Deafness in Australian Cattle Dogs associated to QTL on chromosome 20 in genome-wide association study analyses.

Pigment-associated deafness is a common hereditary condition in a range of dog breeds. The aim of this study was to perform a genome-wide association analysis to investigate the genetic architecture of deafness in Australian Cattle Dogs. Genotypes for 104 757 polymorphisms in 216 dogs were available for analyses after quality control. A genomic relationship matrix was used in the mixed model analyses to account for polygenic effects, as we tested each polymorphism for its association with deafness, in a case/control experimental design. Three approaches were used to code the genotypes and test for additive, recessive and dominant SNP effects. The genome-wide association study analyses identified a clear association peak on CFA20, with the most significant SNPs on this chromosome (1.29 × 10-4 ) in the vicinity of MITF. Variants in MITF have been associated with white pigmentation in dogs and with deafness in humans and other species, supporting the premise that canine deafness is associated with variants in or near this gene. A recessive inheritance for the peak in CFA20 is possible given the significant results in the recessive model; however, the estimated heritability was low (4.54 × 10-5 ). Further validation, identification of variants and testing in other dog breeds are needed.

Vitamin D insufficiency prior to bariatric surgery: risk factors and a pilot treatment study.

OBJECTIVE: To assess vitamin D status and the influences of race, sun exposure and dietary vitamin D intake on vitamin D levels, and to evaluate two vitamin D repletion regimens in extremely obese patients awaiting bariatric surgery. METHODS: A cross-sectional analysis of dietary vitamin D, sun exposure, PTH [intact (iPTH) and PTH(1-84)] and 25-hydroxyvitamin D (25OHD; differentiated 25OHD2 and 25OHD3) in 56 obese [body mass index (BMI) > 35 kg/m(2)] men and women (age 20-64 years). In a pilot clinical trial, 27 subjects with 25OHD levels < 62 nmol/l were randomized to receive ergocalciferol or cholecalciferol for 8 weeks. RESULTS: Serum 25OHD was low (mean 45 +/- 22 nmol/l) and was inversely associated with BMI (r = -0.36, P < 0.01). Each BMI increase of 1 kg/m(2) was associated with a 1.3 nmol/l decrease in 25OHD (P < 0.01). BMI, sun exposure, African American race and PTH predicted 40% of the variance in 25OHD (P < 0.0001). Serum 25OHD significantly increased at 4 and 8 weeks in both treatment groups (P < 0.001), whereas PTH(1-84) declined significantly in subjects treated with cholecalciferol (P < 0.007) and tended to decrease following ergocalciferol (P < 0.09). CONCLUSIONS: In severely obese individuals, those who are African American, have higher BMI and limited sunlight exposure are at greatest risk for vitamin D insufficiency. These demographic factors can help to identify at-risk patients who require vitamin D repletion prior to bariatric surgery. Commonly prescribed doses of ergocalciferol and cholecalciferol are effective in raising 25OHD. Further investigation is needed to evaluate whether these regimens have differential effects on PTH, and to determine the optimal regimen for vitamin D repletion in the extremely obese patient.

Prevalence of deafness in dogs heterozygous or homozygous for the merle allele.

BACKGROUND: Deafness in dogs is frequently associated with the pigment genes piebald and merle. Little is known about the prevalence of deafness in dogs carrying the merle allele. OBJECTIVE: To determine the prevalence of deafness in dogs heterozygous and homozygous for the merle allele of the mouse Silver pigment locus homolog (SILV) gene. ANIMALS: One hundred and fifty-three privately owned merle dogs of different breeds and both sexes. METHODS: Hearing was tested by brainstem auditory-evoked response and classified as bilaterally hearing, unilaterally deaf, or bilaterally deaf. DNA from buccal cells was genotyped as either heterozygous or homozygous for the merle allele. Deafness association tests among merle genotype, eye color, and sex were performed by the chi(2) test. RESULTS: Deafness prevalence in merles overall was 4.6% unilaterally deaf and 4.6% bilaterally deaf. There was a significant association between hearing status and heterozygous versus homozygous merle genotype. For single merles (Mm), 2.7% were unilaterally deaf and 0.9% were bilaterally deaf. For double merles (MM), 10% were unilaterally deaf and 15% were bilaterally deaf. There was no significant association with eye color or sex. CONCLUSIONS: Deafness prevalence in merle dogs was greater than that in some dog breeds homozygous for the piebald gene, such as the English Cocker Spaniel, but comparable to, or lower than, that in the Dalmatian and white Bull Terrier. Dogs homozygous for the merle allele were significantly more likely to be deaf than heterozygotes.

