Biomedical subjects

J Fiet

Publications and source records attributed to J Fiet.

At least 37 records · Page 2Linked to original sources

PubMed1999

The cortisol-cortisone shuttle in children born with intrauterine growth retardation.

We evaluated the involvement of a possible dysfunction of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the fetal growth retardation and poor growth rates of children born with intrauterine growth retardation (IUGR). Children with IUGR have a nephron deficit and are also at risk of developing cardiovascular diseases, high blood pressure, glucose intolerance, and dyslipidemia later in life. The major site of 11beta-HSD2 production is the kidney and its deficit causes hypertension. We investigated plasma concentrations of cortisol (F) and cortisone (E) and the F/E ratio in 26 control children and in 40 IUGR children without catch-up growth. We also determined cholesterol, HbA1C, insulin, and glucose levels in plasma. Mean F values were 106 +/- 54.2 ng/mL in control children and 114.6 +/- 53.2 ng/mL in IUGR children. Mean E values were 19.5 +/- 7.1 ng/mL in control children and 17.9 +/- 6.85 ng/mL in IUGR children. The mean F/E ratio for control children was 5.5 +/- 1.7. Eight (20%) of the IUGR children (IUGR children of group 1) had high F/E ratios more than 2 SD above the normal mean: 13.15 +/- 4.26, (p < 0.0001) as compared to control children, whereas the other 32 children (IUGR children of group 2) had normal F/E ratios: 5.40 +/- 1.43 (p = 0.68). Childhood height was significantly lower for group 1 than group 2 children (-3.63 SD and -2.92 SD, respectively: p < 0.01) and was negatively correlated with the F/E ratio (p < 0.01). Systolic blood pressure was higher for group 1 (p = 0.005) and for group 2 (p = 0.015) than for control children. The diastolic pressure in IUGR children of group 1 was higher than that in control children (p = 0.013) and slightly higher than that in group 2 (p = 0.1, ns). Cholesterol concentrations were higher in group 1 than in group 2 (p = 0.029), and controls (p = 0.017) and correlated positively with F/E (0.02 < p < 0.05). Fasting insulin concentrations were higher in group 1 than in group 2 (ns) and controls (ns). There was no difference in mean fasting glucose concentrations, or HbA1C between the three groups. Twenty percent of our children with IUGR and poor growth rates had high F/E ratios, suggesting a possible partial 11beta-HSD2 deficit. Whether these children are at high risk of developing cardiovascular diseases as adults remains to be further evaluated.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1999

Insulin secretion and insulin sensitivity in diabetic and non-diabetic subjects with hepatic nuclear factor-1alpha (maturity-onset diabetes of the young-3) mutations.

OBJECTIVE: To evaluate insulin secretion and sensitivity in affected (diabetes mellitus or impaired glucose tolerance; n=7) and in unaffected (normal glucose tolerance; n=3) carriers of hepatocyte nuclear factor-1alpha (maturity-onset diabetes of the young-3 (MODY3)) gene mutations. METHODS: Insulin secretion was assessed by an i.v. glucose tolerance test (IVGTT), hyperglycemic clamp and arginine test, and insulin sensitivity by an euglycemic hyperinsulinemic clamp. Results were compared with those of diabetic MODY2 (glucokinase-deficient) and control subjects. RESULTS: The amount of insulin secreted during an IVGTT was decreased in affected MODY3 subjects (46+/-24 (s.d.) pmol/kg body weight (BW)) as compared with values in MODY2 (120+/-49pmol/kg BW) and control (173+/-37pmol/kg BW; P=0.0004) subjects. The amount of insulin secreted during a 10mmol/l glucose clamp was decreased in affected MODY3 subjects (171+/-78pmol/kg BW) and MODY2 subjects (302+/-104pmol/kg BW) as compared with control subjects (770+/-199pmol/kg BW; P=0.0001). Insulin secretion in response to arginine was decreased in affected MODY3 subjects. Milder and heterogeneous defects were observed in the unaffected MODY3 subjects; the amount of insulin secreted during the hyperglycemic clamp was 40-79% of that of controls. The response to arginine was abnormally delayed. Insulin sensitivity was decreased in diabetic but not in non-diabetic MODY3 subjects. CONCLUSIONS: Beta-cell dysfunction in response to glucose and arginine is observed in affected and unaffected MODY3 subjects. The MODY3 and MODY2 subtypes present different insulin secretion profiles. Secondary insulin resistance might contribute to the chronic hyperglycemia of MODY3 patients and modulate their glucose tolerance.

