Clark T. Sawin

Low Serum Thyrotropin Concentrations as a Risk Factor for Atrial Fibrillation in Older Persons

BACKGROUND Low serum thyrotropin concentrations are a sensitive indicator of hyperthyroidism but can also occur in persons who have no clinical manifestations of the disorder. We studied whether low serum thyrotropin concentrations in clinically euthyroid older persons are a risk factor for subsequent atrial fibrillation. METHODS We studied 2007 persons (814 men and 1193 women) 60 years of age or older who did not have atrial fibrillation in order to determine the frequency of this arrhythmia during a 10-year follow-up period. The subjects were classified according to their serum thyrotropin concentrations: those with low values (< or = 0.1 mU per liter; 61 subjects); those with slightly low values (> 0.1 to 0.4 mU per liter; 187 subjects); those with normal values (> 0.4 to 5.0 mU per liter; 1576 subjects); and those with high values (> 5.0 mU per liter; 183 subjects). RESULTS During the 10-year follow-up period, atrial fibrillation occurred in 13 persons with low initial values for serum thyrotropin, 23 with slightly low values, 133 with normal values, and 23 with high values. The cumulative incidence of atrial fibrillation at 10 years was 28 percent among the subjects with low serum thyrotropin values (< or = 0.1 mU per liter), as compared with 11 percent among those with normal values; the age-adjusted incidence of atrial fibrillation was 28 per 1000 person-years among those with low values and 10 per 1000 person-years among those with normal values (P = 0.005). After adjustment for other known risk factors, the relative risk of atrial fibrillation in elderly subjects with low serum thyrotropin concentrations, as compared with those with normal concentrations, was 3.1 (95 percent confidence interval, 1.7 to 5.5; P < 0.001). The 10-year incidence of atrial fibrillation in the groups with slightly low and high serum thyrotropin values was not significantly different from that in the group with normal values. CONCLUSIONS Among people 60 years of age or older, a low serum thyrotropin concentration is associated with a threefold higher risk that atrial fibrillation will develop in the subsequent decade.

Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study

Osteoporosis is not a problem confined to women; it has important medical and socioeconomic consequences for men as well (1-3). With advancing age, men lose bone mineral density (4, 5), which leads to increased risk for fracture after minimal trauma (6). It is estimated that 13% of white men older than 50 years of age will experience a fracture during their lifetime (7). Approximately 30% of all hip fractures occur in men (8), and the morbidity and mortality after such fractures are much greater in men than in women (9-11). As the aging population grows worldwide, a better understanding of risk factors that contribute to low bone mineral density in elderly men will be needed. The effect of sex hormones on bone mineral density in elderly men is of particular interest because it could have diagnostic and therapeutic implications, as it does in women (12, 13). Both androgens and estrogens have been shown to be important for bone health in young men, but their role in elderly men is not as clear (14, 15). Testosterone, the predominant circulating androgen in men, is produced mainly by Leydig cells of the testes and is regulated by luteinizing hormone (16, 17). Hypogonadism in men, whether caused by primary or secondary failure of Leydig cell function, results in low testosterone levels. Young adult men who are hypogonadal because of medical conditions or castration have low bone mineral density (18-20); testosterone replacement improves bone mineral density in these men (19, 21). Given the association between hypogonadism and bone mineral density in young men and the decrease in serum testosterone levels with increasing age (22, 23), it has been assumed that hypogonadism related to aging explains low bone mineral density in elderly men. However, evidence to support this association remains weak. Results of studies that include men of a wide age range or hypogonadal men with an identifiable medical cause (such as orchiectomy or pituitary tumors) are not generalizable to elderly men from the general population. Among studies specifically of elderly men from the general population, several failed to show an association between testosterone levels and bone mineral density (24-28). It could be that an association with bone mineral density exists only below the normal reference range for testosterone (29) and that continuous measurement of testosterone levels, as was done in most studies, missed this relation. Previous studies may have also been limited by the fact that single measurements of sex hormones obtained at the same time as bone mineral density measurement may not adequately reflect the influence of these hormones on bone metabolism. Recent evidence suggests that estrogens may also be important for bone health in young and older men (14, 27, 28, 30-36). However, the magnitude of effect of estrogen levels on bone mineral density in elderly men is not known, nor is the relative effect of testosterone and estrogens clearly defined. Only a small fraction of estradiol, the major circulating form of estrogen, is produced directly by the testes; the main source is peripheral conversion of testosterone and adrenal sex steroids by the aromatase enzyme (17, 37). Thus, some or all of the effect of low testosterone on bone mineral density in elderly men could be explained by low estradiol levels. We examined the association of testosterone and estradiol status with bone mineral density among men from the Framingham Study, a population-based cohort with a large number of elderly men who had repeated measurement of sex hormones before bone mineral density assessment. We explored the association of a threshold effect of low testosterone level on bone mineral density in these men by considering different definitions of hypogonadism based on sex hormone measures. Methods The Framingham Study began in 1948 in Framingham, Massachusetts, with the initial goal of evaluating risk factors for heart disease in a population-based cohort (38). As part of this ongoing study, participants have received comprehensive medical examinations every 2 years. The Framingham Osteoporosis Study, designed to study risk factors for osteoporosis, started in 19881989 as a component of the 20th biennial examination and involved surviving members of the cohort, most of whom were white (39). We studied the 448 men of the cohort who had bone mineral density measurements in 19881989 and sex hormones measurements during previous biennial examinations. Assessment of Sex Hormones Total testosterone, total estradiol, and luteinizing hormone were measured in all male participants at four consecutive biennial examinations from 1981 to 1989. Serum samples were measured by using radioimmunoassay for total testosterone (Diagnostic Products Corp., Los Angeles, California; interassay coefficient of variation, 11%; reference range for young adult men, 10 to 35 nmol/L [3 to 10 ng/mL]), total estradiol (Diagnostic Products Corp.; lower