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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 10 3570-3574
Copyright © 1999 by The Endocrine Society

Original Studies

Apparent Cortisone Reductase Deficiency: A Functional Defect in 11ß-Hydroxysteroid Dehydrogenase Type 11

A. Jamieson, A. M. Wallace, R. Andrew, B. S. Nunez, B. R. Walker, R. Fraser, P. C. White and J. M. C. Connell

Department of Medicine and Therapeutics (A.J.) and MRC Blood Pressure Group (R.F., P.C.W., J.M.C.C.), Western Infirmary, Glasgow G11 6NT; Department of Pathological Biochemistry (A.M.W.), Royal Infirmary, Glasgow G4 0SF; Department of Medical Sciences (B.R.W.), University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom; and University of Texas Southwestern Medical Center (B.S.N., P.C.W.), Dallas, Texas 75235-9063

Address correspondence and requests for reprints to: Dr. Robert Fraser, MRC Blood Pressure Group, Western Infirmary, Glasgow G11 6NT, Scotland; E-mail: rfraser{at}clinmed.gla.ac.uk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
A 36-yr-old woman was referred to the endocrine clinic for investigation of oligomenorrhea, hirsutism, and acne. She was plethoric and overweight with central fat distribution. Plasma cortisol was normal, but her adrenal glands were enlarged (CT scan). Urinary tetrahydrocortisone excretion rate was consistently high, raising the possibility of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) deficiency. In addition, 5ß- reduction of cortisol and cortisone was markedly enhanced. The levels of all cortisol metabolites were suppressed normally with dexamethasone, but conversion of oral cortisone acetate to plasma cortisol was delayed and subnormal compared with that of healthy volunteers. This was accompanied by a larger than normal increase in plasma cortisone concentration. Thus, the defect appears to be in 11ß-HSD1 activity and not in 5ß-reductase activity. Three close relatives of the subject showed no comparable abnormalities, and analysis of the coding region and exon/intron boundaries of the 11ß-HSD1 gene of the case revealed no differences from the consensus sequence. The defect may lie outside the coding region. Alternatively, some other inherited or acquired defect may lead to inhibition of this enzyme system.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MAINTENANCE of the appropriate local concentration of glucocorticoid is crucial to local tissue function. In addition to the modulation of adrenocortical secretion rate, this is now known to be largely dependent on metabolism by target tissues (1, 2, 3). Thus, the potential mineralocorticoid effect of cortisol in the kidney, gut, and other Na+/K+ exchanging cells is prevented by oxidizing it to inactive cortisone, a reaction catalyzed locally by 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) (4, 5). Genetic (6, 7, 8) or drug-induced (9) deficiency of this enzyme results in severe mineralocorticoid hypertension. In contrast, in tissues such as the liver (10, 11, 12, 13), adipose tissue (14, 15), brain (16), and the adrenal gland itself (17), the maintenance of high local glucocorticoid concentrations is ensured by 11ß-HSD type 1 (18), which catalyses the reactivation of cortisone to cortisol.

Despite their similar names and related function, the 11ß-HSD enzymes are encoded by genes on different chromosomes, they belong to different gene families, and they have contrasting coenzyme requirements (2, 3, 4, 5, 18). Congenital 11ß-HSD2 deficiency has been described in fewer than 100 cases, and a number of mutations have been identified (19, 20). By contrast, a syndrome consistent with 11ß-HSD1 deficiency has been described in only 3 female patients (21, 22, 23, 24), 2 of whom are siblings. No mutation in the coding regions of the 11ß-HSD1 gene was found in one of these patients (25). In these patients, the ratio of metabolites of cortisol (the tetrahydrocortisols produced by 5{alpha}- and 5ß-reductase enzymes) to those of cortisone (tetrahydrocortisone produced by 5ß-reductase) is very low. In addition, 5ß-reduced metabolites of cortisol and cortisone are excreted in preference to 5{alpha}-reduced metabolites. As a result of enhanced peripheral clearance of cortisol, there is less negative feedback suppression of ACTH-dependent steroids including adrenal androgens, and the patients present with features of adrenal androgen excess. In the absence of confirmation of a genetic defect in 11ß-HSD1, Shackleton and colleagues (24) termed this syndrome "apparent cortisone reductase deficiency" and suggested that, whether the syndrome is explained by impaired reactivation of cortisone to cortisol by 11ß-HSD1, or whether it is enhanced inactivation of cortisol and/or cortisone by 5ß-reductase remains to be confirmed.

