Biomedical subjects

L K Nieman

Publications and source records attributed to L K Nieman.

At least 55 records · Page 3Linked to original sources

PubMed1995

Effects of insulin-like growth factors I and II and insulin on the immortalized hypothalamic GTI-7 cell line.

Insulin and insulin-like growth factor I (IGF-I) participate in energy metabolism, regulate cellular growth and differentiation, and are thought to act locally in a paracrine manner through specific receptors. Systemic levels of these peptides in humans and primates are directly associated with levels of activity of the reproductive axis. To date, it is unclear whether these peptides participate in reproductive function by acting at the level of the GnRH neuron. In this study we examined the effects of IGF-I, IGF-II and insulin on immortalized GnRH-secreting neurons, the GTI-7 cell line. The GTI-7 cells expressed all three members of the insulin receptor family as determined by analysis of 125I-IGF-I, 125I-IGF-II and 125I-insulin binding sites. Insulin receptors bound insulin, IGF-II and IGF-I with a ratio of potency of 1:5:20. IGF-I and IGF-II receptors bound both IGF-I and IGF-II. The ratio of potency of IGF-I/IGF-II was 1:5 for the IGF-I receptor and 100:1 for the IGF-II receptor. The binding characteristics of the growth factors at 22 degrees C suggested the possibility that these cells may secrete IGF binding proteins. To ensure that changes in GnRH levels in the media were due to secretion and not to changes in cell number, the mitogenic effect of these peptides on GTI cells was evaluated. Both insulin and IGF-I were strong mitogens (48-hour incubation), restoring cell number to that of serum-replete cultures at a dose of 0.1 ng/ml. A 100-fold higher dose of IGF-II was required to produce a similar level of mitogenicity, implicating an action through the IGF-I and/or insulin receptor. Due to these mitogenic effects, the effect of insulin, IGF-I and IGF-II on GnRH secretion was studied after short-term exposure. Insulin and IGF-I did not affect GnRH secretion, but IGF-II had a biphasic effect on GnRH release after 2 h of incubation (a maximum stimulatory effect occurred with a 0.1 ng/ml dose). In order to examine the signal transduction mechanism, the role of cytoplasmic calcium mobilization in IGF-II-induced GnRH secretion was examined in single cells using calcium imaging. The effect of IGF-II on GnRH secretion appeared to operate via a calcium-independent mechanism. The studies document an insulin/IGF system in the GTI-7 neuronal cell line and show that insulin and IGFs can exert direct effects on the immortalized GnRH neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding Sites↗

PubMed1995

Selective venous sampling from the cavernous sinuses is not a more reliable technique than sampling from the inferior petrosal sinuses in Cushing's syndrome.

The purpose of this study was to compare ACTH levels in unstimulated samples obtained from the cavernous sinuses (CS) to unstimulated and CRH-stimulated samples obtained from the inferior petrosal sinuses (IPS) in 15 patients with surgically proven Cushing's disease. After unstimulated samples were obtained through 5-French catheters placed in both IPS, tracker catheters were introduced into both cavernous sinuses, and unstimulated samples were obtained within 5 min of the initial set. The Tracker catheters were removed, CRH was administered, and CRH-stimulated samples were obtained from the IPS. We compared the central to peripheral ACTH ratios in unstimulated samples from the cavernous sinuses to unstimulated and CRH-stimulated samples from the IPS as a basis for distinguishing pituitary from ectopic ACTH production. In addition, we compared the ability of the intercavernous and interpetrosal ACTH ratios to correctly predict the site of the microadenoma. Unstimulated levels of ACTH in the cavernous sinuses were generally higher than unstimulated levels of ACTH in the petrosal sinuses. However, 3 of 15 patients failed to show central to peripheral ACTH ratios greater than 2 in unstimulated samples from the cavernous sinuses and were thus falsely negative for the diagnosis of Cushing's disease (test sensitivity, 80%). By comparison, the test sensitivity for the petrosal sinus samples was 87% for the unstimulated samples and 100% for the CRH-stimulated samples. Lateralization was correct in 6 of 15 patients based on CS samples and in 9 of 15 patients based on IPS samples. Because of the 20% false negative rate, CS sampling without CRH stimulation is not recommended for the differential diagnosis of ACTH-dependent hypercortisolism.

