Interpretation of Abnormal Dexamethasone Suppression Test is Enhanced With Use of Synchronous Free Cortisol Assessment.

CONTEXT: Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding. OBJECTIVE: We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic workup. DESIGN AND SETTING: Cross-sectional study conducted in a tertiary medical center. PARTICIPANTS: Adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy [OCP], 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n = 196; 16 women on OCP). MEASUREMENTS: Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay). MAIN OUTCOME MEASURES: Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol. RESULTS: Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95% CI, 81.7-91.7); all false-positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false-positive results (21.1% vs 4.9%, P = 0.02). CONCLUSIONS: Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL.

Early assessment of postoperative adrenal function is necessary after adrenalectomy for mild autonomous cortisol secretion.

BACKGROUND: The diagnostic threshold for mild autonomous cortisol secretion using low dose, overnight, dexamethasone suppression testing is recognized widely as a serum cortisol ≥1.8 mcg/dL. The degree to which these patients require postoperative glucocorticoid replacement is unknown. METHODS: We reviewed adult patients with corticotropin (ACTH)-independent hypercortisolism who underwent unilateral laparoscopic adrenalectomy for benign disease with a dexamethasone suppression testing ≥1.8 mcg/dL at our institution from 1996 to 2018. Patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL were compared with those with a dexamethasone suppression testing >5 mcg/dL. RESULTS: We compared 68 patients with a preoperative dexamethasone suppression testing of 1.8 to 5 mcg/dL to 53 patients with a preoperative dexamethasone suppression testing >5 mcg/dL. Preoperative serum ACTH (mean 10.0 vs 9.2 pg/mL), adenoma size (mean 3.4 vs 3.5 cm), and side of adrenalectomy (37 and 47% right) were similar between groups (P > .05 each). Patients with a dexamethasone suppression testing 1.8 to 5 mcg/dL were older (mean values 58 ± 11 vs 52 ± 16 years ; P = .01), less likely to be female (63 vs 81%; P = .03), had greater body mass indexes (33.1 ± 8.4 vs 29.1 ± 5.6; P = .01), and had lesser 24 hour preoperative urine cortisol excretions (32.6 ± 26.7 vs 76.1 ± 129.4 mcg; P = .03). Postoperative serum cortisol levels were compared in 22 patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL to 14 patients with a dexamethasone suppression testing >5 mcg/dL. Those with dexamethasone suppression testing 1.8 to 5 mcg/dL had greater postoperative serum cortisol levels (8.0 ± 5.7 vs 5.0 ± 2.6 mcg/dL; P = .03), were less likely to be discharged on glucocorticoid replacement (59% vs 89%; P = .003), and had a decreased duration of treatment (4.4 ± 3.8 vs 10.7 ± 18.0 months; P = .04). CONCLUSION: Assessment of early postoperative adrenal function with mild autonomous cortisol secretion is necessary to minimize unnecessary glucocorticoid replacement.

Adrenal Venous Sampling for Assessment of Autonomous Cortisol Secretion.

Context: Autonomous cortisol secretion (ACS) can be unilateral or bilateral irrespective of the presence of an adrenal tumor. A reliable method to distinguish between unilateral and bilateral ACS is lacking. Objective: Evaluate the use of adrenal venous sampling (AVS) to distinguish between unilateral and bilateral ACS. Design and Methods: This was a prospective study of AVS in patients with adrenal tumors who received a diagnosis of ACS or adrenal Cushing syndrome (CS). Unilateral secretion was defined as >2.3-fold difference in cortisol levels between the two adrenal veins. Metanephrine levels were used to ascertain correct catheter position. Results were correlated with findings on CT and iodine-131-cholesterol scintigraphy. Results: Thirty-nine patients underwent AVS; there were no complications. The procedure was inconclusive in six patients and repeated with success in one, giving a success rate of 85%, and leaving 34 procedures for evaluation (adrenal CS, n = 2; ACS, n = 32). Of 14 patients with bilateral tumors, 10 had bilateral and 4 had unilateral overproduction. Of 20 patients with unilateral tumors, 11 had lateralization to the side of the tumor and the remaining had bilateral secretion. Cholesterol scintigraphy findings were concordant with those of AVS in 13 of 18 cases (72%) and discordant in 5 (28%). Conclusion: Laterality of ACS does not always correspond to findings on CT images. AVS is a safe and valuable tool for differentiation between unilateral and bilateral cortisol secretion and should be considered when operative treatment of ACS is a possibility.