In this report, we describe the clinical presentation, biochemical diagnosis, and genetic analysis of a further case of apparent cortisone reductase deficiency, and we provide evidence that the primary functional defect is impaired activity of 11ß-HSD1.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Case report

A 36-yr-old woman was referred to the endocrine clinic for investigation of oligomenorrhea, hirsutism, acne, and obesity. These abnormalities had progressed since a single successful pregnancy at 28 yr of age (normal male child), and attempts at further conception (unprotected intercourse for 4 yr) had been unsuccessful. Menarche had occurred at age 14, and she had taken oral contraceptives until 6 months before conception. Gonadrotropin concentrations since pregnancy had been essentially normal, as were those of prolactin and progesterone, but plasma androstenedione concentration had been, on one occasion, mildly elevated at 10.7 nmol/L -1 (0.6–8.8 nmol/L). External genitalia were normal. Laparoscopic examination and magnetic resonance imaging excluded the presence of polycystic ovaries or ovarian tumor. She had also been treated with cyproterone acetate and ethinyl estradiol (Dianette, Schering AG, Burgess Hill, West Sussex, UK), with no symptomatic improvement, and had had a period of clomiphene therapy, which failed to induce ovulation. She had received no therapy for more than 12 months before the referral.

At the time of referral she was plethoric and overweight (84.7 kg; body mass index, 32 kg/m2) with central fat distribution. Thyroid function was normal. There was evidence of old striae but no recent bruising. There was also a marked increase in terminal hair on the face and limbs, and acne was present on the face and upper trunk. A computed tomography (CT) scan revealed diffuse enlargement of the adrenal glands, but plasma cortisol concentrations and circadian rhythm were normal. A 24-h urinary steroid profile analysis excluded any adrenal steroid biosynthetic defect. However, tetrahydrocortisone (THE) excretion rate was massively raised on three consecutive days (Table 1Go), while concurrent levels of cortisol metabolites were in the lower part of the normal range. Androsterone, etiocholanolone, and cortolone excretion rates were also raised. On this evidence, a provisional diagnosis of cortisone reductase deficiency was made, and additional dynamic tests of cortisol and cortisone metabolism were undertaken.


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  		Table 1. a. Basal steroid excretion rates measured in Glasgow (µmol/24 h)

 
Dynamic tests

The effect of a standard low-dose dexamethasone suppression test (0.5 mg orally every 6 h for 48 h) on plasma and urinary steroid levels was examined, and the ability of the patient to convert cortisone to cortisol was also evaluated. For the latter assessment, endogenous cortisol secretion was suppressed (0.25 mg dexamethasone at just before midnight), and the fasting patient was given cortisone acetate (25 mg orally). Plasma samples were taken before and at intervals of 15 min, until 150 min afterwards for measurement of cortisol and cortisone concentrations. A 24-h urine collection was made before and during the test. Blood samples were taken for DNA extraction from the patient, and DNA and 24-h urine collections were obtained from her two sisters, her brother and her father.

Normative data

The dynamic test of conversion of oral cortisone to plasma cortisol was also performed in 10 healthy women (mean age 29 yr, range 20–40 yr) during the menstrual phase of their cycle (confirmed by measurement of estradiol and progesterone).

