Diplopia in autoimmune thyroid disease.

Diplopia without obvious exophthalmos, caused by infiltrative endocrine ophthalmopathy, developed in 12 patients with clinical and laboratory confirmation of autoimmune thyroid disease. In eight patients, the diplopia alone prompted medical attention, which led to the diagnosis of autoimmune thyroid disease. A hypotropia secondary to restrictive tightening of the inferior rectus muscle, producing vertical diplopia, was the most common manifestation of the disorder. The ocular muscle imbalance in autoimmune thyroid disease is caused by mechanical orbital restriction of the extraocular muscle, not by an innervational defect. Evidence of orbital restriction of the eye muscles can establish the diagnosis, regardless of the patient's thyroid function.

The effects of diethylstilbestrol and medroxyprogesterone acetate on kinetics and production of testosterone and dihydrotestosterone in patients with prostatic carcinoma.

Alterations in the metabolism of testosterone (T) and dihydrotestosterone (DHT) induced by diethylstilbestrol (DES) or medroxprogesterone acetate (MPA) could account for the beneficial therapeutic effect of these agents in prostatic carcinoma. To investigate this possibility we sutdied plasma kinetics of T and DHT in 17 elderly patients with prostatic carcinoma, before and after treatment with DES (1 or 5 mg/d) or MPA (10 or 30 mg/d) for 30 days. Metabolic clearance rates (MCR) were determined with the single injection technique and by use of two compartment model, plasma concentrations (PC) of T and DHT by radioimmunoassay, the per cent of T bound to plasma protein (T-binding) by charcoal adsorption of the unbound steroid. Production rate (PR) and PC of T were lower, PR and PC of DHT were higher in our patients than in normal men. With both DES regimens, PR, PC and MCR of either androgen declined; however, T was suppressed to a much greater extent than DHT. In either instance, the decrease may have been caused by direct suppression of testicular androgen synthesis and/or by decreased gonadotropin stimulation. Enhanced T-binding played an additional role in reducing the free testosterone index. High and low dose of DES were equally effective. The low dose regimen of MPA did not influence androgen metabolism. MPA in the higher dose suppressed PR and PC of T and DHT, possibly due to effects on testicular synthesis or by gonadotropin suppression as suggested for DES. In contrast to DES, MPA failed to cause profound changes in MCR of either androgen or in T-binding. When judged by its influence on the metabolism of T and DHT in prostatic carcinoma, MPA in higher doses is much less effective than either dose regimen of DES.

PIP: The effects of diethylstilbestrol(DES) and medroxyprogesterone acetate (MPA) on plasma kinetics and production of testosterone(T) and dihydrotestosterone (DHT), and on plasma protein binding of T were measured in 17 patients (50-93 years of age) suffering with metastatic carcinoma of the prostate both before and during treatment for this disease. Blood samples were obtained before injection of 30 mcCi tritiated T or tritiated DHT and at 10, 15, 20, 40, 55, 70, and 90 minutes after injection. T and DHT were measured by radioimmunoassay. Metabolic clearance rates were measured as well. Production rate (PR) and plasma concentrations (PCs) of T and DHT were higher in these patients than in normal men. When DES was given, PR, PC,and metabolic clearance rates of T and DHT declined, with T suppressed to a greater extent. There was also enhanced T-binding. In patients treated with MPA, 10 mg given for 30 enhanced T-binding. In patients treated with MPA, 10 mg given for 30 days, significantly different changes were seen in the kinetics of T and DHT in 8 patients. Patients treated with 30 mg of MPA for 30 days showed suppression of PR and PC of T and DHT. MPA failed to cause profound changes in the metabolic clearance rate of either androgen or in T-binding. These results indicate that MPA is less effective than DES.

The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection.