Adenoma↗

PubMed1995

Effects of aging on menstrual cycle hormones and endometrial maturation.

OBJECTIVE: To investigate changes in menstrual cycle hormones and endometrial maturation that may contribute to the decline in fertility with aging. DESIGN: Prospective controlled clinical study. SETTING: Normal human volunteers in an academic research institution. SUBJECTS: Women with regular menstrual cycles. INTERVENTIONS: Thirty-two women, aged 20 to 30 or 40 to 50 years, had daily blood drawing starting on cycle day 6 to 10 and continuing until 2 days after the onset of next menses. In addition, 60 women, aged 20 to 30 or 40 to 50 years, had a total of 93 endometrial biopsies performed on day 7 to 9 after the LH surge. MAIN OUTCOME MEASURES: Serum LH, FSH, E2, inhibin, P, and placental protein 14 (PP14) levels and histologic maturation of the endometrium. RESULTS: Serum FSH levels were increased whereas inhibin concentrations were reduced in the luteal-follicular transition of women > 40 years. No other hormonal changes were seen in this population, including P and PP14 secretion. Disruption of endometrial maturation occurred at a similar frequency in both age groups. CONCLUSIONS: Follicular recruitment, but not luteal function or endometrial maturation, is disturbed in cycling women > 40 years and may contribute to the decline in fertility with aging.

Adult↗

PubMed1994

Cushing's syndrome in children and adolescents. Presentation, diagnosis, and therapy.

BACKGROUND AND METHODS: Cushing's syndrome is rare in children and adolescents. We analyzed the clinical presentation, diagnostic evaluation, and treatment of 59 patients with Cushing's syndrome between the ages of 4 and 20 years who were admitted to the National Institutes of Health during the period from 1982 to 1992. The cause of hypercortisolism was identified by low- and high-dose dexamethasone suppression tests, the ovine corticotropin-releasing hormone (CRH) stimulation test, imaging studies, and bilateral sampling of the inferior petrosal sinuses combined with administration of CRH. RESULTS: Fifty patients had Cushing's disease, six had primary adrenal disease, and three had ectopic corticotropin secretion. The initial signs were excessive weight gain in 90 percent of the patients and growth retardation in 83 percent. Most patients (81 percent) had normal bone age at the time of diagnosis. Forty-seven percent had hypertension, whereas only 19 percent had mental or behavioral problems. The high-dose dexamethasone suppression test and the CRH stimulation test identified 68 and 80 percent, respectively, of the patients with Cushing's disease. Magnetic resonance imaging of the pituitary indicated the presence of tumor in 52 percent of the patients with pituitary adenomas. The maximal central-to-peripheral ratio of plasma corticotropin during sampling of the interior petrosal sinuses was > or = 2.5 in all the patients with Cushing's disease and < 2.5 in those with ectopic corticotropin secretion. Remission of hypercortisolism was achieved in 48 of the 49 patients who underwent transsphenoidal surgery for Cushing's disease, in all 6 of the patients who underwent adrenalectomy for primary adrenal disease, and in the 2 patients in whom the ectopic source of corticotropin could be identified. CONCLUSIONS: Weight gain and growth retardation are common clinical characteristics of Cushing's syndrome in children and adolescents. Diagnostic evaluation of such patients with CRH stimulation alone and combined with inferior petrosal sinus sampling and imaging studies is accurate, and therapy is usually successful.

Adenoma↗

PubMed1994

The metyrapone and dexamethasone suppression tests for the differential diagnosis of the adrenocorticotropin-dependent Cushing syndrome: a comparison.

