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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

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↗
PubMed1988

Blood pressure and body size in precocious puberty.

Blood pressure increases with age in normal children. This increase appears to be related to body size. To assess the role of body size as a determinant of blood pressure in precocious puberty, we compared the blood pressure of 81 children with precocious puberty with the blood pressure standards for normal children from the NHLBI Task Force on Blood Pressure Control in Children. Children with precocious puberty had significantly increased blood pressure for chronologic age (p less than 0.05) but generally appropriate blood pressure for height age or weight age. These data are consistent with the hypothesis that increased body size causes the increased blood pressure for chronologic age in children with precocious puberty. Physicians who evaluate such children should assess whether blood pressure is appropriate for height age rather than chronologic age.

Age Determination by Skeleton↗
PubMed1988

Macronodular adrenal hyperplasia in Cushing disease.

Computed tomographic (CT) scans of the adrenal glands were obtained in nine patients with Cushing disease as a result of an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma and macronodular hyperplasia of the adrenal glands. The findings were compared retrospectively with those in six patients with Cushing syndrome as a result of an autonomous adrenal adenoma and 16 with Cushing syndrome as a result of ectopic ACTH production. Seven of nine patients with macronodular adrenal hyperplasia had hyperplastic adrenal glands in addition to single or multiple focal adrenal nodules. The six patients with hypercortisolism caused by an autonomous adrenal adenoma showed atrophic (four patients) or normal (two patients) ipsilateral and contralateral adrenal glands. Fourteen of 16 patients with the ectopic ACTH syndrome had hyperplasia of the adrenal glands without nodularity, and only two had focal nodules.

ACTH Syndrome, Ectopic↗
PubMed1988

Abnormal growth hormone secretory dynamics in children with familial hypercholesterolemia.

Growth hormone secretory dynamics and plasma somatomedin C concentrations were assessed in four prepubertal patients with defects in the low-density lipoprotein (LDL) receptor pathway before and after 2 months of treatment with mevinolin, an HMG-CoA reductase inhibitor that reduces intracellular cholesterol. Pre- and posttreatment mean 24-hour growth hormone levels and pulse amplitude were similar and tended to be higher than in age-matched prepubertal controls. Pre- and posttreatment somatomedin C levels were also similar and lower than in age-matched prepubertal controls. All patients responded to growth hormone provocative testing with a peak response of greater than 7 ng/ml, independent of treatment status. Growth velocity was not significantly altered in any patient following 2 months of treatment with mevinolin, and was within the normal range for age. Thus, children with defects in the LDL receptor pathway express abnormalities in growth hormone secretion and somatomedin C generation comparable to those seen in other chronic diseases. Treatment with mevinolin has no apparent effect on these biochemical abnormalities, suggesting that it may not have long-term effects on growth. Regardless of mevinolin therapy, children with defects in the LDL receptor pathway may manifest a degree of growth retardation and, hence, growth rate and skeletal maturation should be closely monitored.

Child↗
PubMed1988

Acute exercise stimulates the renin-angiotensin-aldosterone axis: adaptive changes in runners.

The plasma concentrations of aldosterone and its known regulators, plasma renin, potassium and ACTH, were examined during graded intensities of treadmill exercise (50, 70 and 90% of maximal oxygen uptake, VO2max). Sedentary men (n = 7) and two groups of runners of different training status (moderately trained, 15-25 miles/week, n = 7; highly trained, greater than 45 miles/week, n = 7) were studied in an attempt to define whether physical training causes changes in aldosterone homeostasis. Acute exercise was associated with elevations in plasma aldosterone, renin activity, potassium and ACTH in all three groups of subjects at exercise intensities of 70 and 90% VO2max. There were no differences in any of the responses among the three groups except for a blunted response of PRA at 90% VO2max in highly trained athletes. The exercise-induced rise of plasma aldosterone concentration did not correlate with changes in the concentration of its regulatory substances. We conclude that exercise stimulates the renin-angiotensin-aldosterone axis in an intensity-dependent fashion. With increased physical training identical hormonal and metabolic responses result at increased absolute workloads.

Adrenocorticotropic Hormone↗
PubMed1988

Effect of gonadotropin secretion rate on the radiosensitivity of the rat luteinizing hormone-releasing hormone neuron and gonadotroph.