Adolescent↗

PubMed1999

[Acne in the male resistant to isotretinoin and responsibility of androgens: 9 cases, therapeutic implications].

INTRODUCTION: Treatment failures with isotretinoin in female patients are frequently related to endocrinological dysfunctions. Such a concept has never been discussed in male patients. CASE REPORTS: An extensive endocrinological work-up has been performed in nine male patients who presented with an acne refractory to conventional treatment and to isotretinoin. Adrenal dysfunction was found in four patients and isolated 5-alpha reductase hyperactivity in 2 cases. Three work-ups were normal. A suppressive treatment in three patients with adrenal dysfunction provided immediate efficacy. COMMENTS: These results would provide insight into the mechanism of refractory acne in men.

Acne Vulgaris↗

PubMed1999

Assessment of the follicular cortisol:cortisone ratio.

Cortisol and cortisone concentrations in serum and follicular fluid (FF) from women undergoing in-vitro fertilization (IVF) treatment were monitored. Four groups were included: group 1, women in their natural menstrual cycle having an endogenous mid-cycle surge of gonadotrophins; group 2, women in their natural menstrual cycle receiving human chorionic gonadotrophin (HCG) for ovulation induction; group 3, women receiving exogenous gonadotrophins for ovarian stimulation and HCG for ovulation induction; and group 4, women receiving exogenous gonadotrophins for ovarian stimulation, follicles being aspirated immediately before administration of HCG. In this study, 12 follicles contained oocytes which resulted in clinical pregnancy after IVF. Cortisone concentrations were significantly higher in FF compared with that of matched serum samples, while the opposite was observed for cortisol, resulting in cortisol:cortisone ratios being significantly lower in FF compared with serum. FF from group 4 showed significantly higher cortisone concentrations than FF from each of the other three groups. FF from group 1 showed significantly higher cortisone concentrations and significantly lower cortisol:cortisone ratios in comparison with groups 2 and 3. None of the observed parameters pinpointed any of the follicles containing oocytes which resulted in a clinical pregnancy. The intrafollicular concentrations of cortisol and cortisone suggest that pre-ovulatory follicles actively convert cortisol to cortisone. Neither FF concentrations of cortisol and cortisone nor the cortisol:cortisone ratio seem to reflect implantation potential of the derived pre-embryos.

Adult↗

PubMed1998

Assessment of microsatellite instability in urine in the detection of transitional-cell carcinoma of the bladder.

Loss of heterozygosity (LOH) and alterations in microsatellite DNA markers have been reported in bladder-cancer tumors. We have studied, in a blinded fashion, using PCR-based microsatellite analysis, genetic alterations of cells exfoliated in urine of 59 Caucasian patients and control patients; 31 with initially confirmed bladder transitional-cell carcinoma (TCC), 17 with signs and symptoms suggestive of bladder cancer, 6 control patients who underwent renal transplantation, and 5 control patients with urolithiasis. Microsatellite analysis of cells exfoliated in the urine allowed the diagnosis of 83% (10/12) of patients with bladder TCC recurrence confirmed by cystoscopy, while 100% of patients followed up for transitional-cell carcinoma of the bladder for up to 12 months without evidence of tumor recurrence upon routine cystoscopy showed no microsatellite alterations. None of the patients without neoplasia (negative controls) had any microsatellite alterations, whereas all patients who underwent renal transplantation had additional new alleles corresponding to contamination with donor's renal and urothelial cells (positive controls). No control patients had any evidence of transitional-cell carcinoma by cystoscopy. Our results provide objective evidence that non-invasive molecular detection of bladder TCC by microsatellite analysis is reproducible with a sensitivity of 83% and a specificity of 100% in Caucasian patients. This non-invasive procedure represents a potential clinical tool for the detection and the screening of bladder TCC.

Adult↗

PubMed1998

Endothelin 1 receptors, signal transduction and effects on DNA and proteoglycan synthesis in rat articular chondrocytes.