PURPOSE: Weight loss is a strong predictor of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. Men with acquired immunodeficiency syndrome (AIDS) lose body cell mass. Hypogonadism is also common. This study tested the efficacy of a testosterone transscrotal patch (6 mg/day) in improving body cell mass and treating hypogonadism in these patients. SUBJECTS AND METHODS: This multicenter, randomized, double-blinded, placebo-controlled trial was conducted from August 1995 to October 1996 in 133 men, 18 years of age and older, who had AIDS, 5% to 20% weight loss, and either a low morning serum total testosterone level (<400 ng/dL) or a low free testosterone level (<16 pg/mL). Outcomes included weight, body cell mass as measured using bioelectrical impedance analysis, quality of life, and morning measurements of serum testosterone and dihydrotestosterone levels, lymphocyte subsets, and HIV quantification. RESULTS: There were no significant differences in baseline weight, CD4 cell counts, or HIV serum viral quantification between treatment arms. Morning total and free testosterone levels increased in those treated with testosterone, but not with placebo. Following 12 weeks of treatment there were no differences (testosterone-placebo) in mean weight change (-0.3 kg [95% confidence interval (CI): -1.4 to 0.8]) or body cell mass (-0.2 kg [95% CI: -1.0 to 0.6]) in the two groups. There were also no changes in quality of life in either group. CONCLUSION: Hypogonadal men with AIDS and weight loss can achieve adequate morning serum sex hormone levels using a transscrotal testosterone patch. However, this system of replacement does not improve weight, body cell mass, or quality of life.

Moderate hypocalcemia due to normal serum 1,25-dihydroxyvitamin D levels in an asymptomatic kindred with familial hypoparathyroidism.

Hypoparathyroidism was diagnosed in nine members of a kindred of three generations. This study investigated why these persons were asymptomatic and without developmental abnormalities, in contrast to the common presentation of idiopathic hypoparathyroidism. In the hypocalcemic subjects, serum calcium level was 7.4 +/- 0.8 mg/dl (mean +/- SD) and ionized serum calcium level was 3.48 +/- 0.21 mg/dl. Immunoreactive parathyroid hormone values were inappropriately low. Injection of EDTA in one patient lowered ionized calcium levels, but immunoreactive parathyroid hormone values did not rise. Serum levels of 1,25-dihydroxyvitamin D and other vitamin D metabolites were normal or elevated and substantially higher than in other hypoparathyroid states. The normally observed positive correlation between the fasting urinary calcium/creatinine ratio and serum 1,25-dihydroxyvitamin D that reflects the dependence of net bone resorption on 1,25-dihydroxyvitamin D was upheld in hypoparathyroid patients. It is proposed that the subjects with familial hypoparathyroidism in this kindred had moderate asymptomatic hypocalcemia without developmental abnormalities because normal or elevated serum 1,25-dihydroxyvitamin D levels enhanced intestinal calcium absorption. This may represent one point in the spectrum of idiopathic hypoparathyroidism. Alternately, both the moderate degree of hypocalcemia and the normal serum calcitriol values could have been related to mild, partial hypoparathyroidism, which could have been inherited in this kindred.

Effects of iodinated glycerol on thyroid function studies in elderly nursing home residents.

Iodinated glycerol is used as a mucolytic expectorant in the treatment of respiratory disorders. Iodine can inhibit the biosynthesis of thyroid hormone and induce hypothyroidism, particularly in patients with a history of thyroid disease. Such effects have not been reported in individuals without known thyroid disease who are being treated with organically bound iodine in the form of iodinated glycerol. In the course of a thyroid screening program for nursing home residents, eight subjects were identified who were being treated with iodinated glycerol. Five of these were found to have thyrotropin elevations; one showed a low serum thyroxine level and a decreased free thyroxine index. None of these residents had a history of thyroid disease. Abnormalities of thyroid function improved or resolved after discontinuation of therapy. Elderly nursing home residents without known thyroid disease are at risk of thyroid suppression when given iodinated glycerol.

Thyroid stimulating hormone elevation without antithyroid antibody elevation in nursing home patients.

OBJECTIVES: To investigate the relationship between antithyroid antibody elevation and thyrotropin (TSH) elevation. SETTING: Large state veterans home. METHODS: Seven hundred seventy-six residents were screened for TSH elevation. Seventy-two residents with TSH elevation and no history of thyroid disease or recent iodine exposure later had determinations of antithyroglobulin and antimicrosomal antibodies. The relationship between TSH levels and antibody titers was explored. RESULTS: Eleven percent of the residents had TSH elevation. Thirty-two percent of men and 64% of women with TSH elevation had elevation of antithyroid antibodies. Those residents with the highest antithyroid antibody titers had significantly greater TSH elevation. CONCLUSION: Previous investigators have found similar percentages of individuals with TSH elevation who lack antithyroid antibody elevation. We hypothesize that TSH elevation without elevated antibody titers may be the result of a previously described involutional histologic lesion of the thyroid.

Follow-up of mild hypothyroidism in a nursing home.

