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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0656
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6616-6622
Copyright © 2005 by The Endocrine Society

Sulfur Amino Acids in Cushing’s Disease: Insight in Homocysteine and Taurine Levels in Patients with Active and Cured Disease

Antongiulio Faggiano, Daniela Melis, Raffaele Alfieri, MariaCristina De Martino, Mariagiovanna Filippella, Francesco Milone, Gaetano Lombardi, Annamaria Colao and Rosario Pivonello

Departments of Molecular and Clinical Endocrinology and Oncology (A.F., M.F., M.D.M., F.M., G.L., A.C., R.P.), Biochemistry and Medical Biotechnology (R.A.), and Pediatrics (D.M.), "Federico II" University, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Rosario Pivonello, M.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University, Via Sergio Pansini 5, 80131 Naples, Italy. E-mail: rpivone{at}tin.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Cushing’s syndrome is associated with an increased cardiovascular risk. Although a series of cardiovascular risk factors have been identified, sulfur amino acids (SAAs), recently indicated as independent cardiovascular risk factors, have been poorly investigated in patients with Cushing’s syndrome.

Aim: The aim of this cross-sectional controlled study was to evaluate serum and urinary levels and urinary excretion rate (ER) of SAAs in patients with Cushing’s disease (CD) during the active disease and after long-term disease remission.

Subjects and Methods: Forty patients with CD (20 with active disease and 20 with cured disease for at least 5 yr) and 40 controls entered the study. Serum and urinary concentrations and urinary ER of SAAs, namely methionine, cystine, homocysteine, and taurine, were measured by means of cationic exchange HPLC. Serum folic acid and vitamin B12 levels were also evaluated in patients and controls and correlated to SAA levels.

Results: CD patients with active disease had higher serum and urinary concentrations of cystine and homocysteine, and lower serum and higher urinary concentrations and ER of taurine than cured patients and controls. Vitamin B12 levels were significantly decreased in patients with active disease compared with cured patients and controls, whereas folic acid levels were slightly decreased in patients than in controls. In patients with active CD, urinary cortisol concentrations were significantly and inversely correlated to serum taurine and directly correlated to taurine urinary ER, and fasting serum glucose levels were significantly correlated to taurine urinary ER. At the multiple regression analysis, urinary cortisol concentrations were the best predictors of taurine ER.

Conclusions: CD is associated with hyperhomocysteinemia and hypotaurinemia. Glucocorticoid excess, acting directly or indirectly, seems to be the most responsible for this imbalance in SAA levels. The long-term disease remission is accompanied by normalization of SAA levels. Hyperhomocysteinemia and hypotaurinemia might contribute to the increased cardiovascular risk of CD.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
CUSHING’S SYNDROME (CS) is known to be associated with an increased prevalence of atherosclerosis and an increased cardiovascular risk (1, 2, 3, 4, 5). In Cushing’s disease (CD), the most common form of CS, the metabolic syndrome, mainly characterized by the abdominal obesity and insulin resistance, seems to play a pivotal role in determining the increased cardiovascular risk both during active disease and after disease remission (6, 7).

Sulfur amino acids (SAAs), including cysteine, homocysteine, methionine, and taurine (8), have been indicated recently as independent factors influencing the cardiovascular risk (9, 10, 11, 12). In particular, the balance between homocysteine and taurine levels seems to be crucial for the integrity of cardiovascular system. Indeed, circulating homocysteine levels are directly correlated to carotid wall thickness (13) and inversely correlated to the endothelium-dependent coronary blood flow (14) in healthy subjects. Moreover, homocysteine has been suggested to induce endothelial dysfunction by promoting the generation of hydrogen peroxide and superoxide anions (15) and by reducing the secretion of the antioxidant glycoprotein superoxide dismutase (16). Conversely, taurine seems to counteract the homocysteine actions, inhibiting the secretion of hydrogen peroxide and superoxide anions (15), and to restore the superoxide dismutase secretion (16). Furthermore, daily intake and urinary output rate of taurine are inversely correlated with the incidence of coronary heart disease in healthy subjects (17).

Contrasting data have been reported about the effects of glucocorticoids on SAA metabolism. In fact, both increase and decrease of serum homocysteine levels were reported after long-term treatment with corticosteroids in patients with autoimmune diseases (18, 19). Serum homocysteine levels were found to be increased in patients with CS (20). Conversely, serum taurine levels were reported to decrease after physical exercise in parallel with an increase in serum cortisol levels in healthy subjects (21), whereas no data are currently available on serum taurine levels in patients with CS. In addition, in these patients, plasma levels of cystine, the dimer of cysteine, were found to be increased during active disease and to normalize after stable remission of the disease (22). No definitive data are currently available on methionine levels in patients with CS.

