Salt-losing Syndrome Research Articles

Neonatal systemic pseudohypoaldosteronism type I

An 18-day-old male infant was admitted to the hospital due to recurrent hyperkalemia for more than 10 days. The neonate had milk refusal and dyspnea. The blood gas analysis revealed recurrent hyperkalemia, hyponatremia and metabolic acidosis. Adrenocortical hormone replacement therapy was ineffective. Additional tests showed a significant increase in aldosterone levels. Family whole exome sequencing revealed that the infant had compound heterozygous in the SCNNIA gene, inherited from both parents. The infant was diagnosed with neonatal systemic pseudohypoaldosteronism type I. The infant's electrolyte levels were stabilized through treatment with sodium polystyrene sulfonate and sodium supplement. The infant was discharged upon clinical recovery. This study provides a focused description of differential diagnosis of salt-losing syndrome in infants and introduces the multidisciplinary management of neonatal systemic pseudohypoaldosteronism type I.

Errate: Salt-Losing Syndrome in a Girl with Type I and II Pseudohypoaldosteronism

The author has requested a correction to an error in this sentence in the Case Report section: The girl was homozygous for the SCNN1A gene (variant NM_001159576: c.1053-25A>G) and heterozygous for the CUL3 gene (variant NM_003590: c.265+59C>T). The corrected sentence reads: The girl was homozygous for the SCNN1A gene (variant NM_001159576: c.1053-25A>G) and heterozygous for the CUL3 gene (variant NM_003590: c.264+59C>T). This correction has been made to the original publication. Reference: Agnieszka Szmigielska. Salt-Losing Syndrome in a Girl with Type I and II Pseudohypoaldosteronism. Am J Case Rep 2022; 23: e937536. DOI: 10.12659/AJCR.937536.

Antenatal glucocorticosteroids treatment: mechanisms of child healths programming

Synthetic glucocorticoids are widely used in pregnancies at risk of preterm delivery and in pregnant women at risk of having a child with severe 21-hydroxylase deficiency. The positive effects of reducing mortality in preterm and virilisation in girls with congenital adrenal hyperplasia are now unquestionable. The adrenogenital syndrome responding to 21-hydroxylase deficiency is a common, potential fatal disease. Its incidence calculated on the basis of neonatal screening data makes 1 case for 14000 live newborns among the worldwide population, 1 for 9638 – In Russia. DEX passes through the placenta and decreases fetal ACTH production thereby suppressing the fetal production of androgens. The prenatal treatment does not preclude from a life-long treatment in future and it is not prevention of a salt-losing syndrome at the postnatal period, and dexamethasone safety in relation to cognitive development of children prenatally treated with dexamethasone is still up for debate. Adding to the concern is the fact that the doses of DEX that the fetus is exposed to are estimated to be 60 times the normal fetal cortisol level. The glucocorticoid and the mineralocorticoid receptors are highly expressed in the hippocampus, amygdala, and prefrontal cortex. These areas, important for executive functioning, emotional regulation, and memory, are vulnerable to high doses of GCs. Most experimental data from animal have shown that prenatal exposure to synthetic glucocorticoids programs the foetal HPA and may lead to altered susceptibility to metabolic and cardiovascular disease i.e. metabolic syndrome, high blood pressure. Prenatal glucocorticoid exposure also leads to modification of HPAassociated behaviours and cognition.

Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit.

Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal life-threatening hypovolemia and hyperkalemia. The very high plasma aldosterone levels detected under hypovolemic or hyperkalemic challenge can lead to increased or decreased sodium reabsorption, respectively, through the Na(+)/Cl(-) cotransporter (NCC). However, the role of ENaC deficiency remains incompletely defined, because constitutive inactivation of individual ENaC subunits is neonatally lethal in mice. We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1. Compared with control mice fed a regular-salt diet, knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC protein, despite high plasma aldosterone levels. In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized. Finally, shift to a regular diet after the rescue diet reinstated the symptoms of severe PHA-1 syndrome and significantly reduced NCC phosphorylation. In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet. We further conclude that hyperkalemia becomes the determining factor in regulating NCC activity, regardless of sodium loss, in the ENaC-mediated salt-losing PHA-1 phenotype.

