Steroid Carboxylic Acids
Ronald Hobkirk in Steroid Biochemistry, 1979
Other corticosteroids are also converted to etienic acids by tissues. Neher and Wett-stein167,168 isolated two steroids, 11β-hydroxy-3-oxo-androst-4-ene-17β-carboxylic acid and 11β,18-dihydroxy-3-oxo-androst-4-ene-17β-carboxylic acid, from pig adrenals. It is unlikely that either is on the main route of aldosterone synthesis. They may have been artifacts generated during isolation of adrenal steroids, since the susceptibility of the corticosteroid side chain to decomposition makes this entirely possible. In other cases, a metabolic origin of the 18-hydroxy etienic acids seems more likely. A steroid with properties resembling 11β,18-dihydroxy acid was formed when 11-deoxycorticosterone was incubated with quartered rat adrenal glands.165
Factors Controlling the Biosynthesis of Aldosterone
Ronald Hobkirk in Steroid Biochemistry, 1979
Although corticosterone is believed to be the main precursor of aldosterone, it is not an obligatory intermediate in the conversion of progesterone to aldosterone. Progesterone and deoxycorticosterone were shown to be substrates that can be hydroxylated in position 18 and serve as precursors of aldosterone in normal and tumoral human adrenal cortex.50 18-Hydroxy-deoxycorticosterone was isolated and identified from rat adrenal cortex.51 Frog adrenocortical slices were shown to be able to transform radioactive 18-hydroxyprogesterone and 18-hydroxy-deoxycorticosterone to aldosterone.48 It was demonstrated that addition of radioinert 18-hydroxycorticosterone or corticosterone could inhibit the transformation of labeled progesterone to aldosterone, while 18-hydroxy-deoxycorticosterone showed no inhibition when added to incubation media of rat adrenal, suggesting that 18-hydroxy-deoxycorticosterone is not an important intermediate in aldosterone synthesis.52 18-Hydroxy-deoxycorticosterone is largely secreted by zona fasciculata-reticularis and, to a lesser extent, by zona glomerulosa. Adrenal blood flow is centripetal from the periphery, and 18-hydroxycorticosterone formed by inner zones — although not excluded — has little opportunity to serve as substrate for aldosterone formation.
Adaptation to Intermittent Hypoxia and its use for Protecting the Heart from Stress and Ischemic Damage
Felix Z. Meerson, Alexander V. Galkin in Adaptive Protection of The Heart: Protecting Against Stress and Ischemic Damage, 2019
The third complex reveals itself as stable enough shifts in the regulation of water-salt metabolism and the myogenic tone of resistive vessels. Adaptation is attended with partial atrophy of the hypothalamic supraoptic nucleus and of the adrenal glomerular zone, i.e., structures that through aldosterone and the antidiuretic hormone ensure retention in the organism of a certain reserve of water and sodium chloride.1,22 This is accompanied by a decline in the myogenic component of the vascular tone and decreased rigidity of arteria and arterioles, which should attenuate the extent of pressor reflexes. Clearly, such shifts must cause the organism to lose the excess of water and salt and, other things being equal, must diminish the probability of hypertension. Indeed, in spontaneously hypertensive rats adaptation to hypoxia largely impedes the development of hypertension, which is rather close to the hypertensive disease of man.23 A similar effect of adaptation is observed with deoxycorticosterone-salt hypertension.24
Sex differences in the hypothalamic-pituitary-adrenal axis response following a single or multiple days of sleep restriction
Published in Stress, 2020
Katelyn N. Buban, Elizabeth A. Shupe, Stephen W. Rothwell, T. John Wu
Relative expression of 11β-hydroxylase, which is an enzyme involved in the biosynthesis of CORT via the conversion of deoxycorticosterone to the active corticosterone (White, Pascoe, Curnow, Tannin, & Rösler, 1992), was measured in the adrenal glands to assess for adrenal insufficiency following PSD. Adrenal insufficiency is a form of adrenal fatigue or exhaustion believed to be caused by a period of overactivation of the adrenal glands, whereby the adrenals are unable to produce CORT due to either a change in local enzymatic activity, or due to a disruption in higher level systems involved in CORT release (Guilliams & Edwards, 2010). 11β-hydroxylase expression, was increased in males but not females following both one and three days of sleep deprivation. While, females showed greater 11β-hydroxylase expression overall compared to their male counterparts. These findings suggests that it is not adrenal insufficiency caused by changes in enzymes that is responsible for the dysregulation in HPA axis reactivity, and that there might be sex-specific differences in baseline enzymatic activity that might contribute to overall sex differences in the HPA axis reported in the literature (Rao & Androulakis, 2017). Therefore, the alterations seen at the level of the adrenal glands might be due to changes in higher-order systems such as the adrenal-sympathetic system or they might be sex-specific strategies employed by the adrenals to combat disruptions elsewhere in the HPA axis.
