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Biomedical subjects

D L Loriaux

Publications and source records attributed to D L Loriaux.

At least 73 records · Page 4Linked to original sources
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

Cushing syndrome due to primary pigmented nodular adrenocortical disease: findings at CT and MR imaging.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing syndrome in infants, children, and young adults. It is characterized by non-adrenocorticotropic hormone-dependent hypersecretion of cortisol by multiple, pigmented nodules of hyperplastic adrenocortical cells. With a single exception, adrenal glands have been described as normal with computed tomography (CT) in all previous series. Eight patients had Cushing syndrome due to surgically proved PPNAD. Four of the eight patients had stigmas of Carney complex (lentigines, calcified Sertoli cell tumors of the testes, and cardiac and soft-tissue myxomas). CT and/or magnetic resonance (MR) imaging demonstrated unilateral or bilateral nodularity in five of six patients examined. Macronodules (greater than 10 mm) were seen in the two oldest patients. As the clinical presentation of Cushing syndrome in this group of patients may be atypical (severe osteoporosis or short stature), the detection of multiple, small adrenocortical nodules with CT or MR imaging supports, or may even suggest, the diagnosis of PPNAD.

Adolescent↗
PubMed1989

Growth hormone responses to growth hormone-releasing hormone in Hand-Schüller-Christian Disease.

Bolus doses of GH-releasing hormone (GHRH), 1 microgram/kg i.v., were given to two groups of adult patients with growth hormone deficiency (GHD): 9 with Hand-Schüller-Christian disease (HSCD, presumed hypothalamic GHD) and 9 with idiopathic GHD (IGHD, etiology unknown). Six patients in each group were then given further GHRH doses daily for 5 days, and the GH responses to GHRH were measured over 3 h on day 1 and day 5. Plasma levels of insulin-like growth factor-I (IGF-I) were measured twice daily on days 1 and 5 during GHRH treatment. All patients with HSCD had measurable GH responses to the first dose of GHRH, with a mean peak response of 6.4 +/- 2.1 ng/ml (mean +/- SE). Only 5 of 9 patients with IGHD had GH responses above the detection limits of the assay; their mean peak response, 1.3 +/- 0.2 ng/ml, was significantly lower than the GH responses of the HSCD patients (p less than 0.05). Responses in both groups of patients were lower than those previously observed in normal adult men (35 +/- 8 ng/ml; p less than 0.01). Five days of daily stimulation with GHRH significantly (p less than 0.01) increased the GH response in both groups of patients. The rise was greater in patients with HSCD than with IGHD (HSCD, 5.1 +/- 2.5 ng/ml on day 1, vs. 12.0 +/- 6.8 ng/ml on day 5; IGHD, 1.4 +/- 0.3 ng/ml vs. 2.9 +/- 0.6 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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

Failure of bronchial lavage to detect elevated levels of adrenocorticotropin (ACTH) in patients with ACTH-producing bronchial carcinoids.

Saline lavage of the major bronchial segments was performed in five patients immediately preceding lobectomy to remove an ACTH-producing bronchial carcinoid. Lavage fluid from each bronchus was concentrated, and ACTH determinations were performed. Elevated concentrations of ACTH were not demonstrated in the aspirate from the bronchus containing the known tumor. Two additional patients with ectopic ACTH syndrome from an unknown primary source also underwent selective segmental bronchial lavage for ACTH determination. Neither patient demonstrated ACTH gradients in the lavage specimens. One was found to have an ACTH-producing bronchial carcinoid 18 months after negative lavage. Selective segmental bronchoscopic lavage with measurement of ACTH levels on the aspirate is not an effective technique for detecting ACTH-producing bronchial carcinoid tumor.

Adrenocorticotropic Hormone↗
PubMed1989

Direct administration of testosterone increases rat tibial epiphyseal growth plate width.