A homozygous missense mutation in SCNN1A is responsible for a transient neonatal form of pseudohypoaldosteronism type 1

Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disorder of mineralocorticoid resistance characterized by salt wasting, hyperkalemia, high aldosterone levels, and failure to thrive. An autosomal recessive form (AR-PHA1) is caused by mutations in the epithelial sodium channel ENaC with usually severe and persisting multiorgan symptoms. The autosomal dominant form of PHA1 (AD-PHA1) is due to mutations in the mineralocorticoid receptor causing milder and transient symptoms restricted to the kidney. We identified a homozygous missense mutation in the SCNN1A gene (c.727T>C/p.Ser(243)Pro), encoding α-subunit of ENaC (α-ENaC) in a prematurely born boy with a severe salt-losing syndrome. The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo. Interestingly, the patient's sibling born at term and harboring the same homozygous Ser(243)Pro mutation showed no symptom of salt-losing nephropathy. In vitro expression of the αSer(243)Pro ENaC mutant revealed a slight but significant decrease in ENaC activity that is exacerbated in the presence of high Na(+) load. Our study provides the first evidence that ENaC activity is critical for the maintenance of salt balance in the immature kidney of preterm babies. Together with previous studies, it shows that, when the kidney is fully mature, the severity of the symptoms of AR-PHA1 is related to the degree of the ENaC loss of function. Finally, this study identifies a novel functional domain in the extracellular loop of ENaC.

Sodium and Potassium Balance Depends on αENaC Expression in Connecting Tubule

Mutations in α, β, or γ subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans. In contrast, mice with selective inactivation of αENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis. To investigate the relative importance of ENaC-mediated sodium absorption in the CNT, we used Cre-lox technology to generate mice lacking αENaC in the aquaporin 2-expressing CNT and CD. Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of αENaC in the CCD and weak αENaC expression in the CNT. These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice. Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice. With dietary sodium restriction, these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia. Plasma aldosterone levels were significantly elevated under both standard and sodium-restricted diets. In summary, αENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing.

Activation of the Epithelial Sodium Channel (ENaC) by Serine Proteases

The study of human monogenic diseases [pseudohypoaldosteronism type 1 (PHA-1) and Liddle's syndrome] as well as mouse models mimicking the salt-losing syndrome (PHA-1) or salt-sensitive hypertension (Liddle's syndrome) have established the epithelial sodium channel ENaC as a limiting factor in vivo in the control of ionic composition of the extracellular fluid, regulation of blood volume and blood pressure, lung alveolar clearance, and airway mucociliary clearance. In this review, we discuss more specifically the activation of ENaC by serine proteases. Recent in vitro and in vivo experiments indicate that membrane-bound serine proteases are of critical importance in the activation of ENaC in different organs, such as the kidney, the lung, or the cochlea. Progress in understanding the basic mechanism of proteolytic activation of ENaC is accelerating, but uncertainty about the most fundamental aspects persists, leaving numerous still-unanswered questions.

Hipoplasia adrenal, hipogonadismo y talla baja por una nueva mutación del gen DAX-1 (pGly168fsX17)

Various genes play a role in the morphogenesis of the adrenal cortex, among them the DAX-1 gene. We report an 18-year-old man who showed complete adrenal failure in the neonatal period, hypogonadotropic hypogonadism and pathological short stature associated with a mutation of the DAX-1 gene that has not previously been described. The patient was admitted to hospital at the age of 16 days due to salt-losing syndrome with hyperpotassemia. After this episode, he received no treatment for 2 years, when he began to show progressive anorexia, salt avidity, asthenia, cutaneous hyperpigmentation and finally shock, with hypoglycemia, hyponatremia, metabolic acidosis and hyperpotassemia. Puberal development was spontaneous but incomplete. The patient received treatment with testosterone-depot. He reached a definitive testicular volume of 6 ml and pubarche V. His final height is 150 cm (target height 164 cm). Amplification of the DAX-1 gene showed mutation g 2080-2081 insertion in the first position of codon 168, which produces a premature shutdown of protein DAX-1 at position 184.

