Circadian variation of cytosol glucocorticoid receptors in human polymorphonuclear leukocytes (PMN) and mononuclear cells (MN) in a normal population.

UNLABELLED: Glucocorticoid cytosol and whole cell receptors from human PMN's have been quantified, and compared to those of human MN leukocytes on the same blood sample. The normal cytosol PMN receptor density (N = 15) averaged 1,254 +/- 105 (SE) molecules bound/cell at 0900 h and increased significantly to 1,497 +/- 98 at 2,100 h (P less than 0.02). MN cell cytosol receptor density was 1,198 +/- 145 at 0900 h and increased significantly to 1,551 +/- 117 molecules bound/cell at 2,100 h (P less than 0.01). Corresponding whole cell receptor densities at 0900 h were 2,845 +/- 273 (PMN) and 3,547 +/- 290 (MN) and these did not change significantly at 2,100 h. CONCLUSIONS: Cytosol receptors in normal human PMN and MN cells increased significantly at 2,100 h from the 0900 h level while serum cortisol levels were dropping. Whole cell receptors in the same PMN and MN cell samples did not change significantly between 0900 and 2,100 h. The normal circadian variation in serum cortisol influences the distribution of the glucocorticoid receptor between the cytosol and the nucleus, but does not influence the amount of receptor available to the whole cell. This is the first time that an endogenous physiological variation of cortisol concentration has been utilized to demonstrate a corresponding change in receptor capacity in vivo.

Cortisol secretion by an incidentally discovered nonfunctional adrenal adenoma.

We describe a middle-aged man with late-onset multiple sclerosis and an incidentally discovered asymptomatic adrenal mass. He had no symptoms or signs of hypercortisolism. A 24-h profile revealed fluctuating serum cortisol values (between 15.1 and 4.7 micrograms/dl) and inappropriately low plasma ACTH values. Urinary cortisol excretion was 89 and 106 micrograms/day on two occasions. After a 4-h ACTH infusion, serum cortisol rose from 6.3 to 108 micrograms/dl. The serum dehydroepiandrosterone level, 33 ng/dl before ACTH stimulation, did not change. During dexamethasone administration, the lowest daily urinary cortisol excretion was 37 micrograms/day, and 17-ketosteroid excretion was 8 mg/day. The response to metyrapone showed a rise of serum 11-deoxycortisol to 25.6 micrograms/dl and of ACTH to 169.5 pg/ml. After removal of the tumor, most likely an adenoma, the circadian pattern of cortisol and ACTH was normal. During a 4-h ACTH infusion, the serum cortisol level rose from 10 to 27 micrograms/dl, and dehydroepiandrosterone rose from 62 to 90 ng/dl. During dexamethasone administration, daily urinary cortisol excretion decreased to 12 micrograms/day, and 17-ketosteroid excretion dropped to 3.9 mg/day. These data show that while the tumor appeared clinically to be nonfunctional, it was producing cortisol and possibly androgens autonomously, albeit at levels too low to cause complete suppression of the pituitary-adrenal axis.

Steroid use in the elderly. Guidelines for avoiding adverse effects.

The effects of aging on adrenal function should be considered when prescribing steroid for the elderly. For glucocorticoids, the changes of decreased production and decreased clearance are relatively balanced, resulting in levels that are still within the normal range. Responses of the hypothalamic-pituitary-adrenal axis to stress are not altered. However, androgens appear to be affected by an "adrenopause," the mechanism(s) and the clinical relevance of which remain to be elucidated. The risk/benefit factors in steroid use are always of utmost concern. The physician may consider lowering the steroid dose in elderly patients of asthenic build because of the diminution of muscle mass and plasma volume that occurs with aging. Despite the physiologic changes that accompany aging, steroid used carefully and appropriately can be both safe and effective in the elderly.

Vitamin B-12 (cobalamin) deficiency: a heretofore undescribed control mechanism for plasma corticosteroid-binding globulin concentration in man.