The aim of this cross-sectional study was to evaluate serum and urinary levels as well as urinary excretion rate (ER) in the whole spectrum of SAAs in patients with CD, during active disease and after long-term disease remission.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Forty patients with CD, 20 with active CD (16 women, 4 men, 20–45 yr of age) and 20 cured from CD for at least 5 yr (16 women, 4 men, 24–52 yr of age), and 40 sex-, age-, and body mass index-matched healthy subjects were enrolled in this cross-sectional controlled study after their informed consent had been obtained. Among the patients in active disease, six were newly diagnosed, whereas the remaining 14 had undergone unsuccessful neurosurgery, followed in four of them by pituitary irradiation, with subsequent disease persistence or relapse. Among the patients with cured disease, 16 had undergone successful neurosurgery, whereas the remaining four were cured after surgery plus pituitary irradiation. In patients with active disease, the disease duration ranged from 1 to 14 yr (median, 4 yr), whereas in cured patients, disease duration ranged from 1 to 12 yr (median, 4.5 yr) and the disease-free duration from 5 to 10 yr (median, 7 yr). The criteria for the diagnosis of CD were as follows: 1) presence of a clinical syndrome suggestive of hypercortisolism; 2) high daily urinary cortisol excretion with inappropriately high plasma ACTH concentrations; 3) high basal serum cortisol concentrations with lack of the physiological circadian rhythm; and 4) failure of urinary and serum cortisol suppression after low-dose but greater than 50% decrease after high-dose dexamethasone test. The criteria to define the cure of CD were as follows: 1) remission or amelioration of the clinical syndrome related to hypercortisolism; 2) normal or low urinary daily cortisol excretion and plasma ACTH concentrations; 3) normal or low serum cortisol concentrations with restoration of physiological circadian rhythm; and 4) suppression of urinary and serum cortisol concentrations after high- and low-dose dexamethasone test. At the diagnosis, a CRH and/or desmopressin test was performed in all patients: the response to one or both of these tests supported the diagnosis of CD in 35 of the 40 patients of the study. Pituitary magnetic resonance imaging was performed in all patients revealing a microadenoma in 30 patients, a macroadenoma in two patients, and absence of an adenoma in eight patients; the pituitary origin of CS was diagnosed in these eight patients by the results of bilateral inferior petrosal sinus sampling. The diagnosis of CD was confirmed by the histological and immunohistochemical analysis of the removed tumor in all 34 patients who had undergone neurosurgery; in the six newly diagnosed patients, CD was diagnosed on the basis of the presence of clinical and biochemical hypercortisolism, the concordant response to dexamethasone and CRH test, and the presence at magnetic resonance imaging of a pituitary tumor. In patients subjected to neurosurgery and/or pituitary irradiation, a definitive hypoadrenalism occurred in four patients, who were replaced by cortisone acetate at the dose of 25–32.5 mg/d. Moreover, residual anterior pituitary function was normal after treatment in all patients but four with secondary hypogonadism and two with diabetes insipidus, who were receiving a standard replacement therapy. The adequacy of replacement therapy was periodically monitored during the follow-up by measuring daily water balance, blood pressure, serum and urinary electrolyte levels, and evaluation of regularity of menses in women and integrity of libido and sexual potency associated with serum testosterone levels in men, beyond the measurement of urinary cortisol levels. All cured patients had been followed at least yearly to verify the persistent control of cortisol secretion and the possible onset of pituitary insufficiencies. The presence of GH and/or IGF-I deficiency was excluded in active disease by measuring serum IGF-I levels and in patients with cured disease by performing a GHRH plus arginine test: patients with normal IGF-I and GH peak higher than 9 mg/liter after the stimulation test were considered for the study, according to the consensus conference on diagnosis of GH deficiency (23, 24). None of the patients had been taking drugs for CD or any medications known to interfere with SAAs levels. A familial history of cardiovascular diseases, defined by the occurrence of cardiac or cerebral ischemia or stroke or vascular thrombosis in at least one of the first-degree relatives before 60 yr of age, has been considered an exclusion criteria for the study.