Functional expression of a pseudohypoaldosteronism type I mutated epithelial Na+ channel lacking the pore-forming region of its alpha subunit.

The autosomal recessive form of type I pseudohypoaldosteronism (PHA-I) is an inherited salt-losing syndrome resulting from diminution-of-function mutations in the 3 subunits of the epithelial Na+ channel (ENaC). A PHA-I stop mutation (alpha(R508stop)) of the ENaC alpha subunit is predicted to lack the second transmembrane domain and the intracellular COOH-terminus, regions of the protein involved in pore function. Nonetheless, we observed a measurable Na+ current in Xenopus laevis oocytes that coexpress the beta and gamma subunits with the truncated alpha subunit. The mutant alpha was coassembled with beta and gamma subunits and was present at the cell surface at a lower density, consistent with the lower Na+ current seen in oocytes with the truncated alpha subunit. The single-channel Na+ conductance for the mutant channel was only slightly decreased, and the appearance of the macroscopic currents was delayed by 48 hours with respect to wild-type. Our data suggest novel roles for the alpha subunit in the assembly and targeting of an active channel to the cell surface, and suggest that channel pores consisting of only the beta and gamma subunits can provide significant residual activity. This activity may be sufficient to explain the absence of a severe pulmonary phenotype in patients with PHA-I.

Acute pyelonephritis as a cause of hyponatremia/hyperkalemia in young infants with urinary tract malformations

Obstructive uropathy causes tubular resistance to aldosterone and severe metabolic imbalance may be precipitated by an episode of pyelonephritis. In the last 3 years we investigated 52 episodes of pyelonephritis (positive urine culture, elevated C reactive protein, fever, elevated neutrophil count) in 50 children between 15 days and 15 months of age. Ultrasonography voiding cystography and renal scintiscan were performed in all cases and i.v. urography in some. A salt-losing syndrome with hyponatremia and hyperkalemia (Na < 125 meq/liter; K > 6.3 meq/liter) was observed in 17 infants < 3 months, accompanied by plasma aldosterone concentration of 5000 to 23,000 pg/ml (normal value, < 1000 pg/ml). All these children had a severe urinary tract (UT) malformation (ureteropelvic junction stenosis in 7 cases, vesicoureteral reflux in 7, posterior urethral valves in 2, double system in 1). Thirteen infants < 3 months, 7 with no urinary tract malformations, did not have electrolyte imbalance. Pyelonephritis was diagnosed in 20 other patients ages 4 to 15 months, including 16 with severe UT malformations; 4 had normal UTs. We conclude that a salt-losing syndrome with tubular resistance to aldosterone can occur during pyelonephritis in young infants with congenital UT malformation, that the risk diminishes considerably or disappears after 3 months of age and that in the absence of UT malformation pyelonephritis does not cause acute sodium loss of clinical relevance.

Congenital Adrenal Hyperplasia

The incidence of congenital adrenal hyperplasia in Saudi Arabia and the frequency of the carrier rate are not well known. Both figures should be high, considering the commonness of first-degree consanguinity in this part of the world. We present 25 cases of congenital adrenal hyperplasia, most of them due to a defect of the 21 hydroxylase enzyme, diagnosed and followed over three years at Suleimania Children's Hospital in Riyadh. There were ten boys and 15 girls exhibiting all degrees of masculinization, mostly Grade III (53%) and Grade IV and V (13.3% each). The degree of masculinization of the external genitalia in the girls (46XX) was sufficiently pronounced in seven patients to lead to sex identity errors at birth. This aggravated the psychological reactions in the families, particularly before the surgical correction. The frequency of neonatal deaths in the patients' families related to a similar disorder was high (12%). The mean age at onset of the salt-losing crises in affected infants was 9 days in females and 25 days in males and this was the most common clinical presentation of the disorder (80%). Systemic neonatal screening and intrauterine diagnosis in at risk families must be done to provide hormonal intervention and thus prevent the formation of ambiguous genitalia and avoid the resulting plastic surgery that must be performed in female patients.