A comparison of techniques to sample salamander assemblages along highland streams of Maryland.

Amphibians may be useful indicators of biological condition in small streams so determining which sampling technique maximizes encounters at the least cost and at the optimal time of year is important. Area constrained surveys (ACS), used by the Maryland Biological Stream Survey, were tested against cover board surveys, drift fences with pitfall and funnel traps, quadrat leaf litter searches, and leaf litter bags. Sixteen, 100 m-long sites were established in headwater streams in the Savage River State Forest in Garrett County, Maryland. Each technique was randomly assigned to a 25 m stream section within each overall sampling site, and sites were sampled once each month from May to October (2005) with additional sampling in March and April (2006). Area constrained surveys yielded means of 2.7 taxa and 14.9 total individuals per sampling visit, which was significantly higher than the yield of all other methods in all months except October and March, when yields were low for all techniques. Area constrained surveys were also significantly more cost-effective per taxon and per individual compared to all other methods. September produced the most taxa and individuals, October and March produced the least, and yields for April through August were similar to September. We employed removal sampling at four sites in April 2006, but abundance could not be estimated because a significant linear decrease in the accumulated catch versus catch per unit effort did not occur for three of the sites.

Abnormal 24-hr mean plasma concentrations of dehydroisoandrosterone and dehydroisoandrosterone sulfate in women with primary operable breast cancer.

The 24-hr mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate were measured in 11 women with primary operable breast cancer, ages 31 to 78 years, and in 37 normal women, ages 21 to 75 years. In contrast to the marked and progressive decline of DHA and dehydroisoandrosterone sulfate concentration with age in the normal women, the concentrations of both steroids were age invariant in the cancer patients. The premenopausal patients had subnormal plasma DHA and dehydroisoandrosterone sulfate levels, while the post menopausal patients had supranormal levels. Since the plasma DHA/androsterone ratio was normal in the premenopausal patients and significantly elevated in the postmenopausal patients, it is postulated that the subnormal plasma adrenal androgen levels in the premenopausal patients were due principally to diminished production of these steroids, while the elevated plasma levels in the postmenopausal patients were due principally to slowed metabolic removal. Reports in the literature that DHA inhibits the development of breast cancer in mice suggest that the subnormal plasma DHA levels in premenopausal breast cancer may have clinical significance.

Distortion product otoacoustic emissions in geriatric dogs.

Recordings of distortion product otoacoustic emissions (DPOAE) were taken from 28 geriatric dogs aged 12.2 ± 2.2 years and 15 control dogs aged 5.9 ± 3.0 years (mean ± standard deviation) to demonstrate frequency-specific changes in cochlear responses. Recordings were performed for primary frequencies of 2-12 kHz in 2 kHz increments. Brainstem auditory evoked response (BAER) recordings were also made from geriatric dogs for comparison with DPOAE responses. Significant decreases in DPOAE response amplitudes were observed at frequencies of 6-12 kHz in geriatric dogs compared to control dogs, reflecting loss of cochlear outer hair cells along the length of the cochlea. Significant decreases in response amplitudes were not seen at frequencies of 2 or 4 kHz. Decreases in BAER response amplitudes subjectively paralleled the depressed DPOAE amplitudes. No significant linear regression relationships were found for DPOAE response amplitude vs. age despite the progressive nature of age-related hearing loss. The reductions in response at all frequencies starting at the age where dogs are considered geriatric indicate that age-related hearing loss begins earlier in the life span. DPOAE recordings provide a means to assess cochlear function across different portions of the auditory spectrum for assessing hearing loss associated with aging, and potentially for losses from other causes of decreased auditory function.

