Clinical Endocrinology (1996) 45, 613–614

Hydroxysteroid dehydrogenases as hormonalregulators

Vivian James6 Brookmans Avenue, Brookmans Park AL9 7QJ, UK

In the last few years, our appreciation of the role of steroidmetabolizing enzymes, such as the dehydrogenases and reduc-tases, has undergone a considerable re-evaluation. Originallytheir major role was thought to be mainly as promoters ofsteroid hormone catabolism, providing a means of extinguish-ing hormone activity, but now they are recognized as versatileand important regulators exercising selective metabolic con-trol in certain peripheral tissues. The classic example of thisfunction is 5a-reductase which, by converting testosterone todihydrotestosterone, changes one potent androgen to another,each having different tissue specificities. The change in ourunderstanding of these processes has been immeasurably aidedby studies of those metabolic disorders in which there is analteration in the activity of the enzyme, and thus studies ofpatients with 5a-reductase deficiency have, apart from eluci-dating the pathophysiology of the disease, also considerablyadvanced our understanding of androgen physiology. Thisknowledge has also made it possible to develop improveddiagnostic techniques which are based on a proper under-standing of the abnormal biology which underlies the disorder.

Other examples in which clinical studies have benefitedboth the basic scientist and the clinician are abundant and 11b-hydroxylase deficiency, causing congenital adrenal hyper-plasia, is another familiar and important example.

An enzyme which is attracting considerable interest is 11b-hydroxysteroid dehydrogenase (11-HSD). Its role is to promotethe interconversion of the 11-oxo and 11-hydroxy-cortico-steroids, which in man are principally cortisone and cortisol.The operation of this shuttle has important endocrine con-sequences, since because of the highly specific location ofthe enzyme in mineralocorticoid (MC) target tissues such asthe renal tubule, it is able to play a key role in determining theactivity of the MC receptor. The discovery that this receptor hadequal affinities for aldosterone and cortisol (Krowzowski &Funder, 1983) posed the difficult problem of how aldosteronecould obtain privileged access to the MC receptor, given thatthe concentration of cortisol to which the receptor is exposed isconsiderably in excess of that of aldosterone. The explanationderives from the activity of 11-HSD, which effectively convertscortisol to cortisone. Since cortisone does not bind to thereceptor, the receptor is left accessible to aldosterone (Edwardset al., 1988; Funderet al., 1988).

The predicted consequence of a deficiency of this enzyme is

that the MC receptors would be exposed to high concentrationsof cortisol rendering the usual MC control mechanismsinoperative. This is the situation which occurs in the syndromeof apparent mineralocorticoid excess (AME) in which hypo-kalaemia and hypertension occur together with low levels ofrenin and aldosterone. The cause was correctly postulated byUlick et al. (1979) on the basis of observations on the pattern ofurinary metabolites. It has since been confirmed from tissuestudies that gene mutations in 11-HSD occur in AME (White,1996).

The postulated mechanism predicts that the metabolic patternof urinary cortisol metabolites would be different from normal,with an increase in the fraction of cortisol metabolites and adecrease in those of cortisone. This has provided the basis for adiagnostic test. It involves measuring the major metabolites ofcortisol and cortisone in urine, i.e. tetrahydrocortisol (THF),alloTHF, and tetrahydrocortisone (THE). The ratio of themetabolites of cortisol to those of cortisone is significantlyhigher in patients with AME.

However, the situation is complicated by the discovery thatthere are at least two iso-enzymes of 11-HSD. The form thatoccurs in MC target tissues is 11-HSD-II, which has a lowKm

for cortisol, and effectively converts only cortisol to cortisone.Another form, 11-HSD-I, is found in glucocorticoid targettissues, such as the liver and cardiovascular system, and thisform predominantly converts cortisone to cortisol, thus main-taining cortisol levels in these tissues. The overall metabolicpicture of cortisol metabolism revealed by urinary metaboliteanalysis is that produced by the activity of both these enzymes.Apart from this complication, these measurements are tech-nically difficult to perform and require sophisticated laboratoryequipment, and considerable technical skill.

