P. Reed Larsen | Harvard Medical School (original) (raw)

Papers by P. Reed Larsen

JAMA: The Journal of the American Medical Association, 1980

... References 1. Gerstner HB, Huff JE: Clinical toxicology of mercury. J Toxicol Environ Health ... more ... References 1. Gerstner HB, Huff JE: Clinical toxicology of mercury. J Toxicol Environ Health 2:491-526, 1977. ... JAMA 222:88-89, 1972. Hormonal Content of Thyroid Replacement Preparations Robert W. Rees-Jones, MD; Arturo R. Rolla, MD; P. Reed Larsen, MD ...

American Journal of Physiology-Endocrinology and Metabolism, 1980

Sixteen-week-old control and obese rats survive longer than 8-wk-old control rats. In addition, u... more Sixteen-week-old control and obese rats survive longer than 8-wk-old control rats. In addition, unlike the 8-wk-old group, they conserve tissue RNA and protein. To evaluate the basis for this, the effects of starvation on circulating fuels and hormones and the urinary excretion of nitrogen and 3-methylhistidine (3MH) were compared in the three groups. Urinary nitrogen and 3MH diminished during prolonged starvation in 16-wk-old obese and control rats, suggesting that both groups are able to conserve protein and curtail muscle proteolysis. In contrast, urine nitrogen and 3MH did not decrease in 8-wk-old control rats. Protein conservation in the older rats was associated with diminished blood levels of alanine and increased levels of lipid fuels, ketone bodies, and free fatty acids. Although ketone bodies and free fatty acids were also increased during the first few days of starvation in 8-wk-old rats, there was no evidence of protein sparing. In all groups, as fat stores became exhaus...

Obstetrical and Gynecological Survey, 2001

Background-An association between maternal subclinical hypothyroidism and low intelligence quotie... more Background-An association between maternal subclinical hypothyroidism and low intelligence quotient (IQ) in the oVspring has recently been shown. Objective-To provide evidence for the causality of the association by testing the hypothesis that severity of maternal hypothyroidism correlates inversely with IQ of the oVspring. Methods-IQ scores were compared among 8 year old oVspring of 124 control mothers whose thyroid stimulating hormone (TSH) concentrations were < 98th percentile of a cohort of 25 000 mothers at 17 weeks gestation, of 28 untreated hypothyroid women whose TSH was between the 98th and 99.85th percentiles, and of 20 untreated women whose TSH concentration was > 99.85th percentile. Results-Mean (SD) IQs for each group of children (in ascending order of maternal TSH concentration) were 107 (13), 102 (15), and 97 (14). The diVerence between the extremes was significant (p = 0.003). The percentage of children with IQs > 1 SD below the control mean was 15, 21, and 50 respectively (p = 0.003). The odds ratio of having an IQ > 1 SD below the control mean, after controlling for socioeconomic status, was 4.7 (p = 0.006) for the third group compared with the controls. Conclusions-The inverse correlation between severity of maternal hypothyroidism and IQ of the oVspring supports a causal relation and makes the need to screen for and treat pregnant women for hypothyroidism even more compelling.

The Journal of Clinical Endocrinology & Metabolism, 1987

Endocrinology, 1978

The basal concentration and metabolic clearance of radiolabeled and endogenous thyroglobulin (Tg)... more The basal concentration and metabolic clearance of radiolabeled and endogenous thyroglobulin (Tg) were measured in normal male rats. Serum Tg concentrations (by RIA) in Sprague-Dawley adult males ranged from 70-680 ng/ml (mean +/- SD, 218 +/- 177). In male Fisher rats, basal serum Tg concentrations were 32-263 ng/ml. The fractional disappearance rate of endogenously radioiodinated rat Tg and of endogenous rat Tg after thyroidectomy were both about 8%/h. The MCR of endogenously labeled Tg was 2.4 +/- 1.1 ml/100 g/h. Using this clearance and the mean serum Tg concentration in these rats, a daily thyroidal release rate of about 201 microgram Tg/100 g BW would be required to provide the T4 metabolized daily by the rat, the Tg released into the circulation comprises about 7% of the total rat Tg produced in a 24-h period.