Heritability and segregation analysis of deafness in U.S. Dalmatians.

Hereditary loss of hearing affects many breeds of the domestic dog, but the Dalmatian has the highest prevalence. Approximately 30% are affected in the United States (U.S.) population. It is widely accepted that a relationship exists between deafness and pigmentation in the dog and also in other animals. While the Dalmatian exemplifies this relationship, the genetic origin and mode of inheritance of deafness in this breed are unknown. The goals of this study were to: (1) estimate the heritability of deafness in an extended kindred of U.S. Dalmatians and (2) determine, through complex segregation analysis, whether there is a major segregating locus that has a large effect on the expression of deafness. A kindred of 266 Dalmatians was assembled, of which 199 had been diagnosed using the brainstem auditory evoked response to determine auditory status. Of these, 74.4% (N = 148) had normal hearing, 18.1% (N = 36) were unilaterally deaf, and 7.5% (N = 15) were bilaterally deaf. A heritability of 0.73 was estimated considering deafness a dichotomous trait and 0.75 considering it as a trichotomous trait. Although deafness in the Dalmatian is clearly heritable, the evidence for the presence of a single major gene affecting the disorder is not persuasive.

Cognitive dysfunction predicts poorer emotion recognition in bariatric surgery candidates.

OBJECTIVE: Deficits in traditional cognitive domains (e.g. executive function and memory) are common in persons with severe obesity, but it is unclear if this pattern of dysfunction extends to social cognition. The present study examined whether cognitive impairment was associated with poorer emotion recognition in bariatric surgery candidates. METHODS: One hundred sixteen bariatric surgery candidates (mean age = 43.62 ± 11.03; 81% female) completed the computerized Integneuro test battery as part of a larger study visit. In addition to assessing traditional cognitive domains, the Integneuro also includes an emotion recognition measure. This task presents 48 faces (eight different individuals depicting neutral, happiness, fear, sadness, anger and disgust), and participants must choose the correct verbal label from six expression options. Number of correct responses and average reaction time for correct responses served as primary dependent variables. RESULTS: Stepwise multiple regression analyses revealed that older age, more maze errors, and history of hypertension predicted less accuracy in emotion recognition (adjusted R2 = .22, F[3, 111] = 11.86, p < .001) and that slower switching of attention-digits, worse long-delay recall, and older age predicted speed of responses (adjusted R2 = .26, F[3, 111] = 13.00, p < .001). DISCUSSION: Results show that cognitive dysfunction is associated with poorer performance on a computerized test of emotion recognition, consistent with those in persons with a range of psychiatric and neurological disorders. Additional work is needed to clarify the mechanisms and functional impact of these impairments, especially in relation to weight loss following bariatric surgery.

The relationship between serum levels of insulin and sex hormone-binding globulin in men: the effect of weight loss.