limit of assay detection, 2 pg/mL; interassay coefficient of variation, 4%; reference range for young adult men, 7 to 184 pmol/L [2 to 50 pg/mL]), and luteinizing hormone (Serono Laboratories, Randolph, Massachusetts, in 1981 to 1983, then Diagnostic Products Corp. for the three biennial examinations from 1983 to 1989; intraclass correlation, 0.92; interassay coefficient of variation, 6%; reference range for young adult men, 3 to 13 IU/L). Data were originally collected in traditional units, and cutoff values were defined on the basis of these units. Conversions to SI units were performed in accordance with the publication policy of Annals of Internal Medicine. Assessment of Bone Mineral Density In 19881989, bone mineral density was measured at the proximal femur (femoral neck, Ward triangle, and trochanter) and lumbar spine by using dual-photon absorptiometry (LUNAR DP3, Lunar Corp., Madison, Wisconsin) and at the radial shaft (measured at the junction of the proximal two thirds and the distal one third of the radius) by using single-photon absorptiometry (LUNAR SP2, Lunar Corp.) (39). If participants had a history of fracture or hip joint replacement, the contralateral side was scanned. Because the lumbar spine was assessed during a callback examination, the number of participants for whom this measurement was available is smaller than that for the proximal femur or radial shaft. All bone mineral density scans were reviewed to ensure that correct placement and analysis were performed according to the manufacturers recommendations. Scans for which placement was incorrect, those that did not include the complete anatomic region of interest, and those found to include metal or other attenuating material were considered technically inadequate and were deleted. The coefficients of variation in normal persons for bone mineral density at the proximal femur were 2.6% for the femoral neck, 4.1% for Ward triangle, and 2.8% for the trochanter; the coefficients of variation were 2.2% and 2.0% for the lumbar spine and radial shaft, respectively. Assessment of Other Covariates Factors previously shown to be associated with bone mineral density in men were also assessed (15, 39-46). These variables were age, body mass index, serum 25-hydroxyvitamin D level, calcium intake, physical activity, cigarette smoking, alcohol intake, thiazide diuretic use, and glucocorticoid use. Age, body mass index, serum 25-hydroxyvitamin D, calcium intake, and physical activity were determined in 19881989 at the time of the bone mineral density assessment. Serum 25-hydroxyvitamin D was measured by using a competitive binding-protein assay (47) (interassay coefficient of variation, 10%) and was categorized as low (<50 nmol/L), medium (50 to 75 nmol/L), or high (>75 nmol/L). Information on dietary calcium intake, including supplements, was collected by using the Willett 126-item food frequency questionnaire (48, 49) and was categorized as low (<500 mg/d), moderate (500 to 1000 mg/d), or high (>1000 mg/d). Physical activity was assessed by using the Framingham Physical Activity Index, a weighted 24-hour score of typical daily activity based on hours spent performing heavy, moderate, light, or sedentary activity (50, 51). Information on smoking and alcohol intake was available from previous biennial examinations. Participants were characterized as current smokers if they smoked cigarettes during 1981 to 1989, former smokers if they reported smoking before 1981 but not between 1981 and 1989, and never-smokers if they reported no cigarette use since inception of the study in 1948. Alcohol intake was defined according to the average ounces of alcohol consumed per week between 1981 and 1989. Information on thiazide diuretic use among participants was available from three consecutive examinations from 1983 to 1989, and information on glucocorticoid use was available from all four examinations from 1981 to 1989. Statistical Analysis To examine the association between sex hormone status and bone mineral density, we averaged hormone values for each participant if measurements were available from at least three of four examinations from 1981 to 1989. We excluded one participant whose serum estradiol value was considered unreliable. All analyses were performed by using SAS software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Gonadal Status and Bone Mineral Density Hypogonadism in men is the loss of testicular function, which includes primary and secondary failure of the Leydig cell function in the testes, leading to a deficiency in serum testosterone levels. Studying hypogonadal elderly men from the general population is difficult, however, because there are no standard definitions of hypogonadism, and symptoms and signs are not well correlated with hormonal status (52, 53). Therefore, to examine whether hypogonadism was associated with low bone mineral density in our population-based sample of elderly men, we created a definition based on the mean total testosterone o