Abiraterone and spironolactone in prostate cancer: a combination to avoid
Published in Acta Clinica Belgica, 2019
Bert Dhondt, Sarah Buelens, Jeroen Van Besien, Matthias Beysens, Elise De Bleser, Piet Ost, Nicolaas Lumen
One of these agents, abiraterone acetate (AA), is an inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17), the pivotal enzyme in the biosynthesis of androgens in the testes, adrenal glands and PC cells. CYP17 catalyzes the conversion of pregnenolone and progesterone to dehydroepi-androsterone (DHEA) and androstenedione, respectively, the direct precursors of testosterone [14]. In two multicenter, double-blind, placebo-controlled phase III trials in mCRPC patients who previously received docetaxel (COU-AA-301) [10] and chemotherapy-naive patients (COU-AA-302) [11], AA significantly improved overall and progression-free survival. Even though AA is well tolerated, some important adverse effects were identified in its clinical trials. AA is an inhibitor of several hepatic CYP enzymes, which might play a role in the observed hepatotoxicity, characterized by elevated serum bilirubin, aspartate transferase (AST) and alanine transaminase (ALT) [10,11]. In addition, AA leads to a decrease in cortisol levels and a compensatory increase in adrenocorticotropic hormone (ACTH), causing accumulation of steroids with mineralocorticoid properties upstream of CYP17-catalyzed steps including corticosterone (CS) and deoxycorticosterone (DOC), but not aldosterone. This can lead to mineralocorticoid-related side effects, such as hypertension, hypokalemia and fluid retention [14]. To relieve these mineralocorticoid excess and related side effects, prednisone is associated to AA, because it suppresses ACTH secretion through a feedback mechanism.
Decision-making for adrenocortical carcinoma: surgical, systemic, and endocrine management options
Published in Expert Review of Anticancer Therapy, 2018
Soraya Puglisi, Paola Perotti, Deborah Cosentini, Elisa Roca, Vittoria Basile, Alfredo Berruti, Massimo Terzolo
Aldosterone-producing ACC is rare and is generally associated with severe hypertension and marked hypokalemia [12]. Screening by measuring plasma aldosterone and plasma renin activity (PRA) (or direct renin concentration) is recommended in all hypertensive and/or hypokalemic patients with adrenal masses [13]. In some cases, pseudo-aldosteronism is present, due to increased production of deoxycorticosterone. Pure estrogen excess is rare and may cause gynecomastia, loss of libido and testicular atrophy in men, while in women menstrual irregularities [8]. Hypersecretion of sexual steroids is frequently associated to cortisol excess in ACC patients. Baseline 17-OH progesterone levels are frequently increased, as well as androstenedione and DHEAS, which leads to increased plasma testosterone in females with signs of androgen excess (hirsutism, acne, alopecia) [3]. Measurement of steroid precursors in blood or urine may be exploited for diagnostic purposes. However, the value of increased DHEAS levels to predict malignancy of an adrenal mass is rather low [14]. More recently, it was demonstrated that serum steroid paneling by LC-MS/MS is a useful tool to discriminate ACC from other adrenal tumor lesions. In this study, both the number of steroids secreted in high amounts and the marked elevation of several steroid intermediates without biological activity was characteristic of ACC and useful for the differential diagnosis. The cortisol precursor 11-deoxycortisol was found the most discriminating between ACC and non-ACC adrenal lesions [15].
Related Knowledge Centers
- 11-Deoxycorticosterone
- 11Β-Hydroxyprogesterone
- Deoxycortisol
- Deoxycortisone
- 11-Hydroxyprogesterone