Synthesis and progestational activity of 16-methylene-17 alpha-hydroxy-19-norpregn-4-ene-3,20-dione and its derivatives.

16-Methylene-17 alpha-hydroxy-19-norpregn-4-ene-3,20-dione 1 and its 17 alpha-acylated derivatives were synthesized. The length of the 17 alpha-side-chain ranges from C2-C6. As anticipated, compound 1 did not show any progestational activity or receptor binding activity; whereas, the acylated compounds, especially the butyrate, showed remarkable ability to bind to progesterone receptors. These compounds also showed progestational activity in an in vitro T47D cell culture assay in which progestins increase alkaline phosphatase activity and in an in vivo ovulation inhibition assay. All of the compounds synthesized were without estrogenic activities. The results showed that acylation of 16-methylene-17 alpha-hydroxy-19-norprogesterone can increase progestational activity. The progestational activities of these compounds varied with the 17 alpha-side chain.

Suppression of endogenous corticosterone levels in vivo increases the steroidogenic capacity of purified rat Leydig cells in vitro.

In vitro studies have shown that corticosterone (B) directly inhibits testosterone (T) production by purified Leydig cells but does so only at high concentrations. 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) in Leydig cells oxidatively inactivates B, lowering its effective concentration, thus protecting against the suppressive effect of glucocorticoid on T production. The aim of the present study was to assess the significance of B at physiological levels in modulating T production and 11 beta-HSd activity in Leydig cells. To determine the effects of endogenous B on Leydig cell steroidogenesis, male rats (200-250 g body wt) were adrenalectomized (ADX), while control rats were subjected to sham surgery (SHAM). Seven days after surgery: T and LH were measured in serum; T production was measured in aliquots of spent culture media from 3-h incubations of purified Leydig cells; 11 beta-HSD activity and messenger RNA was measured in purified Leydig cells. ADX rats had elevated serum T (P < 0.05) in contrast to SHAM control or ADX rats that received B replacement (1 mg/100 g body wt per day, i.p., on the final 3 days). Serum LH levels were uninfluenced by ADX, with or without B replacement (SHAM), 0.45 +/- 0.16 ng/ml; ADX, 0.35 +/- 0.13 ng/ml; ADX + B, 0.61 +/- 0.09 ng/ml, NS, P > 0.05). This indicated that the alteration of T production was induced by a mechanism that is independent of LH. ADX nearly doubled LH-stimulated T production by purified Leydig cells, from 106.3 +/- 9.3 (SHAM) to 183.2 +/- 16.7 (ADX) ng/10(6) cells.3 h (mean +/- SEM for three replications of the experiment, P < or = 0.02). T production by Leydig cells from the ADX + B treatment group was suppressed to 53% of SHAM values, indicating that B inhibits T production after ADX. The oxidative activity of 11 beta-HSD in Leydig cells exceeded its reductive activity, and both activities declined after ADX. The decline in 11 beta-HSD activities after ADX was prevented by B replacement. Similarly, the steady state levels of 11 beta-HSD messenger RNA declined in Leydig cells after ADX, and this decline was prevented by B replacement. We conclude that physiological levels of B exert a tonic, negative control directly on Leydig cell steroidogenesis and also induce intracellular 11 beta-HSD activity, thereby protecting against B-mediated inhibition of T production. By modulating the level of active glucocorticoid in Leydig cells, 11 beta-HSD is thus a significant determinant of their steroidogenic capacity.

Expression of 11 beta-hydroxysteroid dehydrogenase during decidualization of human endometrial stromal cells.