Local injection of hormones into the tibial epiphyseal growth plate offers a possible model to answer whether sex steroids can affect bone growth directly. To answer this question, we injected different doses of testosterone enanthate (4, 40, 120 and 400 micrograms/100 g of rat weight) once into the tibial epiphyseal growth plate of castrated 35-day-old male rats. The contralateral tibia was injected with sesame oil and served as control. All animals were sacrificed at age 42 days. Tibias were removed for measurement of epiphyseal growth plate width and blood was collected for measurement of serum IGF-I and testosterone. The lower doses of testosterone enanthate (4, 40 and 120 micrograms/100 g) did not produce any significant change in epiphyseal growth plate width. Testosterone at the largest dose tested (400 micrograms/100 g) increased epiphyseal growth plate width by about 15% compared to control (p less than 0.01). At this dose, serum testosterone was not increased, suggesting that the effect on epiphyseal growth plate width was not due to higher systemic testosterone concentrations. No differences in IGF-I levels were observed among the groups. We conclude that direct administration of testosterone enanthate at a dose of 400 micrograms/100 g into the rat tibial epiphyseal growth plate can increase epiphyseal growth plate width.

Animals↗
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↗
PubMed1989

Primary pigmented nodular adrenocortical disease. A light and electron microscopic study of eight cases.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing's syndrome, which is adrenocorticotropic hormone-independent and involves both adrenal glands. The characteristic pathological features include multiple pigmented cortical nodules and atrophy of the internodular cortex. The adrenal size ranges from small to normal or slightly enlarged. Review of the gross, light microscopic, and ultrastructural features of eight cases seen at the National Institutes of Health revealed several very unusual findings. We observed the following in our patients: macronodules up to 3.0 cm; microscopic foci of necrosis; mitoses; cortical hyperplasia rather than internodular atrophy; focal confluence of nodules giving a diffuse pattern of cortical involvement, and a focal trabecular growth pattern. The nodules were composed primarily of eosinophilic, lipid-poor cells similar to those of the zona reticularis. However, lipid-rich cells similar to those of the zona fasciculata were also demonstrated in the nodules by both light and electron microscopy. This suggests that the adrenal cortical nodules of PPNAD may be derived from not only the zona reticularis, but also the zona fasciculata.

Adolescent↗
PubMed1988

Stable isotope dilution method using thermospray liquid chromatography/mass spectrometry for quantification of daily cortisol production in humans.

A thermospray high-performance liquid chromatography/mass spectrometry method for the separation and quantification of cortisol in human serum has been developed. The technique does not require derivatization, allows for both qualitative and quantitative determinations, provides increased specificity not available from conventional high-performance liquid chromatography, and has a detection limit of 5 pmol on-column. This isotope dilution mass spectrometry method, using d3-cortisol as an internal standard, allows precise determinations even at low isotopic ratios (2%-5 mole%). Evidence that this technique can be applied to the quantification of serum cortisol and to the determination of daily cortisol production in humans is presented.

Chromatography, High Pressure Liquid↗
PubMed1988

Glucocorticoid receptor-mediated effects on rat fibrosarcoma growth.

Glucocorticoid receptors are present in most normal and malignant mammalian cells. To examine the hypothesis that the growth of methylcholanthrene-induced malignant sarcoma is glucocorticoid dependent, we evaluated the behavior of malignant fibrosarcoma (MCA) in adrenalectomized rats treated with either normal saline or deoxycorticosterone acetate and in intact rats treated with placebo or with the glucocorticoid receptor antagonist RU 486. Survival, tumor weight, and loss of body weight (an index of cachexia) were measured. In MCA-bearing rats, neither survival nor loss of body weight was affected by bilateral adrenalectomy or by treatment with RU 486. Tumor weight and time-integrated tumor volume, however, were significantly less in bilaterally adrenalectomized rats without deoxycorticosterone acetate replacement than in animals treated with deoxycorticosterone acetate. Similarly, tumor weight and time-integrated tumor volume were less in intact animals treated with RU 486 than in intact animals treated with placebo. The glucocorticoid receptors in the tumor cells had similar binding capacity (Ro) and equilibrium dissociation constant (Kd) as in control rat fibroblasts. These results suggest that the growth of MCA sarcoma cells is partially dependent upon glucocorticoids. This effect of glucocorticoids, however, was not of sufficient magnitude to improve survival and prevent cachexia. We conclude that glucocorticoids appear to influence MCA sarcoma growth in the rat, and that glucocorticoid receptor blockade, perhaps in combination with other antitumor agents, merits future study in the treatment of malignant tumors.

