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Absence of Cushingoid Phenotype in a Patient with Cushing’s Disease due to Defective Cortisone to Cortisol Conversion

Division of Medical Sciences (J.W.T., N.D., J.M., P.M.S.) and Department of Ear, Nose and Throat Surgery (A.J.), Queen Elizabeth Hospital, University of Birmingham, United Kingdom B15 2TH; Regional Endocrine Laboratory (G.H.), Department of Clinical Biochemistry, Selly Oak Hospital, Birmingham, United Kingdom B29 6JD; and Regional Endocrine Unit (P.W.), Southampton General Hospital, Southampton, United Kingdom SO16 0XW

Address all correspondence and requests for reprints to: Prof. P. M. Stewart, M.D., F.R.C.P., F. Med. Sci., Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom B15 2TH. E-mail: P.M.Stewart{at}bham.ac.uk

	Abstract

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Cushing’s syndrome invariably presents with a classical phenotype comprising central adiposity, prominence of dorsal, supraclavicular and temporal fat pads, bruising, abdominal striae, proximal myopathy, and hypertension. We report the case of a 20-yr-old student with pituitary-dependent Cushing’s syndrome who was spared this classical phenotype because of a defect in the peripheral conversion of cortisone to cortisol.

She presented to her general practitioner with secondary amenorrhea. Clinical examination revealed normal fat distribution (body mass index, 20.9 kg/m²), absence of hirsutism, myopathy, or bruising; her blood pressure ranged from 115/70 to 122/82 mm Hg. She was investigated for biochemical hypercortisolemia because of a mildly elevated random circulating cortisol (serum cortisol, 661 nmol/liter). Cushing’s syndrome was confirmed on the basis of repeatedly elevated urinary free cortisols (831–1049; reference range, <350 nmol/24 h), failure of low-dose dexamethasone suppression (611 nmol/liter) and loss of circadian cortisol secretion. Investigations suggested Cushing’s disease; there was suppression after high-dose dexamethasone (<20 nmol/liter) and a 950% increase in ACTH after stimulation with CRH. Pituitary magnetic resonance imaging revealed a 3-mm adenoma within the pituitary gland. Urinary corticosteroid metabolites were analyzed by gas chromatography-mass spectrometry and demonstrated a decreased THF+allo-THF/THE ratio of 0.66 (mean ± SE in Cushing’s disease, 1.74 ± 0.24) suggesting a defect in 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an enzyme that converts the inactive glucocorticoid cortisone to active cortisol. Transphenoidal microadenomectomy was performed, and histology confirmed the diagnosis of a corticotroph adenoma. Postoperatively, serum cortisol was undetectable and replacement therapy was commenced.

Subsequent investigations revealed a significantly impaired ability to convert an oral dose of cortisone acetate (25 mg) to cortisol, reduced serum cortisol to cortisone ratios, and a reduced serum half-life for cortisol (57.3 min). These results provide strong evidence for a partial defect in 11ß-HSD1 activity and concomitant increase in cortisol clearance rate.

We have described a case of Cushing’s disease that failed to present with a classical phenotype, and we postulate that this is due to a partial defect of 11ß-HSD1 activity, the defect in cortisone to cortisol conversion increasing cortisol clearance and thus protecting the patient from the effects of cortisol excess. This observation may help to explain individual susceptibility to the adverse effects of glucocorticoids.

	Introduction

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CUSHING’S SYNDROME PRESENTS with a classical phenotype that comprises central obesity, prominence of dorsal, temporal, and supraclavicular fat pads, abdominal striae, hypertension, and edema. Although the causes of the hypercortisolemia are many and varied, the classical phenotype is conserved. However, these features are reversible, and in the majority of patients their severity appears to correlate with the degree of circulating hypercortisolemia. Exceptions to this are patients with glucocorticoid resistance (1) in which circulating cortisol levels are elevated and there is inadequate suppression with dexamethasone. As a consequence of either mutations or a functional defect within the glucocorticoid receptor (GR), patients are not Cushingoid. Conversely, Cushing’s syndrome can occur because of increased GR numbers in the setting of eucortisolemia (2).