This study showed that endothelins (ETs) stimulate DNA and proteoglycan synthesis in monolayer culture of rat articular chondrocytes (AC) by interacting with specific cell surface receptors. The high affinity receptors bound [125I]ET-1 with a Kd of 0.54 nM and Bmax of 81.4 pM/microgram DNA (approximately 40 000 binding sites per cell) was demonstrated. [125I]ET-1 binding was completely inhibited by unlabelled ET-1 or ET-2, and by BQ123 (ETA receptor antagonist), whereas ET-3 and IRL1038 (ETB receptor antagonist) did so only weakly. SDS-PAGE of cell extracts containing [125I]ET-1 cross-linked to the receptors, followed by autoradiography of the gels revealed a single 50-kDa band. These findings indicate that most of the receptors are subtype ETA. Although mRNA transcripts specific for both ETA and ETB receptors were found by RT-PCR, the ETA mRNA was more abundant. ET-1 increased the production of cAMP, cGMP and prostaglandin E2 (PGE2) and protein kinase C (PKC) activity in a concentration- and time-dependent manner. ET-1, and to a lesser degree ET-2, stimulated DNA synthesis, whereas ET-3 was inactive. Stimulation of DNA synthesis by ET-1 was strongly inhibited in a concentration-dependent manner by BQ123 and, to a much lesser degree, by IRL1038, which is consistent with an ETA receptor. ET-1 also stimulated proteoglycan synthesis and increased the amount of mRNA specific for the aggrecan gene. These findings strongly suggest that ET-1 is involved in regulating chondrocyte proliferation and metabolism in health, and presumably in disease.

Animals↗

PubMed1998

Crystal structure of 11,18-oxidosteroids obtained by hypoiodination of cortisol acetonide.

The photochemical hypoiodination of cortisol acetonide, without neutralization of the excess of acidity during the work-up of the reaction, led to a mixture of 11 beta,18-oxido-17 alpha,21-dihydroxy-4-pregnen-3,20-dione and 11 beta,19-oxido-17 alpha,21-dihydroxy-4-pregnen-3,20-dione. Side chain cleavage of the former compound gave 11 beta,18-oxido-4-androsten-3,17-dione. The crystal structures of both of these 11 beta,18-oxidosteroids were determined by X-ray. The ring conformations are discussed and compared with those of aldosterone.

Crystallography, X-Ray↗

PubMed1998

[Peripheral adrenal insufficiency in AIDS].

BACKGROUND: Lesions of adrenal glands are common findings at autopsy of patients with acquired immunodeficiency syndrome (AIDS). In contrast the diagnosis of symptomatic adrenal insufficiency is rarely established during the lifetime of these patients. PATIENTS: We report four new cases and review the literature. All four patients had full blown AIDS with a mean CD4 cell count of 19 mu/L. One or more opportunistic disease was present at the time of diagnostic: cytomegalovirus retinitis in two cases, disseminated Mycobacterium avium infection in two, Kaposi's sarcoma in two and Candida esophagitis in one. RESULTS: The clinical presentation constantly included fatigue, weight loss, severe orthostatic hypotension and gastrointestinal disturbances. Cutaneous hyperpigmentation was present in three cases. In most cases biological abnormalities were typical, such as hyponatremia, urinary Na/K ratio > or = 1, and hyperkalemia. Serum cortisol levels were within the range of normal in three cases but response to the cosyntropin challenge was typically impaired in all cases. Clinical and biological manifestations returned to normal in 1 to 3 weeks after initiation of therapy with cortisol, associated to fludrocortisone in three cases. However, 13 months after diagnosis, three patients were dead. CONCLUSION: Usually asymptomatic, diagnostic of symptomatic adrenal insufficiency must be suspected even when clinical presentation is atypical because rapid efficiency of hormonal treatment.

AIDS-Related Opportunistic Infections↗

PubMed1998

Hypoxia reduces endothelin production by rat alveolar type II cells in primary culture.

