Elevated plasma adrenocorticotropin (ACTH) with adrenal hyperplasia: a new factor in ACTH regulation?

We report a patient with Cushing's syndrome in whom the etiology of the hypercortisolemia could not be definitely established despite extensive biochemical investigations. Results included raised basal serum cortisol, plasma ACTH, and urinary free cortisol; failure to suppress even a paradoxical rise in serum cortisol after dexamethasone (1 mg overnight, 2, 8, and 16 mg/day); and a definite but not exaggerated rise in 11-deoxycortisol after metyrapone. After iv CRF, plasma ACTH rose from 22 to 30 pmol/L. Abdominal computed tomographic scanning showed adrenal hyperplasia; the presence of an adrenal adenoma, although suspected, was not established. An unusual finding was the presence in the urine of large amounts of 21-deoxycortisol metabolites, including 3 alpha,11 beta,17 alpha-trihydroxy-5 beta-pregnan-20-one and 5 beta-pregnane 3 alpha,11 beta,17 alpha,20 alpha-tetrol. On the basis of preoperative biochemical/radiological findings, a provisional diagnosis of ACTH-dependent Cushing's syndrome associated with autonomous bilateral adrenal hyperplasia was made. Incomplete bilateral adrenalectomy was performed; adrenal hyperplasia was histologically confirmed, but no tumor was found. However, ACTH was measured 1) just before operation when the patient was receiving treatment with metyrapone, and 2) postoperatively when the patient was receiving steroid replacement only, and on these occasions ACTH levels were lower than during the initial investigations. Pituitary scans before and after adrenalectomy were similar, offering no evidence of pituitary infarction. We propose that abnormal production of 21-deoxycortisol contributed to the aberrant regulation of ACTH and cortisol in this case, providing an example of a previously unreported cause of hypercortisolemia.

Acute changes in serum thyrotrophin in treated Addison's disease.

Serum and salivary cortisol, plasma ACTH and serum TSH, free T4, free T3, PRL, LH and FSH were measured before and hourly after the morning steroid replacement therapy of five patients with Addison's disease. In the 4 h after hydrocortisone the levels of TSH fell in all five patients, the levels (mIU/l) decreasing from 6.8 to 3.8; 0.9 to 0.6; 24.3 to 13.2; 28.1 to 7.4 and 17.2 to 11.6. No such change was seen when the procedure was repeated with the morning steroid dose withheld. In two patients, dexamethasone produced similar changes in serum TSH to those observed with hydrocortisone. Steroid therapy had no consistent effect on LH, FSH and PRL levels. Our results show that the time interval between taking medication and withdrawing blood samples should be considered when interpreting TSH levels in treated Addison's disease.

A comparison of propranolol and nadolol pharmacokinetics and clinical effects in thyrotoxicosis.

For a comparison of propranolol and nadolol pharmacokinetics and clinical effects, 20 newly diagnosed patients with thyrotoxicosis were randomly selected to receive as sole therapy, either propranolol, 40 mg every 6 hours for 14 days, or nadolol, 80 mg each morning for 14 days. The study was repeated when the patients were in the euthyroid state. There was a similar and highly significant degree of beta blockade and amelioration of symptoms of thyrotoxicosis at the end of the dosage interval (trough), i.e., 24 hours after nadolol or 6 to 8 hours after propranolol. Trough and peak serum levels of propranolol were significantly lower when the patients were in a thyrotoxic state than when they were in a euthyroid state, whereas the pharmacokinetics of nadolol were not appreciably altered by thyrotoxicosis. In thyrotoxicosis, trough levels of propranolol and nadolol were significantly inversely correlated with derived creatinine clearance values. In the symptomatic treatment of thyrotoxicosis, nadolol, a once-daily nonmetabolized beta blocker, has certain advantages compared with propranolol. It is preferred by patients, is more convenient, and probably aids compliance.

Delayed abortion in an area of easy accessibility.

Abortions performed late in pregnancy are associated with higher death and complication rates, are more expensive, and are emotionally more taxing for patients and staff than abortions performed early in pregnancy. To examine potential correlates of late abortion, we studied 1,066 women having abortions at two Washington, DC, abortion facilities. We found the following variables to be statistically significantly related to the gestational stage of pregnancy at the time a woman seeks an abortion: history of irregular periods, level of education, type and number of pregnancy symptoms volunteered, moral feelings of the women about abortion, confided suspicion of pregnancy to another person, knowledge of the legality of abortion, contraceptive use, pregnancy symptoms elicited by professional personnel, and length of time the sexual partner was known. Yet, these variables are responsible for only a small percentage of the problem, since much variation in gestational age was unexplained by our analysis. This result and the finding that most of the important determinants of delay were individually oriented factors strongly imply that the problem of late abortions is one that will not be greatly influenced by public health interventions.