Subclinical hypercortisol-assessment of bone fragility: experience of single osteoporosis center in Sicily.

AIM: Hypercortisolism is known to cause osteoporosis. Some evidence suggests that osteoporotic fractures may be the presenting manifestations of otherwise-asymptomatic hypercortisolism. The aim of our research was to investigate the prevalence of subclinical hypercortisolism (SH) in postmenopausal women evaluated for bone fragility. PATIENTS AND METHODS: One hundred consecutive postmenopausal women attending the Osteoporosis Centre in the Department of Internal Medicine of the University of Messina (Messina, Italy), for the first time, were screened and a total of 50 patients (age 58±5 years) were studied. Hypercortisolism was diagnosed by unsuppressed serum cortisol levels after 2 day low dose dexamethasone suppression test. RESULTS: Among the 50 postmenopausal women studied, 3 had SH. This prevalence was 6%. The three patients with SH had a normal bone mineral density (BMD) at lumbar spine and were osteopenic at femoral neck, and presented one or more vertebral fractures at spinal radiography. CONCLUSIONS: Physicians should always consider SH among the causes of bone fragility, especially in individuals with vertebral fractures and the presence of an only slightly reduced BMD.

Analysis of cortisol, cortisone and dexamethasone in human serum using liquid chromatography tandem mass spectrometry and assessment of cortisol: cortisone ratios in patients with impaired kidney function.

BACKGROUND: We developed a high sensitivity method for simultaneous measurement of cortisol, cortisone and dexamethasone. Using this method, we compared concentrations of cortisol, cortisone and their ratios in samples from intensive care unit (ICU) and non-ICU patients, and cortisol and dexamethasone concentrations in patients with Cushing's and suspected Cushing's syndrome. METHODS: Two hundred microliters of human serum aliquots were extracted using solid phase extraction and analyzed using liquid chromatography-tandem mass spectrometry. Primary mass transitions monitored for cortisol, cortisone and dexamethasone were m/z 363/121, 361/163 and 393/373 respectively. RESULTS: The limits of quantification for cortisol and cortisone were 0.3 µg/l (0.8 nmol/l) and for dexamethasone it was 0.5 µg/l (1.2 nmol/l). Total imprecision was <10.9%. Median cortisol to cortisone ratio of ICU patient samples was found to be 2 times higher than non-ICU samples. 54.2% of patients after 1mg dose of overnight dexamethasone could be categorized as consistent with Cushing's syndrome. CONCLUSIONS: The method has high sensitivity and specificity. High cortisol to cortisone ratios in samples from ICU patients suggest change in activity of 11ß-hydroxysteroid dehydrogenase in modulation of systemically available cortisol. Simultaneous measurement of dexamethasone and cortisol can be used to differentially diagnose diseases causing increased concentrations of cortisol.

High prevalence of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas: a challenge to management.