The American Journal of Medicine, 1982

Annals of Internal Medicine, 1984

Thirty-two patients with primary hypothyroidism were given oral thyroxine as Levothroid or Synthr... more Thirty-two patients with primary hypothyroidism were given oral thyroxine as Levothroid or Synthroid to see if the two preparations had similar effects. The serum thyroxine was used as an index of bioavailability and the serum thyrotrophin as an index of biologic activity. The serum thyroxine was lower in all 32 patients when taking Synthroid than when taking Levothroid. In 15 patients the serum thyroxine level fell low enough to raise the serum thyrotrophin; in all 15 the serum thyrotrophin rose when taking Synthroid. Direct measurement of thyroxine in the tablets showed that the tablets of Synthroid contained 20% to 30% less thyroxine than their stated content. Thus, the decreased bioavailability (lower serum thyroxine) and decreased biologic action (higher serum thyrotrophin) of Synthroid were due to the lower content of thyroxine. An incidental observation is that the range of serum thyroxine in treated hypothyroid patients is 7.6 to 16.6 micrograms/dL, higher than in normal persons. Because oral thyroxine is widely used, a cooperative effort among manufacturers, the United States Pharmacopeia and Food and Drug Administration, and clinicians to ensure the potency and biologic action of oral thyroxine is in order. Meanwhile, it seems reasonable to use oral thyroxine that is close to the stated content.

Pediatrics, 1979

The Northwest Regional Screening Program to detect congenital hypothyroidism in infants born in O... more The Northwest Regional Screening Program to detect congenital hypothyroidism in infants born in Oregon, Montana, Alaska, and Idaho (combined birthrate of 69,000/yr) was added to our ongoing screening program in 1975. The program utilizes dried blood filter paper specimens collected routinely in the first few days of life in all four states and again at about 6 weeks of age in Oregon only. The screening tests consist of an initial thyroxine (T4) measurement; a thyroid-stimulating hormone (TSH) determination is performed on those specimens with T4 concentrations in the lowest 3% group. Serum samples obtained by venipuncture are requested for confirmation of the diagnosis. In the first two years of the program, 25 infants with primary hypothyroidism were detected among 110,667 infants screened, a frequency of 1:4,430. Fourteen cases of thyroxine-binding globulin deficiency were also detected, a frequency of 1:7,900. Using the T4 followed by TSH testing approach, the frequency of reques...

Pediatrics, 1977

A screening program for the detection of neonatal hypothyroidism has been in effect in Oregon sin... more A screening program for the detection of neonatal hypothyroidism has been in effect in Oregon since May 1975. Blood samples are obtained from all newborn infants to test for phenylketonuria and other metabolic diseases. A second specimen is obtained from more than 90% of these infants who are retested at 4 to 6 weeks of age. These Guthrie filter paper blood samples are analyzed for thyroxine (T4), and all samples with a low T4 value are analyzed for thyroid stimulating hormone (TSH). At the outset of the program, it was speculated that the screening might detect infants who had reduced

Journal of Biological Chemistry, 1994

The selenoenzyme, type 1 iodothyronine deiodinase (type 1 DI), catalyzes the activation of thyrox... more The selenoenzyme, type 1 iodothyronine deiodinase (type 1 DI), catalyzes the activation of thyroxine (T4) to 3,5,3&amp;#39;-triiodothyronine (T3) but 3,3&amp;#39;,5&amp;#39;-triiodothyronine (rT3) is the preferred substrate for the human enzyme. Since the dog type 1 DI has a significantly lower affinity for rT3, we cloned the dog type 1 DI to identify amino acids critical for rT3 binding. The Km of the transiently expressed dog enzyme for rT3 5&amp;#39;-deiodination is 25-fold higher than that of the human enzyme. However, the Ki of T4 for rT3 deiodination by dog type 1 DI is only 3-fold higher than that for the human, suggesting that the differences between the two proteins affect binding of rT3 more than that of T4. Comparative competition studies in which rT3 or T4 is used to block covalent bromoacetyl T3 binding to the two proteins support this. Mutational studies showed that the critical differences between the dog (D) and human (H) enzymes are Asn (D) 45 Gly (H), Gly (D) 46 Glu (H), and Leu (D) 60:Phe (H) 65. Substitution of the human residues for those of the dog at these positions causes the predicted changes in the Km (rT3) and vice versa. A Phe65 to Leu mutation alone in the human enzyme increases the Km (rT3) 10-fold. We speculate that Phe65 is especially important for rT3 binding due to an interaction between the tyrosyl ring of rT3 and the aromatic ring of Phe65.

New England Journal of Medicine, 1979

ESCHERICHIA COLI L-asparaginase, an antileukemic agent, acts by hydrolyzing plasma L-asparagine t... more ESCHERICHIA COLI L-asparaginase, an antileukemic agent, acts by hydrolyzing plasma L-asparagine to L-aspartic acid and ammonia, resulting in depletion of plasma L-asparagine levels.1 , 2 Cells susceptible to the cytotoxic effects lack asparagine synthetase and thus require exogenous asparagine for growth.3 Administration of L-asparaginase has been associated with modest decreases in the plasma concentrations of albumin, cholesterol, insulin, fibrinogen and various clotting factors.2 , 4 We report on a transient but dramatic reduction in serum thyroxine-binding globulin with consequent changes in results of thyroid-function studies in patients receiving L-asparaginase. Methods Thyroid function was monitored in patients with acute lymphocytic leukemia receiving Esch. coli L-asparaginase. . . .

