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Division of Endocrinology and Metabolism (E.C., G.P.C.), Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece; and Section on Pediatric Endocrinology (E.C., T.K., T.I., G.P.C.), Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20892
Address all correspondence and requests for reprints to: Evangelia Charmandari, M.D., Division of Endocrinology and Metabolism, Clinical Research Center, Biomedical Research Foundation of the Academy of Athens, 4 Soranou tou Efessiou Street, Athens, 11527, Greece. E-mail: evangelia.charmandari{at}googlemail.com.
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Abstract |
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 Top Abstract IntroductionGeneralized Glucocorticoid...Conclusions and future...References |
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Evidence Acquisition: We conducted a systematic review of the published, peer-reviewed medical literature using MEDLINE (1975 through February 2008) to identify original articles and reviews on this topic.
Evidence Synthesis: We have relied on the experience of a number of experts in the field, including our extensive personal experience.
Conclusions: The clinical spectrum of primary generalized glucocorticoid resistance is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess. The molecular basis of the condition has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction and reduce tissue sensitivity to glucocorticoids. A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology. The study of functional defects of natural hGR mutants enhances our understanding of the molecular mechanisms of hGR action and highlights the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.
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Introduction |
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TopAbstractIntroductionGeneralized Glucocorticoid...Conclusions and future...References |
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isoform, which results from alternative splicing of hGR in exon 9, is ubiquitously expressed in almost all tissues and cells and represents the classic hGR that functions as a ligand-dependent transcription factor.
In the absence of ligand, hGR resides mostly in the cytoplasm of cells as part of a hetero-oligomeric complex, which contains chaperon heat shock proteins (HSPs) 90, 70, and 50, as well as other proteins (7). HSP90 regulates ligand binding, as well as cytoplasmic retention of hGR by exposing the ligand-binding site and masking the two nuclear localization (NL) sequences, NL1 and NL2, which are located adjacent to the DNA-binding domain (DBD) and in the ligand-binding domain (LBD) of the receptor, respectively. Upon ligand-induced activation, the receptor dissociates from this multiprotein complex and translocates into the nucleus (7, 8). Within the nucleus, the receptor binds as a homodimer to glucocorticoid response elements (GREs) in the promoter regions of target genes and regulates their expression positively or negatively depending on GRE sequence and promoter context (9, 10). Alternatively, the ligand-activated hGR can also modulate gene expression independently of DNA binding, by interacting possibly as a monomer with other transcription factors, such as activator protein-1, nuclear factor-
B, p53, and signal transducers and activators of transcription (11, 12, 13, 14). After transcriptional activation or inhibition of glucocorticoid-responsive genes, hGR dissociates from the ligand and has a lower affinity for binding to GREs. The unliganded hGR remains within the nucleus for a considerable length of time and is then exported to the cytoplasm; both within the nucleus and cytoplasm, the hGR may be recycled and/or degraded in the proteasome (15) (Fig. 1A
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uses its transcriptional activation domains, activation function (AF)-1 and AF-2, as surfaces to interact with nuclear receptor coactivators [p160, p300/cAMP-response element-binding protein (CBP), and p300/CBP-associated factor] and chromatin-remodeling complexes [switching sucrose nonfermenting and the vitamin D receptor-interacting protein (DRIP)/thyroid hormone receptor-associated protein (TRAP)] (16, 17, 18, 19, 20). The p160 coactivators, such as the steroid receptor coactivator 1 and the glucocorticoid receptor-interacting protein 1 (GRIP1), interact directly with both the AF-1 of hGR through their carboxyl-terminal domain and the AF-2 of hGR through multiple amphipathic LXXLL signature motifs located in their nuclear receptor-binding (NRB) domain (21). They also have histone acetyltransferase activity, which promotes chromatin decondensation, and allows the transcription initiation complex of the RNA-polymerase II and its ancillary components to initiate and promote transcription (16, 17, 18, 19) (Fig. 1B
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Alterations in any of the molecular mechanisms of hGR action described above may lead to alterations in tissue sensitivity to glucocorticoids, which may take the form of resistance or hypersensitivity and may be associated with significant morbidity (22, 23, 24, 25). One such condition that we have extensively investigated over the years is the primary generalized glucocorticoid resistance (26, 27, 28, 29, 30).