Neonatal diagnosis of orotic aciduria: An experience with one family

2. Ulick S: Diagnosis and nomenclature of disorders of the terminal portion of the aldosterone biosynthetic pathway. J Clin Endocrinol Metab 43:92, 1976. 3. Royer P, Lestradet H, deMenibus CH, Vermeil G: Hypoaldosteronisme familial chronique ~. debut neo-natal. Ann Pediatr (Paris) 8:133, 1961. 4. Visser HKA, Cost WS: A new hereditary defect in the biosynthesis of aldosterone: Urinary C2~-corticosteroid pattern in three related patients with a salt-losing syndrome, suggesting an 18-oxidation defect. Acta Endocrinol (Copenh) 47:589, 1964. 5. David R, Golan S, Drucker W: Familial aldosterone deficiency: Enzyme defect, diagnosis, and clinical course. Pediatrics 41:403, 1968. 6. R6sler A, Rabinowitz D, Theodor R, Ramirez LD, Ulick S: The nature of the defect in a salt-wasting disorder of Jews of Iran: J Clin Endocrinol Metab 44:279, 1977. 7. Veldhuis JD, Kulin HE, Santen R J, Wilson TE, Melby JC: Inborn error in the terminal step of aldosterone biosynthesis: Corticosterone methyloxidase type II deficiency in a North American pedigree. N Engl J Med 303:117, 1980. 8. Kowarski A, Katz H, Migeon C J: Plasma aldosterone concentration in normal subjects from infancy to adulthood. J Clin Endocrinol Metab 38:489, 1974. 9. Siegler RL, Crouch RH, Hackett TN Jr, Walker M, Jubiz W: Potassium-renin-aldosterone relationships during the first year of life. J PEDIATR 91:52, 1977. 10. Pratt JH, Holbrook MM, Dale SL, Melby JC: The measurement of urinary tetrahydroaldosterone by radioimmunoassay. J Steroid Biochem 8:677, 1977. 11. Mattox VR, Nelson AN: Determination of urinary tetrahydroaldosterone glucosiduronic acid by radioimmunoassay. J Steroid Biochem 14:243, 1980. 12. Zurbriigg RP: Congenital adrenal hyperplasia. In Gardner LI, editor: Endocrine and genetic diseases of childhood and adolescence, ed 2. Philadelphia, 1975, WB Saunders, p 476.

Reinstitution of mineralocorticoid therapy in congenital adrenal hyperplasia. Effects on control and growth.

The results of reintroduction of mineralocorticoid substitution therapy (9-alpha-fluorohydrocortisone) in five children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are described. All children had shown a salt-losing syndrome in infancy, but were off mineralocorticoids during several years; at the start of this study they all had elevated plasma renin activity (PRA). Four of them had increased and fluctuating pregnanetriol excretion during the year preceding reintroduction of mineralocorticoids, indicating poor control despite substantial substitution with hydrocortisone: 26 +/- 1.9 mg/m2/day (mean +/- S.E.M.). Reintroduction of mineralocorticoid therapy at ages 5.0-9.4 years resulted in a marked improvement of control, significant reduction in hydrocortisone requirements (to 17.6 +/- 1.4 mg/m2/day) and improvement in linear growth. The data suggest that, in all children with CAH and elevated PRA, continuation throughout childhood of mineralocorticoid therapy in addition to glucocorticoid therapy is necessary for optimal control and linear growth.

Tubular Na, K-ATPase deficiency, the cause of the congenital renal salt-losing syndrome.