Metabolism, 1991

Previous studies have shown that thyroid status affects the response of brown adipose tissue (BAT... more Previous studies have shown that thyroid status affects the response of brown adipose tissue (BAT) to the sympathetic nervous system. For example, hypothyroidism is associated with the development of a marked synergism between LX,-and p-adrenergic pathways to stimulate type II iodothyronine 5'-deiodinase activity. Hypothyroidism also attenuates the respiratory response (thermogenesis) of isolated brown adipocytes to norepinephrine. To explore the interactions of the sympathetic nervous system and thyroid status in these cells, we compared the thermogenic and 5'-deiodinase responses to adrenergic agonists in isolated brown adipocytes from hypothyroid rats during treatment with 3,5,3'-triiodothyronine (T,). The fivefold synergism of q-and 5-adrenergic catecholamines to increase the deiodinase activity was progressively reduced, reaching a control euthyroid value of unity after 5 days of T, treatment. Hypothyroidism reduced both the 0,max (twofold to threefold) and increased the concentration of agonist required for 50% stimulation (lo-fold) for both norepinephrine and forskolin. In hypothyroid cells, there was a twofold synergism between the o,-agonist cirazoline and forskolin to increase respiration, which was blocked by prazosin and reproduced by the calcium ionophore, A23187. This synergistic effect of the q-agonist was lost within 2 days of T, administration. These studies identify a second Ca'+-dependent intraadrenergic synergism, which functions to ameliorate the reduced cyclic adenosine monophosphate (CAMP) responsiveness of the hypothyroid brown adipocyte.

Metabolism, 1971

Abstract The method of Sterling et al. for measuring triiodothyronine in human serum has been mod... more Abstract The method of Sterling et al. for measuring triiodothyronine in human serum has been modified to provide greater sensitivity. The changes in technique include greater separation of triiodothyronine from thyroxine during paper chromatography, quantitation of triiodothyronine using a more dilute binding-protein solution, and the use of modifications which minimize the artifacts due to unknown substances in the chromatography paper. Complete recovery is obtained of known quantities of triiodothyronine added to human serum in amounts of 0.7 to 4.7 ng/ml. Mean triiodothyronine concentrations in human serum using this method are 1.8 ± 0.4 (SD) in normals, 6.7 ± 3.3 (SD) in untreated hyperthyroid subjects, and 0.66 ± 0.39 (SD) in hypothyroid patients. These values are 18 to 30% lower than those previously reported. We have examined the influence of thyroxine on the determination of triiodothyronine using both labeled and unlabeled hormone. The results suggest that about 0.3 to 0.4% of the total thyroxine present in serum is deiodinated to triiodothyronine. This appears to occur during the paper chromatographic step. Because of these observations, it would appear that the modified method, while quite satisfactory for clinical purposes, does not as yet provide the sensitivity and precision required for studies of triiodothyronine kinetics.

Metabolism, 1978

A method for the isolation of small quantities of labeled 3,5,3' -triiodothyronine (T3) f... more A method for the isolation of small quantities of labeled 3,5,3' -triiodothyronine (T3) from serum or thyroid extracts is described. Conjugates of rabbit anti-T3 antibody to Sepharose 4B are incubated with 0.5 to 1 ml of human or rat serum at pH 8.6 for 1 hr. The tubes are centrifuged and washed with buffer followed by 6 M guanidine to remove nonspecifically bound labeled thyroxine (T4). The fraction of T3 and T4 bound to the Sepharose conjugate varies depending on the concentration of serum in the initial incubation tubes, the T3 and T4 content, and the specificity of the antiserum used. In a system that contains 0.5 ml of normal human serum, 1 ml of glycine-acetate buffer (pH 8.6), and 0.25 ml settled Sepharose-anti-T3 conjugate, the T3 to T4 binding ratio was generally 150-200, with up to as much as 50% of T3 bound to the pellet. The coefficient of variation of the method is less than 5%, and it may be performed in a matter of hours. There is no detectable conversion of T4 to T3 during the separation process. Using this technique, conversion of T4 to T3 was evaluated in euthyroid rats after injection of 125l-T4. Over the period of 36-72 hr after injection, a ratio of T3 to T4 of 0.74 +- 0.06 x 10-2 (mean +- SE) was present in the plasma. Using the calculated metabolic clearance rates for T3 and T4 in these animals, fractional conversion of T4 to T3 was estimated to be 27%, in good agreement with results obtained by other techniques. This method would appear to be of value for specific isolation of the small quantities of T3 produced from T4 after in vivo or in vitro T4 to T3 conversion.