OBJECTIVE: To develop criteria for interpreting results of the metyrapone test for the differential diagnosis of the adrenocorticotropin (ACTH)-dependent Cushing syndrome and to compare its diagnostic accuracy with that of the high-dose dexamethasone suppression test. DESIGN: Retrospective cohort study. SETTING: Inpatient research ward. PATIENTS: 186 patients believed to have the ACTH-dependent Cushing syndrome who had the metyrapone test, the dexamethasone test, and a surgical procedure to remove the source of excessive ACTH. MEASUREMENTS: The sensitivity, specificity, and diagnostic accuracy were determined for the metyrapone test using urine excretion of hydroxysteroid and plasma levels of 11-deoxycortisol. For the dexamethasone suppression test, urine excretions of 17-hydroxysteroid (17-OHS) and free cortisol were used. MAIN RESULTS: 156 patients had pituitary disease, 15 had ectopic ACTH secretion, and 15 had no diagnosis after pituitary surgery. Of those 15 patients, 14 were ultimately classified as having pituitary disease on the basis of follow-up, and 1 was found to have ACTH-independent Cushing syndrome. After administration of metyrapone, stimulation of 17-OHS excretion greater than 70% or of a plasma 11-deoxycortisol level greater than 400-fold did not result in the misclassification of any of the patients with surgically confirmed cases of ectopic ACTH secretion. When these criteria were combined, the percentage of correct predictions (122 of 186 [71%; 95% CI, 62% to 79%]) was higher than that for either steroid alone (116 of 186 [62%; CI, 52% to 71%]) for excretion of 17-OHS and that for plasma 11-deoxycortisol (82 of 186 [44%; CI, 34% to 54%]). When the criteria for both the metyrapone test and the dexamethasone test were combined, the percentage of correct predictions (153 of 186 [82%; CI, 75% to 87%]) was higher than that obtained when the criteria for either test alone were used (P = 0.001). Similar results were found when the 15 patients with indeterminate surgery were assigned to the appropriate group on the basis of follow-up. When the criteria for both the metyrapone and dexamethasone tests were combined to identify patients with the pituitary Cushing syndrome, the sensitivity and diagnostic accuracy improved to 88% and 89%, respectively. CONCLUSIONS: The metyrapone test, which can be done in 48 hours, has a sensitivity and specificity for the diagnosis of the Cushing syndrome identical to that of the standard 6-day high-dose dexamethasone suppression test. Combining both tests results in greater accuracy than that obtained with either test alone.

Adrenocorticotropic Hormone↗

PubMed1994

The antiprogestin RU486 delays the midcycle gonadotropin surge and ovulation in gonadotropin-releasing hormone-induced cycles.

OBJECTIVE: To investigate whether the antiprogestin RU486 acts primarily on the hypothalamus to delay the midcycle gonadotropin surge and thus gain insight into the site(s) of action of P in the control of ovulation. DESIGN: Prospective, crossover, single-blinded clinical study. SETTING: Outpatient clinic in an academic research environment. PATIENTS: Women with hypothalamic amenorrhea. INTERVENTIONS: RU486 or a placebo was given orally at a low dose of 1 mg/d for 5 days, starting when the dominant follicle reached 14 to 16 mm, to women with hypothalamic amenorrhea undergoing ovulation induction with GnRH pulses of unvarying frequency and dose. Blood samples and ovarian ultrasounds were obtained daily in the late follicular phase and every 3 to 4 days in the remainder of the cycle. MAIN OUTCOME MEASURES: Follicular diameter and plasma levels of LH, FSH, E2, and P. RESULTS: RU486 consistently delayed the timing of the midcycle gonadotropin surge and ovulation. Gonadotropin and steroid levels were suppressed during RU486 treatment, but follicular growth progressed normally in most patients. CONCLUSIONS: RU486 does not act primarily on the hypothalamus to delay ovulation. Rather, this compound appears to antagonize P at the pituitary level to suppress gonadotropin and steroid hormone secretion. P may thus act on the pituitary, independent of any hypothalamic effects, to regulate the timing of the midcycle gonadotropin surge and ovulation.

Adult↗

PubMed1994

Expression of Clara cell 10-kD gene in the human endometrium and its relationship to ovarian menstrual cycle.