The course of untreated mild hypothyroidism was followed in 67 nursing home residents (mean age 78 years). The diagnosis was based on a normal free thyroxine index (FTI) and elevated thyrotropin concentration (TSH 4.6 to 15.0 microIU/mL, nl less than or equal to 4.5 microIU/mL. FTI and FSH were measured in follow-up 42-378 (mean 161) days after the diagnosis of mild hypothyroidism had been made. In 45 patients initial TSH was less than 6.8 microIU/mL; in 23 of these subjects TSH returned to normal during the observation period, whereas in 22 TSH remained elevated. In all 22 residents whose initial TSH was greater than 6.8 microIU/mL, TSH remained elevated at follow-up. In 4 subjects whose initial TSH concentrations ranged from 5.0 to 9.6 microIU/mL, FTI fell below normal 91-141 days after the diagnosis of mild hypothyroidism was made. Clinical progression of the signs or symptoms of hypothyroidism was not detected in the 4 patients who developed hypothyroxinemia. Three demonstrated positive thyroid antibody titers, and 1 had myasthenia gravis. These observations suggest a need for replacement therapy in debilitated patients with mild hypothyroidism and evidence of thyroid autoimmunity.

Pathophysiology of the ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome occurred after induction of ovulation with menotropins (follicle-stimulating hormone and luteinizing hormone) and implantation of an intrauterine pregnancy. Serial determinations of aldosterone, deoxycorticosterone, 17 beta-estradiol, progesterone, human chorionic gonadotropin, urinary and plasma electrolytes, and fluid balance were obtained. Plasma renin activity, aldosterone, deoxycorticosterone, and antidiuretic hormone rose markedly. Hydration for four days improved urinary output but also accelerated sodium and fluid retention. Subsequent restriction of salt and water stabilized the patient. Spontaneous abortion was followed by prompt diuresis without a change in therapy. Regression analysis of the authors' data, the clinical observations, and other data in the literature suggest that the ovarian hyperstimulation syndrome is produced by excessive secretion of an unknown hormone that regulates peritoneal fluid during the normal menstrual cycle, and that elevations of plasma renin, aldosterone, and antidiuretic hormone are secondary.

Testosterone free index correlates best with dehydroepiandrosterone sulfate.

Correlation coefficients for dehydroepiandrosterone sulfate (DHEAS) were determined in women on menotropin. DHEAS was significantly correlated with testosterone free index (TFI), 0.78**; percentage free testosterone (%FT), 0.66**; androstenedione (delta 4A), 0.66*; luteinizing hormone (LH), 0.55**; LH/follicle-stimulating hormone (FSH) ratio, 0.55**; 17-OH-progesterone (17-P), 0.55**; testosterone (T), 0.53**; weight (WT), 0.40**, urinary estriol glucuronide (E3G), 0.33*; and free cortisol index (FFI), 0.32*, with 43 df but not with prolactin (PRL), 0.25. Normal male DHEAS (3.5 +/- 1.2, 25) (microgram/ml; mean +/- standard deviation, n) was higher than normal female DHEAS (2.4 +/- 1.1, 27), P less than 0.01 and DHEAS in women on oral contraceptives (1.9 +/- 1.1, 17) was slightly lower than in normal females, P greater than 0.2. In the combined population (male, female, and females on oral contraceptives) DHEAS was correlated with TFI (0.56**), T (0.54**), %FT (0.52**), delta 4A (0.40**), and age (-0.40**) with 66 df and 17-P (0.30*) with 54 df. TFI appears to be one determinant of plasma DHEAS, **P less than 0.01. *P less than 0.05.

Association of elevated estradiol with remote testicular trauma in young infertile men.

OBJECTIVE: To determine the incidence of remote testicular trauma and of possible related permanent hormonal and seminal changes in infertile men. DESIGN: Retrospective clinical study of hormonal and seminal parameters in a subpopulation of infertile men. SETTING: Andrology Clinic in an academic research environment. PARTICIPANTS: Infertile men, with and without history of remote testicular trauma, and fertile volunteers. MAIN OUTCOME MEASURES: Percentage of infertile men with history of blunt testicular trauma, concentrations of reproductive hormones, and semen parameters. RESULTS: Significant remote blunt testicular trauma was reported by 16.8% of infertile men. This had occurred 2 to 17 years (mean, 16.4 years) before evaluation, mostly with contact sports at adolescent age. Estradiol concentrations after testicular trauma were 19% and 25% higher than in infertile men without history of testicular injury and in fertile controls. Elevated E2 levels did not correlate with T. Infertile men with and without history of testicular trauma showed changes in seminal parameters. CONCLUSION: The incidence of remote blunt testicular trauma in infertile men is unexpectedly high. After injury, FSH-stimulated aromatization of T may increase testicular E2 production, interfere with spermatogenesis, and cause infertility. Consistent use of protective devices in contact sports is recommended.