This study evaluated the expression of the corticosteroid-metabolizing enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) during in vitro decidualization of human endometrial stromal cells. The cultured stromal cells displayed both NADP(+)-dependent (type 1) and NAD(+)-dependent (type 2) 11 beta HSD activities under basal conditions. Although the cells did not respond to estradiol (E2) added alone, catalytic levels of both isoforms were enhanced by medroxyprogesterone acetate (MPA) and further enhanced by E2 plus MPA. Type I messenger RNA (mRNA) was undetected by Northern analysis of total RNA, but was evident as a 1.5-kilobase band in polyadenylated selected RNA from E2- plus MPA-treated cultures. Use of RT-PCR to augment the sensitivity of mRNA detection revealed the presence of type I mRNA as a faint band in the MPA-treated cultures and as an intense band in the E2- plus MPA-treated cultures. Thus, type I mRNA is present as a low abundance message in the cultured stromal cells whose steady state levels parallel progestin-enhanced enzyme activity. As the expression of several progestin-regulated decidualization markers is also augmented by E2, the results of the present study reveal a correlation between enhanced 11 beta HSD expression and the decidualization reaction. Time-course measurements indicated that elevated 11 beta HSD expression is an early event in the decidualization response, which precedes E2- plus MPA-enhanced PRL production by several days. Clear dose-response effects on both type 1 and type 2 11 beta HSD activities were obtained in cells incubated with 10(-8) mol/liter E2 added together with MPA at concentrations that approximated circulating progesterone levels from the luteal phase (10(-9) mol/liter) through pregnancy (10(-7) mol/liter). Corticosteroids are thought to exert toxic and teratogenic effects on the implanting embryo and could influence trophoblast invasion by regulating extracellular matrix turnover. Therefore, the novel finding that decidualization involves marked enhancement of the corticosteroid-metabolizing capacity of stromal cells suggests a mechanism by which decidual cells could affect the health and invasiveness of implanting trophoblastic cells.

Accelerated stability studies on 16-methylene-17 alpha-acetoxy-19-nor-pregn- 4-ene-3,20-dione (Nestorone).

The stability of the contraceptive steroid, Nestorone (16-methylene-17 alpha-acetoxy-19-nor-pregn-4-ene-3,20-dione) in the solid state and in aqueous solutions, was investigated using reverse-phase high-performance liquid chromatography. In the solid state, whether as a powder or when it is incorporated into Silastic implants, the steroid does not undergo detectable degradation even under severe experimental conditions. In solution, the drug undergoes slow degradation that is dependent on temperature and pH of the medium. The decomposition is defined by first-order mechanism. As expected, the reaction rate increases with increasing storage temperature. The linearity of the Arrhenius plot indicates that there is no change in the reaction mechanism within the temperature range studied. In alkaline media, the drug degrades at a faster rate through hydrolytic rather than an oxidative mechanism. The major hydrolytic degradation product, 16-methylene-17 alpha-hydroxy-19-nor-pregn-4-ene-3,20-dione, was separated and identified by mass spectrometry.

Different patterns of metabolism determine the relative anabolic activity of 19-norandrogens.

Testosterone, the principal androgen secreted by Leydig cells, exerts a wide range of actions including growth of the male reproductive tract (androgenic effects) and growth of non-reproductive tissues such as muscle, kidney, liver, and salivary gland (anabolic effects). As androgenic steroids were discovered some were found to have relatively more anabolic than androgenic activity. The results reviewed in this report suggest that these differences result, in part, from the differential metabolism of the steroids in individual tissues and the varied activities of the individual metabolites. In the accessory sex organs (e.g. the prostate) testosterone is 5 alpha-reduced to dihydrotestosterone (DHT) which, due to its higher affinity for androgen receptors (AR), amplifies the action of testosterone. In contrast, when 19-nortestosterone (NT) is 5 alpha-reduced, its affinity for AR decreases, resulting in a decrease in its androgenic potency. However, their anabolic potency remains unchanged since significant 5 alpha-reduction of the steroids does not occur in the muscle. 7 alpha-methyl-19-nortestosterone (MENT) does not get 5 alpha-reduced due to steric hindrance from the 7 alpha-methyl group. Therefore, the androgenic potency of MENT is not amplified as happens with testosterone. These metabolic differences are responsible for the increased anabolic activity of NT and MENT compared to testosterone. Part of the biological effects of testosterone are mediated by its aromatization to estrogens. The fact that MENT is also aromatized to 7 alpha-methyl estradiol, a potent estrogen, in vitro by human placental and rat ovarian aromatase suggests that some of the anabolic actions of MENT may be mediated by this estrogen.

Mutations in putative glycosylation sites of rat 11 beta-hydroxysteroid dehydrogenase affect enzymatic activity.

