Studies of the control of plasma aldosterone concentration in normal man. 3. Response to sodium chloride infusion.

The peripheral plasma levels of aldosterone, renin activity, potassium, sodium, corticosterone, and cortisol were measured in six normal subjects four times daily-10 a.m., 2 p.m., 5 p.m., 11 p.m.-on 3 consecutive days. A constant daytime activity program was maintained throughout the study. After 5 days on a 10 mEq sodium/100 mEq potassium isocaloric intake, the mean upright 10 a.m. plasma renin activity was 1773+/-186 ng/100 ml per 3 hr and the mean plasma aldosterone, 81+/-14 ng/100 ml. These two parameters fell continuously throughout the day parallel to the fall in plasma cortisol and corticosterone. In response to 2 liters of normal saline infused from 10 a.m. to 2 p.m. on 2 consecutive days, plasma aldosterone levels fell significantly to 13+/-5 ng/100 ml at 2 p.m. after the 1st day's infusion and to 6+/-1 ng/100 ml at 2 p.m. after the 2nd. Plasma renin activity demonstrated a parallel fall to 368+/-63 ng/100 ml per 3 hr and 189+/-27 ng/100 ml per 3 hr at 2 p.m. on the 1st and 2nd days, respectively. There was no significant alteration in plasma levels of cortisol, corticosterone, potassium, or sodium on the 2 days of sodium loading in comparison with the control day. In an additional study, five normal supine subjects received 500 ml saline/hr for 6 hr. As in the 2 day study, plasma aldosterone and renin activity had parallel decrements at 1, 2, 4, and 6 hr after the start of the saline infusion. From these studies, it is concluded that plasma renin activity is the dominant factor controlling plasma aldosterone when sodium-depleted normal subjects are acutely repleted.

Adrenocortical hydroxylase deficiencies in acne vulgaris.

To investigate the possible occurrence of partial 11- or 21-hydroxylase deficiences in acne, an androgen-dependent disorder, 11 women with chronic nodulocystic acne were subjected to a 24-hr infusion of ACTH and their urine analyzed for tetrahydro S and pregnanetrio. The results obtained were compared to those found in 8 control women. Seven of the patients exhibited elevated excretion of either tetrahydro S or pregnanetriol, probably indicative of partial 11- or 21-hydroxylase deficiencies, respectively.

Reduction of testosterone to 5 alpha-dihydrotestosterone by human and rat uterine tissues.

Incubations of adult rat uterine tissue and human endometrial and myometrial homogenates with [1,2,6,7-3H]testosterone resulted in the formation of 5 alpha-[3H]dihydrotestosterone. The rat uterine homogenates showed higher activity than the minced tissue. The activity in human tissue was found to be less than rat tissue on a per unit weight basis. The human endometrium has been found to possess significantly higher activity than myometrium. These results support the hypothesis that androgens may exert their effect on uterus via 5 alpha-reduced metabolites.

Side-effects of spironolactone therapy in the hirsute woman.

Spironolactone, an aldosterone antagonist with antiandrogenic activities, is often used to treat hirsute women. Several investigators have reported beneficial effects of such treatment, but the dosages used and side-effects encountered differ in their reports. To clarify this issue, 26 consecutive premenopausal women with idiopathic hirsutism were prospectively evaluated during spironolactone treatment. Sixteen women initially received 100 mg spironolactone twice daily on days 4-21 of their menstrual cycles. In 11 women (68%), the dosage had to be decreased or the medication discontinued due to side-effects. The major side-effect, metrorrhagia with 14-day cycles, occurred in 9 women (56%). This side-effect, while not dangerous, was intolerable to these women. In one woman, spironolactone was discontinued because of urticaria and in another because of scalp hair loss. Ten women initially received 50 mg spironolactone twice daily on days 4-21 of their menstrual cycles. Two developed metrorrhagia, but no other side-effects were noted. Because of the incidence of metrorrhagia at higher dosages, we recommend that spironolactone be administered cyclically at a starting dosage of 50 mg twice daily on days 4-21 of the menstrual cycle. Alternatively, one may consider adding cyclical estrogen/progesterone therapy to continuous spironolactone therapy.

Blood pressure response to thyrotropin-releasing hormone in euthyroid subjects.