The purpose of the study was to describe endothelin (ET) production and to characterize the effect of hypoxia on preproendothelin-1 (preproET-1) messenger ribonucleic acid (mRNA) expression and ET secretion by rat type II pneumocytes in vitro. Rat type II pneumocytes were incubated in a sealed chamber containing a normoxic (21% O2) or hypoxic (1% O2) atmosphere for increasing durations. Immunoreactive ET (irET) was measured in cell supernatants using a radioimmunoassay. Rat preproET-1 mRNA was detected by Northern blot. Rat type II pneumocytes expressed preproET-1 mRNA, contained irET and secreted irET in a time-dependent manner. ET secretion was dependent on de novo ribonucleic acid (RNA) and protein synthesis. Hypoxia decreased irET secretion by 27% and reduced the steady-state level of preproET-1 mRNA by 60% whereas intracellular irET concentration was unchanged. Inhibition was partially reversible with the return to a normoxic atmosphere. Inhibition of nitric oxide synthesis did not prevent the inhibitory effect of hypoxia. In conclusion, rat type II pneumocytes in primary culture secreted immunoreactive endothelin and expressed preproendothelin-1 messenger ribonucleic acid. Hypoxia reversibly reduced endothelin-1 production through a reduction of the steady-state preproendothelin-1 messenger ribonucleic acid level. Nitric oxide synthesis did not mediate the inhibitory effect of hypoxia.

Animals↗

PubMed1997

The mechanism of inhibition of endothelin-1-induced stimulation of DNA synthesis in rat articular chondrocytes.

Endothelin-1 (ET-1) is a potent mitogen for rat articular chondrocytes (AC) in short term culture (24 h). Prolonged incubation (72 h) of AC with ET-1 resulted in inhibition of [3H]thymidine incorporation. This inhibition seemed to be mediated by prostaglandins (PGs) released in response to ET-1, since indomethacin (INDO) enhanced ET-1-induced [3H]thymidine incorporation. In agreement with this hypothesis, exogenous prostaglandins (PGE2, PGF2alpha and TxB2) blocked all basal, ET-1-induced and ET-1 induced-INDO-enhanced [3H]thymidine incorporation and ET-1 stimulated PGE2 release in a time and concentration-dependent manner. INDO also blocked cGMP production and 6-anilino-5,8-quinolinedione, a relatively specific inhibitor of cGMP formation, enhanced the stimulation and suppressed the inhibition of ET-1-induced DNA synthesis. In addition, 8-bromo-cGMP, an analogue of cGMP, blocked at all time periods studied, both basal and ET-1-induced incorporations of [3H]thymidine. Thus, PGs produced in response to ET-1 counteract the ET-1-induced stimulation of [3H]thymidine incorporation into rat AC by increasing cGMP production.

Aminoquinolines↗

PubMed1997

Constitutive expression of FGF2/bFGF in non-tumorigenic human prostatic epithelial cells results in the acquisition of a partial neoplastic phenotype.

Fibroblast growth factor 2 (FGF2), also known as basic fibroblast growth factor (bFGF), belongs to the FGF family, which consists of at least 9 closely related members. FGF2 is a potent mitogen for fibroblasts derived from normal prostate and, to a lesser extent, for prostatic epithelial cells. Its role in the physiology of the normal prostate seems to be limited to stromal cells, whereas in prostate cancer FGF2 may also have an autocrine/paracrine effect on epithelial cells. In order to better understand the effects of FGF2 on the prostatic epithelium, especially its role in the progression of prostate cancer by establishing an autocrine-stimulation loop, we transfected FGF2 cDNA into a human prostatic epithelial cell line, PNT1A, immortalized with SV40 large-T antigen. This cell line is non-tumorigenic and expresses a high-affinity FGF2 receptor, FGFR1/flg. We characterized 3 independent FGF2-transfected clones and found that the establishment of an FGF2 autocrine loop on these cells led to (i) serum-independent growth, (ii) increased proliferation and (iii) anchorage-independent growth. Such results argue in favor of the possible action of FGF2 on progression of prostate cancer via an FGF2 autocrine loop on epithelial cells.

Animals↗

PubMed1997

Constitutive and inducible expression of endothelin-1 in primary rat articular chondrocyte culture.