It is known that there is an inverse relationship between the serum levels of insulin and sex hormone-binding globulin (SHBG) in women, but the relationship in men has not been reported. It is not known whether changes in the one cause changes in the other, or whether they change in opposite directions in response to some third factor. Because obesity raises insulin levels and lowers SHBG levels in both sexes, we proposed to study the cause-effect question by determining whether the relationship between changes in SHBG and insulin levels during active weight loss. We studied 70 healthy weight-stable men with body mass index (BMI) from 20.7-94 (normal, 22.5 +/- 2.5) and restudied 17 of them during diet-induced weight loss. Fasting serum insulin levels in the weight-stable men showed a positive linear correlation with BMI, increasing 1 microU/mL per unit increase in BMI (P < 0.0001). SHBG levels in the weight-stable men showed a negative linear correlation with BMI, decreasing 0.2 nmol/L per unit increase in BMI (P < 0.0002). In the weight-stable men, there was an inverse hyperbolic correlation between SHBG and insulin levels; SHBG (nmol/L) = 13.1 + [30.1 divided by insulin (microU/mL)] (P < 0.002). During weight loss, insulin levels decreased at an average rate of 6.1 microU/mL per unit decrease in BMI, a much higher slope than the positive slope vs. BMI in weight stable men. During weight loss, SHBG levels increased at an average slope of 0.43 nmol/L per unit decrease in BMI, much higher than the negative slope of 0.2 nmol/L per unit increase in BMI in weight-stable men. Values for the SHBG vs. insulin coordinates in the weight-losing subjects did not differ significantly from those expected from the SHBG vs. insulin equation in weight-stable subjects. The stability of the SHBG-insulin relationship during weight loss despite the profoundly altered relationship of each separate component to BMI strongly suggests a close metabolic link between SHBG and insulin. As SHBG is not known to alter the production or metabolism of insulin, whereas insulin has been shown in vitro to decrease the synthesis of SHBG, it seems a reasonable conclusion that the predictable inverse relationship between serum insulin and SHBG indicates that insulin controls SHBG synthesis in vivo.

Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women.

The 24-h mean plasma concentration of total testosterone (T) was measured in 33 healthy, regularly cycling, nonobese women between 21 and 51 yr of age. Percent free T was measured in 17 of them. Plasma dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were measured in 24 of them, and the DHEA-to-T and DHEAS-to-T ratios were calculated. It was found that the concentration of total T showed a steep decline with age; the regression equation was: T (nanomoles per L) = 37.8 x age-1.12 (r = -0.54; P < 0.003). According to this equation, the expected T concentration of a woman of 40 would be 0.61 nmol/L, about half that of a woman of 21 (1.3 nmol/L). The percent free T did not vary significantly with age, so free T concentration likewise showed a steep decline with age. The DHEA-to-T and DHEAS-to-T ratios were both age invariant, clearly because the levels of DHEA and DHEAS also decline steeply with age, as previously reported.

Sex differences in the twenty-four-hour mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate (DHAS) and the DHA to DHAS ratio in normal adults.

The 24-h mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate (DHAS) and the DHA to DHAS ratio were determined in 37 normal women, aged 21-75 yr, and 32 normal men, aged 21-72 yr. As predicted from our study of sex differences in the metabolism of DHAS, women showed a markely higher DHA to DHAS ratio than men at all ages; the geometric mean for women was 7.5 x 10(-3) and that for men was 3.9 x 10(-3) (P less than 0.0001); and the mean for premenopausal women (6.7 x 10(-3) did not differ significantly from that for postmenopausal women (8.6 x 10(-3)). The two steroids showed a clear-cut linear inverse correlation between concentration and age in both sexes, and menopause was "nonevent" in the age progression for both steroids in the women. The slopes of the concentration vs. age curves were considerably greater in the women, as a reuslt of which the sex differences in concentrations of these steroids changed with age. Under age 50 yr, the plasma DHA concentration of women was considerably higher than that of men [462 +/- 187 (mean +/- SD) vs. 336 +/- 103; P less than 0.025], while the concentrations of DHAS showed no significant sex difference ((77 +/- 38 vs. 101 +/- 67; P greater than 0.1). In persons 50 yr of age or over, plasma DHA concentrations were about the same in women and men (238 +/- 119 vs. 287 +/- 121; P greater than 0.1), but plasma DHAS concentrations were very much lower in women (31 +/- 21 vs. 83 +/- 49; P less than 0.0001).

Effects of obesity on estradiol metabolism: decreased formation of nonuterotropic metabolites.