Patients with Cushing’s disease have markedly elevated cortisol production rates driven by excess ACTH. However, the tissue-specific actions of cortisol are not only determined by production rates and GR activation, but are also determined by the rate of cortisol metabolism. In peripheral tissues, cortisol is metabolized at a prereceptor level by the enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD). This enzyme exists in two isoforms; type 1 is widely distributed in many tissues including liver, gonad, and adipose tissue (3) and is a nicotinamide adenine dinucleotide phosphate-dependent bidirectional enzyme that in vivo predominantly acts as a reductase generating active cortisol (F) from the inactive glucocorticoid cortisone (E) (Fig. 1). The type 2 enzyme is a nicotinamide adenine dinucleotide-dependent dehydrogenase converting F to E (Fig. 1) and is predominantly expressed in mineralocorticoid target tissues that include kidney and placenta. It is the lack of functional 11ß-HSD2 that underlies the condition of apparent mineralocorticoid excess (AME), a rare inherited form of potentially life-threatening mineralocorticoid hypertension (4). In addition, saturation of the 11ß-HSD2 isozyme explains the mineralocorticoid excess state characterizing ectopic ACTH secretion.

View larger version (21K): [in this window] [in a new window]   Figure 1. Metabolism of cortisol by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) and 2 (11ß-HSD2) and by 5- and 5ß-reductases, ultimately leading to the generation of tetrahydro metabolites that are excreted in the urine and can be measured by gas chromatography-mass spectrometry.

11ß-HSD activity can be assessed in vivo using several techniques. The ratio of urinary free cortisol (UFF) to urinary free cortisone (UFE) is perhaps the most robust marker of renal 11ß-HSD2 activity. Both cortisol and cortisone are metabolized by 5- and 5ß-reductases, principally in the liver, to generate tetrahydro metabolites, tetrahydrocortisol (THF), allo-THF, and tetrahydrocortisone (THE) (Fig. 1). These are excreted in the urine, and the ratio of THF+allo-THF/THE provides a measure of the activity of 11ß-HSD1 in the setting of an unchanged UFF/UFE ratio (5). Furthermore, it is also possible to assess the activity of 11ß-HSD1 by measuring the conversion of oral cortisone acetate to cortisol (6). Although no mutations have been described in the HSD11BI gene or its promoter, the clinical phenotype of defective cortisone to cortisol generation has been described. A total of eight patients with the syndrome of apparent cortisone reductase deficiency (ACRD) have been reported in the literature (7, 8, 9, 10, 11, 12, 13), and with one exception, all have been females presenting with hirsutism, oligomenorrhea, and androgen excess. THF+allo-THF/THE ratios are typically less than 0.1 (normal, 0.7–1.3), and the defect in E to F conversion, by increasing the metabolic clearance of cortisol, stimulates ACTH production and adrenal androgen excess. Here, we describe the first case of a patient with Cushing’s disease protected from the classical phenotype by a defect in 11ß-HSD1 activity. This case demonstrates the degree to which peripheral metabolism of cortisol is important, and it also has wider implications in determining individual susceptibility to the effects of glucocorticoids.