Endothelin-1 (ET-1) mRNA expression and protein production were examined in primary rat articular chondrocyte (AC) cultures by RT-PCR and radioimmunoassay, respectively. We found that serum-starved rat AC express ET-1 mRNA and produce the peptide constitutively. Treatment of cells with 10% FCS resulted in a marked increase in ET-1 levels with a peak at 48 h (5.6-fold). A similar concentration-dependent effect was also obtained in the presence of interleukin 1beta (3.1-fold), tumour necrosis factor alpha (3. 5-fold), lipopolysaccharide (2.7-fold), transforming growth factor beta1 (3.5-fold), epidermal growth factor (5.0-fold) and insulin-like growth factor-I (4.4-fold). In addition, ET-1 was found to induce, over a period of 24 h, a potent concentration-dependent stimulation of DNA synthesis in rat AC. These findings demonstrate for the first time the constitutive expression and production of ET-1 by rat AC which could be modulated by several cytokines and growth factors, suggesting a possible role for ET-1 in autocrine regulation of chondrocyte function.

Animals↗

PubMed1997

Exhaustive screening of the 21-hydroxylase gene in a population of hyperandrogenic women.

21-hydroxylase (21-OH) deficiency accounts for the vast majority of nonclassic (NC) forms of congenital adrenal hyperplasia (CAH), and is associated with symptoms detectable either in childhood (precocious puberty) or sometimes only later in adulthood (hirsutism, acne, amenorrhea). While the severe forms of the disease responsible for salt wasting or simple virilization have been extensively studied, the NC 21-OH deficiency is less well characterized, especially in adults. We studied the 21-OH gene (CYP21) in a population of 69 unrelated hyperandrogenic subjects suspected to be homozygous or heterozygous for NC 21-OH deficiency, based on basal and adrenocorticotrophin (ACTH)-stimulated plasma 17-hydroxyprogesterone (17-OHP, 17-OHPSI) and 21-desoxycortisol (21-DOF, 21-DOFSI) levels. To identify all mutations involved, determination of the whole gene sequence, including exons, exon-intron junctions, and promoter region, was performed, followed by a study of large rearrangements and identification of compound heterozygotes. Alterations were identified in at least one allele of 55 hyperandrogenic subjects. Two NC alterations, Val282Leu and Pro454Ser, were detected in 68% and 7% of the affected alleles, respectively, whereas mutations involved in severe forms were identified in 21% of them. These results document the utility of a molecular diagnosis in hyperandrogenic women suspected of being either heterozygous or homozygous for NC 21-OH deficiency and clearly indicate the importance of genetic counseling in such a population.

17-alpha-Hydroxyprogesterone↗

PubMed1997

IL-1 beta inhibits ET-1 production by ATII cells in vitro: evidence for involvement of cyclooxygenase 2 pathway.

The aim of this study was to characterize the effect of alveolar macrophage (AM) secretory products on endothelin (ET)-1 production by rat alveolar type II (ATII) cells in primary culture. We quantified preproendothelin (ppET)-1 mRNA by Northern blot and ET-1 concentrations in cell supernatants by enzyme-linked immunosorbent assay. Conditioned medium (CM) from rat adherent AM decreased the ppET-1 mRNA levels in ATII cells and reduced ET-1 concentrations in cell culture supernatants. This effect was mediated by interleukin (IL)-1 beta as shown by pretreatment of CM with an anti-IL-1 beta neutralizing antiserum. IL-1 beta effect was dependent on protein synthesis, was partially prevented with indomethacin, and was totally prevented with dexamethasone. Specific inhibition of cyclooxygenase 2 activity completely reversed the effect of IL-1 beta. We conclude that rat AM inhibit ET-1 production by rat ATII cells in vitro through IL-1 beta secretion. The IL-1 beta-mediated inhibition is dependent on the cyclooxygenase 2 pathway. Downregulation of ET-1 production by activated AM could limit the intra-alveolar burden of this profibrogenic peptide and thus could prevent fibrosis development.

Animals↗

PubMed1997

Endothelin-1 secretion by alveolar macrophages in systemic sclerosis.

Endothelin-1 (ET-1), a potent fibroblast/smooth muscle cells mitogen, has been implicated in the pathogenesis of systemic sclerosis lung disease (SSc). Since monocytes and macrophages are thought to be activated in SSc, we hypothesized that alveolar macrophages (AM) and their precursors blood monocytes from patients with SSc produced more ET-1 than cells from healthy subjects. ET-1 and big ET-1 concentrations were measured in plasma, in bronchoalveolar lavage (BAL) fluids and in cell culture supernatants from monocytes and alveolar macrophages derived from 13 patients with definite SSc with lung involvement and from 10 control subjects. Plasma and BAL fluid ET-1 and big ET-1 levels were similar in both controls and patients with SSc. ET-1 and big ET-1 concentrations in unstimulated alveolar macrophage supernatants were similar in both groups. In contrast, LPS-stimulated alveolar macrophages from patients with SSc secreted higher amounts of ET-1 and big ET-1 than control subjects. ET-1 and big ET-1 concentrations in monocyte supernatants (either LPS-stimulated or not) were not different in patients and controls. These results show that AM from patients with SSc are hyperresponsive to LPS in vitro in terms of ET-1 and big ET-1 production and suggest that AM could participate in vivo in the overproduction of this potentially profibrotic mediator in patients with SSc.