Six of eight patients with Addisonian pernicious anemia were found to have diminished corticosteroid-binding globulin (CBG) concentrations, which returned within 2 weeks to normal after the im administration of cobalamin. T4-binding globulin was found to be completely normal before and after cobalamin replacement. Other estrogen-responsive proteins, i.e. ceruloplasmin, alpha 1-trypsin inhibitor, haptoglobin, transferrin, and alpha 2-macroglobulin, also did not follow CBG concentration in a parallel fashion. The immunoglobulins similarly did not follow a course parallel to that of CBG. The CBG concentration in two untreated patients had a normal increase in response to estrogen administration, similar to that described in CBG deficiency from other causes. No clue was found regarding the mechanism by which B12 influences the putative hepatic control of CBG concentration. It is speculated that at least two control points may be necessary for a normal CBG concentration. Patients with a genetic deficiency of CBG may also have to have cobalamin deficiency in order for them to reach a concentration approaching zero.

ACTH-induced cortisol production in multiple sclerosis.

We measured the total daily urinary cortisol produced by each of 8 patients with multiple sclerosis during intravenous therapy with adrenocorticotropic hormone (ACTH). Results indicated marked daily variation from patient to patient as well as in the same patient, suggesting that ACTH infusions do not result in reliable, consistent, high-level production of cortisol. We attempted to express the quantity of cortisol produced as an equivalent amount or oral prednisone. This comparison is difficult to make; but, given certain assumptions, the figures suggest that 40 U or 80 U ACTH infusions do not elicit the quantities of steroid generally considered to be indicated for the therapy of major allergic, autoimmune, or neoplastic diseases.

Effects of (Bu2)-cAMP and clomiphene on serum concentrations of several proteins and hormones in gonadectomized monkeys.

Sixteen mumol kg-1 of dibutyryl cyclic adenosine 3',5'-monophosphate [(Bu)2cAMP] given intramuscularly to gonadectomized green monkeys (Cercopithecus aetheops sabeus) for two-week periods, produced a significant elevation in the serum concentrations of thyroxine-binding globulin (TBG), fibrinogen, and haptoglobin. No changes were noted in cortisol-binding golbulin (CBG), cortisol, thyroxine, transferrin, total proteins, and albumin. Clomiphene citrate (12.5 mg orally) given concomitantly with (Bu)2cAMP blocked partially the (Bu)2cAMP-induced fibrinogen increment, but not the change in TBG concentration.

Surgical management of Cushing's syndrome.

Twenty-seven operations for Cushing's syndrome were reviewed. Included were five cases of adenoma and 22 of adrenal cortical hyperplasia. Preoperative laboratory data, particularly the metyrapone test, were highly accurate in distinguishing adenoma from hyperplasia. Bilateral flank incisions are preferable to the transabdominal approach, with fewer complications, less postoperative ileus, and shorter hospital stays. The inability to inspect both glands simultaneously is of little consequence because biochemical testing data are sufficiently accurate to obviate the need for gross evaluation. The use of perioperative prophylaxis seems to be of importance for preventing thromboembolism in these hypercoagulable patients. The preoperative use of adrenal cortical blocking agents has not proved to yield significant advantages.

Pituitary pigmentary hormones. Relationship of melanocyte-stimulating hormone to lipotropic hormone.

Pituitary control of pigmentation has known for more than 60 years. Since 1969, beta-melanocyte-stimulating hormone (beta-MSH) has been accepted as the main pituitary pigmentary hormone in man. Its "constant companionship" with adrenocorticotrophic hormone (ACTH) has also been repeatedly demonstrated. Current investigations challenge both of these concepts. Human beta-MSH immunoreactivity has been shown to be actually due to beta-lipotropic hormone (beta-LPH), a larger molecule that within itself contains the entire amino acid sequence of beta-MSH. Human beta-MSH does not exist in vivo; it is merely an extraction artifact formed by enzymatic degradation of beta-LPH. It would appear likely that beta-LPH, not beta-MSH, is the constant companion of ACTH.

