Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review

Abstract

Advances in technology have allowed for the sensitive, specific, and simultaneous quantitative profiling of steroid precursors, bioactive steroids and inactive metabolites, facilitating comprehensive characterization of the serum and urine steroid metabolomes. The quantification of steroid panels is therefore gaining favor over quantification of single marker metabolites in the clinical and research laboratories. However, although the biochemical pathways for the biosynthesis and metabolism of steroid hormones are now well defined, a gulf still exists between this knowledge and its application to the measured steroid profiles. In this review, we present an overview of steroid hormone biosynthesis and metabolism by the liver and peripheral tissues, specifically highlighting the pathways linking and differentiating the serum and urine steroid metabolomes. A brief overview of the methodology used in steroid profiling is also provided.

Keywords: Serum metabolome; Steroid biosynthesis; Steroid metabolism; Steroid metabolome; Urine metabolome.

Graphical abstract

Fig. 1

Schematic overview of adrenal steroidogenesis and peripheral modulation of steroid bioactivity. Arrows are labelled with the catalyzing enzyme and isoform where appropriate. Essential accessory proteins are also indicated: cytochrome b₅ (b₅); cytochrome P450 oxidoreductase (POR); ferredoxin (FDX); ferredoxin reductase (FDXR); hexose-6-phosphate dehydrogenase (H6PDH); PAPS synthase 2 (PAPSS2); steroidogenic acute regulatory protein (StAR).

Fig. 2

Schematic overview of steroidogenesis in the gonads. Steroidogenic pathways in the testicular Leydig cells are shown in the black box, while those in the ovaries are shown in the grey box and are further subdivided into the theca and granulosa cells. Arrows are labelled with the catalyzing enzyme and isoform where appropriate. Essential accessory proteins are also indicated: cytochrome b₅ (b₅); cytochrome P450 oxidoreductase (POR); ferredoxin (FDX); ferredoxin reductase (FDXR); PAPS synthase (PAPSS); steroidogenic acute regulatory protein (StAR).

Fig. 3

Schematic overview of androgen biosynthesis. Bioactive androgens (testosterone (T), 5α-dihydrotestosterone (DHT), 11-ketotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) can be generated by three partially independent pathways which operate across multiple tissues: (1) the classic Δ⁵ pathway, (2) the alternative DHT biosynthesis pathway, and (3) the 11-oxygenated androgen pathway. Arrows are labelled with the catalyzing enzyme and isoform where appropriate. Essential accessory proteins are indicated: cytochrome b5 (b₅); cytochrome P450 oxidoreductase (POR); ferredoxin (FDX); ferredoxin reductase (FDXR); hexose-6-phosphate dehydrogenase (H6PDH); PAPS synthase 2 (PAPSS2); steroidogenic acute regulatory protein (StAR).

Fig. 4

Schematic overview of the major phase 1 reactions contributing to steroid metabolism. (a) A-ring reduction to (5α)tetrahydro metabolites. The formation of 3β,5β-tetrahydro metabolites is sterically unfavorable (not shown). (b) 11β-oxidation/reduction by HSD11B1 modulates the bioactivity of glucocorticoids, mineralocorticoids and 11-oxygenated androgens. (c) 17β-oxidation/reduction regulates the bioactivity of androgens and estrogens. (d) 20-reduction to a hydroxy group with α- or β-stereochemistry. (e–h) Hydroxylations: major positions are indicated for different structural steroid classes. (i) 21-oxidation leading to the formation of the so-called cortolic acids from cortisol. (j)17,20-cleavage: cortisol, cortisone and their metabolites can undergo metabolism by 17,20-lyase activity. (k) Microbial 21-dehydroxylation: steroids excreted with bile can undergo metabolism by the gut microbiome prior to reabsorption.

Fig. 5

Schematic overview of the major phase 2 reactions contributing to steroid metabolism – sulfation (a) and glucuronidation (b). Important target positions of steroid conjugation are indicated, with stereochemistry for the different structural classes of steroids.

Fig. 6

Schematic overview of the pathways linking mineralocorticoids and their precursors to their urine metabolites. The pathway of mineralocorticoid biosynthesis is indicated on the left. The metabolism of each steroid is shown from left to right and the structures of the major urine products are shown. Phase 2 conjugation reactions are not indicated in the figure.

Fig. 7

Schematic overview of the pathways linking glucocorticoids and their precursors to their urine metabolites. The glucocorticoid biosynthetic pathway is shown on the left. The metabolism of each steroid is shown from left to right and the structures of the major urine products are shown. Phase 2 conjugation reactions are not indicated in the figure.

Fig. 8

Schematic overview of the pathways linking androgens and their precursors to their urine metabolites. Major serum androgen precursors and androgens are shown on the left. The metabolism of each steroid is shown from left to right and the structures of the major urine products are shown. 5α-dihydrotestosterone (DHT), the most potent androgen, is derived from testosterone by 5α-reduction and, thus, its formation is only reflected by urine androsterone. Phase 2 conjugation reactions are not indicated in the figure.