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Biomedical subjects

L K Nieman

Publications and source records attributed to L K Nieman.

At least 91 records · Page 5Linked to original sources
PubMed1990

Petrosal sinus sampling: discordant lateralization of ACTH-secreting pituitary microadenomas before and after stimulation with corticotropin-releasing hormone.

Petrosal sinus sampling was performed 171 times in 157 patients with known or suspected Cushing disease. In all cases, samples for measuring adrenocorticotropic hormone (ACTH) levels were obtained from both inferior petrosal sinuses and a peripheral vein, both before and after intravenous corticotropin-releasing hormone (CRH) administration. In seven examinations in seven patients, a ratio, or gradient, between the ACTH levels in the inferior petrosal sinuses existed in the samples obtained prior to CRH stimulation; however, poststimulation samples demonstrated reversal of the gradient, suggesting lateralization to the contralateral side of the pituitary gland. Data from surgical exploration of the pituitary gland were available for six of these patients, all of whom had adenomas. Prestimulation samples provided correct lateralization in three patients, and in two patients the poststimulation samples provided correct lateralization. One patient had a midline adenoma. When the results of pre- and poststimulation petrosal sinus sampling conflict, neither can be relied on uniformly to provide correct lateralization of ACTH-secreting pituitary adenomas.

Adenoma↗
PubMed1990

Time to recovery of the hypothalamic-pituitary-adrenal axis after curative resection of adrenal tumors in patients with Cushing's syndrome.

The recovery time of the hypothalamic-pituitary-adrenal (HPA) axis after curative resection of adrenal tumors in patients with Cushing's syndrome is poorly documented. Eight consecutive patients were treated with a standardized hydrocortisone replacement strategy after curative resection of a cortisol-secreting tumor and the time to recovery of the HPA axis was determined. Hypercortisolism was documented by elevated 24-hour urinary free cortisol levels. Cure was documented by undetectable postoperative morning serum cortisol levels. Each patient received replacement hydrocortisone after surgery and was reevaluated every 3 to 6 months with an adrenocorticotrophic hormone (ACTH) stimulation test. Each patient was also monitored carefully for symptoms and signs of adrenal insufficiency, which was defined as symptoms consistent with this diagnosis that responded to increases in hydrocortisone levels. After surgical resection, each patient was cured of hypercortisolism. Subsequently, despite replacement hydrocortisone, each patient had symptoms of hypocortisolism, and in four of eight patients the dose of hydrocortisone was increased to relieve the symptoms. Patients required a median time of 15 months (range, 9 to 22 months) to recover a normal ACTH stimulation test and 19 months (range, 12 to 24 months) to allow discontinuation of replacement doses of hydrocortisone. The results suggest that surgical resection of a cortisol-secreting adrenal tumor will result in rapid cure of hypercortisolism, but complete recovery of the HPA axis and discontinuation of replacement steroids will require between 1 and 2 years. Normal adrenal function, as assessed by the cortisol response to ACTH, returns despite replacement doses of hydrocortisone, and replacement doses of hydrocortisone can be tapered rapidly or discontinued after a normal ACTH stimulation test.

Adenoma↗
PubMed1989

Primary adrenal causes of Cushing's syndrome. Diagnosis and surgical management.

Cushing's syndrome is rare with only 20% of patients having a primary adrenal cause of hypercortisolism. We have developed a strategy to evaluate patients with suspected Cushing's syndrome and to localize the pathologic condition responsible for the hypercortisolism. This report reviews the last 11 consecutive patients who had a primary adrenal cause of hypercortisolism. Each patient had elevated 24-hour urine free cortisol and 17-hydroxycorticosteroid excretion consistent with hypercortisolism. All but one patient had undetectable plasma ACTH levels. No patient suppressed urinary steroid levels with high-dose dexamethasone and only one patient increased plasma ACTH or cortisol levels with oCRH, findings that were consistent with a pituitary-independent form of hypercortisolism. No patient had a pituitary tumor detected by computed tomography or magnetic resonance imaging, and eight patients had adrenal tumors accurately imaged. MRI of the adrenal glands correctly diagnosed adenoma in 5 of 6 patients with adenomas, carcinoma in 1 patient, and ACTH-producing pheochromocytoma in 1 patient. One tumor classified as carcinoma by MRI appeared on pathologic examination to be an adenoma. Three patients underwent petrosal sinus sampling for measurement of ACTH before and after oCRH administration, and each had petrosal sinus ACTH levels equal to peripheral levels, consistent with a primary adrenal cause of hypercortisolism. Two of these patients had typical bilateral pigmented micronodular adrenocortical disease and the third patient had macronodular adrenocortical hyperplasia. Each of the 11 patients was cured of hypercortisolism by unilateral or bilateral adrenalectomy and no patient has developed recurrent disease during the 7 to 29 month follow-up period. New modalities including the ovine CRH test, MRI, and petrosal sinus sampling have improved the evaluation of certain patients with Cushing's syndrome.

