Beta-Cortol

Chemical synthesis of glucuronidated metabolites of cortisol

During in vivo metabolism the addition of six atoms of hydrogen to cortisone at the appropriate location and configuration can lead to formation of either 3 alpha,17,20 alpha,21-tetrahydroxy 5 beta-pregnan-11-one (cortolone) or 3 alpha,17,20 beta,21-tetrahydroxy-5 beta-pregnan-11-one (beta-cortolone). Likewise, metabolic reduction of cortisol can lead to formation of either 5 alpha-pregnane-3 alpha,11 beta,17,20 alpha,21-pentol (cortol) or the 20 beta isomer (beta-cortol). This paper describes the chemical syntheses of the C-3 beta-D-glucosiduronates of cortolone, beta-cortolone, cortol and beta-cortol-conjugates which are normal excretory products of man. The foregoing conjugates are characterized as free acids (or salts), as methyl esters and as polyacetate methyl esters.

Short-Term Fasting Attenuates Overall Steroid Hormone Biosynthesis in Healthy Young Women

Context: Fasting is stressful for the human body. It is managed by metabolic adaptations maintaining energy homeostasis and involves steroid hormone biosynthesis, but the exact interplay between energy and steroid metabolism remains elusive. Women with polycystic ovary syndrome (PCOS) suffer from disturbed metabolism and androgen excess, while in women with anorexia nervosa, cortisol and androgen production are decreased. By contrast, starvation of steroidogenic cells shifts adrenal steroid biosynthesis toward enhanced androgen production.
Aim: This study investigated the effect of fasting on steroid production in healthy women.
Methods: Twenty healthy young women fasted for 48 hours; steroid profiles from plasma and urine samples were assessed at baseline, after 24 hours, and 48 hours by liquid and gas chromatography-mass spectrometry.
Results: Fasting did not change overall steroidogenesis, although it increased progestogen production and lowered relative mineralocorticoid, glucocorticoid, and androgen production. The largest decrease in urine metabolites was seen for β-cortol, dehydroepiandrosterone, and androstenediol; higher levels were found for pregnanediol in urine and progesterone and aldosterone in serum. Activity of 17α-hydroxylase/17,20-lyase (CYP17A1), essential for androgen biosynthesis, was decreased after fasting in healthy women as were 21-hydroxylase (CYP21A2) and 5α-reductase activities. By contrast, hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) activity for cortisol inactivation seemed to increase with fasting.
Conclusion: Significant changes in steroid metabolism occurred after 48 hours of fasting in healthy women. In contrast to metabolic changes seen at baseline in PCOS women compared to healthy women, and after starving of steroidogenic cells, no androgen excess was observed after short-term fasting in healthy young women.

Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates

Androgen excess in women with polycystic ovary syndrome (PCOS) may be ovarian and/or adrenal in origin, and one proposed contributing mechanism is altered cortisol metabolism. Increased peripheral metabolism of cortisol may occur by enhanced inactivation of cortisol by 5alpha-reductase (5alpha-R) or impaired reactivation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) resulting in decreased negative feedback suppression of ACTH secretion maintaining normal plasma cortisol concentrations at the expense of androgen excess. We have tested whether any enzyme dysregulation was related to circulating insulin or androgen concentrations in women with PCOS and have sought to clarify their relationship with obesity. First, to avoid obesity-related effects on cortisol metabolism, 18 lean women with PCOS were compared with 19 lean controls who were closely matched for body mass index (BMI). Second, the impact of obesity was studied in a cross-section of 42 PCOS women of a broad range of BMI. We measured 24-h urinary excretion of steroid metabolites by gas chromatography/mass spectrometry and fasting metabolic and hormone profiles. Urinary excretion of androgens [androsterone (P = 0.003), etiocholanolone (P = 0.02), and C19 steroid sulfates (P = 0.009)], cortisone metabolites [tetrahydrocortisone (THE) (P = 0.02), alpha-cortolone (P < 0.001), beta-cortol + beta-cortolone (P < 0.001), cortolones (P < 0.001), and E metabolites (P < 0.001)], and TCM (P = 0.002) were raised in lean PCOS subjects when compared with controls. A significantly higher 5alpha-tetrahydrocortisol (5alpha-THF)/5beta-THF ratio (P = 0.04) and a significantly lower alpha-THF + THF + alpha-cortol/THE + cortolones ratio (P = 0.01) were found in lean PCOS women compared with lean controls, indicating both enhanced 5alpha-R and reduced 11beta-HSD1 activities. A decreased THE/cortolones ratio (P = 0.03) was also found in lean PCOS women compared with lean controls, indicating increased 20 alpha/beta-HSD activity. In the group of 42 PCOS subjects, measures of 5alpha/5beta reduction were positively correlated with the homeostasis model insulin resistance index (HOMA-R): alpha-THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5alpha /total 5beta and HOMA-R (r = 0.37; P = 0.02). A positive correlation was also found between measures of 5alpha-R and BMI (r = 0.37; P = 0.02). No correlation was found between measures of 11beta-HSD1 activity and indices of insulin sensitivity or BMI. We have demonstrated that there is an increased production rate of cortisol and androgens as measured in vivo in lean PCOS women. Insulin seems to enhance 5alpha reduction of steroids in PCOS but was not associated with the elevated cortisol production rate. The changes in 5alpha-R, 11beta-HSD1, and 20alpha/beta-HSD enzyme activities observed in PCOS may contribute to the increased production rates of cortisol and androgens, supporting the concept of a widespread dysregulation of steroid metabolism. This dysregulation does not seem to be the primary cause of PCOS because no correlation was found between serum androgen levels or urinary excretion of androgens with measurements of either 5alpha-R or 11beta-HSD1 activities.

