Active Cushing's Disease Research Articles

Increased prevalence of thyroid autoimmunity in patients successfully treated for Cushing's disease

Cushing's disease is characterized by abnormalities of immune function. To evaluate the prevalence of autoimmune thyroid diseases in patients with Cushing's disease (CD), after successful treatment and the possible association between previous nodular goitre or positive thyroid autoantibodies during the active phase of CD and the subsequent development of autoimmune thyroid diseases after cure. Twenty patients with CD and 40 sex- and age-matched healthy controls were considered for the study. In CD patients, thyroid ultrasonography and measurement of circulating free thyroxine (fT4), free triiodothyronine (fT3), thyroid stimulating hormone (TSH), antithyroglobulin (anti-Tg) and antithyroperoxidase (anti-TPO) antibodies were performed at diagnosis and 6 months after disease cure while in controls they were performed only at study entry. Serum fT3, and fT4 levels were similar in patients, either during the active phase or after cure of the disease, and controls. Conversely, in the patients, serum TSH levels were significantly lower during active disease (0. 4 +/- 0.05 mU/l, P = 0.001) and significantly higher after disease cure (4.7 +/- 0.1 mU/l, P < 0.001) than in controls (2.3 +/- 0.4 mU/l). Four patients (20%) and 11 controls (27.5%) had positive anti-Tg and/or anti-TPO titre at study entry, while eight patients (40%) developed positive anti-Tg and/or anti-TPO titre after disease cure. The prevalence of positive antithyroid antibodies titre in cured CD patients was significantly higher than that observed in the same patients during the active disease (P = 0.008) and in controls (P = 0.031). A significantly higher prevalence of autoimmune thyroiditis was found in patients cured from CD (35%) than in patients with active CD (0%) (P = 0.016) and in controls (10%) (P = 0.031). A significant association was found between the presence of autoimmune thyroiditis after CD cure and the presence of a previous nodular goitre (P = 0.017) or positive thyroid autoantibodies titre (P = 0.007) during the active phase of the disease. Patients successfully treated for Cushing's disease have an increased prevalence of thyroid autoimmunity and autoimmune thyroiditis as compared to a control population. Therefore, patients with hypercortisolism need an accurate evaluation of thyroid function after remission of the disease in order to prevent the eventual onset of subclinical or overt post-thyroiditis hypothyroidism.

A critical analysis of the value of simultaneous inferior petrosal sinus sampling in Cushing's disease and the occult ectopic adrenocorticotropin syndrome.

The clinical, biochemical, and radiological features of pituitary ACTH-dependent Cushing's syndrome (CS) [Cushing's disease (CD)] are often indistinguishable from those of occult ectopic ACTH-dependent CS (oEAS). We have evaluated, retrospectively, the results of simultaneous bilateral inferior petrosal sinus (IPS) ACTH sampling before and after CRH stimulation in 128 patients with ACTH-dependent CS: 107 patients with CD, 6 with oEAS, 1 with an adrenal adenoma, 1 with a pituitary gangliocytoma, and 1 with Nelson's syndrome; while, in the remaining 12, the source remains unclear. One hundred seven patients received human-sequence CRH (hCRH), and 11 received ovine CRH; another 6 patients underwent stimulation with desmopressin and hCRH, and 4 with desmopressin alone. A successful bilateral IPS catheterization and sampling (IPSCS) rate of 87.5% was obtained only after considerable experience had been gained. Sixty-nine patients with CD underwent successful bilateral IPSCS: the IPS-to-peripheral ratio of plasma ACTH value (IPS/P) rose from 9.5 +/- 1.4 to a maximum ratio of 55.8 +/- 7.5 in 67 patients, after CRH stimulation. The maximum ratio was obtained at 5 min in 60 of the 69 patients with CD; however, all 69 patients obtained a ratio of more than 2, at that time. In contrast, the 6 patients with occult ACTH-secreting neoplasms had a maximal IPS/P ratio of 1.3 +/- 0.16, and this did not change after CRH stimulation. A bilateral IPS/P ratio more than 2, obtained 5 min after CRH stimulation, had a sensitivity of 97% and a specificity of 100% in diagnosing CD. Two patients with proven active CD had an IPS/P ratio of less than 2. After successful bilateral IPSCS, the gradients between the IPS ACTH concentrations [IPS ACTH gradient (IPSG)] of more than 1.4, at 5 min after CRH stimulation, had a sensitivity of 83% in correctly lateralizing the pituitary microadenoma, compared with 72% sensitivity for magnetic resonance imaging (MRI) scanning. Furthermore, when IPSG and MRI findings were contradictory, IPSG was more often correct than MRI scanning. Although oEAS is a relatively uncommon cause of ACTH-dependent hypercortisolism (5.5% in our series), the accurate diagnosis of ACTH-dependent CS and localization of an intrapituitary microadenoma requires bilateral IPSCS with CRH stimulation, provided that the appropriate technical experience is available. hCRH is as effective a secretagogue as ovine CRH, and either may be used. The value of the combination of CRH and desmopressin stimulation requires more detailed investigation.