Adolescent↗
PubMed1989

Corticotropin-releasing hormone: clinical applications.

Corticotropin-releasing hormone, a 41-amino-acid peptide, is an important hypothalamic factor regulating the pituitary secretion of adrenocorticotropic hormone (ACTH). This hormone, while rarely involved in the etiology of Cushing's syndrome, seems to play a major role in the pathogenesis of non-Cushing hypercortisolemic states. The administration of synthetic human and ovine CRH has been found useful in the differential diagnosis of Cushing's syndrome and in the preoperative localization of intrasellar ACTH-secreting tumors.

Adrenal Insufficiency↗
PubMed1989

The effect of pulsatile human corticotropin-releasing hormone administration on the adrenal insufficiency that follows cure of Cushing's disease.

Successful transsphenoidal surgery for Cushing's disease leads to secondary adrenal insufficiency in most patients. This form of transient adrenal insufficiency is thought to result from hypothalamic and pituitary suppression due to the preceding hypercortisolism. Whether the rate-limiting step in the recovery of adrenal function in this setting is the hypothalamic CRH neuron or the pituitary corticotroph cell, however, is not known. We studied this question by examining the response to ovine CRH (oCRH) before, during, and after prolonged pulsatile administration of human CRH (hCRH) beginning 1-2 weeks after curative microadenomectomy for Cushing's disease. Five patients cured of Cushing's disease received eight hCRH injections (1 microgram/kg) daily for 7 days. This CRH regimen was found previously to normalize plasma ACTH and cortisol patterns in patients with secondary adrenal insufficiency who had normal ACTH responses to a single injection of oCRH (hypothalamic adrenal insufficiency). The plasma ACTH and cortisol responses to oCRH (1 microgram/kg at 2000 h) were assessed immediately before, 2.5 h after, and 7 days after the end of pulsatile hCRH administration. To control for time-related improvement in the hormonal response to ovine CRH, an additional five patients cured of Cushing's disease underwent oCRH tests 1-2 and 3-4 weeks after transsphenoidal surgery, but did not receive hCRH. There was no significant difference in basal or oCRH-stimulated plasma ACTH and cortisol levels among any of the three oCRH tests in the patients who received hCRH. The baseline and oCRH-stimulated plasma ACTH and cortisol levels 1-2 and 3-4 weeks after surgery in the patients who did not receive pulsatile hCRH were similar to the values at those times in the patients who received pulsatile hCRH. Compared to normal subjects, however, both the hCRH-treated and non-hCRH-treated patients had significantly decreased peak and time-integrated plasma ACTH and cortisol responses to oCRH. We conclude that an impaired pituitary response to CRH contributes to the postoperative hypocortisolism of patients recently cured of Cushing's disease, and that this impaired pituitary response to CRH is not reversible by 1 week of pulsatile hCRH administration.

Adolescent↗
PubMed1989

The ovine corticotropin-releasing hormone (CRH) stimulation test is superior to the human CRH stimulation test for the diagnosis of Cushing's disease.