Obesity is associated with an increased incidence of reproductive dysfunction and estrogen-linked diseases. In the present study, we have examined the principal oxidative biotransformations of estradiol in 13 obese premenopausal females and 10 obese males compared to those in 9 premenopausal female and 15 male controls. These studies were carried out using a recently devised, sensitive radiometric method which permits the assessment of the total in vivo oxidative metabolism of estradiol at specific sites (i.e. 17 alpha, 16 alpha, or C-2) on the steroid molecule. Our results indicate that obesity (greater than 60% above ideal body weight) is associated with significant decreases in hydroxylation at C-2 in both sexes (P less than 0.001 for females and P less than 0.02 for males) and in oxidation at 17 alpha in premenopausal females (P less than 0.05) compared to that in age-matched, normal weight controls. Analysis of the plasma 3H2O specific activity curves suggested a slight decrease in the rate of 17-oxidation in obese subjects. The extent of hydroxylation at 16 alpha was not significantly affected by obesity. These metabolic alterations documented in obesity could result in a relative hyperestrogenic state, since, unlike the other estrogen metabolites, the 2-hydroxyestrogen compounds display relatively little peripheral estrogenic activity. This metabolic alteration on a prolonged basis might be contributory to the prevalence of certain hormonally related diseases in obese individuals.

Subnormal plasma adrenal androgen levels in men with uremia.

The 24-h mean plasma concentrations of 8 hormones were measured in 11 men with chronic uremia and 32 normal men. Our findings confirm previous reports of subnormal levels of testosterone, T3, and T4 and elevated levels of LH, PRL, and cortisol. In addition, we observed a new finding: markedly subnormal levels of the adrenal androgens dehydroisoandrosterone (DHA) and DHA sulfate. The mean DHA level in the patients was 164 +/- 46 (SD) ng/dl, compared with 320 +/- 124 in age-matched controls (P < 0.0001); the geometric mean DHA sulfate level was 40 micrograms/dl (95% confidence limits, 11-113) in the patients and 76 micrograms/dl (95% confidence limits, 26-214) in age-matched controls (P = 0.005). The depression of adrenal androgen levels in the face of elevated cortisol levels suggests a biosynthetic block in the adrenal cortex at the step where the C-19 and C-21 pathways diverge, namely the removal of the 2-carbon side chain by C-17, 20-lyase. If a similar defect were present in the testes, it could account for the diminished synthesis of testosterone, which is a further metabolite of DHA in the testes.

Plasma free and non-sex-hormone-binding-globulin-bound testosterone are decreased in obese men in proportion to their degree of obesity.

It is known that plasma total testosterone (T) is decreased in obese men in proportion to the degree of obesity, but similar information is not available for plasma free T and non-sex-hormone-binding globulin (SHBG)-bound T. We measured the 24-h mean plasma total T in 48 healthy (non-weight-stable men, aged 18-55 yr, with body mass indexes (BMI) ranging from 21-95 kg/m2. Free T and non-SHBG-bound T were calculated using the measured total T, the concentrations of albumin and SHBG, and the association constants of T to albumin and SHBG. Total body fat content was measured by deuterium-water isotope dilution. Findings were as follows. 1) BMI was very highly correlated with total body fat content (r = 0.96; P less than 0.001); thus, the degree of obesity can be calculated just as appropriately from simple height and weight measurements as from measurements of total body fat content. 2) Total, non-SHBG-bound, and free T were all highly correlated inversely with BMI; for total T, r = -0.727, P less than 0.01; for non-SHBG-bound T, r = 0.677, P less than 0.01; and for free T, r = -0.653, P less than 0.01. Thus, free T and non-SHBG-bound T are decreased in obese men in proportion to the degree of obesity, just as is the case for total T; percentage-wise, the decrease was the same for all 3 parameters.

Effect of massive weight loss on hypothalamic-pituitary-gonadal function in obese men.