Subclinical hypothyroidism in the elderly: to treat or not to treat?

Patients with subclinical hypothyroidism (SCH) have normal concentrations of thyroid hormone and elevated thyrotropin (TSH) levels. These individuals may experience mild symptoms of hypothyroidism. Such symptoms are nonspecific and also can be associated with aging or nonthyroidal illness. SCH is not uncommon in the elderly, particularly in females with positive thyroid antibodies and in those who have undergone partial thyroidectomy or I131 treatment for Graves' disease. Patients with SCH with markedly increased TSH levels or high-titer thyroid antibodies are at higher risk of progressing to overt hypothyroidism. Management options include observation only, with long-term follow up, or substitution with thyroid hormone. Replacement will prevent the development of overt hypothyroidism when reliable follow-up cannot be assured and may improve subtle, nonspecific symptoms of thyroid hormone deficiency. If a decision in favor of replacement therapy has been made, the dose of thyroid hormone should be increased gradually with the objective of returning the TSH level to normal without inappropriately elevating the serum thyroxine concentration. The patient should be carefully observed to see if hypothyroid symptoms, mental status or cardiac function improve with therapy. Continued administration of thyroid hormone would serve prophylactic purposes even if improvement did not occur.

Misleading elevation of the free thyroxine index in nursing home residents.

The significance of an elevated free thyroxine index (FTI) as an indicator of hyperthyroidism was studied while screening 651 elderly nursing home residents. Eleven subjects had FTI elevations. Most of these patients were chronically ill and/or malnourished. Clinical assessment, repeated FTI determinations, and subsequent measurements of levels of triiodothyronine, free thyroxine by equilibrium dialysis, and thyrotropin (thyroid-stimulating hormone) by sensitive assay showed that all subjects with FTI elevation were euthyroid. The FTI elevation in the chronically ill institutionalized elderly patient is not necessarily an expression of hyperthyroidism.

Androgen deficiency in the aging male: when to evaluate and when to treat.

Aging can be associated with an abnormal decline in testosterone production, mainly due to pituitary failure, and is reflected by low serum testosterone concentrations. Manifestations of testosterone deficiency can be subtle, can be misinterpreted as consequences of normal aging, and include lack of libido and energy, mood changes, impaired strength, and development of osteoporosis. The most important factor in the evaluation and treatment of this age-related, usually unrecognized abnormality is the public awareness of its frequent occurrence that will stimulate the use of appropriate screening tests, beginning with a morning testosterone level. Replacement therapy by parenteral or transdermal testosterone administration can be highly beneficial in alleviating the manifestations of hypogonadism and improving quality of life. Careful screening and meticulous follow-up are mandatory. The long-term effects of testosterone replacement on the cardiovascular system, the prostate, and on longevity are unknown.

Elevated free cortisol index in pregnancy: possible regulatory mechanisms.

Biologically active plasma free cortisol increases markedly in pregnancy. In this investigation the free cortisol index (FFI) in the plasma of pregnant and nonpregnant women was measured by a charcoal adsorption technique. The circadian FFI patterns were virtually identical in the two groups, but in gravid women there was a substantial and sustained elevation of the FFI. Sequential studies during gestation and post partum revealed increasing responsiveness of the maternal adrenal glands to adrenocorticotropic hormone (ACTH) and decreasing suppressibility of the FFI by dexamethasone as pregnancy advanced. Persistence of normal circadian rhythmicity in spite of a continuously elevated FFI and resistance to dexamethasone suppression suggest control of cortisol secretion by normal regulatory mechanisms in pregnancy with resetting of the maternal feedback mechanisms to higher levels. This resetting and the lack of manifestations of cortisol excess in pregnancy might result from tissue refractoriness to cortisol. Elevated free cortisol would be needed to maintain homeostasis. The necessary increase in the production of cortisol could be facilitated by an enhanced responsiveness of the maternal adrenal glands to ACTH.

Prevalence of previously undiagnosed hypothyroidism in residents of a midwestern nursing home.