11 beta-hydroxysteroid dehydrogenase (11-HSD) catalyzes the interconversion of corticosterone and 11-dehydrocorticosterone in rats, or cortisol and cortisone in humans. The 'liver' or 'Type I' isozyme is a widely distributed glycoprotein that utilizes NADP+ as a co-factor. To study the role of glycosylation in maintaining enzymatic activity, we introduced mutations into the two potential N-linked glycosylation sites (asparagine-X-serine, residues 158-160 and 203-205) predicted from the rat cDNA sequence. Mutagenesis was performed by a PCR based technique, and wild-type (WT) and mutant cDNAs were expressed in Chinese hamster ovary cells after cloning into the pCMV4 vector. At each putative glycosylation site, asparagine (N) was changed to glutamine (Q) or aspartic acid (D), and serine (S) changed to alanine (A). All three modifications of the first site (N158Q, N158D, S160A) had minimal (75-100% of WT) effects on dehydrogenase activity and caused a mild (50-75% of WT) decrease in reductase activity. In contrast, mutations at the second site had marked effects, with N203Q and N203D completely abolishing both dehydrogenase and reductase activities and S205A decreasing both activities to about 20% of WT. The double mutation of S160A and S205A also abolished all activity, even though the enzyme carrying each mutation alone was, at least, partially active. The results suggest that N203 (which is highly but not completely conserved in short chain dehydrogenase enzymes) is essential for activity of 11-HSD. N-linked glycosylation may be necessary for full activity or stability of the enzyme.

Cloning of cDNA encoding an NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase in sheep kidney.

11 beta-Hydroxysteroid dehydrogenase (11-HSD) catalyzes the conversion of cortisol to cortisone and corticosterone to 11-dehydrocorticosterone. This activity may be required to confer normal ligand specificity upon the mineralocorticoid receptor. Although an isozyme of 11-HSD was previously isolated from rat liver, a different isozyme is apparently expressed in mineralocorticoid target tissues. We isolated a sheep kidney cDNA clone encoding this isozyme by expression screening using Xenopus oocytes. The cDNA is 1.8 kb in length and encodes a protein of 427 amino acid residues with a predicted M(r) of 46,700. When expressed in oocytes, this enzyme functions as an NAD(+)-dependent 11 beta-hydrogenase with very high affinity for steroids, but it has no detectable reductase activity. It is 37% identical in amino acid sequence to an NAD(+)-dependent isozyme of 17 beta-hydroxysteroid dehydrogenase, but only 20% identical to the NADP(+)-dependent liver isozyme of 11-HSD. It is expressed at high levels in the kidney and adrenal and at lower levels in the colon. The corresponding gene is present in a single copy in the sheep genome. In humans, this gene is a candidate locus for the syndrome of apparent mineralocorticoid excess, a form of hypertension postulated to result from 11-HSD deficiency in mineralocorticoid target tissues.

NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase. Cloning and characterization of cDNA from sheep kidney.

11 beta-Hydroxysteroid dehydrogenase (11-HSD) catalyzes the conversion of cortisol to cortisone and corticosterone to 11-dehydrocorticosterone. This activity may be required to confer normal ligand specificity upon the mineralocorticoid receptor. Although an isozyme of 11-HSD was previously isolated from rat liver, a different isozyme is apparently expressed in mineralocorticoid target tissues. We isolated a sheep kidney cDNA clone encoding this isozyme by expression screening using Xenopus oocytes. The cDNA is 1.8 kilobase pairs in length and encodes a protein of 427 amino acid residues with a predicted M(r) of 46,700. When expressed in oocytes, this enzyme functions as an NAD(+)-dependent 11 beta-dehydrogenase with very high affinity for steroids, but it has no detectable reductase activity. It is 37% identical in amino acid sequence to an NAD(+)-dependent isozyme of 17 beta-hydroxysteroid dehydrogenase but only 20% identical to the NADP(+)-dependent liver isozyme of 11-HSD. It is expressed at high levels in the kidney and adrenal and at lower levels in the colon. The corresponding gene is present in a single copy in the sheep genome. In humans, this gene is a candidate locus for the syndrome of apparent mineralocorticoid excess, a form of hypertension postulated to result from 11-HSD deficiency in mineralocorticoid target tissues.