The ovine CRH (oCRH) stimulation test is useful in distinguishing Cushing's disease from the syndrome of ectopic ACTH secretion. Most patients with Cushing's disease have increased plasma ACTH and cortisol responses to oCRH, while patients with the ectopic ACTH syndrome do not. We predicted that the homologous hormone human CRH (hCRH) might be an equally useful diagnostic agent, with the theoretic advantage of being less immunogenic. This study compared the responses to hCRH and oCRH (1 microgram/kg, iv) in 15 patients with Cushing's disease. Plasma ACTH and cortisol levels increased in most patients during the first hour after administration of either hCRH or oCRH. However, the peak and time-integrated hormonal responses to hCRH were smaller than the responses to oCRH. All but 1 patient had an ACTH and/or cortisol response to oCRH that exceeded 4 times the intraassay coefficient of variation. Three patients had neither an ACTH nor a cortisol response to hCRH by the same criterion. Thus, when administered at equivalent doses, hCRH is a less effective stimulus of ACTH and cortisol secretion in patients with Cushing's disease. Based upon the observation that the oCRH stimulation test has greater sensitivity than the hCRH stimulation test for the diagnosis of Cushing's disease, we conclude that oCRH is the preferred analog to use for CRH testing in patients with Cushing's syndrome.

ACTH Syndrome, Ectopic↗
PubMed1989

Repeat transsphenoidal surgery for Cushing's disease.

Transsphenoidal resection of adrenocorticotrophic hormone (ACTH)-producing pituitary adenomas has the potential of curing most patients with Cushing's disease. However, transsphenoidal exploration of the pituitary is not always curative, and patients who have remission of hypercortisolism following surgery occasionally develop a recurrence. Whether repeat pituitary surgery should be performed for recurrent or persistent Cushing's disease has not been evaluated previously. To determine the efficacy of transsphenoidal surgery in recurrent or persistent Cushing's disease, we performed transsphenoidal surgery in 31 patients (22 women and nine men) who had previously undergone a transsphenoidal operation and two female patients who had had previous pituitary irradiation only. In 24 (73%) of the 33 patients, remission of hypercortisolism was achieved by surgery. Although preoperative computerized tomography (CT) scanning identified an adenoma in only three of the 33 patients, in 20 patients a discrete adenoma was identified at pituitary exploration. The incidence of hypercortisolism was greatest if an adenoma was identified at surgery and the patient received selective adenomectomy (19, or 95% of 20 patients), if there was evidence at surgery or by preoperative CT scanning that the previous surgical exposure of the pituitary was incomplete (seven, or 78% of nine patients), if an adenoma was seen on preoperative CT scanning (three of three patients), or if the patient had had prior pituitary irradiation without surgery (two of two patients). In contrast, only five (42%) of 12 patients who received subtotal or total hypophysectomy had remission of hypercortisolim. Surgically induced hypopituitarism occurred in six (50%) of these 12 patients, but in only one (5%) of the 20 patients who underwent selective adenomectomy. Three (13%) of the 24 patients who were in remission from hypercortisolims following repeat surgery developed recurrent hypercortisolism 10 to 47 months postoperatively. Repeat transsphenoidal exploration of the pituitary and treatment limited to selective adenomectomy should be considered in patients with hypercortisolism despite previous pituitary treatment. If an adenoma is identified during surgery, the chance of remission of Cushing's disease is high and the risk of hypopituitarism is low; however, if no adenoma can be found and partial or complete hypophysectomy is performed, remission of hypercortisolism is less likely and the risk of hypopituitarism is about 50%.

Adenoma↗
PubMed1988

The use of anti-progesterones as a medical IUD.

Mifepristone holds promise as a safe and effective anti-progesterone. Widespread use of mifepristone to regularize cycles or prevent pregnancy, however, cannot be recommended at this time. The drug is promising for these uses but the dose and timing of administration required to achieve optimum effect are unknown. Menses are consistently induced in the mid to late luteal phase at a wide range of doses. Further work needs to be done to examine the luteolytic properties of the drug when given at this time. Knowledge about the serum concentration of the parent compound and its less active metabolites after oral administration may help to explain variable biological effects. The effects of other modes of administration, such as transdermal or transvaginal application which avoid a first-pass effect by the liver, should also be explored. Practical issues of the timing of administration need to be resolved. The drug is not effective when given in the absence of luteal phase levels of progesterone. Thus, verification of luteal phase status before the administration of the drug would be ideal. Basal body temperature monitoring may be one way to do this. There is no other convenient way to determine serum levels of progesterone that would be feasible on a large-scale outpatient basis. Since mifepristone does not regulate the timing of ovulation, the optimal time of administration may vary from cycle to cycle. This presumes a high degree of willingness on the part of the woman to observe her cycles and participate in decisions regarding the timing of the drug. Mifepristone, the first clinically available anti-progesterone, represents a significant advance in fertility control.(ABSTRACT TRUNCATED AT 250 WORDS)