Hypothyroidism in the elderly may be associated with nonspecific symptoms. To determine the prevalence of undiagnosed hypothyroidism in residents of a skilled nursing facility, we screened 434 male and 137 female residents, aged 60 years or older, for thyroid dysfunction. Overt hypothyroidism was found in three men and two women. Subclinical hypothyroidism was diagnosed in 42 men (9.7%) and 20 women (14.6%). Tests for thyroid antibodies were positive in all patients with overt hypothyroidism and in 12 (34%) of the 35 men and 12 (67%) of the 18 women with subclinical hypothyroidism who had thyroid antibody testing. All residents with newly diagnosed overt hypothyroidism and 54 (87%) of the 62 with subclinical hypothyroidism had been under medical observation for 1 year or longer. The institutionalized elderly should be screened for hypothyroidism because this abnormality may otherwise remain undiagnosed. The detection of subclinical hypothyroidism is important, as affected individuals are at risk for further decline in thyroid function.

Desoxycorticosterone in normal pregnancy. III. Evidence of a fetal source of desoxycorticosterone.

The source of the markedly increased secretion of desoxycorticosterone (DOC) in pregnancy has not been precisely defined. Earlier studies indicated that elevated DOC does not arise from the maternal adrenal glands. The previously observed steep gradient between fetal and maternal DOC and DOC sulfate concentrations seemed to point to a fetal source. A recent study suggests that Doc may also be derived from extra-adrenal conversion of maternal progesterone. The present investigation documents a lack of synchrony between maternal diurnal plasma cortisol and DOC patterns. Not only were the previous observations of steep gradients of DOC and DOC sulfate between fetal and maternal circulations confirmed, but also the finding of extremely high urinary excretion of DOC sulfate indicated that the sulfurylated steroid passes across the placenta. A direct linear correlation was noticed between cortisol and DOC in amniotic fluid. These observations suggest that the increased DOC arises from within the fetoplacental unit but do not rule out a maternal source.

Desoxycorticosterone in normal pregnancy. I. Sequential studies of the secretory patterns of desoxycorticosterone, aldosterone, and cortisol.

Plasma concentrations of desoxycorticosterone (DOC) and aldosterone are markedly elevated in pregnancy. Although DOC secretion in nongravid women has been assumed to be dependent mainly on adrenocorticotropic hormone (ACTH), in a previous study of women in the third trimester of pregnancy it was found to be unresponsive to ACTH, dexamethasone, and variations in salt intake. In this study plasma DOC, aldosterone, and cortisol levels, as well as their responses to ACTH stimulation and overnight dexamethasone suppression, were observed sequentially in seven normal women during the course of pregnancy and at three months post partum. Plasma DOC, aldosterone, and cortisol levels rose substantially during gestation, but increments in DOC did not necessarily coincide with those of the other two. Responses of all three corticosteroids to ACTH were enhanced during the first two trimesters compared to the nongravid state; DOC became unresponsive in the third trimester, while aldosterone and cortisol rose to an even greater extent. Elevated maternal DOC was not decreased significantly by dexamethasone at any stage of pregnancy, while plasma cortisol was suppressed. Nonsuppressibility of DOC with dexamethasone and also the lack of correlation of the rise in DOC with the increase in cortisol during the course of pregnancy suggest that increased DOC secretion in pregnancy does not arise from ACTH-dependent pathways of the maternal adrenal. The loss of responsiveness of DOC to ACTH in the third trimester suggests that the maternal adrenals have undergone an alteration in their steroidogenic response to ACTH, but also may indicate that their output of DOC has reached a maximal rate.

Danazol and its principal metabolites interfere with binding of testosterone, cortisol, and thyroxin by plasma proteins.

Danazol and its three principal metabolites (2-hydroxy-methylethisterone, 2-hydroxymethyl-1,2-dehydroethisterone, and ethisterone) competitively displace cortisol and testosterone from plasma proteins. This effect is in addition to the reported inhibition of the production of testosterone-binding globulin and thyroxin-binding globulin. We saw no competitive inhibition of thyroxin binding. Concentrations of total testosterone, total cortisol, and total thyroxin were low, whereas percentages of free testosterone, free cortisol, and free thyroxin were abnormally high in women being treated with danazol. Values for testosterone, cortisol, and thyroxin in danazol-treated patients should therefore be appropriately corrected before interpretation. Protein-binding assays for testosterone or cortisol that involve testosterone- or cortisol-binding globulin may be invalid in danazol-treated subjects because of the competitive binding of danazol and its metabolites to these proteins.