Endogenous urinary steroids in premenopausal women with uterine leiomyomas

Objectives: To study the effect of endogenous steroids on the presence of uterine leiomyomas.
Methods: Urine samples of 27 premenopausal women with leiomyomas and 25 age-matched healthy premenopausal women were collected. The concentration of estrogens and androgens in the urine samples of the two groups were determined using a gas chromatography mass spectrometer and the two groups were compared. To study metabolic changes in patients indirectly, the concentration ratios of precursor metabolite to product metabolite of the two groups were also compared.
Results: Urinary concentrations of 17beta-estradiol, 5-androstene-3beta, 16beta, 17beta, triol, 11-keto-ethiocholanolone, 11beta-hydroxy-androsterone, 11beta-hydroxy-etiocholanolone, THS, THA, THE, alpha-cortol and beta-cortol were significantly higher in patients than in controls. The concentration ratios of 17beta-estradiol/estrone and 11/beta-hydroxy-ethiocholanolone/11beta-hydroxy-androsterone increased in patients.
Conclusions: The presence of uterine leiomyomas correlates with an increase in urinary concentrations of estrogens and androgens, and it appears to be caused by a decrease in patients' metabolism of steroids.

A gas chromatographic method for the determination of neutral steroid profiles in urine, including studies on the effect of oxytetracycline administration on these profiles in men

A capillary gas chromatographic method for the determination of 'total' metabolic profiles of urinary neutral steroids was developed. The method is based on anion exchange chromatographic separation and purification of monoglucuronide-, monosulphate- and double-conjugated neutral steroids on DEAE-Sephadex A-25 microcolumns and the final analysis of the individual steroids in these conjugate groups is carried out by capillary column gas-liquid chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The method was shown to provide a convenient and accurate determination of total metabolic profiles of neutral steroids in urine and thus, can be used for metabolic studies of steroids and for diagnostic purposes. In the present investigation the effect of a tetracycline antibiotic on the production and metabolism of neutral steroids in men was studied during a 5-day oral administration of oxytetracycline. The results showed that the influence of oxytetracycline on neutral steroids was minor and mainly restricted to the changes in urinary neutral steroid glucuronide excretion. Oxytetracycline decreased the mean daily excretion of total neutral steroid monoglucuronides by 20% and a statistically significant decrease was found in the urinary excretion of 3 alpha-hydroxy-5 beta-androstan-17-one-glucuronide (etiocholanolone, 31%, P less than 0.05), 5 beta-pregnan-3 alpha,20 alpha-diolglucuronide (pregnanediol, 32%, P less than 0.05) and corticosteroid glucuronides, including 3 alpha,11 beta,17 alpha,20 beta,21-pentahydroxy-5 beta-pregnan- and 3 alpha,17 alpha,20 beta,21-tetrahydroxy-5 beta-pregnan-11-one-glucuronides (beta-cortol and beta-cortolone, 36%, P less than 0.05). The reason for this effect is unknown, but may be partly due to inhibition of intestinal hydrolysis of biliary steroid conjugates, which previously was shown to result in an interruption of enterohepatic circulation of steroids and an increased excretion of steroid conjugates by the faecal route.