Aging and the thyroid: Decreased requirement for thyroid hormone in older hypothyroid patients

In 84 patients, aged 23 to 84, with primary hypothyroidism, the daily dose of thyroxine needed to lower the serum thyrotropin level into the normal range was significantly less in older patients than in younger ones (p less than 0.01). Most of the difference between middle-aged (40 to 60 years) and older patients (greater than 60 years) was due to a decrease in the required dose in men; there was no difference in the dose needed by women in these age groups. Previous hyperthyroidism did not affect the dose of thyroxine required; it is unlikely that residual autonomous thyroid tissue affected the dose. Although the wide range of doses needed precludes use of these data in calculating a dose of thyroxine for an individual patient, doses of 100 micrograms per day or less were common in patients over age 40, and a few patients over age 60 needed 50 micrograms per day or less. Thus, (1) there is a sound physiologic basis for the common practice of using low doses of thyroxine, e.g., 25 micrograms per day, as initial therapy in older hypothyroid patients and (2) it may be reasonable to reassess the dose of thyroxine after several years in older patients.

The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM).

To determine whether a difference in HbA(1c) could be safely sustained between a standard therapy (STD) arm and an intensive therapy (INT) arm, while maintaining HbA(1c) levels in both arms within a range acceptable in community practice. The effects of intensive treatment on various parameters were studied in this feasibility trial. We report here the results of 24 months of INT on peripheral and autonomic neuropathy.A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: (1) an evening insulin injection, (2) the same injection adding daytime glipizide, (3) two injections of insulin alone, and (4) multiple daily injections. Peripheral neuropathy was diagnosed clinically by a history and physical examination, and by abnormal autonomic neuropathy Valsalva ratio (VR < 1.2) and RR variation (RRV < 10). An average HbA(1c) separation of 2.07% was achieved with INT, having HbA(1c) at or below 7.3% (p = 0. 001 versus STD). Baseline prevalence of peripheral neuropathy was 53% in STD, and 48% in INT. By 24 months, the prevalence increased to 69% in STD (p = 0.005 versus baseline), and to 64% in INT (p = 0. 008 versus baseline, but no different than STD). Though INT did not reverse all elements of peripheral neuropathy, there was a decreased prevalence of cranial neuropathy (p = 0.053 versus STD) and more frequent preservation of touch sensation in the upper extremities (p = 0.03 versus STD) in INT. At baseline, an abnormal Valsalva ratio and/or RR variation was seen in 38% of STD and 31% of INT. By 24 months in STD, the prevalence rose to 55% (p = 0.0067 versus baseline), and in INT, to 48% (p = 0.012 versus baseline and no different from STD). The prevalence of erectile dysfunction increased from 53% at baseline to 73% at 2 years, p = 0.002 in STD, and from 51% to 73% at 2 years (p = 0.003 versus baseline) and no different from STD. There was no change in the frequency of abnormal gastrointestinal or sweating symptoms. Our conclusion was that 2 years of meticulous glycemic control did not decrease overall prevalence of peripheral or autonomic neuropathy. In fact, the prevalence rose equivalently and significantly in both treatment arms. There was some benefit, however, in decreased frequency of cranial neuropathy and better preservation of touch sensation in INT.

Serum Thyrotropin and Thyroid Hormone Levels in Elderly and Middle‐Aged Euthyroid Persons

Objective: To determine whether serum thyrotropin (TSH) levels are altered in euthyroid older persons compared with middle‐aged adults.

The aging thyroid. Relationship between elevated serum thyrotropin level and thyroid antibodies in elderly patients

The relationship of thyroid antibodies and the serum level of thyrotropin in older adults (over age 60) was studied to determine whether thyroid antibodies were a good clue to thyroid failure in elderly persons. Of those with thyroid failure, evidenced by clearly elevated serum thyrotropin values (more than 10 microU/ml), 67 percent had positive antimicrosomal antibody levels, a prevalence much greater (p less than 0.001) than that among those of comparable age with normal thyroid function (18 percent). Nevertheless, one third (33 percent) had thyroid failure without positive antimicrosomal antibody levels; this was true whether or not a low serum thyroxine value was present. Furthermore, of those with positive antimicrosomal antibody levels, most (68 percent) did not have thyroid failure. Thus, although positive antimicrosomal antibody levels occurred more often in elderly patients with thyroid failure than in those with normal thyroid function, a sizable fraction of those with thyroid failure did not have positive antimicrosomal antibody levels. Hence, measurement of thyroid antimicrosomal antibodies is not a good test of early thyroid failure in older patients; direct demonstration of a clearly elevated serum thyrotropin value is a better approach.

Prevalence of thyroid disease and abnormal thyroid tests in older hospitalized and ambulatory persons.

To determine the utility of laboratory tests for diagnosing thyroid disease in the hospitalized elderly, we measured serum thyroid‐stimulating hormone (TSH), thyroxine (T4), free thyroxine index (FT4I), triiodothyronine (T3), and free triiodothyronine index (FT3I) in 125 geriatric inpatients, mostly men, and compared the results to those in elderly ambulatory patients. Hypothyroidism (TSH > 10 μU/mL with a low T4 and FT4I or clinical findings) was present in 7.8% (nine of 116) of male inpatients compared to only 0.7% of male ambulatory controls (P < 0.01). Only a few women were studied but 17% (two of 12) were hypothyroid compared to 2.4% of ambulatory elderly women. Three of the hypothyroid inpatients had no clinical clue to their hypothyroidism. Further, decreased thyroid reserve or subclinical hypothyroidism (TSH > 10 μU/mL with a normal T4 and FT4I and no overt clinical findings), a condition which may lead to overt hypothyroidism, was more common in male inpatients (4.3%) than in male ambulatory controls (1.8% [P < 0.01]). Thus, a clearly elevated serum TSH (> 10 μU/mL) was more common in inpatient (12.1%) than in ambulatory (2.4%) elderly men (P < 0.01).