Clara cell 10-kD (cc10-kD) protein has been suggested to be the human counterpart of rabbit uteroglobin (UG). Like UG, this protein is also a potent inhibitor of phospholipase A2 (PLA2) and a substrate of transglutaminase. Although it has been established that UG gene expression in the rabbit endometrium is stimulated by progesterone, the expression of cc10-kD gene in the human endometrium is not clearly understood. The present study was undertaken to determine whether the cc10-kD gene is expressed in the human endometrium and whether its level of expression changes in relation to the ovarian menstrual cycle. Using reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence, we demonstrate that the cc10-kD gene is expressed in different stages of the menstrual cycle and that the highest level of expression is reached during the luteal phase. These results suggest that like rabbit UG, cc10-kD gene expression in the human endometrium may be stimulated by progesterone. Since cc10-kD is a potent inhibitor of PLA2 activity, this protein may play an important physiological role in regulating eicosanoid levels in the human uterus.

Animals↗

PubMed1994

Adrenocorticotropic hormone--secreting islet cell tumors: are they always malignant?

PURPOSE: To evaluate the frequency with which benign occult islet cell tumors cause ectopic adrenocorticotropic hormone (ACTH) syndrome. MATERIALS AND METHODS: Ten patients with Cushing syndrome due to the production of ACTH by a pancreatic islet cell tumor were studied. In addition, 53 cases of ACTH-secreting islet cell tumors in the English-language literature were reviewed. RESULTS: All 10 of the authors' patients had malignant islet cell tumors. Liver metastases were present in all 10 patients at presentation. Five patients are dead, four patients are alive with liver metastases, and one patient is alive without gross evidence of residual tumor after distal pancreatectomy and right hepatectomy. Eight of the 10 islet cell carcinomas produced gastrin in addition to ACTH. In the 53 reported cases of ectopic ACTH production, there was only one benign adenoma with a prolonged follow-up. CONCLUSION: When ectopic ACTH production is caused by an islet cell tumor, the tumor is large and malignant and has usually metastasized to the liver by the time Cushing syndrome is diagnosed. No occult ACTH-producing islet cell tumor was encountered in the authors' experience or in a review of the literature.

ACTH Syndrome, Ectopic↗

PubMed1994

A comparison of the standard high dose dexamethasone suppression test and the overnight 8-mg dexamethasone suppression test for the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome.

To improve the overnight 8-mg dexamethasone (DEX) suppression test (DST) for differential diagnosis of Cushing's syndrome and to develop optimal criteria for its interpretation, we increased the number of blood samples and measured the suppression of both plasma ACTH and cortisol. Forty-one patients who were subsequently proven at surgery to have Cushing's syndrome were studied (34 Cushing's disease and 7 ectopic ACTH secretion). DEX (8 mg, orally) was administered at 2300 h. Blood samples for ACTH and cortisol measurements were obtained at 0800, 0830, and 0900 h on the day before and at 0700, 0800, 0900, and 1000 h on the morning after DEX treatment. The conventional 6-day DST was also performed, with measurement of both urinary free cortisol and urinary 17-hydroxysteroids as indices of suppression. Optimal criteria for the diagnosis of Cushing's disease were developed for both the overnight 8-mg and the 6-day tests using receiver operating characteristic curves. The results were compared with those using the previously published criteria for diagnosis of Cushing's disease by the overnight 8-mg test (> 50% suppression of plasma cortisol at 0700-0800 h). In our patients, the previously published criterion for the overnight 8-mg test yielded high sensitivity (88%), but low specificity (57%), in making the diagnosis of Cushing's disease. When the time of cortisol measurement and the diagnostic criteria for Cushing's disease were revised to achieve 100% specificity, the sensitivity of the overnight 8-mg test was 71%, which was not significantly different from that of the 6-day test (79%; P = NS). Addition of plasma ACTH levels to the test did not improve diagnostic accuracy compared to that with measurement of plasma cortisol levels alone. When the revised 8-mg overnight dexamethasone suppression test was combined with the 6-day dexamethasone suppression test, sensitivity increased to 91%, with a specificity of 100%, which was significantly better than that of the overnight 8-mg test alone (P < 0.002). We conclude that the overnight 8-mg DST has low specificity for the diagnosis of Cushing's disease when performed as originally described. However, with revised sampling times and diagnostic criteria, the overnight test has sensitivity and specificity similar to those of the conventional 6-day DST. The diagnostic performance of a criterion that combines the results of both tests is better than the diagnostic performance of either test alone.