OBJECTIVE: The prevalence of subclinical hypercortisolism (SH) in unilateral incidentalomas (UI) has been extensively studied; however, patients with bilateral incidentalomas (BI) have not been thoroughly investigated. We therefore aimed to describe the characteristics of patients with BI compared to their unilateral counterparts. The surgical outcome in a small number of patients is reported. DESIGN: Observational retrospective study in a single secondary/tertiary centre. PATIENTS: One hundred and seventy-two patients with adrenal incidentalomas (41 with BI). MEASUREMENTS: Morning cortisol (F), ACTH, dehydroepiandrosterone sulphate (DHEA-S), midnight F, 24-h urine collection for cortisol (UFC), low-dose dexamethasone suppression test (LDDST), fasting glucose, insulin, and oral glucose tolerance test (OGTT). Primarily, SH was defined as F-post-LDDST>70 nmol/l and one more abnormality; several diverse cut-offs were also examined. RESULTS: No difference was noted in age, body mass index, or prevalence of diabetes and impaired glucose tolerance between patients with UI and those with BI. Patients with BI had higher F-post-LDDST (119·3 ± 112·8 vs 54·3 ± 71·5 nmol/l, P<0·001) and lower DHEA-S (1·6 ± 1·5 vs 2·5 ± 2·3 µmol/l, P=0·003) but similar UFC, ACTH and midnight F levels, compared to UI. SH was significantly more prevalent in BI (41·5%vs 12·2%, P<0·001). Fourteen patients were operated on; four underwent bilateral interventions. In 10 patients, unilateral adrenalectomy on the side of the largest lesion resulted in significant improvement in F-post-LDDST (P=0·008) and a decrease in midnight F (P=0·015) levels. CONCLUSIONS: Subclinical hypercortisolism is significantly more prevalent in bilateral incidentaloma patients, posing great dilemmas for its optimum management.

Assessment of left ventricular diastolic function and Tei index by tissue Doppler imaging in patients with Cushing's Syndrome.

BACKGROUND: The aim of this study was to assess left ventricular (LV) function and the Tei index by tissue Doppler imaging (TDI), and also to evaluate the relationship of serum cortisol level with the Tei index and LV function in patients with Cushing's Syndrome (CS). METHODS: We prospectively evaluated 22 patients with CS and 23 control subjects. LV function was assessed by echocardiography. Early diastolic (Em), late diastolic (Am), peak systolic (Sm), mitral annular velocities, Em/Am, the Tei index, and E/Em were calculated by TDI. Mitral inflow velocities, color M-mode flow propagation velocity (Vp), relative wall thickness (RWT), and LV mass index (LVMI) were assessed by two-dimensional echocardiography. RESULT: Peak (E) velocity and the ratio of E to peak late (A) velocity (E/A) were lower in those with CS than in those without. Patients with CS had significantly higher RWT, IVRT, and LVMI than those controls. Vp was lower in the CS-patients than that in control subjects. Em and Em/Am were lower in patients with CS than those in controls. In patients with CS, the Tei index was significantly higher than control subjects. CONCLUSION: Serum cortisol level was positively correlated with the Tei index and E/Em ratio but negatively correlated with Em, Sm, and EF only in patients with CS. Serum cortisol level positively correlated with the Tei index and E/Em ratio but negatively correlated with Em, EF, and Sm. The parameters obtained from lateral mitral annulus by TDI can be used for identification of LV diastolic dysfunction in patients with CS.

Assessment of bilateral inferior petrosal sinus sampling (BIPSS) in the diagnosis of Cushing's disease.

BACKGROUND: The differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) remains a challenging issue for clinical endocrinologists. In this respect, bilateral inferior petrosal sinus sampling (BIPSS) appears to be the most sensitive and specific test. Here, we report our 15-year experience of analyzing the performance of BIPSS, both in the correct diagnosis and in the precise lateralization of tumors in patients with Cushing's disease (CD). METHODS: Between 1992 and 2006, 18 patients with CD (16 females, 2 males; age range, 14-56 years) were admitted to Taipei Veterans General Hospital and subjected to BIPSS plus ovine corticotropin-releasing hormone (oCRH) stimulation. Four of them had previously undergone transsphenoidal hypophysectomy (TSH) and had a recurrence thereafter. BIPSS was performed by inserting a catheter in the right and left inferior petrosal sinus for ACTH assay via a femoral vein puncture. An inferior petrosal sinus/peripheral ACTH ratio (C/P ratio) > or = 2 at baseline > or = 3 after oCRH injection indicated a pituitary origin of ACTH secretion, and an interpetrosal ACTH gradient (IPS ratio) > or = 1.4 at baseline or after oCRH indicated evidence of lateralization. RESULTS: Positive BIPSS results were found in 16 patients at baseline and in 17 patients after oCRH injection. In 17 out of 18 patients, TSH was subsequently carried out and a pituitary source was confirmed on histopathologic examination. The only 1 false-negative test result was noted in a patient who had undergone previous TSH. Thus, the sensitivities of BIPSS for the diagnosis of CD before and after oCRH stimulation were 89% and 94%, respectively. Moreover, using an IPS ratio > or = 1.4 as a criterion, BIPSS correctly lateralized the tumor in 9 of 17 and 10 of 17 patients at baseline and after oCRH stimulation, respectively, including in 2 patients who had a centrally located tumor and who had an IPS ratio < 1.4. Thus, the sensitivities of lateralization of BIPSS were 53% and 59%, respectively. None of the 4 patients who had previous TSH were precisely localized by BIPSS. If these 4 patients were excluded, the sensitivities of BIPSS for localizing in the patients who had not undergone previous operation increased to 70% (9/13) at baseline and 77% (10/13) after oCRH stimulation, respectively. CONCLUSION: BIPSS combined with oCRH stimulation is a safe and reliable examination both in the differential diagnosis of CD and in the correct lateralization of pituitary microadenoma in patients without previous pituitary surgery. Nevertheless, this procedure may provide misleading results in patients who have received previous pituitary surgery.