To study the ability of weight loss to reverse the hyperestrogenemia-induced hypogonadotropic hypogonadism that occurs in obese men, we measured the 24-h mean plasma free and total estradiol (E2), total estrone, FSH, LH, and free and total testosterone concentrations in 11 healthy obese men (100-305% above desirable body weight) and again 5-39 months later after weight loss of 26-129 kg and restabilization at the new weight. Weight loss produced significant increases in mean plasma total testosterone [240 +/- 116 (+/- SD, 8.5 +/- 4.0) to 377 +/- 113 ng/dL (13.0 +/- 4.0 nmol/L); P less than 0.01], free testosterone [9.5 +/- 5.0 (329 +/- 173) to 13.4 +/- 4.3 ng/dL (464 +/- 149 pmol/L); P less than 0.025], and FSH (6.5 +/- 4.7 to 10.9 +/- 8.5 IU/L; P less than 0.025). Plasma LH was lower than levels in normal men before and after weight loss and did not change significantly (10.3 +/- 4.8 and 10.8 +/- 6.8 IU/L, respectively). There was no change in plasma total E2 [54 +/- 26 (196 +/- 94) to 50 +/- 13 pg/mL (180 +/- 50 pmol/L)], free E2 [1.48 +/- 0.7 (5.37 +/- 2.54) to 1.33 +/- 0.42 pg/mL (4.83 +/- 1.45 pmol/L)], or total estrone [75 +/- 38 (280 +/- 140) to 82 +/- 24 (300 +/- 90) pmol/L], and sex hormone-binding globulin rose from 9.2 +/- 3.2 to 12.9 +/- 5.4 nmol/L (P less than 0.005). The increases in plasma free and total testosterone and sex hormone-binding globulin were proportional to the degree of weight loss. Thus, the hypogonadotropic hypogonadism was largely reversed by the weight loss without any decrease in hyperestrogenemia, its presumed cause. We postulate a change in hypothalamic-pituitary function with weight loss, such that GnRH-gonadotropin secretion becomes less sensitive to suppression by a given amount of estrogen.

Age variation of the 24-hour mean plasma concentrations of androgens, estrogens, and gonadotropins in normal adult men.

The 24-h mean plasma concentrations of androgens (dihydrotestosterone and total and free testosterone), estrogens (estrone and estradiol), and gonadotropins (LH and FSH) were measured in 35 healthy men, aged 21-85 yr, who were rigorously screened to exclude factors known or suspected to alter endocrine function. The plasma total testosterone concentration showed a slow continuous decline with age, decreasing about 35% between 21 and 85 yr of age; the free testosterone level was closely correlated with that of total testosterone over the entire observed concentration range. The concentrations of dihydrotestosterone, estrone, estradiol, and LH were age invariant. The concentration of FSH showed a continuous linear increase with age; the level at age 85 was about 2.5 times the level at age 21. The following conclusions were drawn. 1) Testosterone secretion appears to decline slowly and continuously throughout adult life in men. 2) Measurement of the plasma free testosterone level adds no independent information in healthy men, since its level is closely correlated with that of total testosterone at all concentrations. 3) The continuous rise with age in FSH concentration while LH is age invariant cannot be explained by changes in testosterone or estrogen production, but might be due to a decline of inhibin production with age.

Inhibition of synaptosomal uptake of amino acid transmitters by diamines.

Reports of the inhibitory effects of diaminocarboxylic acids on the uptake of amino acid transmitters led the present authors to examine the effects of simple aliphatic diamines on the synaptosomal uptake of glutamate, aspartate, GABA and glycine. The diamines studied were the series from ethylenediamine through to 1,7-diaminoheptane; DL-2,4-diaminobutyric acid (DABA) was also tested for comparative purposes. The greatest inhibition seen was on the uptake of glycine and GABA. Weaker effects on uptake were seen with glutamate, while aspartate was unaffected. The patterns of inhibition for glycine and GABA were similar and the effects were dose-dependent. 1,2-Diaminopropane was the most inhibitory, followed by ethylenediamine and 1,7-diaminoheptane. The reported inhibitory effects of DL-2,4-diaminobutyric acid on the uptake of GABA and glutamate were confirmed; comparable inhibition of the uptake of glycine and aspartate was seen but the effects on GABA were most potent. Inhibition of the uptake of GABA by 1,2-diaminopropane was approximately one fifteenth that reported for DL-2,4-diaminobutyric acid. The inhibition by diamine of the uptake of glycine and GABA can provide an explanation of the depressant effects of diamines, seen after ventricular administration; however, the excitotoxic effects of the diamines 1,3-diaminopropane through to 1,7-diaminoheptane could not be explained by the present results.