Administration, Oral↗

PubMed1994

Identification and cellular localization of growth hormone receptor gene expression in the human ovary.

While in vivo and in vitro studies in rodents, pigs and women suggest that growth hormone (GH) can stimulate ovarian steroidogenesis, it is not known if this effect is mediated by a direct action on the ovary. The absence of GH receptor (GHR) messenger RNA would mitigate against a direct ovarian effect. We used the reverse transcriptase-polymerase chain reaction and in situ hybridization to examine whether the GHR mRNA was present in homogenates of seven human ovaries or in tissue sections of ten ovaries. GHR gene expression was detected in PCR products after Southern blot hybridization using an oligoprobe directed to the intracellular domain sharing no homology to the prolactin receptor. In situ hybridization using the same digoxigenin-labeled oligoprobe localized the GHR mRNA in the granulosa cells of dominant and antral follicles, corpus luteum, corpora albicans and the endothelium of blood vessels. GHR mRNA was not detected in preantral follicles, theca interna, theca externa, oocytes, or stroma. The presence of GHR mRNA in human granulosa cells and corpus luteum, taken together with previous studies showing GH-induced stimulation of estradiol and progesterone secretion, suggest that GH may play a direct role in the development of the human follicle.

Adult↗

PubMed1994

Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis.

RU486, a synthetic steroid receptor antagonist, has strong antiprogesterone and antiglucocorticoid properties. Chronic RU486 administration in two patients with ectopic secretion of adrenocorticotropin (ACTH) has been associated with decreasing plasma cortisol concentrations. One explanation of this finding is that RU486 may directly inhibit adrenal steroidogenesis. To test this hypothesis, we measured the effect of RU486 on specific steroidogenic enzymatic steps using an in vivo rat and an in vitro monkey model. Hypophysectomized-castrated-ACTH-replaced Sprague-Dawley rats were given RU486 i.p. at daily doses of 0, 0.0005, 0.005, 0.05, 0.5 and 5 mg/kg body weight per day for 7 days. The animals were sacrificed, and blood and adrenal glands collected. Adrenal cortical mitochondria and microsomes were purified from the rats and from two untreated Cynomolgus macaque monkeys. Specific steroidogenic enzyme activities were measured in the rat by the incorporation of 14C-labeled steroid substrates into products. A similar protocol was used to assay the steroidogenesis in the monkey adrenal fractions in the presence and absence of added RU486. Although rat adrenal weights decreased significantly at the highest RU486 dose, plasma levels of corticosterone were similar in control and treated rats. Rat adrenal 3 beta-hydroxysteroid dehydrogenase/isomerase (3-HSD), 21-hydroxylase (21-OH) and 11-hydroxylase (11-OH) activities decreased with increasing RU486 doses, with 21-OH and 11-OH being most severely affected. Monkey adrenal 3-HSD, 21-OH, 11-OH, 17-hydroxylase and 17,20-desmolase similarly decreased in the presence of increasing in vitro concentrations of RU486.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxysteroid Dehydrogenases↗

PubMed1994

Early repeat surgery for persistent Cushing's disease.

The potential efficacy of early repeat transsphenoidal surgery for persistent Cushing's disease has not previously been examined. On 222 patients with no prior pituitary treatment and a preoperative diagnosis of Cushing's disease, 29 (13%) remained hypercortisolemic after an initial transsphenoidal pituitary exploration. Seventeen of these 29 patients underwent further surgery 7 to 46 days after the initial transsphenoidal approach in order to completely excise suspected residual tumor. Patients were followed for 4 to 84 months (mean +/- standard deviation, 34 +/- 25 months) to document sustained remission or recurrence of Cushing's disease (a urine free cortisol level > 90 micrograms/day was considered evidence of recurrence). Of the 17 patients with repeat surgery, 12 (71%) had resolution of hypercortisolism (morning plasma cortisol level < 5 micrograms/dl); however, in three of these 12, hypercortisolism recurred 5, 12, and 24 months later. In 14 patients a lesion that appeared to be a tumor was identified during the initial procedure or on histological examination. Of these, 12 had immediate resolution of hypercortisolism and nine are still in remission. Three patients, in whom no adenoma could be identified during the initial surgery or an examination of the partial hypophysectomy specimen from the initial surgery, had persistent Cushing's syndrome after the second operation. Seven (41%) of the 17 patients developed hypopituitarism requiring treatment with thyroid hormone, gonadal steroid, or vasopressin replacement. The low incidence of identification of an adenoma on computerized tomography or magnetic resonance images (three of 17 patients), the failure to find a corticotrophic adenoma during the initial surgery (10 of 17 patients), and the failure of these 17 patients to respond to the initial transsphenoidal surgery suggest that they may comprise a subset of patients who are more difficult to treat successfully with surgery than most patients with Cushing's disease. Despite that, early reoperation induced immediate remission of hypercortisolism in 71% of cases, but did so at the expense of a high risk of hypopituitarism. However, since the alternative treatments (such as radiation therapy, long-term drug therapy, or bilateral adrenalectomy) also have potential adverse effects, early reoperation deserves consideration for the management of persistent Cushing's disease, especially when an adrenocorticotrophic hormone-secreting adenoma was partially excised during the first surgery.