Assessment of GH reserve before and after successful treatment of adult patients with Cushing's syndrome.

OBJECTIVE: Several studies have demonstrated impaired GH secretion in patients with active Cushing's syndrome (CS). It has been suggested that persistence of GH deficiency, despite treatment of cortisol excess, may delay the recovery of these patients and therefore temporary treatment with GH may have some benefit. However, the time course of restoration of GH secretion after successful treatment of CS has only been investigated in a limited number of mostly paediatric reports. The aim of the present study was the evaluation of GH reserve in adult patients with CS before and after correction of cortisol excess. DESIGN AND PATIENTS: Sixteen patients (12 females, four males) with CS aged 44.7 +/- 5.05 years were recruited. These included seven patients with Cushing's disease, four patients with ectopic ACTH secretion and five patients with adrenal adenoma. All patients were evaluated before any therapeutic intervention. Twelve patients were successfully treated following appropriate surgery and these were further studied. The combined pyridostigmine/GHRH test was used to assess GH reserve in these patients. In a proportion of cases an insulin tolerance test (ITT) was also used. RESULTS: Before any therapeutic intervention, an impaired GH response to PD/GHRH was noted in all patients. Restoration of GH response at 6 months was observed in six patients (50%); at 12 months in two; at 18 months in one patient. Two of the patients with no restoration of GH response at 12 months did not accept further investigation. Only one patient did not achieve an adequate GH response even when tested 30 months following cure of CS. Restoration of GH reserve was more commonly observed in those patients in whom there was recovery of the HPA axis. There was a good correlation between peak GH levels to PD + GHRH and ITT. No statistically significant difference was revealed in IGF-I levels between pre- and post-treatment evaluation. CONCLUSIONS: Adult patients with active Cushing's syndrome demonstrate a profound suppression of stimulated GH secretion. In the majority of these patients the disruption of GH secretion is normalized within a year after successful treatment of endogenous cortisol excess.

Transsphenoidal microsurgical treatment of Cushing disease: postoperative assessment of surgical efficacy by application of an overnight low-dose dexamethasone suppression test.