	Subject and Methods

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Subject

A 20-year-old student presented with a 16-month history of secondary amenorrhea. On examination, she had a normal fat distribution with a body mass index (BMI) of 20.9 kg/m². There was no evidence of hirsutism, bruising, striae, or myopathy (Fig. 2). Her blood pressure ranged from 115/70 to 122/82 mm Hg. She was investigated for Cushing’s syndrome following a mildly elevated random serum cortisol of 661 nmol/liter. UFFs were persistently elevated (831–1049; reference range, <350 nmol/24 h); there was loss of circadian cortisol secretion (758 nmol/liter at 0900 h, 768 nmol/liter at 2400 h) and no suppression of serum cortisol after low-dose dexamethasone [0.5 mg every 6 h for 48 h] (serum cortisol, 611 nmol/liter). Cushing’s disease was suggested on the basis of the 0900 h ACTH concentration of 65.7 ng/liter (reference range, 9–52), suppression following high-dose dexamethasone [2 mg every 6 h for 48 h] (serum cortisol, <20 nmol/liter) and a 950% increase in ACTH after stimulation with CRH (ACTH 23 214 ng/liter). Thyroid function tests were normal. Pituitary magnetic resonance imaging revealed a 3-mm-diameter adenoma within the pituitary gland. Before treatment, urinary corticosteroid metabolites were analyzed by gas chromatography-mass spectrometry and demonstrated a decreased THF+allo-THF/THE ratio of 0.66 (mean ± SE in Cushing’s disease, 1.74 ± 0.24) (5). A summary of the clinical data are presented in Table 1. Transphenoidal microadenomectomy was performed postoperatively, serum cortisol was undetectable (<20 nmol/liter), and the subject was commenced on hydrocortisone replacement therapy. Histology confirmed the diagnosis of a corticotroph adenoma. Subsequently, the subject has begun to menstruate again, although irregularly, and is currently off hydrocortisone replacement therapy with normal circulating and UFF levels.

View larger version (55K): [in this window] [in a new window]   Figure 2. Absence of Cushing’s phenotype in a 20-yr-old with biochemically and histologically proven pituitary-dependent Cushing’s disease (A) before and (B) 6 months after transphenoidal microadenomectomy.

Inhibition of 11ß-HSD1 activity results in a decreased ability to convert oral cortisone acetate to cortisol. Six months postoperatively, the evening replacement dose of hydrocortisone was omitted and at 0900 h the following morning a dose of oral cortisone acetate (25 mg) was given. Serum cortisol and cortisone were measured at 0, 30, 60, 90, 120, 180, and 240 min, and results were compared with six BMI-matched female normal controls (mean BMI ± SE, 22.5 ± 1.8 kg/m²; mean age, 31 ± 5 yr) who underwent the same protocol with the exception that they had an oral dose of dexamethasone (1 mg) at 2400 h on the preceding night.

Serum cortisol half-life was estimated as previously described (14). Briefly, 2 mg dexamethasone was administered orally at 2400 h on the preceding night, and at 0900 h, 5 mg hydrocortisone was injected iv into an antecubital fossa vein. Then, blood samples were taken from a contralateral vein at 0, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, 180, 210, and 240 min. Serum half-life was calculated using nonlinear regression and compared with published data.

Sequence analysis of the HSD11B1 gene and promoter was performed using exon specific primers, a fluorescent di-deoxy chain terminator method, and an ABI prism 377 DNA sequencer.

All data and images published are done so with the full and informed consent of the patient.

	Results

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11ß-HSD1 activity in this patient was significantly reduced, as indicated by a reduced urinary THF+allo-THF/THE ratio of 0.66. In patients with Cushing’s disease, this ratio is invariably elevated [mean ± SE in Cushing’s disease (n = 7), 1.74 ± 0.24 in comparison with normal controls, 1.15 ± 0.11] (5). Total cortisol metabolites were significantly elevated, in keeping with a diagnosis of endogenous Cushing’s syndrome (Table 2). Further analysis revealed enhanced 5ß-reduction of both cortisol and adrenal androgens in comparison with 5-reduced metabolites (THF/allo-THF, 3.23; etiocholanolone/androsterone, 3.12; Table 2). Measurements of cortisol metabolism postoperatively further confirmed inhibition of 11ß-HSD1 activity. There was a reduced ability to convert oral cortisone to cortisol in comparison with BMI-matched controls (Fig. 3A). At 60, 90, and 120 min, cortisol levels were more than 1SD lower than control; they were more than 2 SD lower at 180 and 240 min (at 240 min, 188 nmol/liter vs. 468 ± 90 nmol/liter). Similarly, serum cortisol to cortisone ratios were more than 2 SD values lower than control (Fig. 3B).