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Generalized Glucocorticoid Resistance |
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TopAbstractIntroductionGeneralized Glucocorticoid...Conclusions and future...References |
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Generalized glucocorticoid resistance is a rare, familial or sporadic genetic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids (26, 27, 28, 29, 30). The latter leads to activation of the hypothalamic-pituitary-adrenal (HPA) axis and compensatory elevations in circulating cortisol and adrenocorticotropic hormone (ACTH) concentrations, which maintain circadian rhythmicity and appropriate responsiveness to stressors. The excess ACTH secretion results in adrenal hyperplasia, and increased production of adrenal steroids with mineralocorticoid activity, such as cortisol, deoxycorticosterone (DOC) and corticosterone, and/or androgenic activity, such as androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone-sulfate (26, 27, 28, 29, 30) (Fig. 2A).
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and relates to the pathophysiologic alterations depicted in Fig. 2A. Generally, clinical manifestations of glucocorticoid deficiency have not been reported in subjects affected with the condition, with the exception of chronic fatigue, which might indicate inadequate compensation by the increased cortisol concentrations in certain resistant target tissues, such as the central nervous system or the skeletal muscles. Symptoms and signs of mineralocorticoid excess, such as hypertension and hypokalemic alkalosis, have been reported in many affected subjects, and are attributed to the elevated concentrations of cortisol, DOC, and corticosterone (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42). The increased concentrations of adrenal androgens in subjects with the condition result in manifestations of androgen excess, such as ambiguous genitalia in a chromosomally 46,XX child at birth and gonadotropin-independent precocious puberty in children of either gender, acne, hirsutism and infertility in both sexes, male-pattern hair loss, menstrual irregularities and oligo-anovulation in females, and oligospermia in males (Table 1). The impaired fertility in both sexes is most likely due to the feedback inhibition of gonadotropin secretion by the elevated androgen concentrations. Finally, the increased CRH (inferred) and ACTH concentrations are likely to account for the profound anxiety described in some cases (40) and may predispose affected subjects to the development of intratesticular adrenal rests and/or ACTH-secreting pituitary adenomas (31).
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). This variable clinical phenotype is likely to be due to: 1) variations in the glucocorticoid, mineralocorticoid, or androgen receptor signaling pathways; 2) variations in the degree of tissue sensitivity to glucocorticoids, mineralocorticoids, and/or androgens; 3) variations in the activity of key hormone-inactivating or -activating enzymes, such as the 11β-hydroxysteroid dehydrogenase (43) and 5-reductase (44); and 4) other genetic or epigenetic factors, such as insulin resistance and abdominal (visceral) obesity (28).
The diagnosis of generalized glucocorticoid resistance is suggested by the elevated serum cortisol concentrations, as well as the increased 24-h urinary free cortisol (UFC) excretion in the absence of clinical manifestations of hypercortisolism. The plasma concentrations of ACTH may be normal or high. The circadian pattern of ACTH and cortisol secretion and their responsiveness to stressors are preserved, although at higher concentrations, and there is resistance of the HPA axis to dexamethasone suppression. Sequencing of the hGR gene in association with thymidine incorporation and dexamethasone-binding assays on peripheral blood mononuclear cells are necessary to confirm the diagnosis (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42) (Table 1). In affected subjects, the thymidine incorporation assays reveal resistance to dexamethasone-induced suppression of phytohemagglutinin-stimulated thymidine incorporation, while the dexamethasone-binding assays often show decreased affinity of the hGR for the ligand compared with control subjects (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 45). Finally, once a structural defect has been determined, its adverse effect on receptor function should be confirmed using in vitro mutagenesis and standardized assays that examine the ability of the mutant hGR to activate gene expression. However, it should be noted that even if all these functional characteristics of the receptor are normal, a "post-receptor" defect related to transactivation cannot be excluded. Indeed, sequencing of the coding region of the hGR gene did not reveal mutations or deletions in a number of patients with primary generalized glucocorticoid resistance (36, 45). In these subjects, the promoter regions or introns of the hGR gene were not studied. In addition, several other factors implicated in glucocorticoid signal transduction could be affected in these patients, including the HSPs, coactivators, corepressors, or other transcription factors (13, 14, 16).