OBJECT: Transsphenoidal adenomectomy with resection of a defined pituitary adenoma has been the treatment of choice for CD for the last 30 years. Surgical resection, however, may not always result in long-term remission of CD. This is particularly important in light of the high risk of morbidity and mortality in patients in the unsuccessfully treated cushingoid state. As such, it is interesting to identify prognostic factors that may predict the likelihood of long-term remission. METHODS: The authors review their series of 174 patients who have undergone transsphenoidal procedures for CD over a period of 20 years with minimum follow-up periods of 5 years. Selection of these patients was based on clinical, imaging, and laboratory criteria that included serum cortisol levels, loss of diurnal variation in serum cortisol levels, urinary free cortisol concentration, and results of a dexamethasone suppression test, petrosal sinus sampling, and corticotroph-releasing hormone stimulation tests as indicated. All patients who met the biochemical criteria underwent transsphenoidal microsurgery. The authors found an overall rate of remission of 74% at 5 years postoperatively. Patients in whom morning serum cortisol concentrations were lower than 3 microg/dl (83 nmol/L) on postoperative Day 3, following an overnight dexamethasone suppression test, had a 93% chance of remission at the 5-year follow-up examination. Patients with cortisol concentrations higher than this level uniformly failed to achieve long-term remission. CONCLUSIONS: Transsphenoidal microsurgery is an effective means of control for patients with adrenocorticotrophic hormone-producing microadenomas. Clinical outcome correlated well with the size of the tumor, as measured on preoperative imaging studies, and with postoperative morning cortisol levels following an overnight dexamethasone suppression test. Postoperative cortisol levels can be used as a useful prognostic indicator of the likelihood of future recurrence following transsphenoidal adenomectomy in CD.

Cortisol production rates in subjects with suspected Cushing's syndrome: assessment by stable isotope dilution methodology and comparison to other diagnostic methods.

It can be difficult to establish the diagnosis of Cushing's Syndrome (CS) in patients with mild or nonspecific clinical and biochemical findings, because available diagnostic tests have limited predictive values. We hypothesized that measurement of 24-h cortisol production rates (CPRs) might be a more sensitive indicator of CS in such patients. We measured CPRs in 28 patients with suspected CS (but equivocal biochemical findings) and in 22 healthy control subjects, by infusing tracer amounts of deuterated cortisol, with simultaneous measurements of 24-h urine free cortisol (UFC) levels; and we frequently sampled serum cortisol levels. CPRs were calculated from the ratio of isotopic enrichment to isotopic dilution of cortisol measured by gas chromatography-negative ion chemical ionization mass spectrometry. Nine of the patients proved to have CS by surgery (CS-Yes), whereas 19 patients were determined not to have CS by biochemical testing (CS-No). Mean 24-h UFCs, nocturnal serum cortisol levels, and CPRs were higher in CS-Yes, compared with CS-No and normal subjects. However, one CS-Yes patient had a normal 24-h UFC, two had normal nocturnal serum cortisol levels, and two had normal 24-h CPRs. There was extensive overlap in all of the biochemical parameters between the CS-Yes and the CS-No groups. Thus, measurement of CPR does not seem to offer any diagnostic advantage over available tests for the diagnosis of CS. Patients with proven CS can have normal UFC levels, normal CPRs, or normal nocturnal cortisol levels, whereas patients not thought to have CS may have elevated levels of any one or more these parameters.

Assessment of cortisol and ACTH responses to the desmopressin test in patients with Cushing's syndrome and simple obesity.