View larger version (12K): [in this window] [in a new window]   Figure 3. Serum cortisol concentrations (A) and cortisol to cortisone ratios (B) following oral administration of cortisone acetate (25 mg) in a patient with Cushing’s disease demonstrating a partial defect in 11ß-HSD1 activity in comparison with healthy female controls (n = 6; mean BMI, 22.5 ± 1.8 kg/m2; mean age, 31 ± 5 yr). Data shown are mean values ± SE.

View larger version (12K): [in this window] [in a new window]   Figure 4. Serum cortisol concentrations following iv administration of 5 mg hydrocortisone. Mean serum half-life was calculated using nonlinear regression (57.3 min).

	Discussion

Top Abstract Introduction Subject and Methods Results Discussion References

 
We have described a patient with Cushing’s disease who has been successfully treated by transphenoidal microadenomectomy. Although she had presented with a 16-month history of secondary amenorrhea, she failed to develop a classical Cushing’s phenotype despite the presence of circulating hypercortisolemia and increased cortisol production rate. We have postulated that this could be due to a partial defect in the activity of the enzyme 11ß-HSD1. This was endorsed through a reduced THF+allo-THF/THE ratio, decreased ability to convert oral cortisone acetate to circulating cortisol in comparison with controls, decreased serum F/E ratios, and a decreased circulating cortisol half-life following iv administered hydrocortisone. In conclusion, we have presented strong evidence for a partial defect in the activity of 11ß-HSD1 resulting in an increased metabolic clearance of cortisol. This could not be explained by any obvious mutations in the HSD11B1 gene. The patient was biochemically euthyroid and was not ingesting any putative 11ß-HSD inhibitors that might have mediated a reduction in E to F conversion.

There are many determinants of glucocorticoid action. Functional abnormalities of GR have been postulated (1) that may explain glucocorticoid resistance, and indeed polymorphisms with the GR gene appear to convey altered sensitivity to exogenously administered glucocorticoids (15). Clearly, abnormalities of GR function have an important role to play in determining glucocorticoid action, but in our patient glucocorticoid resistance was excluded through lack of circadian rhythm for serum cortisol and the ability to suppress serum cortisol following high-dose dexamethasone.

The activity of 11ß-HSD isozymes plays a pivotal role in the metabolism and clearance of cortisol, a major component being the activity of 11ß-HSD1 within the liver. To date, eight patients have been reported with ACRD, the underlying defect for which has been postulated to be a functional abnormality in 11ß-HSD1 (8, 9, 10, 11, 12, 13). The condition, which has been almost exclusively reported in women, presents with a mild phenotype comprising oligomenorrhea, hyperandrogenism, and hirsutism, yet biochemically there is almost a complete absence of urinary cortisol metabolites with THF+allo-THF/THE ratios less than 0.1. The global shift in set-point of E to F conversion toward E results in stimulation of the hypothalamo-pituitary-adrenal axis to maintain circulating cortisol levels, but at the expense of ACTH-mediated adrenal androgen excess. Although no mutations have been identified in the coding sequence of the HSD11B1 gene, a functional abnormality of the enzyme remains the most likely cause for this condition. There are many parallels between ACRD and polycystic ovary syndrome. 11ß-HSD1 has been linked to the pathogenesis of polycystic ovary syndrome, and urine corticosteroid metabolite analyses have suggested inhibition of 11ß-HSD1 in some studies, but not others (16, 17, 18). In this patient, the presenting complaint was one of secondary amenorrhea. The mechanism for this remains unclear, but it is likely that ACTH-dependent adrenal androgen excess is important as in those patients with ACRD. Indeed, androstenedione levels were elevated preoperatively (15.1 nmol/liter; reference range, 2.6–10.8).

11ß-HSD1 is also thought to play a role in human obesity. The global set-point of 11ß-HSD in patients with obesity is shifted toward E, as evidenced by reduced urinary THF+allo-THF/THE ratios and a decreased ability to convert oral cortisone to cortisol in comparison with lean controls (19, 20). This peripheral inhibition of 11ß-HSD1 in obesity may account for the reported increase in metabolic clearance rate for cortisol and increased secretion rate.