The differential diagnosis of generalized glucocorticoid resistance includes: 1) mild forms of Cushing's disease, in which hypercortisolism is accompanied by normal or mildly elevated ACTH concentrations; 2) pseudo-Cushing's states, such as generalized anxiety disorder and melancholic depression; 3) conditions associated with elevated serum concentrations of corticosteroid-binding globulin, such as normal pregnancy and estrogen treatment; 4) essential hypertension, hyperaldosteronism, and other causes of mineralocorticoid-induced hypertension; and 5) other causes of hyperandrogenism or virilization, such as idiopathic hirsutism, polycystic ovarian syndrome, and congenital adrenal hyperplasia (CAH) (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42). In most cases, generalized glucocorticoid resistance should be easily distinguished on biochemical grounds. However, it may be difficult to distinguish the condition in its mild biochemical form from other mild forms of hypercortisolism, such as mild or early Cushing's syndrome, hypercortisolemic melancholic depression, anorexia nervosa, chronic active alcoholism, and intensive exercise (46, 47, 48).
The aim of treatment in generalized glucocorticoid resistance is to suppress the excess secretion of ACTH, thereby suppressing the increased production of adrenal steroids with mineralocorticoid and androgenic activity. Treatment involves administration of high doses of mineralocorticoid-sparing synthetic glucocorticoids, such as dexamethasone (1–3 mg/d), which activate the mutant and/or wild-type hGR, and suppress the endogenous secretion of ACTH in affected subjects (26, 27, 28, 29, 30). Adequate suppression of the HPA axis is of particular importance in cases of severe impairment of hGR action, given that long-standing corticotroph hyperstimulation in association with decreased glucocorticoid negative feedback inhibition at the hypothalamic and pituitary levels may lead to the development of an ACTH-secreting adenoma (31). Long-term dexamethasone treatment should be carefully titrated according to the clinical manifestations and biochemical profile of the affected subjects (26, 27, 28, 29, 30).
Molecular mechanisms
The molecular basis of generalized glucocorticoid resistance has been ascribed to mutations in the hGR gene, which impair one or more of the molecular mechanisms of hGR action, thereby altering tissue sensitivity to glucocorticoids. Inactivating mutations within the LBD or the DBD of the receptor, and a 4-bp deletion at the 3'-boundary of exon 6 of the gene, have been described in five kindreds and five sporadic cases (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42). The molecular defects elucidated in the reported cases are summarized in Table 2, while the corresponding mutations in the hGR gene are shown in Table 2 and Fig. 2B. It is worth noting that most of these mutations (seven of 10) were heterozygous, indicating that complete loss-of-function of the receptor is incompatible with life.
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-mediated transactivation of glucocorticoid-responsive genes (26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42).
In transient transfection assays, all mutant receptors demonstrated variable reduction in their ability to transactivate the glucocorticoid-responsive mouse mammary tumor virus promoter in response to dexamethasone compared with the wild-type receptor, with the most severe impairment observed in the cases of R477H (undetectable), I559N (minimal/undetectable), V571A (decreased by 50-fold), and D641V (minimal) mutations (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42). Furthermore, the mutant receptors hGRI559N, hGRF737L, hGRI747M, and hGRL773P exerted a dominant negative effect upon the wild-type receptor. The latter might have contributed to manifestation of the disease at the heterozygote state (31, 35, 38, 40, 42).
Dexamethasone-binding studies showed a variable reduction in the affinity of the mutant receptors for the ligand, with the most severe reduction observed in the cases of I559N (undetectable), I747M (undetectable), and V571A (6-fold) mutations (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42). The only mutant receptor that demonstrated normal affinity for the ligand was the hGRR477H, in which the mutation is located at the DBD of the receptor (41).