OBJECTIVE: The desmopressin test has recently been introduced in clinical practice as an adjunctive tool in the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). It has been reported that the majority of patients with pituitary-dependent CS (Cushing's disease, CD) respond to desmopressin, while no such response is usually observed in other forms of this syndrome. In the present study, the responsiveness of the HPA axis to desmopressin was studied in a group of obese subjects. In addition, the ability of desmopressin administration to differentiate between patients with obesity and the various forms of Cushing's syndrome was investigated. DESIGN AND SUBJECTS: Cortisol and ACTH responses to the administration of desmopressin (10 microg bolus i.v.) were examined in 20 consecutive patients with obesity (14 women and six men; BMI range: 34.5-66.7 kg/m2). Obese subjects had no clinical stigmata of CS. In all obese patients, either an overnight (dex 1 mg at 2300 h) (n = 8) or a formal low-dose (dex 0.5 mg 6-hourly for 2 days) (n = 12) dexamethasone suppression test was performed for the exclusion of Cushing's syndrome. Three of eight subjects showed failure of cortisol suppression (i.e. F > 28 nmol/l) to the overnight dexamethasone suppression test, but they had undetectable cortisol levels (< 28 nmol/l) on further testing with the formal 2-day test. All but two of the remaining subjects had undetectable cortisol levels (< 28 nmol/l) following the formal 2-day, low-dose, dexamethasone suppression test. For comparison, desmopressin responses were also tested in 33 patients with CS of varied aetiologies (25 patients with pituitary-dependent CS, three patients with occult ectopic ACTH secretion and five patients with primary adrenal CS). A positive response was considered to be an increment greater than 20% and 50% from baseline levels of cortisol and ACTH, respectively. RESULTS: Mean cortisol (F) and ACTH levels did not differ from the baseline at any time point following desmopressin administration in the obese group (basal F: 417 +/- 41, peak F: 389 +/- 32 nmol/l, P > 0.05; basal ACTH: 33.5 +/- 4.3, peak ACTH: 50.6 +/- 16.6 ng/l, P > 0.05), or in patients with occult ectopic or primary adrenal CS. In contrast, in the group of patients with CD, there was a significant rise in the mean ACTH and F levels from baseline (basal F: 725 +/- 50, peak F: 1010 +/- 64 nmol/l, P < 0.01; basal ACTH: 88.6 +/- 11.8, peak ACTH: 351 +/- 64 ng/l, P < 0.01). Cortisol responses greater than 20% from baseline were observed in 21/25 (84%) patients with CD, but in only 3/20 (15%) of the obese patients. With regard to ACTH, increments greater than 50% over baseline were observed in 23/25 (92%) of patients with CD, and in only 3/20 (15%) of the obese patients. As previously reported, none of the patients with occult ectopic ACTH secretion or primary adrenal CS had a positive response. CONCLUSIONS: The prevalence of subjects who met the criteria adopted to define positive cortisol and ACTH responses to the desmopressin test was significantly higher in the group of patients with Cushing's disease than in the group of patients with obesity. It is therefore suggested that this test may be occasionally useful in the differentiation between simple obesity and the pituitary-dependent form (but not other forms) of Cushing's syndrome.

[Assessment of prognosis factors in the cure of Cushing's disease surgically treated via a +septotransphenoidal approach]. / Evaluación de los factores pronósticos en la curación de la enfermedad de Cushing intervenida por vía septotransesfenoidal.

INTRODUCTION: In Cushing's disease (CD) pituitary surgery or radiotherapy has been proposed by some authors, when plasmatic cortisol after surgery is not clearly low. AIM: To assess if the different prognostic factors, specially plasmatic cortisol seven days after surgery and/or hypocortisolism phase are predictive of the CD outcome. METHODS: From 1988, 11 women with CD underwent 13 transsphenoidal microsurgery, because two patients relapsed. The mean age of patients was 27 years (11-52). Plasmatic cortisol was measured seven days after pituitary surgery, and since 45 days, every three-six months, basal plasmatic cortisol and after ACTH and urinary free cortisol were determined. RESULTS: Follow-up evaluations ranged from 18-84 months (median, 38 months). After pituitary surgery in 13 cases the cumulative remission was 100%, two cases relapsed. In 10 cases plasmatic cortisol seven days after surgery was less than 137 nmol/l and in three cases higher than 137 nmol/l. Three cases did not presented hypocortisolism phase. The two patients who relapsed, one was after eight months of pituitary surgery an previously showed low plasmatic cortisol and the other relapse 25 months after pituitary surgery without low cortisol plasmatic levels. CONCLUSION: Remission in CD can happen either low or normal plasmatic cortisol levels seven days posttreatment or without hypocortisolism phase. Ours findings ascribe new importance to the different presentations after treatment of CD, and patients with these findings are not a risk for relapse and pituitary surgery or irradiation would not be early indicated.

Bedside assessment of skin-fold thickness. A useful measurement for distinguishing Cushing's disease from other causes of hirsutism and oligomenorrhea.