To test the hypothesis that the functional state of hypothalamic LHRH neurons and pituitary gonadotrophs might alter their radiosensitivity, we determined the experimental conditions under which the gonadotropin response to castration could be impaired by a single dose of cranial irradiation. Single doses of cranial irradiation greater than 2000 rads were lethal to unshielded rats. Shielding of the oropharynx and esophagus allowed the animals to survive doses up to 5000 rads. Doses between 2000 and 5000 rads had no effect on basal gonadotropin levels for as long as 3 months after irradiation. Irradiation caused a dose- and time-dependent impairment, however, in the gonadotropin response to castration. Impairment of the gonadotropin levels of castrate animals occurred in animals that were irradiated either before or after castration. However, rats irradiated in the castrate state showed a decreased susceptibility to irradiation damage. Additionally, stimulation of the pituitary by LHRH agonist (LHRHa) 3 h before irradiation significantly reduced the impairment of gonadotropin secretion 12-20 weeks after irradiation (P less than 0.05). Thus, increased functional activity of the rat hypothalamus or pituitary at the time of irradiation, induced by either castration or acute LHRHa administration, was associated with some protection against the gonadotropin-lowering effect of irradiation. Based upon these data, we hypothesize that stimulation of gonadotropin secretion at the time of therapeutic cranial irradiation in humans might protect against subsequent impairment of gonadotropin secretion.

Animals↗
PubMed1988

Androstanediol glucuronide isomers in normal men and women and in men infused with labeled dihydrotestosterone.

3 alpha-Androstanediol glucuronide (Adiol G) is a major metabolite of dihydrotestosterone (DHT). Adiol G actually represents 2 different compounds, since the glucuronide can be conjugated at the 3-carbon position (Adiol 3-G) or at the 17-carbon position (Adiol 17-G). To determine which glucuronide represents the predominant physiological DHT metabolite and which isomer is the major circulating form, we developed a RIA to directly measure Adiol 3-G in serum extracts. In 10 normal men, mean serum Adiol 3-G and total Adiol G levels were 4.44 +/- 0.49 (+/- SE) nmol/L (208 +/- 23 ng/dL) and 27.9 +/- 2.8 nmol/L (1310 +/- 129 ng/dL), respectively (13.9 +/- 3.0% of Adiol G was Adiol 3-G). In 10 normal women sampled during the early follicular phase, mean serum Adiol 3-G and total Adiol G levels were 2.64 +/- 0.64 nmol/L (124 +/- 30 ng/dL) and 14.9 +/- 1.5 nmol/L (697 +/- 69 ng/dL), respectively (17.4 +/- 3.6% of Adiol G was Adiol 3-G). In 4 normal men infused for 8 h with tritiated DHT, 17.4 +/- 3.4% of the resulting tritiated Adiol G was Adiol 3-G. These results indicate that Adiol 17-G is the predominant circulating form of Adiol G in normal men and women and that it is also the major Adiol G isomer derived from DHT.

Adult↗
PubMed1988

The antiglucocorticoid and antiprogestin steroid RU 486 suppresses the adrenocorticotropin response to ovine corticotropin releasing hormone in man.

The glucocorticoid and progesterone antagonist RU 486 normalizes the clinical and biochemical features of hypercortisolism in patients with nonpituitary Cushing's syndrome, presumably by antagonizing the action(s) of cortisol. Since RU 486 has progesterone agonist activity in addition to its progesterone antagonist action, the possibility that it might have some glucocorticoid agonist action did not seem unreasonable. To test this hypothesis we examined the effects of RU 486 on pituitary ACTH secretion in 10 patients with primary adrenal insufficiency in whom glucocorticoid replacement was withheld for 36 h. Each patient received, in randomized sequence 3-7 days apart, an oral dose of placebo, RU 486 (20 mg/kg), cortisol (0.1 mg/kg), or a combination of RU 486 and cortisol at 1800 h. Two hours later, an iv bolus dose of ovine CRH (1 microgram/kg) was administered, and plasma ACTH levels were measured serially for 3 h. RU 486 suppressed ovine CRH-stimulated ACTH secretion, albeit less than cortisol. Its glucocorticoid agonist effect was calculated to be approximately 1/250th that of cortisol on a weight basis. Additionally, RU 486 partially antagonized cortisol-induced suppression of ACTH secretion. These findings suggest that RU 486 is a partial glucocorticoid agonist and offer some insight as to its action in patients with Cushing's syndrome. Whether this degree of glucocorticoid agonist activity is adequate to support life, however, is not known.

Addison Disease↗