regulation of these potent signaling molecules. Germline mutations that cause dysfunction in these enzymes cause a variety of endocrine disorders. Mutations in SRD5A2, HSD17B3, and HSD3B2 genes that lead to disordered sexual development, salt wasting, and other severe disorders provide a glimpse of the impacts of mutations in steroid hormone transforming enzymes. In a departure from these established examples, this review examines disease-associated germline coding mutations in steroid-transforming members of the human aldo-keto reductase (AKR) superfamily. We consider two main categories of missense mutations: those resulting from nonsynonymous single nucleotide polymorphisms (nsSNPs) and cases resulting from familial inherited base pair substitutions. We found mutations in human AKR1C genes that disrupt androgen metabolism, which can affect male sexual development and exacerbate prostate cancer and polycystic ovary syndrome (PCOS). Others may be disease causal in the AKR1D1 gene that is responsible for bile acid deficiency. However, given the extensive roles of AKRs in steroid metabolism, we predict that with expanding publicly available data and analysis tools, there is still much to be uncovered regarding germline AKR mutations in disease.

The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such as prostate and breast cancer in which the disease can be either castrate resistant or occur post-menopausally, respectively. In these instances, the major precursor steroid of androgens and estrogens is dehydroepiandrosterone (DHEA) and DHES-SO 4 . This article reviews the major pathways by which adrenal steroids are converted to the potent male sex hormones, testosterone (T) and 5αdihydrotestosterone (5α-DHT) and the discrete enzyme isoforms involved in castration resistant prostate cancer. Previous studies have mainly utilized radiotracers to investigate these pathways but have not used prevailing concentrations of precursors found in castrate male human serum. In addition, the full power of stable-isotope dilution liquid chromatography tandem mass spectrometry has not been applied routinely. Furthermore, it is clear that adaptive responses occur in the transporters and enzyme isoforms involved in response to androgen deprivation therapy that need to be considered.

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The mechanisms leading to adrenal cortex development and steroid synthesis in humans remain poorly understood due to the paucity of model systems. Herein, we faithfully recapitulate human fetal adrenal cortex specification processes through stepwise induction of human induced pluripotent stem cells through posterior intermediate mesoderm-like and adrenal progenitor-like states to ultimately generate fetal zone adrenal cortex-like cells (FZLCs), as evidenced by histomorphological, ultrastructural, and transcriptome features and adrenocorticotropic hormone (ACTH)-independent Δ5 steroid biosynthesis. Furthermore, FZLC generation is promoted by SHH and inhibited by NOTCH, ACTIVIN and WNT signaling, and that steroid synthesis is amplified by ACTH/PKA signaling and blocked by inhibitors of delta5 steroid synthesis enzymes. Finally, NR5A1 promotes FZLC survival and steroidogenesis. Together, these findings provide a framework for understanding and reconstituting human adrenocortical development in vitro paving the way for cell-based therapies of adrenal insufficiency.