Studies on the metabolism of testosterone trans-4-n-butylcyclohexanoic acid in the cynomolgus monkey, Macaca fascicularis.

Metabolism of intravenously administered testosterone trans-4-n-butylcyclohexanoate (T bucyclate), a potent, long-acting androgen, was studied in cynomolgus monkeys (Macaca fascicularis). About 5% of the radioactivity of a dose of doubly labeled ester (14C, 3H) was excreted via the gastrointestinal tract. Most of the administered radioactivity was excreted in the urine within 120 h. No intact T bucyclate was recovered from either compartment. Tritium attributed to bucyclic acid and its metabolites was excreted rapidly (peak excretion was at 6h after injection), while 14C excretion, attributed to testosterone and its metabolites, extended over 4 days. Testosterone metabolites were excreted predominantly as sulfate esters. Analysis of urinary products derived from the bucyclic acid moiety of T bucyclate showed no products susceptible to glucuronidase treatment, and showed a mixture of unidentified solvolyzable and unconjugated products. No unmetabolized trans-4-n-butylcyclohexanoic acid was detected in urine or feces. It is concluded that metabolism of testosterone bucyclate is initiated in vivo in cynomolgus monkeys by hydrolysis of ester to testosterone and bucyclic acid. The bucyclate side chain is rapidly cleared, and the testosterone is retained in the circulation.

11 beta-Hydroxysteroid dehydrogenase alleviates glucocorticoid-mediated inhibition of steroidogenesis in rat Leydig cells.

Leydig cells from mature rat testes contain high levels of 11 beta-hydroxysteroid dehydrogenase (11HSD), an enzyme that oxidatively inactivates glucocorticoids. We have proposed that the 11HSD of Leydig cells protects the testis from the effects of high levels of glucocorticoids, as may occur in stress and Cushing's disease. In this paper we investigate whether testicular 11HSD by inactivating glucocorticoids diminishes their ability to inhibit testosterone (T) production. Corticosterone (B) and dexamethasone (DEX) inhibited T production by purified Leydig cells in a dose-dependent manner. Activity was diminished by 50% with 1.5 nM DEX vs. 0.4 microM B. The shapes of the inhibition curves were consistent with a saturable process; inhibition by both steroids was overcome with the glucocorticoid receptor antagonist RU486. We concluded that the effect was mediated by glucocorticoid receptors. Aldosterone, 11 beta-hydroxyprogesterone, and 11-deoxycorticosterone did not decrease T production. The greater potency of DEX compared to B may be due to its resistance to oxidative inactivation by 11HSD. As 11-dehydrocorticosterone, the product of the oxidation of B by 11HSD, did not inhibit T production, it was predicted that inactivation of 11HSD should enhance the inhibitory effect of B. Consistent with this prediction, inhibition by B was increased by carbenoxolone, an inhibitor of 11HSD, becoming more similar to that by DEX. Suppression of T production by DEX (which is not a substrate of 11HSD) was unaffected by carbenoxolone. We conclude that through reduction of the levels of inhibitory glucocorticoids, 11HSD has a novel role among Leydig cell steroid-metabolizing enzymes in the regulation of T production.

Reciprocal changes in plasma corticosterone and testosterone in stressed male rats maintained in a visible burrow system: evidence for a mediating role of testicular 11 beta-hydroxysteroid dehydrogenase.

The purpose of these studies was to investigate the possible role of rat Leydig cell 11 beta-hydroxysteroid dehydrogenase (11HSD) in mediating the inhibitory effects of corticosterone on testosterone production. In a unique communal environment, the visible burrow system, male Long-Evans rats spontaneously segregated into unstressed dominant and stressed subordinate social relationships. Subordinate animals had elevated plasma corticosterone and diminished circulating testosterone levels relative to the dominant animals. The categories of animals were distinguished by behavioral criteria: weight change, wounds received, offensive and defensive behavior, and freedom of movement. As a result of their persistently elevated corticosterone levels, subordinate animals had smaller thymi and larger adrenals and spleens than dominants. We have postulated that Leydig cells are protected against the inhibitory effects of glucocorticoids on testosterone secretion by the inactivating effects of 11HSD. High corticosterone and low 11HSD are predicted to suppress testosterone production, and normal or diminished corticosterone levels combined with normal or elevated 11HSD should permit undiminished testosterone production. Consistent with these predictions, the testes of subordinate animals contained significantly lower 11HSD activity than those of dominant animals. The 11HSD of livers of subordinate and dominant animals were statistically indistinguishable. The results of this study support the postulated role of 11HSD as a protector of Leydig cell function.