Study protocol

Serum and urinary concentrations of methionine, cystine, homocysteine, and taurine were analyzed by cationic exchange HPLC (System Gold; Beckman, Buckinghamshire, UK) as reported previously (22). Cystine was considered in the place of cysteine because of its higher stability and because the cystine levels are direct expression of cysteine levels. The urinary ER of each amino acid was calculated using the following formula, which corrects the amino acid excretion for the ceratinine clearance: serum/urinary creatinine (µmol/liter) x urinary/serum amino acid (µmol/liter)%, as reported by previous studies (25). The mean of three consecutive values, performed in 3 consecutive days, was considered for the evaluation of circulating amino acid concentrations and renal excretion. Vitamin B12 and folic acid plasma levels were measured in all patients and controls using available commercial kits. All subjects were fasted at times blood was collected. Before starting the study, both patients and controls were kept at standardized diet with fixed and specific protein intake, by providing approximately 50, 35, and 15% of total energy intake from carbohydrates, lipids, and mixed proteins, respectively, for 2 wk.

Statistical analysis

The statistical analysis was performed by SPSS for Windows version 10.0 (SPSS, Chicago, IL). Data were expressed as the mean ± SE. ANOVA, followed by Bonferroni’s correction, was used to compare the evaluated parameters. The correlation analysis was performed among SAA concentrations, and serum glucose, insulin, vitamin B12, and folic acid levels, urinary cortisol, and disease duration by calculating the Pearson’s coefficient. The multiple regression analysis was performed among the variables significantly correlated at the linear correlation to look for the parameters independently associated with SAA abnormalities. Statistical significance was set at 5%.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Biochemical study

Fasting glucose and insulin levels were significantly higher in active patients than in controls and remained slightly but not significantly higher in cured patients than in controls. Three patients with active and two with cured CD had diabetes mellitus, whereas impaired glucose tolerance was found in four active and four cured patients with CD. None of the control subjects had impairment of glucose tolerance. Creatinine clearance was slightly but significantly lower in active patients than in controls and similar between cured patients and controls. The results of the biochemical study are shown in Table 1Go. Serum folic acid levels were not significantly different between patients and controls, whereas serum vitamin B12 levels were lower in patients with active disease than in those with cured disease and controls. The folic acid and vitamin B12 levels of patients and controls are shown in Fig. 1Go.


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  		TABLE 1. Biochemical parameters in patients with active and cured CD and controls

 


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  		FIG. 1. Serum folic acid and vitamin B12 levels in patients with active CD, patients cured from CD, and controls.

 
Amino acid study

Serum and urinary concentrations and ER of methionine were similar in patients and controls. Serum and urinary concentrations of cystine and homocysteine were significantly higher in patients with active CD than in patients cured from CD and controls. Cystine and homocysteine urinary ER was similar in patients and controls. Conversely, serum concentrations of taurine were significantly lower and urinary concentrations and ER of taurine were significantly higher in active patients than in cured patients and controls. Serum and urinary amino acid concentrations were similar in cured patients and controls. The results of the amino acid study are shown in Table 2Go. The serum and urinary concentrations and ER of homocysteine and taurine are shown in Fig. 2Go.


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  		TABLE 2. Serum and urinary concentrations and ER of SAAs and plasma vitamin B12 and folic acid concentrations in patients with active and cured CD and controls

 


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  		FIG. 2. Serum and urinary concentrations and ER of homocysteine and taurine in patients with active CD, patients cured from CD, and controls.

 
Correlation study

In active CD patients, vitamin B12 was significantly and inversely correlated to serum homocysteine levels (r = –0.843; P < 0.01). Urinary free cortisol was significantly and inversely correlated to serum taurine (r = –0.80; P < 0.05) and significantly and directly correlated to taurine urinary ER (r = 0.85; P < 0.01). Fasting serum glucose levels were significantly correlated to taurine urinary ER (r = 0.77; P < 0.01). No correlation was found between SAA concentrations and disease duration. At the multiple regression analysis, urinary cortisol levels were the best predictor of taurine urinary ER (t =3.7; P < 0.01). In patients cured from CD and controls, no significant correlation was found between any biochemical parameter and serum or urinary amino acid levels.

Figure 3Go represents an exemplificative scheme of the SAA pathway focusing on the hypothetical reaction impaired in CD.



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  		FIG. 3. Exemplificative scheme of the pathway of the SAAs methionine, cysteine, homocysteine, and taurine, with focus on the hypothetical reactions affected in CD. MTHFR, Methylene-tetrahydrofolate reductase.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The results of the current study demonstrated that CD is associated with a series of abnormalities in SAA levels mainly characterized by increase of serum and urinary levels of cystine and homocysteine, and decrease of serum and increase of urinary levels of taurine, which display an increase in the rate of excretion by the kidney. The hyperhomocysteinemia or the hypotaurinemia might play a role in the development of the increased cardiovascular risk associated with CD and, in general, with CS.