Adolescent↗

PubMed1997

Sandwich-type enzyme immunoassay for big endothelin-I in plasma: concentrations in healthy human subjects unaffected by sex or posture.

A sandwich-type enzyme immunoassay has been developed for measuring human big endothelin-1 (big ET-1) in human plasma and supernatant fluids from human cell cultures. Big ET-1 is the precursor of endothelin 1 (ET-1), the most potent vasoconstrictor known. A rabbit antibody raised against the big ET-1 COOH-terminus fragment was used as an immobilized antibody (anti-P16). The Fab' fragment of a monoclonal antibody (1B3) raised against the ET-1 loop fragment was used as the enzyme-labeled antibody, after being coupled to acetylcholinesterase. The lowest detectable value in the assay was 1.2 pg/mL (0.12 pg/well). The assay was highly specific for big ET-1, demonstrating no cross-reactivity with ET-1, <0.4% cross-reactivity with big endothelin-2 (big ET-2), and <0.1% with big endothelin-3 (big ET-3). We used this assay to evaluate the effect of two different postural positions (supine and standing) on plasma big ET-1 concentrations in 11 male and 11 female healthy subjects. Data analysis revealed that neither sex nor body position influenced plasma big ET-1 concentrations. This assay should thus permit the detection of possible variations in plasma concentrations of big ET-1 in certain pathologies and, in association with ET-1 assay, make possible in vitro study of endothelin-converting enzyme activity in cell models. Such studies could clarify the physiological and clinical roles of this family of peptides.

Adolescent↗

PubMed1997

Convenient chromatographic prepurification step before measurement of urinary cortisol by radioimmunoassay.

We applied various prepurification protocols (extraction with different solvents, liquid/solid separation on bonded silica media, Celite, and Sephadex LH20 chromatography) with a range of commercially available RIA kits to measure cortisol in urine samples. We then compared the results with the concentrations measured by a HPLC method validated with reference to isotope dilution gas chromatography-mass spectrometry. We conclude that chromatography on a commercial, prepacked diol minicolumn (Waters Sep-Pak Vac RC) in combination with dichloromethane extraction is a convenient and very effective purification step before RIA of urinary cortisol in patients not receiving corticoid medication. We tested numerous steroids for interference and found that free polar cortisol derivatives (hydroxylated or hydrogenated) could only partially account for the overestimations routinely encountered when free urinary cortisol concentrations are measured by direct RIA.

Adult↗

PubMed1997

Radioimmunoassay of cortisone in serum, urine, and saliva to assess the status of the cortisol-cortisone shuttle.

We have developed a new assay for cortisone (E) in serum, saliva, and urine involving Celite chromatography followed by RIA with 125I-labeled E and scintillation proximity assay. The chromatography step separates cortisol (F) from E, and in combination with their RIAs, permits assessment of the status of the F-E shuttle. We report the results of basal, postcorticotropin (ACTH), and postdexamethasone E and F concentrations and their circadian fluctuations in the serum, saliva, and urine of healthy volunteers. The serum and urine F/E ratios were increased in patients with ectopic ACTH secretion, whereas in adrenal adenoma and Cushing disease only the urinary ratio was increased. In chronic renal insufficiency this ratio was increased in serum (23.5 +/- 3.9) but diminished in saliva (0.38 +/- 0.11), and in apparent mineralocorticoid excess the ratios were high in serum (44.3 +/- 9.3) and urine (5.35 +/- 0.85) compared with those of healthy subjects (serum 9.8 +/- 3.5, urine 0.52 +/- 0.29, saliva 0.52 +/- 0.29).

11-beta-Hydroxysteroid Dehydrogenases↗