The decreased affinity of the mutant receptors for the ligand most likely reflects the location of the mutations in the LBD of hGR (Fig. 2B). The structure of the hGR LBD contains 12 -helices and four small β-strands that fold into a three-layer helical domain (49, 50). Helices 1 and 3 form one side of a helical sandwich, whereas helices 7 and 10 form the other side. The middle layer of helices (helices 4, 5, 8, and 9) are present in the top half but not in the bottom half of the protein. This arrangement of helices creates a cavity in the bottom half of the LBD, where the agonist molecule is bound (Fig. 2C). H12, which plays an essential function in ligand-dependent activation, adopts the so-called "agonist bound" conformation, where it packs against helices 3, 4, and 10 as an integrated part of the domain structure. After H12, there is an extended strand that forms a conserved β-sheet with a β-strand between helices 8 and 9. This C-terminal β-strand appears to play an important role in receptor activation by stabilizing H12 in the active conformation (51). Deletion of the last few residues that form the β-strand lead to alterations in hormone binding specificity and significant reduction in the receptor-mediated transactivation of target genes, suggesting that the C-terminal region of hGR, downstream of H12, is essential for ligand-binding specificity and agonist potential, although it does not appear to confer differential hormone-binding capacities to the receptor (50, 51).
We next studied the subcellular localization and nuclear translocation of the wild-type and mutant receptors in HeLa cells by creating green fluorescent protein-fused constructs of the receptors. In the absence of dexamethasone, hGR was primarily localized in the cytoplasm of cells. Addition of dexamethasone (10–6 M) resulted in translocation of the wild-type receptor into the nucleus within 12 min. The pathological mutant receptors were also observed predominantly in the cytoplasm of cells in the absence of ligand, except for the mutant receptors hGRV729I and hGRF737L, which were localized both in the cytoplasm and the nucleus of cells. Exposure to the same concentration of dexamethasone induced a slow translocation of the mutant receptors into the nucleus, which ranged from 20 min (R477H) to 180 min (I559N and F737L) (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42). These findings indicate that all hGR mutations affect the nucleocytoplasmic shuttling of hGR, probably through impairment of the NL1 and/or NL2 function. Impairment of the NL1 function may occur as a result of the decreased affinity for the ligand, which may prevent a proper ligand-induced allosteric conformation of the receptor, and, therefore, a normal interaction between NL1 and components of the importin system (52). On the other hand, impairment of the NL2 function might be specifically dependent upon the conformation of the LBD induced by the ligand, and could also be due to the mutations. Differential binding of the mutant and wild-type receptors to HSPs, which partially inactivate NL1 and NL2, might also contribute to the differences observed between the times required for entry into the nucleus (53, 54, 55).
Unlike the wild-type and most mutant receptors, the mutant receptors hGRV729I and hGRF737L were localized both in the cytoplasm and the nucleus of cells in the absence of ligand. The β-isoform of hGR, which has a "defective," nonligand-binding LBD, as well as all hGR mutants that lack their LBD, also localize primarily in the nucleus of cells (35). This suggests that the LBD of hGR plays an important role in the cytoplasmic retention of the receptor in the absence of ligand. Alternatively, defective mechanisms that may relate to delayed nuclear export, such as the calreticulin export pathway and certain motifs in the DBD that function as nuclear export signals, might account for the nuclear localization of the unliganded hGRV729I and hGRF737L (56, 57), an effect that might be similar to the nuclear retention mechanism of hGRβ (35).