BACKGROUND: The known catabolic effects of glucocorticoid excess on protein metabolism prompted us to devise a method to assess this measure in reproductive-aged females with Cushing's disease. Since collagen protein is a major component of skin, decreased abundance of this protein should cause a reduction in skin-fold thickness. To determine whether skin-fold thickness is useful as an added tool in the diagnosis of Cushing's disease, we compared this value in female patients with Cushing's disease with those who presented with a similar set of symptoms. METHODS: This open prospective study was conducted in an endocrinology clinic at a tertiary care center. The study population consisted of 88 females in the reproductive age group who presented to the clinic with hirsutism, oligomenorrhea, and/or obesity. Measurement of skin-fold thickness, body mass index, Ferriman-Gallwey index, and serum testosterone were performed in all patients. RESULTS: Skin-fold thickness in the patients with Cushing's disease was 1.5 +/- 0.2 mm (range, 1.0 to 1.8 mm). This value was significantly (P < .01) lower than that in controls or subjects with other disorders that have a similar set of presenting symptoms. CONCLUSIONS: Bedside assessment of skin-fold thickness is an easy, low-cost, and noninvasive test for distinguishing Cushing's disease from disorders with similar presenting symptoms in females of reproductive age. Assessment of skin-fold thickness should be used as an adjunct to current physical and biochemical study of patients with symptoms suggestive of Cushing's disease.

Assessment of endocrine function after transsphenoidal surgery for Cushing's disease.

OBJECTIVE: We assessed the endocrine outcome after transsphenoidal surgery for Cushing's disease. DESIGN: Five-year (mean) follow-up (range 1 month-12 years) of patients undergoing transsphenoidal surgery for Cushing's disease between 1977 and 1990; review of case notes, current clinical and biochemical assessment including 24-hour urinary free cortisol. SETTING: Northern Ireland. SUBJECTS: Forty-one patients (33F: 8M); mean age at diagnosis 39.1 years (9-72 years). MAIN OUTCOME MEASURES: Measurements of early post-operative 0800 h serum cortisol and 24-hour urinary free cortisol at least 24 hours after withdrawal of oral hydrocortisone therapy. This was followed by low dose dexamethasone testing. Current 24-hour urinary free cortisol measurements. Retrospective definition of cure. RESULTS: Twenty-seven patients were either cured or improved by surgery, 14 were considered definite failures. Of 19 patients cured, eight had unmeasurable early post-operative 0800 h serum cortisol levels while of 15 tested, 13 had complete suppression with dexamethasone and two suppressed normally but to still measurable levels (39 and 60 nmol/l respectively). Seventeen patients in total have subsequently had bilateral adrenalectomy of whom two have developed Nelson's syndrome. Seven of the 41 patients were shown to have definite cyclical cortisol secretion first diagnosed post-operatively in three patients. Hormone deficiency included TSH (5), LH/FSH (1), cortisol (1) and ADH (temporary in 7, permanent in 1). In all, seven patients had some type of permanent hormonal deficiency post-operatively. CONCLUSIONS: Transsphenoidal surgery offers a worthwhile cure rate without the necessity of life-long endocrine therapy. Post-operative endocrine assessment must be rigorous so that early further management can be planned in the significant percentage of patients in whom cure is not achieved. Early complete suppression on low dose dexamethasone testing is very suggestive of cure but repeated and long-term monitoring of 24-hour urinary free cortisol is advisable.

Use of a radioreceptor assay in the assessment of cushingoid features in patients with juvenile rheumatic diseases.

A marked variation has been observed in severity of cushingoid appearance in patients with rheumatic diseases (RD) following steroid administration. We studied ten children with RD to determine if a relationship exists between cushingoid features and an individual's steroid activity as measured by prednisolone equivalents using a radioreceptor assay. Cushingoid features were clinically assessed by a "cushing score" according to the method of Bergrem. Patients were assigned to either the cushingoid (C) or noncushingoid (NC) group at study entry according to their cushing score. Blood was drawn prior to prednisone ingestion and then at 30, 60, 90, 120, 240, and 360 minutes and each sample was assessed for prednisolone equivalents and also for free and total cortisol. Group comparisons of dose-adjusted area under curve (AUC) and peak response are reported. Cushingoid patients had higher plasma prednisolone equivalents (PE) than noncushingoid patients as measured by peak PE and AUC. The PE.6 h/L average AUC for C patients was 248 micrograms PE.6 h/L versus 134 micrograms PE.6 h/L for NC patients. This nearly twofold difference was also noted between mean peak values (C 82 micrograms/L vs. NC 44 micrograms/L). Spearman correlations of Cushing scores with these two parameters indicated significant (p less than 0.05) relationships. A patient's Cushing score correlated best with peak response (rs = 0.78) and also with AUC (rs = 0.72). Measurement of plasma peak PE or AUC could be valuable for individualizing steroid dosing in children with RD.