Abortifacient Agents↗
PubMed1987

The progesterone antagonist RU 486. A potential new contraceptive agent.

Since progesterone supports endometrial nidation of the fertilized ovum, a progesterone antagonist would theoretically block this process and thus have contraceptive potential. We have explored the ability of RU 486, a newly developed competitive progesterone antagonist, to function as a contraceptive agent. A single oral dose of 10 mg per kilogram of body weight given in the midluteal phase consistently induced menses within 72 hours in women with normal cycles and no risk of pregnancy. Bleeding was not prevented by administration of human chorionic gonadotropin in the midluteal phase. This suggested that giving a single dose of RU 486 late in the menstrual cycle might be an effective contraceptive strategy. This concept was tested in monkeys. When given to rhesus females on day 25 of the cycle, a single intramuscular dose of RU 486 (5 mg per kilogram) prevented pregnancy. The vehicle-treated control animals had a 28 percent pregnancy rate (P less than 0.05 by chi-square analysis). No side effects were noted in women or monkeys. These data suggest that a progesterone antagonist such as RU 486 has the potential to be an effective, safe, and convenient contraceptive agent. Further work will be necessary to assess the safety of long-term monthly administration and to define the optimal dose and time of administration in women.

Adult↗
PubMed1987

Cushing syndrome: pituitary CT scanning.

Proper treatment of patients with Cushing syndrome depends on knowledge of whether the condition derives from a pituitary or adrenal adenoma or an ectopic tumor that secretes adrenocorticotropic hormone (ACTH). Fifty-seven patients with Cushing syndrome were prospectively evaluated to determine whether computed tomography (CT) of the pituitary gland is useful in diagnosing or excluding an ACTH-producing adenoma and in predicting the site of the adenoma within the pituitary gland. Findings on CT scans were normal in 35 of 50 patients with surgically confirmed Cushing disease and in seven patients with ectopic ACTH-producing tumors. Of the 15 patients with Cushing disease for whom CT results were abnormal, eight had macroadenomas and seven had microadenomas. This study demonstrates a low sensitivity (30%) and low diagnostic accuracy (39%) of CT in the detection of ACTH-producing pituitary tumors and indicates the need for alternative methods of confirming the pituitary origin of excessive ACTH secretion in most patients.

Adenoma↗
PubMed1987

The corticotropin-releasing hormone test in the postoperative evaluation of patients with cushing's syndrome.

After surgical cure of Cushing's syndrome most patients develop transient secondary adrenal insufficiency that lasts for approximately 1 yr. Since ACTH-secreting pituitary adenomas generally respond to ovine CRH (oCRH), we tested the hypothesis that an early postoperative response to oCRH may indicate the presence of residual pituitary tumor and, therefore, predict recurrence. We also assessed the usefulness of oCRH for monitoring the recovery of the hypothalamic-pituitary-adrenal axis and for clarifying the pathophysiology of this condition. Thirty-four patients cured of Cushing's syndrome (29 with Cushing's disease, 3 with adrenal adenomas, and 2 with the ectopic ACTH syndrome) had an evening oCRH test 1-2 weeks after surgery. Nine patients (6 with Cushing's disease, 2 with adrenal adenomas, and 1 with the ectopic ACTH syndrome) participated in a longitudinal evaluation and had repeated oCRH and 1-h ACTH tests at 2-month intervals for a year after surgery. Patients were considered to be cured on the basis of at least 3 subnormal urinary [less than 20 micrograms/24 h (less than 55 nmol/day)] or morning plasma cortisol levels [0600-0900 h; less than 6 micrograms/dL (less than 170 nmol/L)] in the first 2 weeks after surgery. The plasma ACTH and cortisol responses to oCRH in the early postoperative period were subnormal in 23 and normal in 6 patients with Cushing's disease. Three patients developed recurrent Cushing's disease (3, 3, and 23 months after transphenoidal surgery). All 3 were among the 6 who had a normal early postoperative response to oCRH. All of the 23 patients who had a subnormal response to oCRH in the early postoperative period have remained in remission for an average follow-up period of 14 months (6-42 months). Thus, the recurrence rate was significantly greater in patients with normal oCRH tests in the early postoperative period (P less than 0.001, by chi 2 analysis). Surgically cured patients with adrenal adenomas or ectopic ACTH secretion also had subnormal plasma ACTH and cortisol responses to oCRH during the early postoperative period. During longitudinal evaluation for 12 months after surgery, the ACTH and cortisol responses to oCRH increased progressively (regardless of the cause of Cushing's syndrome). Cortisol responses to oCRH correlated significantly with the cortisol responses to exogenous ACTH (r = 0.89; P less than 0.00001). We conclude that most patients with Cushing's syndrome have suppressed responses to oCRH during the early postoperative period.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1987