Metabolism of testosterone trans-4-n-butylcyclohexyl carboxylate, a high potency androgen, in rodents and primates: in vitro studies.

Testosterone trans-4-n-butylcyclohexyl carboxylate releases continuous physiological levels of testosterone into the circulation of men or monkeys over a period of 8 to 10 weeks from an intramuscular depot and may, therefore, be an agent of choice for androgen replacement therapy. The purpose of this study was to investigate the metabolism of the ester and its side chain. The ester was hydrolysed by blood sera of guinea-pig, rabbit and rat, but not horse or man. It was slowly hydrolysed by rat and cynomolgus liver and the testosterone metabolites androstenedione and androstanediol were formed. Bucyclic acid (trans-4-n-butylcyclohexyl carboxylate) was slowly metabolized to two metabolites, M1 and M2, by cynomolgus liver homogenates. The acid metabolites were analysed by chromatography and mass spectrometry after reaction with diazomethylpyrene to form fluorescent pyrenyl esters. When compared with synthetic compounds using the criteria of chromatographic mobility and mass spectral analysis, the polar metabolite was identified as hydroxy-4-n-butylcyclohexyl carboxylate. The less polar metabolite could not be definitively identified.

11 beta-Hydroxysteroid dehydrogenase in the rat inner ear.

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) was demonstrated specifically in the spiral ligament of the cochlear membranous labyrinth by enzyme assay, Western blotting, and immunocytochemistry. Other cochlear regions and the vestibular membranous labyrinth were devoid of 11 beta-HSD. Spiral ligament 11 beta-HSD exerted predominantly an oxidative activity and was NADP specific, which is similar to 11 beta-HSD in most other tissues. 11 beta-HSD was colocalized with mineralocorticoid and glucocorticoid steroid receptors in the spiral ligament. 11 beta-HSD may control steroid binding to these inner ear steroid receptors and, in addition, may regulate steroid receptor binding in the adjacent stria vascularis in paracrine fashion.

Comparative aspects of 11 beta-hydroxysteroid dehydrogenase. Testicular 11 beta-hydroxysteroid dehydrogenase: development of a model for the mediation of Leydig cell function by corticosteroids.

It has been shown that stress or disease-induced increases in plasma corticosterone result in diminished testosterone secretion from the testes. This article reviews investigations from our laboratories that explore the role of 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) in this process. It is proposed that the level of 11 beta-OHSD in Leydig cells dictates the level of intracellular glucocorticoid available to the glucocorticoid receptor and thus the potency of corticosteroid as an inhibitor of testosterone secretion. Stressed and unstressed rats were housed under simulated natural conditions in a Visible Burrow System. Stressed animals showed elevated plasma corticosteroid, lowered plasma testosterone, and diminished testicular 11 beta-OHSD, Immunocytochemical analysis showed that only Leydig cells of the rat testis contain 11 beta-OHSD and glucocorticoid receptors. Half-maximal inhibition of testosterone by Leydig cells required 1.5 nM dexamethasone or 0.4 microM corticosterone. Glycyrrhetinic acid, an inhibitor of 11 beta-OHSD, increased the potency of corticosterone, but did not affect dexamethasone based inhibition. The glucocorticoid receptor blocker, RU 486, prevented inhibition by both corticosterone and dexamethasone. Other classes of steroid were not inhibitors of testosterone biosynthesis. Thus, 11 beta-OHSD oxidizes corticosterone to the inactive metabolite 11-dehydrocorticosterone, relieving steroid-dependent inhibition of Leydig cell function. Lowered enzyme activity increases glucocorticoid dependent inhibition of testosterone production. We conclude that the evidence supports a role of 11 beta-OHSD in testosterone secretion by the testes.

Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency.