In the serum of two infant sisters with a congenital renal salt-losing syndrome, Na was rather low and K considerably increased. Even with Na levels of 126 mval/1, sodium was excreted in the urine. Creatinine and hippurate clearances were normal. Primary disturbances of the steroid metabolism were not detectable; plasma cortisol was normal, aldosterone and renin were compensatorily increased. Treatment with DOCA was unsuccessful. Whereas the first infant died (in another hospital), the second one throve well with high oral substitution of NaCl. There was no pathological findings other than a moderate hyperplasia of the juxtaglomerular apparatus, in a kidney biopsy. Except for minimal activity in the ascending limb of Henle's loop, there was no membrane bound Na, K-ATPase in the microdissected tubules. This finding most probably explains the renal salt loss, as this enzyme is necessary for the transcellular flow of sodium and potassium.

Steroid excretion by an infant with an unusual salt-losing syndrome: a gas chromatographic-mass spectrometric study.

The excretion of steroids by an infant with pseudohypoaldosteronism is reported. The patient presented with symptoms of hyperkalaemia and hyponatraemia, and was maintained for a period on a high salt intake and mineralocorticoids. However, he collapsed on the 48th day of life and could not be resuscitated.The urinary steroids were identified by combined gas chromatography–mass spectrometry and quantitation was achieved by gas chromatography. The following steroids were identified: tetrahydroaldosterone, tetrahydrocortisone, α- and β-cortolone, 1 β-hydroxytetrahydrocortisone, 1 β-hydroxycortolone, tetrahydrocorticosterone (THB), tetrahydro-11-dehydrocorticosterone (THA), 3α, 20α, 21-trihydroxy-5β-pregnan-ll-one, 5-pregnene-3β, 16α, 20α, 21-tetrol, and 5-androstene-3β, 16αa, 17β-tiiol.The patient evidently secreted an excess of aldosterone so the disorder was probably due to a form of renal-tubule unresponsiveness to this hormone. Some of the urinary steroids normally excreted in large amounts during infancy (16α-hydroxy DHA, 16-oxo-androstenediol, and 16α-hydroxypregnenolone) were not detected in the urine samples, and it is suggested that the precursor of these steroids (pregnenolone) was being fully utilised in the synthesis of aldosterone and cortisol.

Medullary cystic disease of the kidney: study of a case with scanning and transmission electron microscopy and light microscopy.

A case of medullary cystic disease of the kidney with uremia and salt-wasting, treated by nephrectomy and renal transplantation at the age of 14 years, was studied by light microscopy and scanning and transmission electron microscopy. The results confirm previous findings of excessive basement membrane production around renal tubules and cysts, free communication between cysts and nondilated tubules, and a corticomedullary inflammatory infiltrate unlike that of pyelonephritis. The epithelial cells lining the cysts were not typical of those of any one particular segment of the nephron. A finding not previously reported is the presence of numerous intracytoplasmic vesicles and dilated intercellular spaces among the cells lining the cysts, suggesting that abnormally active fluid transport plays a role in the salt-losing syndrome of this disorder.

Juxtaglomerular cells (JGC) in virilizing congenital adrenogenital syndrome with and without salt-losing syndrome : H. Osterwalder. Schweiz. Med. Wschr. 101:1298–1305 (September), 1971

Juxtaglomerular cells (JGC) in virilizing congenital adrenogenital syndrome with and without salt-losing syndrome : H. Osterwalder. Schweiz. Med. Wschr. 101:1298–1305 (September), 1971