Adult↗

PubMed1994

Characterization of the normal progesterone and placental protein 14 responses to human chorionic gonadotropin stimulation in the luteal phase.

OBJECTIVE: To examine whether midluteal phase administration of the luteotrophic hormone hCG can result in higher and more stable serum levels than random sampling of P and placental protein 14 (PP14). DESIGN: Prospective controlled clinical study. SETTING: Normal human volunteers in an academic research environment. PARTICIPANTS: Twenty-six fertile, regularly cycling women. INTERVENTIONS: Blood samples were drawn at 0, 3, 6, 9, 12, 18, and 24 hours and then daily for the next 6 days, after a single IM injection of 5,000 IU hCG or saline given on day 5, 7, or 9 after the LH surge, as detected by rapid plasma assays. MAIN OUTCOME MEASURES: Serum P and PP14 measurements. RESULTS: Peak P and PP14 concentrations occurred at 6 hours and 5 days, respectively, after hCG stimulation on luteal phase day 9. Progesterone but not PP14 levels were significantly higher and less variable after hCG than after saline administration on this day. Progesterone responses exceeded 11.0 ng/mL (35.0 nmol/L) in all women, suggesting that this represents the cutoff limit for normal luteal function. Because PP14 responses were highly variable and inconsistent, it was not possible to determine a threshold for normal endometrial function. CONCLUSIONS: Midluteal phase administration of hCG in normal women induces consistent serum P levels > 11.0 ng/mL (35.0 nmol/L) but highly variable PP14 responses.

Adult↗

PubMed1993

Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states.

OBJECTIVE: The biochemical and phenotypic presentation of mild hypercortisolism in Cushing's syndrome is often indistinguishable from that seen in pseudo-Cushing's states such as depression. Both dexamethasone suppression and corticotropin-releasing hormone (CRH) stimulation tests have been used individually to distinguish these conditions, but neither approach has achieved a diagnostic accuracy greater than 85%. Therefore, we sought to develop a combined dexamethasone-CRH test that would take advantage of the altered sensitivity of patients with Cushing's syndrome to both dexamethasone and CRH and would achieve greater accuracy in the diagnosis of Cushing's syndrome. DESIGN: Prospective cohort study. SETTING: Tertiary care research hospital. PATIENTS: A total of 58 adults referred for evaluation of mild hypercortisolism (urine free cortisol level < 1000 nmol/d). The diagnosis of Cushing's syndrome was confirmed at surgery in 39 patients. The diagnosis of a pseudo-Cushing's state was made in 19 patients on the basis of extended follow-up (mean, 28 months) without progression of cushingoid features. INTERVENTION: The low-dose dexamethasone suppression test, the CRH stimulation test, and the CRH stimulation test started 2 hours after completion of low-dose dexamethasone suppression (the dexamethasone-CRH test) were performed in all patients. MAIN OUTCOME MEASURES: Sensitivity, specificity, and accuracy of the three procedures for diagnosis of Cushing's syndrome were calculated from plasma corticotropin, plasma cortisol, urine free cortisol, and urine 17-hydroxycorticosteroid values. RESULTS: The low-dose dexamethasone suppression test had 74% specificity, 69% sensitivity, and 71% diagnostic accuracy, using the standard criterion (17-hydroxycorticosteroid excretion level > 11.0 mumol/d on the second day of dexamethasone administration). With a urine free cortisol criterion for Cushing's syndrome of greater than 100 nmol/d, the low-dose dexamethasone suppression test had 100% specificity, 56% sensitivity, and 71% diagnostic accuracy. The CRH stimulation test without dexamethasone pretreatment had 100% specificity, 64% sensitivity, and 76% diagnostic accuracy. The diagnostic accuracy of the dexamethasone-CRH test for Cushing's syndrome was significantly greater than the accuracy of either the low-dose dexamethasone test or the CRH test alone (P < .01). A plasma cortisol concentration greater than 38 nmol/L measured 15 minutes after the administration of CRH correctly identified all cases of Cushing's syndrome and all cases of pseudo-Cushing's states (100% specificity, sensitivity, and diagnostic accuracy). CONCLUSION: The dexamethasone-CRH test is a more accurate test to distinguish Cushing's syndrome from pseudo-Cushing's states in patients with mild hypercortisolism.