Hereditary abnormalities of thyroxine-binding globulin concentration. A study of 19 kindreds with inherited increase or decrease of thyroxine-binding globulin.

Nineteen families with hereditary abnormalities of thyroxine-binding globulin (TBG) have been studied, comprising a total of 15 males with absent TBG, and 15 females heterozygotic for this condition, and 14 males with excess of TBG and 44 heterozygotic females. Hereditary TBG excess was associated with thyrotoxicosis in four instances, and with myxoedema in three. The typical biochemical features of TBG abnormality are described, with the clinical histories of patients in whom diagnostic and management problems occurred.

Effects of surgical stress and corticotrophin on the peripheral metabolism of thyroid hormones in rabbits.

The effect of surgical stress and ACTH injection on the peripheral monodeiodination of thyroxine (T4) was studied in the rabbit. These stimuli resulted in a switch from the peripheral formation of tri-iodothyronine (T3) to reverse T3 in normal rabbits and in rabbits whose thyroidal secretion was suppressed by administration of T4. This is analogous to the situation in man. These changes were not due to alterations in the serum binding capacity for thyroid hormones.

Fertility in psychiatric outpatients.

The fertility rates of 223 female schizophrenic outpatients and 479 female nonschizophrenic outpatients were compared to a probability sample of 300 women residing in the same geographic area, metropolitan Atlanta, and from the same social strata as the patients. Age- and race-adjusted comparisons showed that the mean number of children per woman and levels of unwanted and unplanned fertility did not differ in the different diagnostic groups. Furthermore, the rates were not lower for the psychiatric patients than for the general population. In order to reduce an important source of psychiatric morbidity, those in the mental health professions need to pay more attention to the family planning desires of their patients.

The inter-relationship of thyroid hormones, vitamin A and their binding proteins following acute stress.

The effects of surgical stress on the metabolism of the retinol-binding-protein-thyroxine-binding-prealbumin complex were investigated. The immediate postsurgical period was characterized by a rapid decline in the serum concentration of retinol, retinol binding protein and triiodothyronine and an increase in the 24 h urinary excretion of retinol, retinol-binding-protein and thyroxine. Similar, but less pronounced, changes were seen in other subjects suffering acute myocardial infarction but were not observed in normal healthy euthyroid males or in pre-operative euthyroid patients. The preparation of specific anti-retinol binding protein anti-serum and the use of this in 'monorocket' immunoelectrophoresis are also described.

A reassessment of 8-anilino-1-naphthalene sulphonic acid as a thyroxine binding inhibitor in the radioimmunoassay of thyroxine.

The effectiveness of 8-anilino-1-naphthalene sulphonic acid (ANS) in the radioimmunoassay (RIA) of thyroxine (T4) as an inhibitor of the binding of T4 to serum T4-binding proteins is assessed. The optimum ANS concentration is dependent upon the antiserum and the method used for separating free and bound T4. If T4 binding to serum proteins is not completely inhibited, resin separation methods may yield low values, while polyethylene glycol and double-antibody methods may produce high values for T4 concentration. Even with optimum ANS concentration gross errors in measurement of T4 may occur in patients with high thyroxine-binding globulin (TBG) concentrations.

Concentration of thyroxine-binding globulin: value of direct assay.

The concentration of thyroxine-binding globulin (TBG) in the serum can now be measured by direct assays that are simple and inexpensive. Comparison of a direct measurement of TBG concentration with a widely used indirect method (Thyopac-3) showed that the indirect method was inaccurate when TBG concentrations were high. This will result in an increase in the derived free thyroxine index (FTI), so that euthyroid patients with a raised TBG concentration may be at risk of being labelled thyrotoxic. Correction of serum total thyroxine (T4) concentration according to the actual TBG concentration (T4:TBG ratio) provided a better correlation with thyroid state than FTI.

Effect of a single dose of dexamethasone on serum concentrations of thyroid hormones.

In ten euthyroid subjects, in whom endogenous thyroid-stimulating hormone (T.S.H.) production was suppressed by oral thyroxine (T4), a single dose of dexamethasone resulted in reduced serum-3,3'5-triidothyronine (T3) concentration and raised serum-3,3',5'-triiodothyronine (reverse T3 or rT3) concentration after 24 h. These changes were not related to changes in free hormones or binding proteins. Adrenal glucocorticoids may have a pathophysiological role in modulating the peripheral metabolism of thyroid hormones in stress.