Adrenal-Derived 11-Oxygenated 19-Carbon Steroids are the Dominant Androgens in Classic 21-Hydroxylase Deficiency

The conventional steroid panel of patients with 21OHD has been expanded in recent years to include previously neglected androgens.

“The conventional steroid panel of patients with 21OHD has been expanded in the recent years, to include previously neglected androgens (12–14).”

The inverse correlation of 11KT and testosterone in men with classic 21OHD supports their origin from independent sources in well-controlled men.

“similar to our previous studies (12, 17), supporting their origin from independent sources in well-controlled men.”

11-oxyandrogens are the major androgens and androgen precursors found in classic and nonclassic 21OHD.

“11-oxyandrogens are the major androgens and androgen precursors found in classic and nonclassic 21OHD (12, 16)”

The higher PregS serum concentrations in patients with 21OHD vs. age and BMI-matched controls could be partly explained by the relative shift in sulfotransferase type 2A (SULT2A1) substrates.

“This enigma could be partly explained by the relative shift in sulfotransferase type 2A (SULT2A1) substrates, as suggested by the higher PregS serum concentrations in patients with 21OHD vs. age and BMI-matched controls (12).”

11-oxyandrogens, including 11OHA4 and 11KT, have been shown to be elevated in patients with classic and non-classic 21OHD.

“In particular, a set of 11-oxygenated-C19 steroids (11-oxyandrogens), including 11β-hydroxyandrostenedione (11OHA4) and 11-ketotestosterone (11KT), have been shown to be elevated in patients with classic (12, 15) and non-classic 21OHD (16).”

DHEAS is a poor biomarker of 21OHD control, which can be paradoxically low in poorly controlled classic 21OHD patients.

“Moreover, DHEAS is a poor biomarker of 21OHD control, which can be paradoxically low in poorly controlled classic 21OHD patients (12, 29).”

11-oxygenated C19 steroids have been shown to be increased in CAH due to 2OH deficiency.

“11-oxygenated C19 steroids have been shown to be increased in CAH due to 2OH deficiency 130,131”

11-oxygenated adrenal metabolites are bioactive, dominant steroids in CAH.

“These under-recognized 11-oxygenated adrenal metabolites are bioactive, dominant steroids in CAH15,20,49,50.”

Serum levels of 11-oxygenated androgens are higher in patients with 21-OHD CAH on replacement therapy compared with age-matched and sex-matched control individuals.

“Serum levels of 11-oxygenated androgens are higher in patients with 21-OHD CAH on replacement therapy when compared with age-matched and sex-matched control individuals20.”

In CAH, 21-deoxycortisol and 11-oxysteroids may give more direct evidence of adrenal androgen precursor production than traditional markers.

“More recently, it has been found that metabolites such as 21-deoxycortisol and 11-oxysteroids may provide more direct evidence of adrenal androgen precursor production in CAH (218, 219).”

Differences in concentration of 11KA4 measured in adrenal vein and inferior vena cava suggest that 11KA4 is predominantly produced from conversion of 11OHA4 in peripheral tissue expressing HSD11B2 such as kidney.

“However, differences in the concentration of 11KA4 measured in the adrenal vein and inferior vena cava suggest that 11KA4 is predominantly produced from conversion of 11OHA4 in peripheral tissue expressing HSD11B2 such as the kidney [39,69].”

11KA4 is the next most abundant 11-oxygenated androgen precursor in circulation.

“11KA4 is the next most abundant 11-oxygenated androgen precursor in circulation (Table 2) [39,41,68,69,289].”

Although multiple studies have measured circulating concentrations of 11-oxygenated androgens in healthy control groups, there are significant variations in the levels reported and no reference ranges have been established to date.

“However, although multiple studies have measured the circulating concentrations of 11-oxygenated androgens in healthy control groups, there are significant variations in the levels reported and as such, no reference ranges have been established to date [39,41,68,69,289].”

The levels of 11-oxygenated androgens and their precursors are significantly elevated in patients with polycystic ovary syndrome (PCOS) and 21-hydroxylase deficiency.

“While the levels of 11-oxygenated androgens and their precursors have been shown to be significantly elevated in patients with polycystic ovary syndrome (PCOS) and 21-hydroxylase deficiency [41,69], one study reported that the circulating levels of 11KT were also higher than that of testosterone in a healthy female control group (BMI 21.2–26.1 kg/m2) [41].”

Both 11OHA4 and 11OHT may be converted to their 11-keto counterparts by the low levels of HSD11B2 present in the adrenal, though peripheral HSD11B2 may make a more significant contribution.

“Both 11OHA4 and 11β-hydroxytestosterone (11OHT) may be converted to their 11-keto counterparts by the low levels of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) present in the adrenal, though peripheral HSD11B2 may make a more significant contribution (Pretorius et al., 2017, Turcu et al., 2016).”