SAAs mainly include methionine, cysteine, homocysteine, and taurine forming a unique metabolic pathway, which plays an important role in the integrity of cardiovascular system (8). The first part of the metabolic pathway of SAA is represented by the methionine-homocysteine-cysteine pathway. Methionine is an essential amino acid that is converted to homocysteine through a trans-methylation reaction. Homocysteine can follow two different routes: the trans-sulfuration to cysteine and the re-methylation to methionine (7). The reaction of methylation from homocysteine to methionine requires two important enzyme cofactors, namely folic acid and vitamin B12, the latter being important as a cofactor of the methylene tetrahydrofolate reductase, the enzyme responsible of the transfer of the methilic group, for which folic acid represents the carrier, from homocysteine to methionine (8). Conversely, the reaction of trans-sulfuration from homocysteine to cysteine involves a key enzyme, namely cystathionine ß-synthase, whose hepatic expression seems to be induced by glucocorticoids and glucagon and inhibited by insulin (8). The second part of the metabolic pathway of SAAs is represented by the conversion of cysteine to taurine, involving two important enzymes, the cysteine dioxygenase and the cysteinesulfinate decarboxylase, which are influenced by the hypercatabolic states (8).

The hypercysteinemia has been already demonstrated in patients with CD (22) and hypothesized to contribute to the increased prevalence of nephrolithiasis in these patients through the consequent increase of cystine (26). Taking into consideration the effect of glucocorticoid on the SAA pathway enzyme and the evidence of a frequent association of insulin resistance and increased glucagon levels with glucocorticoid excess (27), the increased circulating levels of cysteine, and its dimer cystine, could be due to the direct stimulation exerted by glucocorticoids or, indirectly, to the glucocorticoid-induced insulin resistance and/or increased glucagon levels on cystathionine ß-synthase. Furthermore, it cannot be excluded that an increase of the availability of cysteine is a consequence of inhibition of the enzymes responsible of cysteine conversion to taurine, which would reduce the availability of taurine, or a direct consequence of increased levels of its direct precursor homocysteine.

Hyperhomocysteinemia has been suggested to be an independent risk factor for cardiovascular diseases, such as ischemic heart disease or stroke and deep vein thrombosis (28, 29), and it has been reported in different endocrine and nonendocrine conditions associated with an increased cardiovascular risk (30, 31, 32). The majority of studies evaluating the relationship between hyperhomocysteinemia and cardiovascular risk have focused on folic acid and/or vitamin B12 deficiency as the cause of impairment of remethylation of homocysteine to methionine (33, 34, 35). Hyperhomocysteinemia has been reported recently in patients with different forms of CS (20). In this latter study, a significant reduction of folic acid levels was accompanied by normal vitamin B12 levels. Moreover, the relative folic acid deficiency did not fully explain the hyperhomocysteinemia, which was significantly and directly correlated to cortisol levels of CS patients. The results of the current study, focusing on patients with CD, confirmed the presence of increased circulating levels of homocysteine in these patients but found the hyperhomocysteinemia to be associated only with significantly reduced vitamin B12 and only slightly but not significantly reduced folic acid levels, a finding that does not appear explainable with peculiar dietary habits. The discrepancy between the data reported in the current study and in the previous study (20) might be explained considering the different study populations of the two studies, both in terms of gender and age and in terms of CS etiologies, because the current study focused on pituitary-dependent CS whereas the previous study included all forms of CS. The finding of the current study is indeed supported by the observation of a significant correlation between vitamin B12 and homocysteine levels, suggesting that the relative vitamin B12 deficiency might at least contribute to the hyperhomocysteinemia in CD. The presence of vitamin B12 deficiency in patients with CD seems to be supported by the evidence that glucocorticoid excess is usually associated with macrocytic anemia (36), known to be commonly due to folic acid or vitamin B12 deficiency (37). However, the pathogenesis of vitamin B12 deficiency in patients with CD has been not definitely clarified yet, although it seems not to be related to a decreased intestinal absorption but likely to an increased renal excretion because glucocorticoids were found to inhibit renal vitamin B12 reuptake in animals (38, 39). It is important to outline that the hypothesis of an impairment of the remethylation of homocysteine to methionine has been already indicated as responsible for SSA impairment in patients with renal failure, a pathological condition sharing with CS the hypercatabolic state together with systemic arterial hypertension, impairment of glucose tolerance, dyslipidemia, increased cardiovascular risk, and increased levels of homocysteine and cysteine associated with decreased levels of taurine (40). It has to be also considered that, although the remethylation of homocysteine to methionine is the most likely impairment, the possibility that a stimulation of the trans-methylation from methionine to homocysteine is a concomitant cause of hyperhomocysteinemia in patients with CD cannot be completely ruled out. Finally, it is noteworthy that the methionine levels are surprisingly normal in patients with CD. However, methionine levels, which should be decreased for the impairment of the remethylation and/or trans-methylation, can be compensated by the dietary intake, which is the most important source of methionine, being an essential amino acid, or by the increased breakdown and/or reduced synthesis of protein in CD.