Although the activity of 11ß-HSD1 has an important role in controlling the rate of cortisol metabolism, at an autocrine level regulation and expression of both isozymes of 11ß-HSD are important in controlling the tissue-specific action of glucocorticoids.

11ß-HSD2 is principally expressed in mineralocorticoid target tissues such as placenta and kidney. It exclusively converts F to E, thus protecting the mineralocorticoid receptor (MR) from illicit occupation by cortisol. Genetic defects in the HSD11B2 gene result in the syndrome of AME in which cortisol is allowed to act through the MR, causing life-threatening hypertension and hypokalemia. It is likely that 11ß-HSD2 has a role to play in the pathogenesis of essential hypertension, although this remains to be clarified. Patients with Cushing’s syndrome secondary to ectopic ACTH production often develop mineralocorticoid hypertension. The mechanism underlying this is not a defect in 11ß-HSD2, but rather that the enzyme is saturated due to the exceedingly high substrate concentrations and cortisol is able to spill over on to the MR. As a result, THF+allo-THF/THE ratios are markedly elevated (mean ± SE, 3.95 ± 0.69) (5). Patients with Cushing’s disease develop mineralocorticoid hypertension less frequently, although hypertension is reported in up to 70% of cases. However, THF+allo-THF/THE ratios remain elevated. The mechanism for this is unknown, but it remains possible that milder abnormalities of 11ß-HSD function account for this. The THF+allo-THF/THE ratio in this patient was less than normal reference values and considerably reduced compared with other patients with Cushing’s disease. In addition, patients with AME have a marked decrease in the THF/allo-THF ratio due to a concomitant deficiency of 5ß-reductase. In patients with ACRD, the converse is true, i.e. increased 5ß-reductase is observed. In our patient, the THF/allo-THF ratio was also elevated at 3.23, although similar values have been reported in Cushing’s syndrome (thought to be due to decreased 5-reductase activity).

11ß-HSD1 is widely expressed in many tissues, including liver, adipose tissue, gonad, and bone (3, 21). Although the enzyme is truly bidirectional, in vivo it acts predominantly as a reductase generating cortisol from inactive cortisone. As a result, the enzyme facilitates glucocorticoid hormone action, notably regulating hepatic glucose output and adipocyte differentiation. Loss of enzyme activity in key peripheral tissues may also reduce glucocorticoid effects at an autocrine level in addition to mediating increased cortisol metabolic clearance.

This case highlights that there is clear interindividual variability in the metabolism of cortisol and that this can exert a profound impact upon the phenotypic effects of glucocorticoids. In our patient with Cushing’s disease, inhibition of 11ß-HSD1 appeared to protect the patient from the features of the disease and arguably may decrease the morbidity and perhaps mortality associated with hypercortisolemia. On a wider scale, the level of activity of 11ß-HSD1 may well determine an individuals’ susceptibility to the effects of glucocorticoid. In the future, tissue-specific inhibitors of 11ß-HSD1 may afford reduction in the adverse effects of glucocorticoids and be used as novel adjunctive therapy.

	Acknowledgments

 
P.M.S. is a Medical Research Council (MRC) senior fellow, and J.W.T. is an MRC clinical training fellow.

	Footnotes

 
Abbreviations: 11ß-HSD, 11ß-Hydroxysteroid dehydrogenase; ACRD, apparent cortisone reductase deficiency; AME, apparent mineralocorticoid excess; BMI, body mass index; E, cortisone; F, cortisol; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; THE, tetrahydrocortisone; THF, tetrahydrocortisol; UFE, urinary free cortisone; UFF, urinary free cortisol.

Received May 16, 2001.

Accepted August 6, 2001.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tomlinson, J. W. Articles by Stewart, P. M. Search for Related Content PubMed PubMed Citation Articles by Tomlinson, J. W. Articles by Stewart, P. M.