Adrenalectomy↗
PubMed1988

Hormonal responses to the stress of exercise.

Exercise stimulates the hypothalamic-pituitary-adrenal and renin-angiotensin-aldosterone axes and causes growth hormone and prolactin release in an intensity-dependent fashion. Activation of the different endocrine responses examined occur at different exercise intensities. Subjects of differing training status respond similarly to matched exercise intensities. Highly trained subjects have elevated basal concentrations of ACTH and cortisol and a blunted response to exogenous corticotropin releasing hormone. These data are compatible with mild sustained hypercortisolism in highly trained runners.

Adrenocorticotropic Hormone↗
PubMed1988

Receptor-mediated effects of glucocorticoids on inflammation: enhancement of the inflammatory response with a glucocorticoid antagonist.

Glucocorticoids suppress the inflammatory response by altering leukocyte traffic and function, cytokine secretion and action, and phospholipid metabolism. We employed the glucocorticoid receptor antagonist RU 486, to examine whether glucocorticoids suppress the inflammatory response through a receptor-mediated mechanism and whether basal glucocorticoid secretion exerts antiinflammatory effects in the resting (non-stress) state. To test these hypotheses we evaluated the effects of increasing doses of dexamethasone, RU 486, or dexamethasone plus RU 486 on the exudate volume and concentrations of leukocytes, prostaglandin E2, (PGE2) and leukotriene B4 (LTB4) in intact rats that received subcutaneous carrageenin. Exudate volume, leukocyte concentration and LTB4 and PGE2 levels were all suppressed by dexamethasone in a dose-dependent fashion (P less than 0.005). RU 486 was able to antagonize fully the suppressive effects of dexamethasone on the inflammatory response (P less than 0.001) and to cause increases of exudate volume and leukocyte, PGE2 and LTB4 concentrations when given alone (P less than 0.05). These increases ranged between 30 and 100% above the basal inflammatory response. We conclude that glucocorticoids most likely suppress the inflammatory response by a glucocorticoid receptor-mediated mechanism and under basal conditions exert tonic antiinflammatory effects.

Alprostadil↗
PubMed1988

Ketoconazole inhibits multiple steroidogenic enzymes involved in androgen biosynthesis in the human ovary.

Ketoconazole (KZ) has been shown to inhibit testicular and adrenal steroidogenesis and is useful in the medical management of gonadotropin-independent precocious puberty, prostatic cancer, and Cushing's syndrome. To determine whether KZ similarly affects ovarian steroidogenesis, the authors examined its effect on the activity of the human ovarian 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD), 17-hydroxylase (17-OH), and aromatase (AR) in vitro. A dose-dependent decrease in the activities of 3 beta-HSD and 17-OH was observed with increasing amounts of KZ. With 10, 50, and 100-fold excess KZ, the activity of 3 beta-HSD decreased by 59% (P less than 0.001), 73% (P less than 0.005), and 85% (P less than 0.005), respectively. At equimolar concentrations with substrate (50 microM), KZ inhibited 17-OH by 70% (P less than 0.01). No significant effect on ovarian AR activity was observed, except at the highest concentration of KZ tested. The authors conclude that low concentrations of KZ profoundly inhibit the activity of human ovarian 3 beta-HSD and 17-OH in vitro. These observations suggest that KZ might be useful in the medical management of women with hyperandrogenism, but further experimentation and clinical trials will be necessary.

3-Hydroxysteroid Dehydrogenases↗
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↗