The most innovative and interesting finding of the current study is represented by the presence of hypotaurinemia in patients with CD. Taurine represents the end product of methionine metabolism, but it is also a peculiar SAA, which plays an important role in body osmoregulation, thermoregulation, and neuromodulation (41, 42). Taurine is becoming more and more consistent with a protective factor for cardiovascular system, because it seems to counteract the homocysteine-induced cardiovascular damage (15, 16). Therefore, hypotaurinemia may represent an additional independent factor for the increased cardiovascular risk associated with CS. The results of the current study demonstrated that patients with CD have decreased serum and increased urinary levels associated with an increased urinary ER of taurine. These findings suggested that an impairment of the taurine carrier, responsible for its renal reuptake, is likely the major cause of the taurine loss and therefore the hypotaurinemia of patients with CD. The mechanism underlying this phenomenon is not known. However, the evidence that urinary cortisol levels were inversely correlated to serum taurine levels and directly correlated to taurine ER seems to suggest a direct inhibitory effect of this renal carrier induced by glucocorticoid excess. However, dexamethasone was reported to down-regulate intestinal taurine uptake in human cell lines (43) but not to change renal taurine reuptake in rats (44). Anyway, considering that urinary cortisol levels were also significantly and independently correlated to taurine urinary ER, the results of the current study strongly support the hypothesis that the glucocorticoids excess is directly or indirectly responsible for the impaired renal uptake of taurine and the consequent hypotaurinemia associated with renal taurine loss in patients with CD. Conversely, because the preincubation of rat isolated renal tubules cells with the dimethylester of cystine was reported to inhibit the taurine uptake (45), it could be suggested that hypercystinemia may also be an inhibitor factor for the renal reuptake of taurine in these patients. Furthermore, glucose was demonstrated to induce a down-regulation of both human and rat taurine carrier in cultured cells (46, 47). On the basis of these evidences and the significant correlation between serum glucose levels and taurine urinary ER, the possibility that hyperglycemia inhibit taurine renal reuptake can be also hypothesized. Finally, it has to be outlined that the decreased plasma taurine levels cannot be completely explained by an inhibition of taurine renal reuptake, because it should be compensated by a taurine overproduction due to the hypercysteinemia. Moreover, the activation of cystathionine ß-synthase or the impairment of homocysteine remethylation would cause increased rather than decreased serum taurine levels. Therefore, an inhibition of the cysteine trans-sulfuration to taurine likely contributes to the hypotaurinemia of CD patients. In this respect, because glucagon inhibits cysteine dioxygenase activity (48), it can be hypothesized that the increased glucagon levels might inhibit cysteine dioxygenase and contribute to explain the hypotaurinemia of patients with CD. Anyway, the impairment of cysteine dioxygenase likely plays a pivotal role in SAA balance of patients with CD because it might explain both the increased serum levels of cysteine and, therefore, homocysteine and the reduced serum levels of taurine.

Interestingly, SAA abnormalities completely recover in CD patients after normalization of cortisol secretion with the disease remission. This finding indicates that hyperhomocysteinemia and hypotaurinemia are completely reversible metabolic complications of CS. This suggests that they may contribute to the increased cardiovascular risk of patients with CS during the active phase of disease but not the persistence of relatively increased cardiovascular risk in patients cured from CS.

In conclusion, the results of the current study demonstrated that CD is associated with hyperhomocysteinemia and hypotaurinemia. An impairment of the homocysteine remethylation to methionine, likely related to vitamin B12, an impairment of the renal taurine reuptake, likely due to an inhibition of the renal taurine carrier synthesis or function, together with a stimulation of cystathionine-ß-synthase and an inhibition of cysteine dioxygenase enzymes activity, seem to contribute to these changes in amino acid levels. Glucocorticoid excess is likely directly or indirectly responsible of the totality of these metabolic abnormalities, which are completely normalized after normalization of cortisol secretion with the remission of CD. The contribution of hyperhomocysteinemia and hypotaurinemia to the development of CD-dependent cardiovascular accidents remains to be established.


   Footnotes
 
This work was supported by Italian Minister of University and Research Grant 2004-062974.

First Published Online September 20, 2005

Abbreviations: CD, Cushing’s disease; CS, Cushing’s syndrome; ER, excretion rate; NS, not significant; SAA, sulfur amino acid.

Received March 24, 2005.

Accepted September 12, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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