17-Hydroxycorticosteroids↗

PubMed1993

Comparative analysis of progesterone and placental protein 14 measurements in the evaluation of luteal function.

OBJECTIVE: Our purpose was to investigate the diagnostic accuracy of single or summed measurements of progesterone and placental protein 14, a progestin-dependent endometrial glycoprotein, in the evaluation of luteal function. STUDY DESIGN: Forty-five healthy women had daily blood measurements of luteinizing hormone, progesterone, and placental protein 14 during one menstrual cycle. RESULTS: Thirty-nine women had normal and six had deficient luteal function on the basis of serial progesterone determinations. Luteal insufficiency was not accurately diagnosed by single progesterone or placental protein 14 values or by integrated placental protein 14 measurements. In contrast, the condition was correctly identified in all but one cycle when the sum of progesterone on days 4 and 7 was < 49 nmol/L (15.4 ng/ml). A poor correlation was found between peak or integrated measurements of progesterone and placental protein 14. CONCLUSION: Measurement of serum progesterone, but not placental protein 14, on 2 days of the midluteal phase provides a convenient and reliable test of luteal function.

Adult↗

PubMed1993

Cerebrospinal fluid immunoreactive somatostatin concentrations in patients with Cushing's disease and major depression: relationship to indices of corticotropin-releasing hormone and cortisol secretion.

To further explore the differential effects of peripherally and centrally derived hypercortisolism on neurohormonal systems implicated in the pathophysiology of mood and cognitive disturbances, we examined the cerebrospinal fluid (CSF) concentrations of immunoreactive somatostatin (IR-SRIF) in patients with Cushing's disease and major depression and the relationship of these levels to CSF immunoreactive corticotropin-releasing hormone (CRH) concentrations and urinary free cortisol excretion. In particular, since CSF SRIF levels consistently have been shown to be reduced in depression, we wished to assess whether decreased centrally directed SRIF was more likely a primary or a secondary factor in the hypercortisolism of major depression. CSF SRIF levels were significantly reduced in 11 patients with documented Cushing's disease and in 1 patient with ectopic adrenocorticotropic hormone secretion as compared with both 41 healthy volunteers (19.4 +/- 2.9 vs. 37.4 +/- 1.5 pmol/l; p < 0.01) and 28 patients with major depression (30.2 +/- 2.4 pmol/l; p < 0.05), whose CSF SRIF levels were also significantly reduced as compared with controls (p < 0.05). CSF SRIF levels in the Cushing's disease patients correlated positively with CSF CRH (r = 0.64; p < 0.025), suggesting that either the sustained hypercortisolism in these patients and/or its suppression of central CRH secretion contributed to the reduction in SRIF. A more modest but significant correlation between CSF SRIF and CSF CRH was observed in the healthy volunteers (r = 0.37; d.f. = 37; p < 0.02); in the depressed patients, no linear relationship, but rather an inverted U-shaped relationship was found which significantly fit by a quadratic function (r2 = 0.90; d.f. = 22; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-Releasing Hormone↗

PubMed1993

The limited ability of inferior petrosal sinus sampling with corticotropin-releasing hormone to distinguish Cushing's disease from pseudo-Cushing states or normal physiology.