Suppressibility of plasma adrenocorticotropin by hydrocortisone: potential usefulness in the diagnosis of Cushing's disease.

Repeatedly normal cortisol suppressibility by dexamethasone in 2 patients with Cushing's disease led to the present study of the prevalence of this phenomenon in 58 patients with otherwise incontrovertible evidence of Cushing's disease. Because as many as 23% of these patients manifested this phenomenon, we investigated the suppressibility of plasma ACTH: 1) during i.v. infusion of hydrocortisone, after a priming dose (7 mg), at 3 mg/h in 8 patients and 8 normal controls; and 2) for 2 h, after oral hydrocortisone, 0.25 mg/kg, in 13 patients and 16 controls. The data showed invariable suppression of plasma ACTH to < or = 10 pg/mL (< or = 2.2 pmol/L) after 120 min of the infusion or at 90 min after oral hydrocortisone in 16 fasting normal subjects given oral hydrocortisone between 0800 and 0830 h. Plasma ACTH exceeded 10 pg/mL (2.2 pmol/L) at the same times in 14/14 patients with active Cushing's disease, including 3 patients whose cortisol suppressibility by dexamethasone had been misleadingly normal and in 4/7 patients with intermittent hypercortisolism. Occasional variations in plasma cortisol elevations after the oral dose require that plasma cortisol concentration be monitored at 60 min after the oral hydrocortisone dose, because the present evidence supports the validity of the conclusion that a plasma ACTH concentration below 10 pg/mL excludes Cushing's disease only when plasma cortisol concentration at 60 min lies between 16 and 38 microg/dL. Further evaluation of ACTH suppressibility by cortisol would be worthwhile, to confirm its potential value in facilitating positive diagnosis of Cushing's disease when dexamethasone suppressibility seems misleading.

High prevalence of nodular thyroid disease in patients with Cushing's disease.

In the recent past, we have noted a frequent occurrence of thyroid nodules in our patients with Cushing's disease. We therefore elected to evaluate thyroid structure and function in these patients and also in patients with Cushing's syndrome of primary adrenal origin. In 33 of the 37 patients (30 women and 3 men aged 19-66 years) with endogenous hypercortisolism referred to our Institution during the last five years, measurement of T4, T3, FT4, FT3, TSH serum levels and thyroid ultrasonography were performed, at first admission in 15 cases and subsequently in the course of follow-up in 18 cases. At the time of the study, 16 of the 33 patients had active Cushing's disease while 9 were in remission after successful surgery, 6 patients had an adrenal tumour and 2 patients had previously undergone unilateral adrenalectomy for an adrenal adenoma. Thyroid function and ultrasonography were also evaluated in 55 normal subjects, 40 women and 15 men aged 20-73 years. In 25 patients with Cushing's disease, we found a significantly higher prevalence of thyroid nodular disease than that recorded in 55 control subjects (60.0 vs 20.0%, chi 2 = 10.779, P < 0.005) and comparable to that in patients with active disease (56.2%) and those in remission (66.6%). Multiple nodules were present in 8 Cushing's patients and in 4 normal subjects while a single nodule was detected in 7 patients and in 7 controls. A markedly lower occurrence of thyroid abnormality was found in the 8 patients with adrenal tumours (25.0%, NS vs controls). In 9/17 (52.9%) patients with ultrasonographic evidence of thyroid nodules, these were palpable. As expected, serum thyroid hormone and TSH levels were reduced in patients with active Cushing's syndrome compared to normal controls. We found a significantly higher prevalence of nodular thyroid disease in patients with Cushing's disease with respect to a group of controls in whom the prevalence of thyroid nodules was comparable to that reported for the general population in Europe. The possibility that glucocorticoid excess is responsible for the development of thyroid changes does not seem likely since in our small series of patients with adrenal tumours the prevalence was only slightly higher than that observed in control subjects. Other factors related to hyperactivity of the corticotrophic cell, or a growth factor stimulating both corticotroph and thyrocyte proliferation might be involved. Evaluation of a larger series of patients with adrenal tumours may help to distinguish between these possibilities.