The iv administration of TRH has been associated with side effects, such as nausea, flushing, and urinary urgency. However, few reports mention changes in blood pressure. This study defines the mean and range of the blood pressure responses in 70 euthyroid patients subjected to iv administered TRH. The mean increase was 21.0 +/- 1.4 mm Hg for systolic and 13.9 +/- 1.0 mm Hg for diastolic blood pressure; however, individual peak values increased as much as 56 and 42 mm Hg, respectively. Thus, the hemodynamic response to iv administered TRH can be quite severe in some subjects, and caution is suggested in selecting patients for testing.

Adrenocortical response to marathon running.

Plasma cortisol and plasma aldosterone levels were measured before and immediately upon completion of a marathon run in 7 highly conditioned male subjects in order to evaluate the response of the adrenal cortex to physical exertion. Both cortisol and aldosterone values rose significantly in response to the stress of the muscular exertion of the 26 mile, 385 yard run.

Bedtime insulin added to daytime sulfonylureas improves glycemic control in uncontrolled type II diabetes.

BACKGROUND: To evaluate the possible benefits of the addition of intermediate-acting insulin administered at bedtime to therapy with daytime sulfonylureas in patients with non-insulin-dependent diabetes mellitus for whom maximal doses of oral hypoglycemic agents have not been successful. METHODS: Study subjects were 16 consecutive obese patients aged from 44 to 78 years (mean age, 62 years) with histories of non-insulin-dependent diabetes mellitus for a mean of 9 years. None of the subjects had been able to control their diabetes with maximal doses of oral hypoglycemic agents. All patients received 20 mg glipizide or 10 mg glyburide twice a day, as well as education about the American Diabetes Association diet. Neutral protamine Hagedorn (NPH) insulin was empirically added in doses from 0.1 to 0.2 units/kg given at bedtime. The dose was adjusted on the basis of fasting blood glucose levels. RESULTS: Mean fasting blood glucose decreased from 13.7 +/- 3.4 to 8.3 +/- 2.7 mmol/L at 3 months and 7.3 + 2.0 mmol/L at 1 year. Glycosylated hemoglobin decreased from 9.0% +/- 1.9% to 6.2% +2- 1.16% at 3 months and 6.3% +/- 1.22% at 1 year. CONCLUSION: A late-night dose of NPH insulin was added to a regimen of daytime sulfonylureas in a group of obese patients with type II diabetes whose hyperglycemia was not controlled with maximal doses of oral hypoglycemic agents. This treatment proved to be beneficial and is a useful alternative to conventional insulin therapy in this group of patients.

Gonadotropin, estradiol, and testosterone profiles in homosexual men.

The authors evaluated the gonadotropin-testosterone-estradiol profiles of four homosexual men and four heterosexual men by a multiple-sampling technique. Although there was extensive overlap between the two groups, the homosexual subjects had higher estradiol levels than the heterosexuals (70.3 +/- 19.8 versus 56.8 +/- 10.7 pg/ml) and lower FSH values (5.1 +/- 1.0 versus 13.2 +/- 3.4 mIU/ml). Testosterone and luteinizing hormone levels were comparable in the two groups. These observations suggest that there may be subtle differences in gonadotropin and estradiol secretion in homosexual subjects that can be detected only by repeated sampling.

Effect of long-term amiodarone therapy on thyroid hormone levels and thyroid function.