In this issue ofClinical Endocrinology, Palermoet al. (1996)propose the use of a simpler ratio, that of urinary free cortisol(UFF) to urinary free cortisone (UFE). They suggest that sincethe main source of cortisone is renal, this ratio may be a betterindicator of renal HSD activity, and they present data from anumber of patients with AME which illustrate that this ratio isindeed relatively more abnormal than the ratio of the majorurinary cortisol metabolites. As additional supporting evidencethat the measurement of UFE is reflecting renal 11-HSD-IIactivity, they point out that the ratio of UFF/UFE is lower innormal subjects (0.54) than the ratio of THF + alloTHF/THE(1.21). This argument is not too strong, since if all the cortisolmetabolites including the cortols are included in the latter ratio,then it falls to 0.71, approaching that of UFF/UFE.

Commentary

613q 1996 Blackwell Science Ltd

Nevertheless, this approach has considerable advantages; it islikely to be, as the authors suggest, more specific for HSD-II,and is technically easier to perform. UFF is a widely availableassay (it is an excellent and important diagnostic assay forCushing’s syndrome) and no doubt a similar assay for UFEwould not be too difficult to devise. This would make it simplerto screen for enzyme defects and would facilitate the inves-tigation of, for example, AME type 2. Palermoet al. have nowshown that patients with this condition do exhibit a diminutionof UFE excretion, albeit to a lesser event than is found in AMEtype 1, and it appears that it involves a more complex metabolicdefect.

The importance of 11-HSD-II is not confined to its role inrenal tissue. It occurs in other tissues, notably placenta, and itsrole there may be to protect the fetus from elevated cortisollevels of maternal origin. It has been suggested (Secklet al.1995) that aberrations in the activity of placental HSD-II may,by affecting the exposure of the fetus to cortisol, influence fetaldevelopment and possibly be a factor in the development ofessential hypertension in adult life. Other investigators haveoffered evidence that the activity of the enzyme can affect thesuccess or otherwise of oocyte fertilization by influencing localcortisol concentrations (Michaelet al., 1993). It has also beenproposed that variations in the activity of the other isoform,HSD-I, which plays a role in affecting glucocorticoid receptorexposure to cortisol, may also be important in the developmentof essential hypertension.

These are fundamental consequences of altered steroidenzyme activity and further investigation of this field willundoubtedly make valuable contributions to our knowledgeof clinical endocrinology. It is only by developing more

sophisticated and direct approaches to the assessment of steroidenzyme activity that these, and possibly other, important aspectsmay be properly explored and evaluated.

References

Edwards, C.R.W., Stewart, P.M., Burt, D., Brett, L., McIntyre, M.A.,Sutanto, W.S., DeKloet, E.R. & Monder, C. (1988) Localisation of11b-hydroxysteroid dehydrogenase-tissue specific protector of themineralocorticoid receptor.Lancet, ii, 986–989.

Funder, J.W., Pearse, P.T., Smith, R. & Smith, A.I. (1988) Mineralo-corticoid action : target tissue specificity is enzyme, not receptor,mediated.Science, 242,583–585.

Krowzowski, Z. & Funder, J.N. (1983) Renal mineralocorticoidreceptors and hippocampal corticosterone binding species haveidentical intrinsic steroid specificity.Proceedings of the NationalAcademy of Sciences of the USA, 80, 6056–6060.

Michael, A.E., Gregory, L., Walker, S.M., Antoniw, J.W., Shaw, R.W.,Edwards, C.R.W. & Cooke, B.A. (1993) Ovarian 11b-hydroxysteroiddehydrogenase: potential predictor of conception by in-vitro fertilis-ation and embryo transfer.Lancet, 342,711–712.

Palermo, M., Shackleton, C.H.L., Mantero, F. & Stewart, P.M. (1996)Urinary free cortisone and the assessment of 11b-hydroxysteroiddehydrogenase.Clinical Endocrinology, 45, 605–611.

Seckl, J.R., Benediktsson, R., Lindsay, R.S. & Brown, R.W. (1995)Placental 11b-hydroxysteroid dehydrogenase and the programmingof hypertension.Journal of Steroid Biochemistry and MolecularBiology, 55, 447–455.

Ulick, S., Levine, L., Gunczler, P., Zanconato, G. Ramirez, L.C.,Rauh, W., Rosler, A., Bradlow, H.L. & New, M.I. (1979) A syn-drome of apparent mineralocorticoid excess associated with defectsin the peripheral metabolism of cortisol.Journal of Clinical Endo-crinology and Metabolism, 49, 757–764.

White, P.C. (1996) 11B-Hydroxysteroid dehydrogenase deficiencycauses apparent mineralocorticoid excess. Program and Abstracts;10th International Congress of Endocrinology, p. 692.

614 V. James

q 1996 Blackwell Science Ltd,Clinical Endocrinology, 45, 613–614