Psychiatric phenomenology in Cushing's disease.

We evaluated 20 patients with Cushing's disease (i.e., Cushing's syndrome due to ACTH-secreting pituitary microadenoma) and 20 patients with Major Depressive Disorder (MDD) using the Structured Clinical Interview for DSM-III-R (SCID) and Research Diagnostic Criteria. The diagnosis of Generalized Anxiety Disorder (GAD) was most common in Cushing's disease (79%), followed by MDD (68%), and Panic Disorder (PD) including subthreshold PD (53%). The combination of MDD and GAD and/or PD was also common in Cushing's disease (63%). Behavioral symptoms, if present, usually first occurred at or after the onset of the first physical symptoms. However, the onset of PD was associated with more chronic stages of Cushing's disease. In both Cushing's disease and MDD, more female than male relatives suffered from MDD, whereas more male than female relatives suffered from substance abuse. The data demonstrate a syndrome of anxious depression in patients with active Cushing's disease; such comorbidility has not been previously noted. The data also point to intriguing epidemiological, clinical, and biological associations between Cushing's disease, MDD and substance abuse.

Lack of diurnal rhythm of low molecular weight insulin-like growth factor binding protein in patients with Cushing's disease

A specific radioimmunoassay with antibodies raised against the 25 kD insulin-like growth factor binding protein (25 kD IGFBP) in amniotic fluid was used to measure levels of cross-reacting protein in human serum and plasma. Plasma samples collected continually at 20-min intervals during 24-h in 6 healthy adults revealed a distinct diurnal rhythm in the concentration of 25 kD IGFBP. The lowest levels (9-13 micrograms/l) were found between 13.00 and 24.00 h with a rise after midnight to maximum levels (23-71 micrograms/l) between 03.00 and 09.00 h. There was no relation between the patterns of GH and 25 kD IGFBP. In 3 patients with active Cushing's disease, the levels of 25 kD IGFBP in plasma samples collected during 12 h, 19.00-07.00 h, were generally low and without nocturnal variations. One of the patients studied after extirpation of a pituitary adenoma displayed a nocturnal rhythm with maximum levels of 25 kD IGFBP between 03.00 and 07.00 h. Eight patients treated with stereotactic pituitary irradiation owing to Cushing's disease also showed a distinct nocturnal increase of 25 kD IGFBP. The results indicate the existence of a diurnal rhythm of 25 kD IGFBP in adults. Further, low levels and lack of diurnal rhythm of 25 kD IGFBP are demonstrated in Cushing's disease.

Ovine corticotrophin releasing factor stimulates ACTH release from human corticotrophinoma cells in culture; interaction with hydrocortisone and arginine vasopressin.