Both hyperthyroidism and hypothyroidism have been noted to occur in some patients treated with amiodarone for cardiac arrhythmias. To determine the frequency of the development of thyroidal abnormalities in patients receiving amiodarone, 45 euthyroid patients were prospectively evaluated. Serum samples were obtained for measurement of thyroxine, thyrotropin, triiodothyronine, and triiodothyronine resin uptake prior to initiation of amiodarone treatment and serially over a 12- to 27-month period during which amiodarone was administered. The patients were divided into four subgroups as follows: Group I (n = 22) had elevated thyroxine levels, Group IIA (n = 13) had normal thyroxine levels and normal thyrotropin levels, Group IIB (n = 7) had normal thyroxine levels and elevated thyrotropin levels, and Group III (n = 3) had subnormal thyroxine levels. Demographic factors (such as route of administration, cardiac diagnosis, sex of the patient, or indication for amiodarone therapy) and amiodarone levels had no significant effect on the thyroid hormone parameters. However, Group I patients were statistically older than the patients in the other groups. Linear regression analysis revealed a negative correlation for thyroxine levels and a positive correlation with thyrotropin levels with age for the whole group. The various groups were not statistically affected by duration of therapy, but a positive trend existed for increasing thyroxine levels. Although virtually all patients showed changes in their thyroid hormone levels, chemical hyperthyroidism (elevated thyroxine and triiodothyronine levels without symptoms) developed in only two patients (4 percent), and clinical hyperthyroidism (elevated thyroxine and triiodothyronine levels with symptoms) developed in no patients. Four patients (9 percent) became biochemically and clinically hypothyroid. Thus, amiodarone frequently influences thyroid hormonal parameters, but less commonly causes a change in actual thyroid function. However, hyperthyroidism and hypothyroidism do occur in a significant number of patients.

Corticosteroids and adrenal suppression. Characterising and avoiding the problem.

Glucocorticoids are used for a variety of illnesses. One of their major complications is suppression of the hypothalamic-pituitary-adrenal axis, rendering a patient unable to respond to stress. The risk of this suppression may be minimised by the use of short-acting glucocorticoid preparations, administration of the entire daily dose in the early morning, use of topical and intra-articular preparations where appropriate, and the use of alternate-day therapy where appropriate. Most importantly, glucocorticoids should be used cautiously when indicated, and the duration of therapy limited as much as possible.

Late onset adrenocortical hydroxylase deficiencies associated with menstrual dysfunction.

Forty-eight women with menstrual dysfunction and clinical evidence of excess androgen production were subjected to an adrenocorticotropic hormone stimulation test that demonstrated the presence of a late-onset 11- or 21-adrenocortical hydroxylase deficiency. Adrenocortical suppression therapy with prednisone was then instituted. Eighty-three percent of the women improved and either conceived, established normal regular menstrual cycles, or noted a significant increase in menstrual regularity. In patients desiring fertility, there was an overall pregnancy rate of 64% and a corrected pregnancy rate of 93%. Some of these patients were given clomiphene in addition to the prednisone. The present study has demonstrated that an adrenocortical abnormality, characterized by a partial deficiency of either 11-hydroxylase or 21-hydroxylase, plays a significant role in many women with clinical evidence of hyperandrogenism and menstrual abnormalities. In such women, adrenocortical suppression is indicated and often results in a significant improvement of the menstrual disturbance.

The partial adrenocortical hydroxylase deficiency syndrome in infertile women.

Eighteen infertile women desiring conception were selected for additional diagnostic studies on the basis of clinical evidence of hyperandrogenism characterized by acne and/or facial hirsutism. These 18 patients underwent stimulation tests with adrenocorticotropic hormone which demonstrated the presence of partial adrenocortical hydroxylase deficiences. All patients were then placed on glucocorticoid suppression therapy. Ten patients conceived and, of these, six required no therapy other than prednisone. Four conceived using a combination of prednisone and clomiphene therapy. Of othe eight patients who did not conceive, seven had other significant infertility factors. Therefore, of the patients without other significant fertility factors, 91% conceived. This study demonstrates that partial adrenocortical enzyme defects play a significant role in some women with clinical evidence of hyperandrogenism, and, in such women, either glococorticoid therapy alone or in combination with clomiphene is indicated.

Anticardiolipin antibodies in Hashimoto's disease.

OBJECTIVE: To ascertain the presence and significance of anticardiolipin antibodies in patients with Hashimoto's disease. METHODS: We studied 19 patients (15 women and 4 men; age range, 26 to 79 years) with Hashimoto's disease. IgA, IgG, and IgM anticardiolipin antibodies were measured by enzyme-linked immunosorbent assay. RESULTS: Of the 19 study patients, 4 (21%) tested positive for anticardiolipin antibodies (IgG in 2 and IgM in 2). Patients with anticardiolipin antibodies did not exhibit a higher titer of antithyroglobulin or anti-thyroid peroxidase antibodies in comparison with patients without anticardiolipin antibodies. Moreover, no relationship was found between anticardiolipin antibody levels and thyroid hormone replacement therapy. None of the patients with high levels of IgG or IgM anticardiolipin antibodies had clinical features of the antiphospholipid syndrome. CONCLUSION: Our results showed an increased incidence of anticardiolipin antibodies in patients with Hashimoto's disease. The presence of these antibodies may be a nonspecific marker of activation of the immune system.