Differences in the concentration of individual 11-oxygenated steroids in the adrenal vein and inferior vena cava suggest that 11KA4 and 11KT may instead be formed in peripheral tissues.

“differences in the concentration of the individual 11-oxygenated steroids in the adrenal vein and inferior vena cava suggest that 11KA4 and 11KT may instead be formed in peripheral tissues (Turcu et al., 2016).”

11OHA4 and 11OHT are of adrenal origin.

“Indeed, a recent study showed that while 11OHA4 and 11OHT are of adrenal origin, differences in the concentration of the individual 11-oxygenated steroids in the adrenal vein and inferior vena cava suggest that 11KA4 and 11KT may instead be formed in peripheral tissues (Turcu et al., 2016).”

C19 11-oxygenated steroids are a class of active adrenal androgens recognized more than 60 years ago, which have been restudied recently.

“C19 11-oxygenated steroids are a class of active adrenal androgens recognized 60+ years ago, which have been restudied recently.”

Recent evidence demonstrates involvement of the backdoor pathway in 21-hydroxylase deficiency consequent to 17OHP excess; this pathway likely contributes to androgen excess leading to virilization of the female external genitalia in 21-hydroxylase deficiency, and its activity appears to lessen after the first years of life.

“Recent evidence demonstrate involvement of the “ backdoor pathway ” in 21OHD, consequent to 17OHP excess. This pathway likely contribute to androgen excess leading to virilization of the female external genitalia in 21OHD; interestingly, activity of this androgen pathway appears to lessen after the first years of life.”

Androstenedione and testosterone undergo 11-hydroxylation in the zona reticularis, catalyzed by CYP11B1, resulting in 11-hydroxyandrostenedione and 11-hydroxytestosterone, respectively; both are subsequently reduced by HSD11B2 to 11-ketoandrostenedione and 11-ketotestosterone, respectively; 11-ketotestosterone can still be 5α-reduced to form 11-keto-dihydrotestosterone.

“Both androstenedione and testosterone undergo 11-hydroxylation in the ZR , catalyzed by CYP11B1 (which is expressed in both ZR and ZF ), resulting in 11-hydroxyandrostenedione (11-OHA4) and 11-hydroxytestosterone (11-OHT), respectively. Both steroids are subsequently reduced by HSD11B2 to 11-ketoandrostenedione (11-KA4) and 11-ketotestosterone (11-KT), respectively; 11-KT can still be 5α-reduced”

11-ketotestosterone and 11-keto-dihydrotestosterone are potent androgens, binding and activating the androgen receptor similarly to DHT.

“Different from 11-OHA4 – a peripheral precursor of the more active androgens –, both 11-KT and 11-KDHT are potent androgens, binding and activating the androgen receptor (AR) similarly to DHT.”

11-ketotestosterone seems to have a relevant physiological role during adrenarche, being the most important circulating androgen in females, followed by testosterone and 11-hydroxytestosterone.

“In addition, 11-KT seems to have a relevant physiological role during adrenarche, being the most important circulating androgen in females, followed by testosterone and 11-OHT.”

New evidence identifies the C19 11-oxygenated steroids as a distinctive and relevant group of adrenal-derived androgens.

“However, new evidence identified the C19 11-oxigenated steroids as a distinctive and relevant group of adrenal-derived androgens.”

High concentrations of 11-hydroxytestosterone, 11-ketotestosterone, 11-hydroxyandrostenedione and 11-ketoandrostenedione were observed in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, suggesting that they have a major role in the clinical picture of hyperandrogenism of affected children.

“High concentrations of 11-OHT, 11-KT, 11-OHA4 and 11-KA4 were observed in patients with CAH due to 21OHD, suggesting that they have a major role in the clinical picture of hyperandrogenism of affected children ( 24 - 27 ).”

C19 11-oxygenated steroids are likely better markers of adrenal androgen excess in congenital adrenal hyperplasia than DHEA, androstenedione and testosterone, classically employed to monitor therapeutic control.

“Currently, the C19 11-oxygenated steroids are likely better markers of adrenal androgen excess in CAH than DHEA, androstenedione and testosterone, classically employed to monitor therapeutic control.”

C19 11-oxygenated steroids are also increased in polycystic ovary syndrome, being correlated with markers of metabolic risk such as BMI and HOMA-IR index.

“C19 11-oxygenated steroids are also increased in polycystic ovary syndrome (PCOS), being correlated with markers of metabolic risk, such BMI and HOMA-IR index ( 24 - 27 ).”

Increased A4 feeds enhanced 11-oxygenated androgen pathway activity.

“and increased A4 feeds enhanced 11-oxygenated androgen pathway activity (24) (Fig. 3).”