We have investigated the effects of ovine corticotrophin releasing factor (oCRF) and its interaction with hydrocortisone (HC), and arginine vasopressin (AVP) on ACTH release from human corticotrophinoma cells in culture. Tumour tissue was obtained from six patients (three with active Cushing's disease and three with Nelson's syndrome). Cultures were maintained for periods of up to six months. Ovine CRF (21 nmol) significantly (P less than 0.01) stimulated ACTH release from all tumours. Dose response (21 pmol-21 nmol) effects were observed for the three tumours investigated over 2 and 4 h. Cortisol (20 mumol) significantly (P less than 0.01) inhibited basal ACTH release from one tumour (Nelson's syndrome) by 75% over 4 h, and completely prevented the stimulatory effects of oCRF. AVP directly stimulated ACTH release from two tumours (Nelson's syndrome), and also potentiated the stimulatory action of oCRF during 30 min incubations. These data show corticotrophinoma cells from subjects with Cushing's disease and Nelson's syndrome can be directly stimulated by hypothalamic oCRF and may be potentiated by AVP. Cortisol and oCRF have been shown in one tumour to have antagonistic actions at the pituitary level.

Successful pregnancy after cyproheptadine treatment for Cushing's disease

A patient with active Cushing's disease who became pregnant following treatment with cyproheptadine is described. Despite stopping the cyproheptadine treatment at 3 mth gestation, the previous amelioration of the clinical and biochemical features of the adrenal hyperfunction was maintained and the pregnancy progressed satisfactorily. Moreover, serial evaluation of maternal glucose tolerance proved to be normal and it is suggested that this matabolic aspect is an important determinant in the outcome of pregnancies occurring in patients with Cushing's syndrome.

Reversible gonadotropin Deficiency in Male Cushing's Dusease

Twelve adult males with documented active Cushing's disease were studied. Mean plasma testosterone (T) was significantly decreased: 1.8 +/- 0.3 (SEM) ng/ml (N=6.8 +/- 0.5); gonadotropin measurements in 8 patients, in basal conditions and under LH-RH iv, showed a significant decrease in both FSH and LH. A further study of 11 patients in remission of Cushing's disease indicated a significant increase in plasma T and gonadotropins up to the normal range. One patient with an initial low T value had a normalized T while in remission, then a dramatic decrease when the disease relapsed. We conclude: a hypogonadotropic hypogonadism is found in male Cushing's disease; it disappears as early as hypercortisolism is suppressed. Some possible mechanisms are discussed.

Relationship of Bioassayable and Immunoassayable Plasma ACTH and Cortisol Concentrations in Normal Subjects and in Patients with Cushing's Disease

Plasma ACTH and cortisol concentrations were determined at 5-min intervals over a 3- or 4-h sampling period in 2 normal subjects. Time spans studied were 10:00 AM-1:00 PM, 4:00 PM-8:00 PM, 8:00 PM-11:00 PM, and 4:00 AM-8:00 AM. Similar sampling for 3 h, (onset 9:00-9:30 AM) was performed on 4 patients with Cushing's disease, 3 untreated and 1 in remission following pituitary irradiation. Two of these patients were studied on 2 separate occasions. Plasma ACTH was determined by both immunoassay (I) and bioassay (B). Although in general, these studies demonstrated significant correlation between I-ACTH or B-ACTH concentrations and those of plasma cortisol, a striking finding in both subject categories was the presence of 30- to 50-min episodes during which marked rises in both I- and B-ACTH concentrations occurred without concomittant, or markedly diminished, increments in plasma cortisol concentrations. This could not be explained by biological inactivity of the ACTH, since a highly significant correlation was present between I- and B-ACTH concentrations at all times; r values ranged between 0.86 and 0.98 for normal subjects, and 0.76 and 0.96 for patients with Cushing's disease. The lack of correlation in these episodes also does not appear to be secondary to an 11-beta-hydroxylase block, differences in the rate of change of plasma ACTH concentrations, lack of adrenal "priming" by prior ACTH or incapacity of the adrenal gland to further increase secretion. I/B ACTH ratios were similar in the normal subjects (1.42-1.64) and in the patients with Cushing's disease (1.27-1.47). "Apparent" ACTH half lives calculated from "peaks" of ACTH secretion were 7-12 min for I-ACTH and 3-9 min for B-ACTH in the normal subjects; and 9-13 min and 7-9 min respectively, in the patients with Cushing's disease. Mean plasma ACTH I-and B-concentrations at comparable time periods were higher in patients with active Cushing's disease than in normal subjects. These studies also indicate that in Cushing's disease, the abnormality present resides in ACTH regulatory mechanisms, not in the nature of the ACTH secreted. Approximation of the total amount of immunoassayable ACTH secreted in one normal subject over a 24-h period yielded a value of 73 mug. Total mug/h secreted in the 2 normal subjects were highest in the hour preceding awakening (6:30-7:30 AM; 12.9 and 12.2 mug/h); were 5.3 and 4.0 mug/h between 10:00-11:00 AM, and 1.4 and 1.7 mug/h between 9:00-10:00 PM. In the 3 patients with clinically active Cushing's disease, apparent ACTH secretion between 10:00-11:00 AM varied from 19.2-34.3 mug/h, the magnitude of such secretion being positively correlated with the extent of increased adrenal cortical activity present.