We investigated the ability of the mutant receptors to bind to DNA in EMSAs and chromatin immunoprecipitation assays (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42). The wild-type and all mutant receptors in which the mutations were located in the LBD of hGR preserved their ability to bind to DNA. The only mutant receptor that failed to bind to DNA was the hGRR477H, in which the mutation is located at the C-terminal zinc finger of the DBD of the receptor (41). A major function of the C-terminal zinc finger of the DBD of hGR is to contribute to receptor homodimerization, a prerequisite for potent receptor binding to GREs and efficient transactivation of glucocorticoid-responsive genes (58, 59). This function is achieved by a group of five amino acids in the N-terminal knuckle of the C-terminal zinc finger of the receptor, known as the D loop or dimerization domain. Point mutations in the DBD of the GR may abolish DNA binding, resulting in silencing of transcriptional activation, although they may not affect the ability of the mutant receptors to transrepress activator protein-1, nuclear factor-B, and/or other target gene-dependent transcription, possibly through protein-protein interactions and/or tethering of other cofactors to the transcriptional machinery (59, 60, 61, 62).
To determine whether the mutant receptors displayed an abnormal interaction with the p160 coactivators, we investigated the interaction between the mutant receptors and the GRIP1 coactivator in a glutathione-S-transferase pull-down assay. GRIP1 contains two sites that bind to steroid receptors. One site, the NRB site, is located at the amino terminus of the protein and interacts with the AF-2 of hGR in a ligand-dependent fashion. The other site is located at the carboxyl terminus of the protein and binds to the AF-1 of hGR in a ligand-independent fashion (63, 64, 65). The wild-type and most mutant receptors bound to full-length GRIP1 and the carboxyl-terminal fragment of GRIP1, but not to the NRB fragment of GRIP1, suggesting that these mutant receptors interact with the GRIP1 coactivator in vitro only through their AF-1. Exceptions represented the mutant receptors hGRR477H, which interacted with both the AF-1 and AF-2 of hGR, and hGRI559N, which did not interact with either fragment of GRIP1 (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42).
H12 plays a critical role in the formation of both the ligand-binding pocket and the AF-2 surface that facilitates interaction with coactivators. Upon ligand binding, the receptor undergoes major conformational changes that alter the position of H11 and H12, and generate an interaction surface that allows coactivators to bind to AF-2 through their LXXLL motifs (50). In the agonist-bound conformational state of hGR LBD, H12 adopts a position over the ligand-binding pocket, which allows coactivators to interact within the coactivator cavity, thus forming a transcriptionally active receptor. On the contrary, binding to an antagonist induces structural changes leading to the loss of the helical structure in the C-terminal portion of H11 and movement of H12 over the ligand-binding pocket, a position that prevents coactivator binding and enables corepressor binding (50) (Fig. 2C). It is likely that the presence of various mutations in the LBD of hGR influences the orientation of H12, either by preventing contact between this helix and the ligand or by displacing it from its active position (66, 67, 68). These findings indicate that the hGR mutant receptors may form a defective complex with GRIP1, which is partially or completely ineffective. Furthermore, the mutant receptors may also display an abnormal interaction with other AF-2-associated proteins, such as the p300/CBP cointegrators and components of the DRIP/TRAP complex (16, 17, 18, 19).
Using fluorescence recovery after photobleaching analysis, all hGR pathological mutant receptors had defective transcriptional activity and dynamic motility defects inside the nucleus of living cells (69). In the presence of dexamethasone, these mutants displayed a curtailed 50% recovery time (t1/2) after photobleaching, and, therefore, significantly increased intranuclear motility and decreased chromatin retention. The t1/2 values of the mutants correlated positively with their transcriptional activities and depended on the hGR domain affected. Thus, mutant hGRs possess dynamic motility defects in the nucleus, possibly caused by their inability to interact properly with all key partner nuclear molecules necessary for full activation of glucocorticoid-responsive genes. The motility defect of the mutant receptors is directly proportional to their transactivation defect, indicating that the former is a good overall index of functionality (69).