Effect of oral estramustine phosphate on pituitary, gonadal, and adrenal function in the green monkey (Cercopithecus aethiops sabaeus).

We studied the effects of estramustine phosphate on pituitary, gonadal, and adrenal function in the green monkey. A 2-week course of estramustine phosphate (75 mg per day) reversibly suppressed the luteinizing hormone and testosterone response to luteinizing hormone-releasing hormone but did not affect pituitary-adrenal function assessed by the 11-deoxycorticosterone response to metyrapone. Treatment with oral estramustine phosphate also resulted in a significant increase in corticosteroid-binding globulin but did not affect a series of liver enzymes nor hematology. The results are consistent with a pure estrogen effect produced by hydrolysis of the carbamate-ester bona at a site distant from estrogen target tissues and could explain most of the reported in vivo effects of this compound.

Lipid cell tumor of the ovary: an ultrastructural study.

An ovarian lipid cell tumor without Reinke's crystalloids in a woman with secondary amenorrhea, minimal hirsutism, and elevated 17-ketosteroid excretion was studied by light and electron microscopy. Tumor cells were found in small clumps or scattered singly within a collagenous matrix. The cytoplasm of the tumor cells contained abundant smooth endoplasmic reticula, numerous mitochondria with tubular cristae, lipid droplets, lysosomal dense bodies, and concentric membranous whorls, characteristic of steroidogenic cells. In addition, "peripheral canalicular systems" were found at the outer margins of the nests of the tumor cells. These "peripheral canalicular systems" were bordered by the cell membranes and the surrounding collagenous stroma into which microvilli projected. Since the intercellular canalicular system present between the tumor cells was continuous with the "peripheral canalicular system," both systems probably have a common function related to steroid metabolism. The intercellular and "peripheral" canalicular systems and cytoplasmic microfilaments found in this tumor suggest that this ovarian lipid cell tumor was derived from the ovarian stroma.

Lack of glucagon response to hypoglycemia in diabetic autonomic neuropathy.

Glucagon response to insulin hypoglycemia was tested in diabetics with autonomic neuropathy (N=9), diabetics without neuropathy (N=8), and normals (N=9). With similar levels of hypoglycemia, growth hormone and plasma cortisol increased in all groups. The glucagon response in normals (121+/-19 vs. 308+/-30 pg./ml., mean+/-S.E.M. of baseline vs. hypoglycemia peak) was significantly less in nonneuropathic diabetics than in normals (128+/-13 vs. 209+/-30) and absent in neuropathic diabetes (128+/-23 vs. 115+/-20). Arginine stimulation produced a glucagon response in the neuropathic diabetics (106+/-16 vs. 523+/-103). The data indicate that the capacity to release glucagon during hypoglycemia is lost in diabetic neuropathy while glucagon responsiveness to arginine is retained. Neuropathy in diabetes may contribute to metabolic instability.

Response of serum cholesterol and triglycerides to hormone treatment and the relation of pretreatment values to mortality in patients with prostatic cancer.

