19-hydroxy Steroids in the Aromatase Reaction: Review on Expression and Potential Functions

Abstract

Scientific evidence related to the aromatase reaction in various biological processes spanning from mid-1960 to today is abundant; however, as our analytical sensitivity increases, a new look at the old chemical reaction is necessary. Here, we review an irreversible aromatase reaction from the substrate androstenedione. It proceeds in 3 consecutive steps. In the first 2 steps, 19-hydroxy steroids are produced. In the third step, estrone is produced. They can dissociate from the enzyme complex and either accumulate in tissues or enter the blood. In this review, we want to highlight the potential importance of these 19-hydroxy steroids in various physiological and pathological conditions. We focus primarily on 19-hydroxy steroids, and in particular on the 19-hydroxyandrostenedione produced by the incomplete aromatase reaction. Using a PubMed database and the search term "aromatase reaction," 19-hydroxylation of androgens and steroid measurements, we detail the chemistry of the aromatase reaction and list previous and current methods used to measure 19-hydroxy steroids. We present evidence of the existence of 19-hydroxy steroids in brain tissue, ovaries, testes, adrenal glands, prostate cancer, as well as during pregnancy and parturition and in Cushing's disease. Based on the available literature, a potential involvement of 19-hydroxy steroids in the brain differentiation process, sperm motility, ovarian function, and hypertension is suggested and warrants future research. We hope that with the advancement of highly specific and sensitive analytical methods, future research into 19-hydroxy steroids will be encouraged, as much remains to be learned and discovered.

Keywords: 19-hydroxyandrostenedione; 19-oxoandrostenedione; ACTH; HPA and HPG axes; POR.

Figure 1.

Aromatase reaction. The oxidation of androstenedione to estrone by aromatase complex involves NADPH, NADPH P450 reductase, and aromatase. It does not follow a clear linear trajectory of sequential reactions but has a distributive character, where 19-OH AD and 19-oxo AD freely dissociate from the aromatase binding site and enter blood and/or tissue, or re-enter the aromatase reaction again for further oxidation and estrone production (adapted from [154] and [25]). Inset: A closeup look at the aromatase binding pocket with a substrate androstenedione. The residues lining binding pocket are labelled as: hydrophobic-green, acidic-red, basic blue, polar-purple and S-containing yellow. Residues associated with a doorway/access channel are dash-circled (adapted from [22]) and in dash-circled red Arg 192 and Glu 483 gatekeepers are indicated. Abbreviations: 19-OH AD, 19-hydroxyandrostenedione, 19-oxo AD, 19-oxo-androstenedione.

Figure 2.

Aromatase acts on substrates androstenedione and testosterone, producing a variety of 19-hydroxy steroids. 17β HSD enzymes catalyzing the conversion of T to AD and AD to T, as well as E1 to E2 and E2 to E1 are indicated. 3β HSD mediates oxidation of DHEA to AD. The third substrate for aromatase reaction is 16-α hydroxytestosterone. It has been omitted here, as very little is known about it, and it has not been discussed. T is converted to DHT by the enzyme SRD5A2 (steroid 5-alpha reductase A2). Abbreviations: AD, androstenedione; DHEA, dehydroepiandrostenedione; DHT, dihydrotestosterone; E1, estrone; E2, estradiol; HSD, hydroxysteroid dehydrogenase; SRD5A2, steroid 5-alpha reductase A2; T, testosterone.

Figure 3.

Regulation, detection, and the potential involvement of 19-OH AD in human physiology and pathophysiology. Secretion of 19-OH AD is under control of the hypothalamic pituitary adrenal axis (HPA) and is directly stimulated by ACTH. LH and FSH acting on testis and ovary also increase 19-OH AD secretion via the hypothalamic pituitary gonadal (HPG) axis. Cytokines likely indirectly increase 19-OH AD via ACTH. Positive and negative regulation of 19-OH AD secretion by VIP, epinephrine, and ANP are indicated. 19-OH AD increases blood pressure and renin secretion and is increased during pregnancy and Cushing’s disease. Tissues, where 19-OH AD has been measured, are indicated, and a list of potential involvement in several physiological and pathophysiological processes is presented. Abbreviations: 19-OH AD, 19-hydroxyandrostenedione; ACTH, adrenocorticotropic hormone; ANP, atrial natriuretic peptide; FSH, follicle stimulating hormone; LH, luteinizing hormone; VIP, vasoactive intestinal peptide.