Ectopic primary hyperparathyroidism.

OBJECTIVE: To review an unusual case of ectopic primary hyperparathyroidism. METHODS: We present a case report, including longitudinal results of laboratory studies, and comment on the difficulties with standard imaging techniques, interpretation of parathyroid pathologic findings, and use of invasive localization techniques. RESULTS: A 74-year-old woman underwent repeated assessments because of hypercalcemia. When standard parathyroid 99mTc sestamibi imaging was negative for adenoma and initial surgical exploration of the neck and removal of 3' parathyroid glands were unsuccessful in correcting the hyperparathyroidism, the ectopic adenoma was ultimately localized on an extended-field 99mTc sestamibi scan in the region of the right dome of the diaphragm. The localization was confirmed by selective venous sampling and angiography. The ectopic parathyroid adenoma was embolized, and 1 month later, the serum calcium level was normal. CONCLUSION: Ectopic lesions should be considered when standard imaging techniques are nonrevealing and standard neck exploration fails to disclose a parathyroid adenoma in a patient with persistent hypercalcemia. Selective venous sampling and angiography can assist in localization of ectopic parathyroid adenomas.

Successful therapy for a mixed thyrotropin-and prolactin-secreting pituitary macroadenoma with cabergoline.

OBJECTIVE: To describe the first case of a mixed thyrotropin (TSH)- and prolactin-secreting pituitary macroadenoma that responded to therapy with cabergoline. METHODS: We present a case report with clinical, laboratory, and radiologic details. RESULTS: An 84-year-old woman with central hyperthyroidism due to a mixed TSH- and prolactin-secreting pituitary macroadenoma was successfully treated with orally administered cabergoline, 0.25 mg twice per week. Serial assays of thyroid and pituitary hormones were done, and magnetic resonance imaging of the pituitary was performed before and 16 weeks after initiation of cabergoline therapy. The patient had complete resolution of the increased pituitary hormone indices within 6 weeks after implementation of therapy, and these results were sustained for more than 16 weeks. A magnetic resonance imaging scan showed no change in tumor size at 16 weeks of therapy. CONCLUSION: When medical treatment of TSH-secreting tumors is considered, choices of efficacious drugs are limited. To our knowledge, this report describes the first case of a long-acting dopamine agonist used successfully to control hypersecretion of a mixed TSH- and prolactin-secreting macroadenoma. Oral administration of cabergoline twice a week was effective, convenient, and well tolerated. Further evaluation of cabergoline, when indicated as medical therapy for TSH-secreting tumors, is warranted.

Hypercalcemia associated with squamous cell carcinoma of tongue.

OBJECTIVE: To present a case and to review the relationship between tumor production of parathyroid hormone-related protein (PTHrP) and hypercalcemia in oral squamous cell carcinoma (SCC), with emphasis on tongue cancer. METHODS: We describe a patient with advanced, locally invasive SCC of the tongue in whom hypercalcemia developed as a result of PTHrP production by the tumor. In addition, the medical literature regarding PTHrP and hypercalcemia associated with malignant disease is reviewed. RESULTS: A 65-year-old man, who was admitted to the hospital because of one episode of unresponsiveness, was found to have a large, necrotic, ulcerated lesion overlying the left mandibular area. After biopsy of the tumor and total body imaging, he was diagnosed with advanced, locally invasive, poorly differentiated SCC of the tongue, stage T4 N1 M0. On admission, the serum calcium concentration was 12.5 mg/dL (normal range, 8.5 to 10.7), and the serum albumin level was 2.2 g/dL (normal range, 3.5 to 5.5). The serum intact parathyroid hormone level was 26 pg/mL (normal range, 10 to 65); the PTHrP level was 13.1 pmol/L (normal, <1.3). Hypercalcemia attributable to production of PTHrP by the tongue SCC was diagnosed. Initial treatment of the hypercalcemia with vigorous hydration yielded a limited response. Intravenous administration of pamidronate initially decreased the serum calcium level to 5.2 mg/dL, but then it progressively increased to 8.6 mg/dL during the next 4 weeks. The patient refused further treatment and died after 1 month. CONCLUSION: To our knowledge, this is the first case of hypercalcemia associated with SCC of the tongue in which the serum PTHrP level was measured and reported to be high. It should be measured in other similar cases.