Response to Intensive Therapy Steps and to Glipizide Dose in Combination With Insulin in Type 2 Diabetes: VA feasibility study on glycemic control and complications (VA CSDM)

OBJECTIVE The feasibility study for the VA Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (VA CSDM) prospectively studied 153 insulin-requiring type 2 diabetes patients, randomized between an intensively treated arm and a standard treatment arm during a mean follow-up of 27 months. The glycemic response to each of the progressive, sequential phases of insulin treatment was assessed, along with the incidence of hypoglycemic reactions and the relative efficacy of different doses of glipizide in combination with fixed doses of insulin. RESEARCH DESIGN AND METHODS Five medical centers participated; half of the patients were assigned to the intensive treatment arm aiming for normal HbA1c levels. Age of patients was 60 ± 6 years, duration of diabetes 8 ± 3 years, and BMI 30.7 ± 4 kg/m2. A fourstep management technique was used, with patients moving to the next step if the operational goals were not met: Phase I, evening intermediate or long-acting insulin; phase II, added daytime glipizide; phase III, two injections of insulin alone; and phase IV multiple daily insulin injections. Home glucose monitoring measurements were done twice daily and at 3:00 A.M. once a week. Hypoglycemic reactions and home glucose monitoring results were recorded and counted in each of the treatment phases. RESULTS Baseline HbA1c was 9.3 ± 1.8%, and fasting plus serum glucose was 11.4 ± 3.3 mmol/1. Fasting serum glucose fell to near normal in phase I, and remained so in the other treatment phases. An HbA1c separation of 2.1% between the arms was maintained during the course of the study, while the intensive arm kept HbA1c levels below 7.3% (P = 0.001). Most of the decrease in HbA1c occurred with one injection of insulin alone (phase I, − 1.4%) or adding daytime glipizide (phase II, −1.9% compared with baseline). HbA1c did not decrease further after substituting two injections of insulin alone, with twice the insulin dose. Multiple daily injections resulted in an additional HbA1c fall (−2.4% compared with baseline). However, two-thirds of the patients were still on one or two injections a day at the end of the study Changes in home glucose monitoring levels paralleled those of the HbA1c, as did the increments in number of reported hypoglycemic reactions, virtually all either “mild” or “moderate” in character. For the combination of glipizide and insulin (phase II), the only significant effect was obtained with daily doses up to 10 mg a day; there were no significant additional benefits with up to fourfold higher daily doses, and HbA1c levels had an upward trend with doses >20 mg/day. CONCLUSIONS A simple regime of a single injection of insulin, alone or with glipizide, seemed sufficient to obtain clinically acceptable levels of HbA1c for most obese, insulin-requiring type 2 diabetes patients. Further decrease of HbA1c demanded multiple daily injections at the expense of doubling the insulin dose and the rate of hypoglycemic events. In combination therapy, doses of glipizide >20 mg/day offered no additional benefit.

Transient Gynecomastia in Chronic Renal Failure During Chronic Intermittent Hemodialysis

Abstract Transient gynecomastia was observed in six of seven patients with chronic renal failure that was being treated with chronic intermittent hemodialysis. All seven had tenderness of the breas...

Hypothyroidism After Low-Dose 131I Treatment of Hyperthyroidism

Abstract Sixty-four patients with hyperthyroidism were treated with a single dose of 3 mCi or less of131I before 1951. Nine were lost to follow-up shortly after treatment. The other 55 were found, ...