Cholesterol and triglycerides were measured in plasma samples from patient with cancer of the prostate before and after 3 months treatment with either Premarin, Provera, Provera and diethylstilbestrol, or diethylstilbestrol alone. Cholesterol was also measured before and after one of three doses of diethylstilbestrol or placebo. Pretreatment cholesterol levels at 196 +/- 1.3 mg per 100 ml (X +/- SE, N = 1093) were significantly lower than these reported for similar age group noncancer controls. Significant increases occurred with some of the estrogen treatments. Pretreatment cholesterol levels showed a significant negative correlation with age in Stage III and IV patients of both studies and a positive correlation with hemoglobin in Stage III patients of both studies. Pretreatment triglyceride levels at 120 +/- 1.9 mg per 100 ml (X +/- SE, N = 1089) were similar to levels reported for noncancer controls of similar age. Estrogen treatment produced a significant increase in triglyceride levels. Serum triglycerides were significantly correlated with hemoglobin, weight, and cholesterol and negatively correlated with age, Analysis of covariance for both cholesterol and triglycerides showed highly significant treatment effects, but no stage effects and no stage-treatment interactions. It showed that the pretreatment value is of extreme importance for predicting or explaining the 3-month value. Death rates were calculated by level of pretreatment cholesterol or pretreatment triglycerides for all Stage II and IV patients, all treatments combined, and for Study 2 and Study 3 separately. No consistent trends were evident for cholesterol. Spearman correlation coefficients between category of initial triglyceride value and rank of death rate were computed to test for a quadratic effect. When the absolute values of the initial triglyceride values minus the overall mean were correlated with the death rate, a significant negative correlation was found for all causes of death and for deaths due to cardiovascular disease and prostatic cancer. These results indicate that the death rate is highest near the overal mean for initial triglyceride values and decreases as the initial values deviate above or below the mean. Initial triglyceride levels appear to have potential as indicators of risk of death in patients with prostatic cancer. The percentage of patients dead at 1 year by initial triglyceride levels, measured only in Study 3, revealed a pattern similar to that observed for the death rate, that is, the highest percentages were associated with values near the overall mean.

Response of plasma fibrinogen and plasminogen to hormone treatment and the relation of pretreatment values to mortality in patients with prostatic cancer.

Fibrinogen and plasminogen were measured in plasma samples from prostatic cancer patients before and after 3 months of treatment with either Premarin, Provera, Provera and diethylstilbestrol, one of three doses of diethylstilbestrol, or placebo. Plasminogen levels generally were increased significantly with the estrogens but were unchanged following placebo or Provera treatment. Pretreatment plasminogen levels in Study 3 were significantly lower (p less than .001) than in Study 2. Plasminogen pretreatment levels were significantly correlated with age, hemoglobin, body weight, and blood pressure. Fibrinogen pretreatment levels were significantly elevated above normal. They were not significantly with age, hemoglobin, body weight, or blood pressure. Fibrinogen levels generally were significantly decreased by the estrogens. Comparisons of means of pretreatment fibrinogen and plasminogen levels from patients dying during the first year of the study with the mean pretreatment levels of the patient group alive after 1 year on study yielded no significant differences. Death rates were calculated by pretreatment plasminogen or fibrinogen for all treatments of all Stage III and Stage IV patients combined for Study 2 and Study 3 separately. Such rates were calculated for all causes combined and for deaths from prostatic cancer or cardiovascular disease separately. The levels of plasminogen were significnatly negatively correlated with death rate from all causes combined and with cardiovascular disease considered separately, but not with death from prostatic cancer. The levels of fibrinogen were signigicantly positively correlated with death rates from all cuses and nearly significantly with prostatic cancer, but not cardiovascular disease. Elvated pretreatment fibrinogen levels were associated with an increased proportion of deaths at 1 year from all causes and from cancer of the prostate.

Correlation of pre-treatment serum 17-hydroxycorticosteroid values with survival in patients with prostatic cancer.

Total 17-OHCS values were determined before and after treatment in 715 patients with all stages of prostatic cancer. The pre-treatment 17-OHCS level was an important variable in predicting survival and appeared to be a better prognostic indicator of death in the first year than the patient's age, treatment or stage of disease. Generally, the higher the initial value of serum 17-OHCS the greater the probability of death in the first year of treatment. There was no preponderance of one type of death over another when patients with initial high and low values were compared.

Low platelet adhesiveness and other hemostatic abnormalities in hypothyroidism.

Fifteen patients with definite hypothyroidism and two with probable hypothyroidism had extensive hemostatic profiles done. In 12 of the 16 patients tested, the platelet adhesiveness (platelet retention in a glass bead column) was abnormal, and in 1 more it was borderline. In the six patients who were studied repeatedly, hemostatic abnormalities either markedly improved or disappeared after treatment with L-thyroxine. It is concluded that, in addition to the previously reported coagulation factor deficiencies (which we also observed in some of our patients), low platelet adhesiveness occurs frequently in patients with hypothyroidism.