N-CAM promotes recovery in injured nerves.

The neural cell adhesion molecule, N-CAM, makes critical contributions to the development of the nervous system. It mediates the stability of homophilic adhesion in embryonic neurons and participates in morphologic differentiation. The goal of these studies was to determine N-CAM contributions to nerve regeneration and recovery of function in two species with an excised segment of sciatic nerve. N-CAM was isolated from embryonic brains, affinity purified and admixed in collagen gel for administration. Recovery was compared 30 days after surgery for two types of N-CAM delivery: entubulization versus direct application. For control nerves, tubes contained gel only. In preliminary chicken studies, latency of nerve responses was measured to demonstrate N-CAM's ability to improve upon spontaneous recovery. In subsequent studies of rodent nerves, the direct application of N-CAM significantly improved recovery in evoked nerve response amplitude, number of regenerated axons and behavioral activity. Results demonstrate N-CAM's ability to augment nerve regeneration and suggest a potential for therapeutic use.

Sex difference in the influence of obesity on the retention of a tracer of 3H-estradiol.

The influence of obesity on the retention of a tracer of 3H-estradiol was studied in 15 nonobese premenopausal women, 15 obese premenopausal women (49%-274% above desirable weight), and 27 young men ranging in weight from 5% below to 330% above a desirable weight. The women showed a clear-cut inverse linear correlation between the 72 hr excretion of radioactivity and the percent deviation from desirable weight over the entire weight range examined (y equals 66 minus 0.10x, r equals -0.59, P less than 0.005); the average excretion in the 6 most obese women (145%-272% above desirable weight) was 45 plus or minus 11 (SD)%, significantly lower than the values of 65 plus or minus 12% in 15 nonobese women (P less than 0.025). The obese men showed no correlation whatever between excretion of radioactivity and relative body weight; the average excretion of the 6 most obese men was 55 plus or minus 7, not significantly different from the value of 56 plus or minus 12 in nonobese men. This sex difference makes untenable the hypothesis previously proposed by others that retention of estradiol tracers is obese women (men were not studied ) is due to simple solubility of estrogens in fat. Various alternative possibilities to explain the present data are discussed and it is concluded that a possibility worth examining is that the adipose tissue of women contains specific estrogen binding protein (? receptor) while the adipose tissue of men does not.

Cortisol production in obesity.

Absolute cortisol production was estimated from the urinary excretion of tetrahydro metabolites of cortisol in 74 healthy women varying in weight from 12% below to 218% above desirable weight, and in 37 healthy men varying in weight from 3% below to 139% above desirable weight, and was measured by isotope dilution (after 14C tracers) in 26 of the women and 23 of the men. The relationship of both parameters to urinary creatinine excretion (as a measure of lean body mass) and to percent deviation from desirable weight (relative weight) was determined. Both absolute cortisol production and urinary creatinine excretion showed a significant positive linear correlation with relative weight in the men and women, but cortisol production/g urinary creatinine excretion (by isotope dilution or by tetrahydro metabolite excretion) was weight-invariant in both sexes. The geometric mean of cortisol production/g creatinine was 12.9 mg/g in men and 14.5 mg/g in women; the difference was not statistically significant. The geometric mean of tetrahydro metabolite excretion/g creatinine was 3.7 mg/g in men and 3.8 mg/g in women; the difference was not statistically significant. The average ratio of cortisol production to tetrahydro metabolite excretion was 3.5 in men and 3.8 in women, values not significantly different from one another and closely confirming our previously reported value of 3.6, based on the conversion of cortisol tracers to radioactive urinary tetrahydro metabolites. It is concluded that there is no functionally significant elevation of cortisol production in obese men or women: the increase in absolute production is solely a consequence of greater lean body mass, and the production/U lean body mass is weight-invariant. It appears desirable to make any comparisons of one group of patients with another in terms of cortisol production/g urinary creatinine in order to eliminate body size and obesity as confounding factors, so that disease-related differences may emerge clearly.