Pharmacokinetic properties of the antiglucocorticoid and antiprogesterone steroid RU 486 in man.

RU 486 (17 beta-hydroxy-11 beta-[4-dimethylamino phenyl]-17 alpha-[1-propynyl]estra-4,9-dien-3-one) is a clinically useful glucocorticoid and progesterone antagonist. The authors studied the pharmacokinetic properties of this drug in normal volunteers and patients with Cushing's syndrome using a rat progesterone radioreceptor assay. This assay gave values similar to those obtained with a rat glucocorticoid radioreceptor assay. After a single oral dose of 25 mg/kg (n = 11) or 10 mg/kg (n = 11) to normal volunteers, plasma concentrations of progesterone receptor-reactive material reached maximal levels of 754 +/- 288 (mean +/- S.D.) and 517 +/- 183 micrograms/dl. This occurred at 3.1 +/- 1.9 and 2.5 +/- 1.0 h, respectively. The respective apparent plasma half-lives were 19.2 +/- 7.0 and 20.6 +/- 7.7 h. Four patients with Cushing's syndrome treated chronically (10-20 mg/kg/day) had relatively constant plasma levels of receptor reactivity ranging from 506 to 1184 micrograms/dl. Chromatographic characterization of circulating receptor reactivity showed that the active fraction corresponded to RU 486 and its hydrophilic N-mono- and N-didemethylated metabolites. Less than 0.5% of the daily dose was excreted in the urine of two of these patients as receptor reactivity. The drug bound extensively to circulating albumin, which competed with the glucocorticoid receptor of intact human mononuclear leukocytes for [3H]RU 486 in a concentration-dependent manner.

Adult↗
PubMed1986

Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications.

Primary depression can be associated with substantial hypercortisolism, thus prompting some researchers to suggest that depression shares pathophysiologic features with Cushing's disease. Clinically, depression can be difficult or impossible to distinguish from mild or early Cushing's disease that is associated with depressive features. The purpose of this study was to evaluate whether the pituitary-adrenal responses to ovine corticotropin-releasing hormone could help to clarify the mechanism of hypercortisolism in depression and in Cushing's disease and to assist in the differential diagnosis of these disorders. As compared with controls (n = 34), depressed patients (n = 30) had basal hypercortisolism (P less than 0.001) that was associated with attenuated plasma ACTH responses to ovine corticotropin-releasing hormone (P less than 0.001). This indicates that in patients with depression, the corticotroph cell in the pituitary responds appropriately to the negative feedback of high cortisol levels. In contrast, patients with Cushing's disease (n = 29) had plasma ACTH hyperresponsiveness to ovine corticotropin-releasing hormone (P less than 0.001), despite basal hypercortisolism (P less than 0.001), which indicates a gross impairment of the mechanism by which cortisol exerts negative feedback on the pituitary. Less than 25 percent of the patients with depression or Cushing's disease had peak ACTH responses that overlapped. We conclude that the pathophysiologic features of hypercortisolism in depression and Cushing's disease are distinct in each of the disorders and that the ovine corticotropin-releasing hormone stimulation test can be helpful in their differential diagnosis.