Comparative assessment of ACTH and lipotropin plasma levels in the diagnosis and follow-up of patients with Cushing's syndrome: a study of 210 cases.

PURPOSE: A series of 210 patients with Cushing's syndrome was evaluated at a single center to assess the relative values of adrenocorticotropic hormone (ACTH) and lipotropin (LPH) plasma levels in the etiologic diagnosis of Cushing's syndrome and in the follow-up of treated Cushing's diseases. PATIENTS AND METHODS: These patients included 149 patients with Cushing's diseases, 20 with adrenal tumors, and 41 with ectopic ACTH/LPH syndromes. Hormone levels were measured before therapy and during the follow-up of treated Cushing's diseases. RESULTS: ACTH and LPH plasma levels were moderately elevated in Cushing's diseases, low or undetectable in adrenal tumors, and highly elevated in ectopic ACTH/LPH syndromes, but the overlap between the three etiologic groups was less for LPH than for ACTH. LPH appeared to be as sensitive as ACTH in evaluating the outcome of trans-sphenoidal surgery and in detecting the occurrence of Nelson's syndrome after bilateral adrenalectomy. CONCLUSION: Therefore, plasma LPH determinations provide a better index than ACTH measurements, probably for technical reasons as well as because of the greater stability of LPH in blood.

A simple and economical method for the radioimmunoassay of cortisol in serum.

A simple, economical method is described for the radioimmunoassay of cortisol in serum. Extraction is avoided by heating the diluted serum to inactivate cortisol-binding globulin. The radioimmunoassay is carried out in a single disposable scintillation vial without centrifugation. Free and bound steroid is separated by partition between ammonium sulphate solution and liquid scintillation fluid. Accuracy, precision and sensitivity are satisfactory. Normal ranges obtained are comparable to those obtained by other radioimmunoassay methods for cortisol.

Assessment of 11beta-hydroxylase activity with plasma corticosterone, deoxycorticosterone, cortisol, and deoxycortisol: role of ACTH and angiotensin.

UNLABELLED: In this study we evaluated the role of ACTH and angiotensin on regulation of activities of 11beta-hydroxylases of the adrenal cortex. The ratio of the plasma concentrations of 11 deoxycorticosterone (DOC) to plasma corticosterone (B) reflected the activity of the enzyme of the B and/or aldosterone pathways, and the ratio of plasma 11-deoxycortisol (S) to plasma cortisol (F) as the activity of the enzyme in the F pathway. In normal subjects, both ratios were significantly lower at 0800-0900 h (Doc to B, .01+/-.004, mean+/-SE, n=10; and S to F, .01+/-.003) than at 2000 h (DOC to B, .028+/-.024 and S to F, .015+/-.005). The plasma levels of DOC, B, S and F were all significantly lower at 2000-2100 h than at 0800-0900 h. In contrast 9 patients with Cushing's syndrome exhibited no diurnal change in the ratios. The ratios increased substantially following dexamethasone or metyrapone administration. A high or low salt diet and an angiotensin infusion produced no significant effect on the ratios. The plasma concentration of all four steroids was increased by more than 50% by an infusion of angiotensin. Four hours after administration of 80 mg of Lasix at 0800 h to 10 normal subjects, the ratios of DOC to B and S to F increased significantly (P less than .02), an effect possibly related to a decreased secretion of ACTH. CONCLUSIONS: 1) 11beta-hydroxylase activity of the B and/or aldosterone and F pathways appears to change in parallel with ACTH secretion, and 2) although angiotensin stimulates steroidogenesis of the pathways, it has no apparent effect on 11beta-hydroxylase activity.