Analytical methods

Urinary steroid excretion rates were measured by capillary column chromatography of steroid methyloxime-trimethylsilyl ether derivatives followed by mass spectrometry on a Fisons MD800 mass spectrometer (Fisons Scientific Equipment, Loughborough Leics., UK) (26). These measurements were repeated on baseline urine samples in another laboratory with measurement of urine free cortisol and cortisone, as previously described (27). Plasma cortisol and cortisone concentrations were measured by radioimmunoassay after HPLC separation (28). Commercial radioimmunoassay kits were used to measure plasma concentrations of testosterone (Bayer Corp. Immuno-1, Newbury Berks., UK), dehydroepiandrosterone sulphate (DHAS), (INCSTAR Corp., Wokingham Berks., UK), and sex hormone binding globulin (SHBG) (Pharmacia Biosystems Ltd., Milton Keynes, Bedfordshire, UK). Androstenedione was measured by the radioimmunoassay of Thomson et al. (29).

Total genomic DNA was extracted from patient samples and PCR amplification, and direct sequencing of all exons and intron/exon boundaries of the 11ß-HSD1 gene WAS performed as previously reported (25).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Steroid biochemistry

Basal plasma androgen concentrations (testosterone, androstenedione, and DHAS) were elevated but plasma cortisol was normal. All of these were suppressed normally after administration of low-dose dexamethasone (Table 2Go).


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  		Table 2. Effects of low-dose dexamethasone (LDDST) on plasma hormones

 
Urinary steroid metabolite analyses in two laboratories confirmed remarkably high excretion of the 5ß-reduced metabolite of cortisone (tetrahydrocortisone; THE) (Table 1Go). In contrast, cortisol metabolite excretion was reduced, and this was much more marked for 5{alpha}-reduced metabolites (5{alpha}-tetrahydrocortisol; 5{alpha}-THF) than for 5ß-reduced metabolites (5ß-THF) (see Fig 1Go). Excretion of unconjugated cortisol and cortisone in urine was normal. After dexamethasone administration, excretion all of the metabolites was suppressed (Table 3Go).



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  		Figure 1. Principal metabolites of cortisol measured in urine by gas chromatography and mass spectrometry

 

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  		Table 3. The effects of low-dose dexamethasone suppression test (LDDST) and dexamethasone plus cortisone (Dex + E) administration on urinary steroid metabolites

 
Administration of 25 mg oral cortisone to healthy volunteers resulted in a sustained rise in plasma cortisol, which was obvious within 15 min, consistent with generation after first pass metabolism in the liver (Fig. 2Go). In contrast, plasma cortisone did not rise until after 60 min, suggesting that it was produced by conversion of cortisol to cortisone elsewhere (e.g. by 11ß-HSD2 in the kidney). In the patient with apparent cortisone reductase deficiency, the rise in plasma cortisol was markedly attenuated. However, there was a rise in cortisone during the first hour that fell away by 60 min. Most of the administered cortisone then appeared as THE in the urine during the next 24 hours (Table 3Go).



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  		Figure 2. Plasma cortisol and cortisone after administration of oral cortisone. After dexamethasone suppression, cortisone (25 mg) was administered at time 0000. Data are mean ± SD for controls (open symbols) compared with the patient (closed symbols).

 
The sisters, brother, and father of the index case showed no abnormalities of basal urinary steroid biochemistry on analysis of those compounds listed in Table 1Go, a.

Analysis of the 11ß-HSD1 gene

Analysis of the coding region and intron/exon boundaries of the 11ß-HSD1 gene revealed no sequence deviation from the known human consensus sequence in the patient or her relatives.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The clinical and biochemical features in our patient are consistent with those in the three previously reported cases of apparent cortisone reductase deficiency (21, 22, 23, 24). The urinary steroid profile shows that the overall equilibrium between cortisol and cortisone (represented by the ratio [5{alpha}-THF + 5ß-THF]/THE) favors the inactive steroid, cortisone. The normal ratio of urinary free cortisol/cortisone and the absence of mineralocorticoid excess effectively exclude the possibility that the syndrome is accounted for by enhanced 11ß-HSD2 activity in the kidney (27, 30). It is therefore more likely that the syndrome is the result of 11ß-HSD1 deficiency.