Adrenocorticotropic Hormone↗
PubMed1986

Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa. Pathophysiologic mechanisms in underweight and weight-corrected patients.

To study the pathophysiology of hypercortisolism in patients with anorexia nervosa, we examined plasma ACTH and cortisol responses to ovine corticotropin-releasing hormone before and after correction of weight loss. We also studied patients with bulimia whose weight was normal, since this disorder has been suspected to be a variant of anorexia nervosa. Before their weight loss was corrected, the anorexic patients had marked hypercortisolism but normal basal plasma ACTH. The hypercortisolism was associated with a marked reduction in the plasma ACTH response to corticotropin-releasing hormone. When these patients were studied three to four weeks after their body weight had been restored to normal, the hypercortisolism had resolved but the abnormal response to corticotropin-releasing hormone remained unchanged. On the other hand, at least six months after correction of weight loss their responses were normal. The bulimic patients whose weight was normal also had a normal response to corticotropin-releasing hormone. We conclude that in underweight anorexics, the pituitary responds appropriately to corticotropin-releasing hormone, being restrained in its response by the elevated levels of cortisol. This suggests that hypercortisolism in anorexics reflects a defect at or above the hypothalamus. The return to eucortisolism soon after correction of the weight loss indicates resolution of this central defect despite persistence of abnormalities in adrenal function.

Adrenocorticotropic Hormone↗
PubMed1986

Deficient nocturnal surge of thyrotropin in central hypothyroidism.

In normal individuals, serum TSH concentrations have a circadian pattern characterized by a nocturnal surge which begins in the late afternoon and reaches its peak after midnight. We assessed the nocturnal surge of TSH in 16 patients with pituitary and/or hypothalamic diseases, 6 of whom were judged to be hypothyroid. To assess the magnitude of the nocturnal surge in individual patients, TSH was measured in 5 serum samples obtained during the normal time of the TSH nadir in the late afternoon and in 5 samples obtained during the normal time of the peak of serum TSH after midnight. A significant nocturnal surge of TSH was defined as a significantly greater mean nighttime TSH level than the mean daytime TSH concentration. The nocturnal TSH surge was absent in the 6 patients with central hypothyroidism, while it was present in the 10 euthyroid patients with central lesions. In 6 hypothyroid patients who did not have pituitary or hypothalamic lesions, the nocturnal TSH surge was intact, indicating that hypothyroidism per se does not account for the deficient nocturnal TSH surge in central hypothyroidism. We conclude that central hypothyroidism is characterized by a deficient nocturnal surge of TSH, and accordingly, we suggest that evaluation of the circadian pattern of TSH may be a useful adjunct in making the diagnosis of hypothyroidism in patients with diseases involving the pituitary or hypothalamus.

Adolescent↗
PubMed1986

The ovine corticotropin-releasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing's syndrome.

We gave a standard dexamethasone suppression test and an ovine corticotropin-releasing hormone (CRH) stimulation test to 41 patients with adrenocorticotrophic hormone (ACTH)-dependent hypercortisolism to determine the efficacy of each test in the differential diagnosis of Cushing's syndrome. Twenty-nine of thirty-three patients with Cushing's disease and 0 of 8 patients with ectopic secretion of ACTH responded to the ovine CRH test with increased levels of cortisol. When a cortisol response was judged as positive for Cushing's disease, the CRH test had a diagnostic sensitivity, specificity, and accuracy of 88%, 100%, and 90%, respectively. Twenty-nine patients with Cushing's disease and 1 patient with ectopic secretion of ACTH responded to the dexamethasone suppression test. A combined-test strategy requiring negative results from both tests to exclude a diagnosis of Cushing's disease yielded superior sensitivity (100%) and diagnostic accuracy (98%). Thus, the ovine CRH test works as well as the standard dexamethasone suppression test in discriminating between Cushing's disease and ectopic ACTH secretion. The diagnostic power of each test is enhanced when the two tests are combined.

17-Hydroxycorticosteroids↗