Metabolism, 1979

... of Thyroxine and 3,3',5'Triiodothyronine Metabolism in Rat Kidney and Liver Homogen... more ... of Thyroxine and 3,3',5'Triiodothyronine Metabolism in Rat Kidney and Liver Homogenates Michael M. Kaplan, Jeffrey B. Tatro ... MATERIALS AND METHODS Preparation of Homogenates Male Sprague Dawley rats (Zivic Miller Laboratories, Allison Park, Pa.) were used in all ...

The Journal of Clinical Endocrinology & Metabolism, 1973

ABSTRACT A family with autoimmune thyroid disease (Hashimoto's type) involving at least 3 mem... more ABSTRACT A family with autoimmune thyroid disease (Hashimoto's type) involving at least 3 members in 2 generations is described. In addition, abnormalities of serum immunoglobulins were identified in 2 of 3 generations studied. The possible pathogenetic role of at least one of these immunoglobulins is discussed. Congenital thyroid suppression (partially reversible) was present in all 6 offspring (third generation) of one member with autoimmune thyroiditis. The mechanism of this suppression is not apparent.

Endocrinology, 1977

To compare the biological effects of thyroxine (T4) and triiodothyronine (T3), the results of var... more To compare the biological effects of thyroxine (T4) and triiodothyronine (T3), the results of varying the production rates of T3 and T4 independently were evaluated. In one set of experiments, the responses of hypothyroid rats to thyroid hormones were measured in terms of weight gain, hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alphaGPD) and serum TSH. T4 was given with, and without, 6-n-propylthiouracil (PTU) and alphaGPD activity paralleled, and could completely be accounted for, by the effect of the quantities of the T3 produced. The direct role of T3 production in the maintenance of hepatic alphaGPD activity was supported by finding normal serum T3 and alphaGPD activities, but reduced T4, in rats on low iodine diet for 2 months. Only after 4 months of iodine deficiency was alphaGPD reduced in the presence of a normal serum T3. These results suggest that T4 per se plays minimal role in this system. In contrast, there were significant effects of T4 administration on stimulation of weight gain and suppression of TSH release in hypothyroid animals which were not due to the T3 produced by peripheral conversion. While T3 given parenterally was about tenfold more potent than T4 in acute suppression of TSH, PTU retreatment did not alter the acute decrease in TSH after T4 which lasted for at least 22 h, as opposed to less than 7 h for T3. Despite the direct effect of T4 on TSH suppression , acute reduction in T3 in normal rats resulted in an elevation of serum TSH even though serum T4 concentrations were unchanged or even increased at this time. The results indicate that the thyrotroph, unlike the hepatocyte, can respond acutely to both increases and decreases in either T3 or T4 production. The differential sensitivities of various tissues to T3 and T4 indicate that the relative potencies of these two hormones must be defined experimentally in terms of a specific biological effect.

Endocrinology, 1981

A double column perifusion procedure was used to study the feedback inhibition of L-T3 on TSH sec... more A double column perifusion procedure was used to study the feedback inhibition of L-T3 on TSH secretion from rat anterior pituitary fragments. Matching pituitary halves were pretreated with T3 (10(-7) M) for 2 h before exposure to 10(-8) M TRH, 59 mM K+, or 5 mM Ba2+ . TRH, high K+, and Ba2+ resulted in a 2-fold or greater stimulation of TSH release. T3 significantly inhibited the stimulation by these secretagogues to 0.77, 0.78, and 0.52 of control for TRH, high K+, and Ba2+, respectively. Neither rT3 (10(-7) M) nor T3 added together with TRH had an effect on TSH release by this secretagogue. Perifusion with 3.5 x 10(-5) M cycloheximide or 10(-6) M actinomycin D 1 h before and during T3 administration led to greater TSH release with TRH than in the presence of T3 alone. Neither protein synthetic inhibitor increased TRH responsiveness of pituitary fragments when perifused alone. When cycloheximide was perifused in a similar protocol before high K+ or Ba2+, there again was a significant decrease in the T3-induced inhibition of TSH release by these secretagogues. Cycloheximide alone did not increase TSH release in response to high K+ or Ba2+, eliminating this as a possible explanation for the enhanced TSH response when antibiotic was present with T3. These results indicate that the in vitro effect of T3 on secretagogue-induced TSH release can be blocked by an inhibitor of protein synthesis. The inhibitory effect of T3 on high K+- and Ba2+-induced TSH release suggests that the site of the acute T3 inhibition of TSH release may be subsequent to TRH interaction with its receptor.