However, there are two observations that complicate this interpretation. First, we have confirmed a previous observation in one patient (25) that there is no coding mutation in the 11ß-HSD1 gene in this syndrome. Second, as in previous cases, there are marked changes in relative excretion of 5{alpha}-reduced and 5ß-reduced metabolites in this syndrome. Specifically, 5{alpha}-reduction of cortisol, represented by the cortisol/5{alpha}-THF ratio (31), is impaired, while 5ß-reduction of both cortisol and cortisone (represented by cortisol/5ß-THF and cortisone/THE ratios) is markedly enhanced. Altered relative activities of 5{alpha}- and 5ß-reductases have been reported in association with altered 11ß-HSD activities in both congenital and pharmacological 11ß-HSD2 deficiency (6, 7, 8, 9). The mechanism for the link between activities of these enzymes has not been elucidated. It is possible that the apparent cortisone reductase deficiency syndrome could be explained by a primary increase in 5ß-reductase metabolism of cortisone (24). However, in our patient, cortisone administration resulted in a supranormal rise in plasma cortisone concentration and a subnormal rise in cortisol concentration (Fig. 2Go), highly suggestive that impaired 11ß-HSD1 activity is the major defect accounting for impaired generation of cortisol.

In the absence of a mutation in the coding region of the 11ß-HSD1 gene, it remains unclear why enzyme activity is impaired. The gene defect could lie in a more remote control region, or some other aspect of the 11ß-HSD1 reaction, such as cofactor availability, could be affected. The urinary excretion rates of cortisol and cortisone metabolites in the father and son of the patient described here were normal, suggesting either that the defect is autosomal recessive or, alternatively, that it is acquired. The patient had previously been fertile, and the clinical features of androgen excess had developed during the 4 yr preceding referral. This, together with the lack of evidence of a gene defect in the patient or in her immediate relatives, raises the possibility of an acquired defect. However, at present no physiological or pharmacological cause of such an inhibition has been identified. Licorice derivatives inhibit both 11ß-HSD1 and -HSD2 activity, but the net effect is to raise the ratio of cortisol to cortisone metabolites (9). This patient denied taking these substances. Endogenous inhibitors of 11ß-HSDs have been extracted from human urine but are hypothesized to have similar effects to licorice (32). Finally, adipose tissue possesses 11ß-HSD1 activity (14, 15), and altered cortisol metabolism may accompany obesity (35), including subjects with the polycystic ovarian syndrome (33, 34). However, none of the patients in these previous studies had such dramatic alterations in cortisol metabolism as we observed in this case. Moreover, obesity is associated with enhanced 5{alpha}-reductase rather than 5ß-reductase activity, and normal women have higher apparent 5{alpha}-reductase activity than normal men (36). It seems most likely that her clinical syndrome was aggravated by, rather than caused by, her weight gain.

The most appropriate therapeutic option is uncertain. Adrenal androgen production was successfully suppressed by dexamethasone, indicating normal negative feedback regulation of pituitary function. While this may offer a possible therapeutic option for long-term use, its benefit in reducing hair growth must be weighed against the deleterious effects on weight and suppression of the endogenous hypothalamic-pituitary adrenal axis.

In summary, we have identified a further patient with apparent cortisone reductase deficiency and provided evidence supporting the interpretation that it is caused by an impaired ability to convert cortisone to cortisol and a consequent increase in ACTH-driven androgen production. The defect does not appear to reside in the coding region of the 11-HSD1 gene, raising the possibility that other inherited or acquired defects may affect the ability of this crucial enzyme system to maintain tissue cortisol concentrations.


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  		Table 1B. b. Basal steroid excretion rates measured in Edinburgh

 

   Footnotes
 
1 B.R.W. is a British Heart Foundation Senior Research Fellow. R.F. and J.M.C.C. were funded by the Medical Research Council (Programme Grant 809155), and B.S.N. and P.C.W. by the National Institutes of Health (Grant DK42169). Back

Received April 12, 1999.

Revised June 15, 1999.

Accepted June 21, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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