THE THYROTROPHIN-RELEASING HORMONE TEST IN DISEASES OF THE PITUITARY AND HYPOTHALAMUS

The increase in serum-thyroid-stimulating hormone (T.S.H.) levels measured twenty and sixty minutes after intravenous injection of 200 μg. of synthetic thyrotrophin-releasing hormone (T.R.H.) has been used as a test of pituitary-hypothalamic function. 77 patients with diseases of the pituitary or hypothalamus had T.R.H. tests and routine clinical and biochemical assessment of pituitary and thyroid function. Of 35 patients with acromegaly, 9 of whom had not received treatment directed to the pituitary, only 7 showed a normal response to T.R.H., and 4 of these were in the untreated group. No patient in whom growth hormone (G.H.) levels had returned to normal showed a normal T.S.H. reserve. In the acromegalic patients the T.S.H. reserve was impaired twice as frequently as the corticotrophin reserve (A.C.T.H.). Of 27 patients with various other pituitary lesions, 14 had an impaired or absent T.S.H. response, and 8 of these had other clinical or biochemical evidence of hypothyroidism. Unlike the acromegalic patients, T.S.H. and A.C.T.H. reserve were impaired with equal frequency in this group. Of 15 patients with various hypothalamic lesions, 8 had an impaired or absent response to T.R.H.; 3 patients who responded normally to T.R.H. had other evidence of hypothyroidism. A delayed response to T.R.H., where the twenty-minute T.S.H. level was less than the sixty-minute value, occurred in 13 of 15 in this group. This delayed pattern of response can be used to recognise hypothalamic disease. In patients with pituitary disease, but not in those with hypothalamic disease, a normal T.S.H. response to T.R.H. excludes the diagnosis of hypothyroidism. All patients with non-hormone-secreting pituitary lesions who had no response to T.R.H. were hypothyroid; this was not true in acromegaly or in a patient with active Cushing's disease. Since only 7 of the 26 patients with pituitary disease who showed impaired responses were hypothyroid by other criteria, it is suggested that impaired responses merely indicate a risk of the development of thyroid deficiency.

Clinical application of a new test of pituitary reserve.

ABSTRACT SU-4885 inhibits 11β-hydroxylation of steroids by the human adrenal cortexand leads to a decrease in cortisol secretion, a “compensatory” rise in ACTH secretion, and the secretion of large quantities of 11-desoxycorticosteroids such as compound S. Compound S and its metabolites are readily measurable in biologic fluids as 17-hydroxycorticoids. In normal subjects, therefore, SU-4885 induces a rise in total blood and urinary 17-hydroxycorticoids. Since this response to SU-4885 is dependent upon a rise in ACTH secretion it affords, in patients who do not have frank adrenal insufficiency, a sensitive means of testing the reserve capacity of the pituitary gland to secrete ACTH. Of 9 patients with chromophobe adenomas tested in this manner, 6 were found to have “limited pituitary reserve.” This was true also of 2 out of 5 patients with acromegaly, 3 out of 6 patients with cachexia, and 1 patient with post-traumaticdiabetes insipidus. Of 7 patients with active Cushing's disease due to adrenal hyperplasi...