Familial congenital hypoaldosteronism caused by 18-OH-dehydrogenase deficiency

Extract: In one case studied from the neonatal period through a follow-up period at almost five years of age, a salt-losing syndrome could be related to a defect in 18-OH-dehydrogenase. In the intial course of the disease, treatment with desoxycorticosterone acetate controlled the salt-losing tendency. At that time, the rate of aldosterone secretion was less than 10 μg/day and that of urinary tetrahydroaldosterone was less than μg/day. In contrast, the rate of corticosterone secretion was 5400 μg/day and the F:B ratio was 0.8. Urinary 18 hydroxytetrahydro A (18 OH-THA) was increased to 128 μg/24 h. There was no cortisol insufficiency; secretion rate was 20 mg m2/day and plasma ACTH 0.24 mU/100 ml plasma. At 20 months of age, treatment was stopped because of hypernatremia. From that time on, the child was clinically normal and received no salt supplement. The hormonal results were as follows: At 22 months of age, the secretion rate of aldosterone was less than 5 μg/day and of corticosterone was 8600μg/day on the sixth day of a well-tolerated salt suppression test. 18 OH-THA was 116μg/day; the F:B ratio for urinary metabolites was low, 0.9. At 3 years and 7 months of age, excretion of urinary tetrahydroaldosterone was 10 μg/day, 18 OH-THA was in the normal range, and the F:B ratio remained low, 0.6 (normal salt intake). At 4 years and six months of age, secretion rate was 19 μg/day and the 18 hydrocorticosterone secretion rate was 470 μg/day (ratio 18 OH-B: aldosterone 24.7). Plasma renin activity was 88.8 ng/l/min. The brother of the propositus was observed when 6 years of age. Urinary tetrahydrosterone was 27 μg/day, 18 OH-THA was 75/μg/day, and the urinary F:B ratio was 0.7 while receiving a normal salt intake. The spontaneous clinical improvement of subjects with the salt-losing syndrome is possibly related to the appearance of a certain amount of aldosterone, an increase in secretion of corticosterone, and modification in salt content of a normal diet during this period. Speculation: A salt-losing syndrome due to 18-OH-dehydrogenase deficiency, probably familial, improved spontaneously. Long-term studies showed persistence of the biosynthetic defect. The data presented raise questions concerning clinical recovery that could be correlated with steroid administration and, possibly, with modifications in sodium homeostasis at that period of life.

RENAL CARCINOMA: HOW IT METASTASIZES.

The renal cell carcinoma, known also as hypernephroma and Grawitz tumor, is one of the present-day entities replacing syphilis as a medical enigma. The disorder presents occasionally with anemia, erythremia, pyrexia of unknown etiology, hypercalcemia, or salt-losing syndrome and demands respect (12). For the radiologist, too, there are many confusing aspects concerning the sites and time of appearance of metastases, difficult not only to predict, but also to explain. Because a better understanding of the modes of spread could help in earlier diagnosis, rationale of treatment, and method of follow-up, 152 cases of proved hypernephromas, including 49 followed until necropsy, were studied retrospectively. Spread via the lymphatics and the paravertebral plexus of veins was found to playa more important role than generally appreciated. Lymph Node Metastases Nodes of the renal pedicle and paraaortic areas are sometimes involved at surgery, but little attention is focused on this in subsequent patient follow-up....

A NEW HEREDITARY DEFECT IN THE BIOSYNTHESIS OF ALDOSTERONE: URINARY C21-CORTICOSTEROID PATTERN IN THREE RELATED PATIENTS WITH A SALT-LOSING SYNDROME, SUGGESTING AN 18-OXIDATION DEFECT.

ABSTRACT Two infants with a salt-losing syndrome were observed. They were 5 and 15 weeks old on admission to the hospital. The four parents of these two patients were related. Another 14 year old child in the same family was seen at the age of 3 weeks in the hospital with the same clinical syndrome. All cases gave a good response to deoxycorticosterone acetate (DOCA). External genitalia were normal; total urinary excretion of 17-ketosteroids, 17-ketogenic steroids and 17-hydroxycorticosteroids were normal. The pedigree of the family could be traced back for six generations. The six parents of the three children with the salt-losing syndrome had the same two great-grandparents five generations back. Urinary C21-corticosteroid excretion showed a typical pattern in the infants and the 14 year old child. No aldosterone was detectable. There was a considerable increase in the total »B« compounds: corticosterone (B), 11-dehydrocorticosterone (A) and their tetrahydrometabolites (THA, THB,