Finally, we examined the association between the location of the known mutations in the crystal structure of the LBD of hGR and the molecular mechanisms through which these mutations impaired glucocorticoid signal transduction. Figure 2D illustrates the location of the known hGR mutations in the agonist (upper panel) and antagonist (lower panel) form of the LBD of hGR. Two mutations (I559N and V571A) are located within H5, whereas four mutations (V729I, F737L, I747M, and L773P) are located close to H11 and H12. All mutations within the LBD of the receptor were shown to affect the affinity of the receptor for the ligand, however, this effect was more pronounced in the cases of I559N and V571A mutations located in H5 of the receptor. Nuclear translocation was more delayed in the cases of I559N, V729I, and F737L mutations, implicating mostly H5, H10, and H11. All mutations within the LBD of the receptor affected the in vitro interaction of the receptor with the GRIP1 coactivator but preserved their ability to bind to DNA. The one mutation R477H identified in the DBD of the receptor impaired primarily the ability of the receptor to bind to GREs. The fact that most mutant receptors interacted with the GRIP1 coactivator in vitro only through their AF-1 domain highlights the importance of H10, H11, and H12 of the LBD of the receptor in facilitating the formation of the AF-2 surface that interacts with coactivators.
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Conclusions and future directions |
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TopAbstractIntroductionGeneralized Glucocorticoid...Conclusions and future...References |
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Research studies on the mechanisms of action of glucocorticoids at the cellular and/or molecular level are extremely important. Given the highly complex and stochastic nature of glucocorticoid signaling pathways and the variable effect that hGR gene mutations may have on glucocorticoid signal transduction, glucocorticoid resistance may be generalized or tissue specific and may have important implications for many critical biological processes, such as the behavioral and physiologic responses to stress, the immune and inflammatory reaction, the process of sleep, as well as basic functions, such as growth and reproduction (1, 2, 3). The study of the functional defects of natural hGR mutants sheds light on the mechanisms of hGR action and highlights the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.
We conclude that mutations in the hGR gene impair one or more of the molecular mechanisms of glucocorticoid action, thereby altering tissue sensitivity to glucocorticoids. A consequent increase in the activity of the HPA axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids, however, at the expense of ACTH hypersecretion-related pathology. The variable clinical phenotype of generalized glucocorticoid resistance, in association with the difficulties encountered in establishing the correct diagnosis, may account for the low prevalence of the condition, given that many cases may be unrecognized and misclassified in the medical literature. We recommend screening with 24-h UFC excretion, and sequencing of the hGR gene in patients with manifestations of mineralocorticoid and androgen excess (hypertension, hirsutism, menstrual irregularities, oligo-anovulation, impaired fertility), in whom detailed investigations failed to reveal an underlying etiology.
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Footnotes |
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Disclosure Statement: The authors have nothing to disclose.
First Published Online March 4, 2008
Abbreviations: AF, Activation function; CAH, congenital adrenal hyperplasia; CBP, cAMP-response element-binding protein; DBD, DNA-binding domain; DOC, deoxycorticosterone; DRIP, vitamin D receptor-interacting protein; GR, glucocorticoid receptor; GRE, glucocorticoid response element; GRIP1, glucocorticoid receptor-interacting protein 1; H, helix; hGR, human glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal; HSP, heat shock protein; LBD, ligand-binding domain; NL, nuclear localization; NRB, nuclear receptor binding; TRAP, thyroid hormone receptor-associated protein; UFC, urinary free cortisol.
Received January 7, 2008.
Accepted February 25, 2008.
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References |
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TopAbstractIntroductionGeneralized Glucocorticoid...Conclusions and future...References |
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R477H and hGRG679S associated with generalized glucocorticoid resistance. J Clin Endocrinol Metab 91:1535–1543-reductase 2 deficiency. Endocr Rev 14:577–593This article has been cited by other articles:
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  S. R. Bornstein Predisposing Factors for Adrenal Insufficiency N. Engl. J. Med., May 28, 2009; 360(22): 2328 - 2339. [Full Text] [PDF]
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 E. Singer, S. Strohm, U. Gobel, M. Bieringer, D. Schmidt, W. Schneider, R. Kettritz, and F. C. Luft Cushing's Disease, Hypertension, and Other Sequels Hypertension, December 1, 2008; 52(6): 1001 - 1005. [Full Text] [PDF]
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