To determine whether petrosal sinus sampling is useful to distinguish patients with mild or intermittent Cushing's disease from normal subjects and individuals with pseudo-Cushing states, we performed bilateral inferior petrosal sinus sampling for ACTH before and after the administration of CRH in 7 eucortisolemic volunteers, 8 hypercortisolemic patients with pseudo-Cushing states, and 40 patients with ACTH-dependent Cushing's disease whose urinary free cortisol excretion was within the range found in patients with, pseudo-Cushing states (< 1000 nmol/day; < 360 micrograms/day). The ACTH level, the ratio of the inferior petrosal sinus ACTH to the peripheral venous ACTH concentration (the IPS:P ratio), and the greater ratio of right to left or left to right petrosal sinuses (the R:L ratio) were compared in patients with and without Cushing's disease. Maximal petrosal ACTH values were significantly elevated in patients with Cushing's disease compared to patients with pseudo-Cushing states before CRH administration (P < 0.001), but not after CRH. Maximal petrosal plasma ACTH values after the administration of CRH as high as 808 pmol/L (3670 pg/mL) and 469 pmol/L (2130 pg/mL) were found in patients with pseudo-Cushing states and in normal volunteers, respectively, whereas maximal petrosal ACTH levels as low as 10 pmol/L (46 pg/mL) were observed in patients with surgically proven Cushing's disease. Maximal and minimal IPS:P ratios were significantly greater in patients with Cushing's disease than in subjects without Cushing's disease before, but not after, CRH treatment. R:L ratios did not differ among groups either before or after CRH. All of the subjects without Cushing's disease showed large R:L gradients, consistent with the notion of one dominant petrosal sinus containing a greater percentage of pituitary effluent. The ACTH concentrations, IPS:P ratios, and R:L ratios exhibited great overlap between those with and without Cushing's disease, which resulted in a diagnostic accuracy of 81% at best for the diagnosis of Cushing's disease. We conclude that petrosal sinus sampling is of limited usefulness in distinguishing either normal individuals or patients with pseudo-Cushing states from those with mild Cushing's disease. This limited usefulness must be recognized when interpreting the results of petrosal sinus sampling in patients with mild or intermittent hypercortisolism who may have a pseudo-Cushing state. Because of these limitations, petrosal sinus sampling should be reserved for patients with clear clinical and biochemical evidence of Cushing's syndrome.

Adrenocortical Hyperfunction↗

PubMed1993

A simplified morning ovine corticotropin-releasing hormone stimulation test for the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome.

The objective of this study was to develop criteria for the interpretation of a morning ovine CRH stimulation test for the differential diagnosis of ACTH-dependent Cushing's syndrome. Its design was retrospective review, and its setting was the in-patient unit of a tertiary care center. One hundred and eighteen patients with proven Cushing's disease or ectopic ACTH secretion were studied. The percent change in plasma ACTH and cortisol levels after CRH administration (1 microgram/kg BW) was calculated for each patient using 3 combinations of pre-CRH values (-15, -10, -5, and -1 min) and 6 combinations of post-CRH values (15, 30, 45, and 60 min). The diagnostic performance of these 36 sets of response measures was compared. The mean ACTH concentrations 15 and 30 min after CRH increased by at least 35% above the mean basal value at -5 and -1 min in 93 of 100 patients with Cushing's disease, but in none of the 16 patients with ectopic ACTH secretion. This measure gave the best sensitivity (93%) and specificity (100%). The best cortisol criterion was a mean increase at 30 and 45 min of 20% or more above mean basal values at -5 and -1 min, which gave a sensitivity of 91% and a specificity of 88%. We developed a simplified diagnostic test with 100% specificity using ACTH measurements 5 and 1 min before and 15 and 30 min after CRH administration. Although all patients with ectopic ACTH secretion had less than a 35% increase in ACTH, the probability of Cushing's disease was high at all levels of response, indicating that other tests should be performed to confirm the diagnosis.

ACTH Syndrome, Ectopic↗