False-positive ethylene glycol levels in patients with diabetic ketoacidosis.

OBJECTIVE: To describe two patients with diabetic ketoacidosis and positive ethylene glycol levels and to call attention to the possibility of a false-positive ethylene glycol determination in patients with ketoacidosis. METHODS: Clinical manifestations and laboratory tests in the two patients were summarized. Serum specimens for both patients were analyzed for ethylene glycol, serum ketones, glucose, osmolality, pH, and electrolytes. RESULTS: Respective laboratory findings in our two patients were as follows: serum glucose levels, 56.4 and 45.7 mmol/L; serum acetone, positive in 1:80 and 1:128 dilution; serum osmolality, 366 and 377 mmol/kg; pH, 6.9 and 7.2; and ethylene glycol, 3.46 and 2.45 mmol/L. CONCLUSION: Neither of these two elderly women had ingested ethylene glycol; nevertheless, both had positive results for ethylene glycol on a blood toxicology screen. Review of the literature demonstrates that false-positive ethylene glycol levels can be detected in patients with ketoacidosis. This information is documented in this report and should alert practicing physicians to such a possibility.

Cost effectiveness of routine gonadotropin and androgen measurements in hirsute women.

Many physicians routinely measure the gonadotropins PRL, LH, and FSH and the androgens dehydroepiandrosterone (DHEA), androstenedione (ADIONE), and testosterone, as well as testosterone's biologically active fractions in the evaluation of hirsute women. Is this cost effective? To answer this question, 38 consecutive premenopausal hirsute women were evaluated. Two women each had minor elevations in PRL and FSH, and 11 had minor elevations in LH. Three women had minor elevations in the LH/FSH ratio, and only one was above a ratio of 3, believed to be indicative of polycystic ovarian syndrome. Because these gonadotropin elevations did not correlate with the androgens measured and were of no value in the diagnosis or management of these women, they were not believed to be cost effective. Their routine measurements should be abandoned.

Case report: failure of adrenal scintigraphy to exhibit 131I cholesterol uptake in a CT-demonstrated, surgically proven aldosteronoma.

This is the case of a large 2 x 1.5 cm adrenal tumor demonstrated on CT scan that was proven biochemically and surgically to be an aldosteronoma and that did not concentrate 6-beta(131I)-iodo-methyl-19-norcholesterol (NP-59). Before the publication of this case, all CT-identified aldosteronomas of greater than 1 cm have concentrated NP-59. Previously, an adrenal mass of greater than 1 cm that failed to concentrate NP-59 was excluded from being an aldosteronoma. This concept must be reevaluated with the publication of this case.

Serum androgens and psychopathology in hirsute women.

Twenty consecutive women referred for evaluation and treatment of idiopathic hirsutism were evaluated with regard to levels of serum androgens, degree of hirsutism, nature and prevalence of psychological symptoms, and mood and affects. Androgens measured were total testosterone, free testosterone, biologically active testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and androstenedione. Psychological symptoms were quantified via the Derogatis Symptom Inventory, and mood and affects were measured by the Affects Balance Scale. Results revealed very significant correlations between unbound fractions of testosterone (i.e. free and biologically active testosterone) and both symptom and mood measures of depression (r = 0.60; p < 0.01). Significant inverse correlations were also observed between unbound fractions of testosterone and positive affects measures (e.g. 'contentment' r = -0.51; p < 0.05). Correlations between total testosterone and psychological variables were non-significant in all instances. Measures of degree of hirsutism correlated approximately zero (o) with psychological symptom and mood measures in this sample. When psychiatric 'caseness' criteria were applied to the cohort, seven of the 20 women (35%) were found to be positive. Results are interpreted to suggest that depression among hirsute women appears more likely to have its basis in a deranged neuroendocrine mechanism than in psychosocial causes.