The syndrome of apparent mineralocorticoid excess (AME) is a form of low renin hypertension that is thought to be caused by congenital deficiency of 11 beta-hydroxysteroid dehydrogenase (11HSD) activity. This enzyme converts cortisol to cortisone and apparently prevents cortisol from acting as a ligand for the mineralocorticoid (type I) receptor. It also catalyzes the reverse oxoreductase (cortisone to cortisol) reaction. Four patients with AME and the parents of the first patient described (now decreased) were analyzed for mutations in the cloned HSD11 gene encoding an 11HSD enzyme. A patient with suspected cortisone reductase deficiency was also studied. No gross deletions or rearrangements in the HSD11 gene were apparent on hybridizations of blots of genomic DNA. Direct sequencing of polymerase chain reaction-amplified fragments corresponding to the coding sequences, intronexon junctions, and proximal untranslated regions of this gene revealed no mutations. AME may involve mutations in a gene for another enzyme with 11HSD activity or perhaps another cortisol-metabolizing enzyme.

Differential inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone in rat brain regions and peripheral tissues.

Carbenoxolone (CX), the succinyl ester of glycyrrhetinic acid, causes hypokalemia and hypernatremia. Its pharmacological effects are believed to be due to its inhibition of 11 beta-hydroxysteroid dehydrogenase (11-HSD). There was a marked inhibition of this enzyme in the liver, kidney, pituitary, hippocampus, hypothalamus and amygdala 1 h after intraperitoneal administration of CX (100 mg kg-1) to intact male rats. Intracerebral injection of CX (1.5 mg kg-1) into the 3rd ventricle inhibited the oxidation of corticosterone to 11-dehydrocorticosterone by 11-HSD in the pituitary and hippocampus and produced marked behavioral hyperactivity but had no effect in the liver or kidney. Lower amounts of CX (10-50 micrograms/rat) given intracerebroventricularly (i.c.v) were without significant effect on 11-HSD in the pituitary or amygdala 1 h after infusion but inhibited this enzyme differentially in the hippocampus and hypothalamus. Inhibition of 11-HSD activity in the hippocampus and hypothalamus was observed up to 6 h after i.c.v. administration of CX (50 micrograms/rat) together with some decrease in activity of this enzyme in the pituitary at 3 h. The findings that low doses of CX given i.c.v. can alter the activity of 11-HSD in specific brain regions without affecting its activity in peripheral tissues, and only marginally in the pituitary, provides a method to study the central role of this enzyme independently of systemic effects.

Developing a radioimmunoassay for anordrin: the synthesis of propionyl and hemisuccinyl esters of anordiol.

We describe the chemical synthesis of the 2 beta-propionate-17 beta- hemisuccinate and 2 beta-hemisuccinate-17 beta-propionate diesters of anordiol (2 alpha,17 alpha-diethynyl-A-nor-5 alpha-androstane-2 beta,17 beta-diol) and the method for coupling them to bovine serum albumin and Affi-gel 102, in order to prepare antibodies for radioimmunoassay of anordrin. In addition, we describe the chemical synthesis of the following derivatives: 2 beta-ol-17 beta-propionate, 2 beta-propionate-17 beta-ol, 2 beta-hemisuccinate-17 beta-ol, and 2 beta-ol-17 beta-hemisuccinate.

Inhibition by glycyrrhetinic acid of rat tissue 11 beta-hydroxysteroid dehydrogenase in vivo.

Inhibition of 11 beta-hydroxysteroid dehydrogenase (11-HSD) in the major organs of the rat by the inhibitor glycyrrhetinic acid (a component of licorice) was investigated. The inhibitor decreased 11-HSD levels in most organs after intraperitoneal injection. The effect was dose dependent, was maximally effective 3 hours after administration, and was completely reversed at 24 hours. The magnitude and patterns of effectiveness differed between tissues. It was concluded that the inhibition of 11-HSD by glycyrrhetinic acid is not restricted to one or a few organs, but is broadly based.

The forms and functions of 11 beta-hydroxysteroid dehydrogenase.

In this review, we consider the relationship between the structure and function of 11 beta-hydroxysteroid dehydrogenase (11-HSD) purified from rat liver. The rat liver enzyme is a single domain glycoprotein with a unique active site and belongs to the short chain alcohol dehydrogenase family. Evidence supporting the presence in other tissues of 11-HSD isoforms is discussed.